Non-peptidergic small diameter primary afferents expressing VGluT2 project to lamina I of mouse spinal dorsal horn

PubMed Central

2011-01-01

Background Unmyelinated primary afferent nociceptors are commonly classified into two main functional types: those expressing neuropeptides, and non-peptidergic fibers that bind the lectin IB4. However, many small diameter primary afferent neurons neither contain any known neuropeptides nor bind IB4. Most express high levels of vesicular glutamate transporter 2 (VGluT2) and are assumed to be glutamatergic nociceptors but their terminations within the spinal cord are unknown. We used in vitro anterograde axonal tracing with Neurobiotin to identify the central projections of these putative glutamatergic nociceptors. We also quantitatively characterised the spatial arrangement of these terminals with respect to those that expressed the neuropeptide, calcitonin gene-related peptide (CGRP). Results Neurobiotin-labeled VGluT2-immunoreactive (IR) terminals were restricted to lamina I, with a medial-to-lateral distribution similar to CGRP-IR terminals. Most VGluT2-IR terminals in lateral lamina I were not labeled by Neurobiotin implying that they arose mainly from central neurons. 38 ± 4% of Neurobiotin-labeled VGluT2-IR terminals contained CGRP-IR. Conversely, only 17 ± 4% of Neurobiotin-labeled CGRP-IR terminals expressed detectable VGluT2-IR. Neurobiotin-labeled VGluT2-IR or CGRP-IR terminals often aggregated into small clusters or microdomains partially surrounding intrinsic lamina I neurons. Conclusions The central terminals of primary afferents which express high levels of VGluT2-IR but not CGRP-IR terminate mainly in lamina I. The spatial arrangement of VGluT2-IR and CGRP-IR terminals suggest that lamina I neurons receive convergent inputs from presumptive nociceptors that are primarily glutamatergic or peptidergic. This reveals a previously unrecognized level of organization in lamina I consistent with the presence of multiple nociceptive processing pathways. PMID:22152428

Ultrastructure of the central subnucleus of the nucleus tractus solitarii and the esophageal afferent terminals in the rat.

PubMed

Hayakawa, Tetsu; Takanaga, Akinori; Tanaka, Koichi; Maeda, Seishi; Seki, Makoto

2003-03-01

The central subnucleus of the nucleus tractus solitarii (ceNTS) receives afferent projections from the esophageal wall and projects to the nucleus ambiguus, thus serving as a relay nucleus for peristalsis of the esophagus. Here we examine the synaptic organization of the ceNTS, and its esophageal afferents by using transganglionic anterograde transport of cholera toxin-conjugated horseradish peroxidase (CT-HRP). When CT-HRP was injected into the subdiaphragmatic esophagus, many anterogradely labeled terminals were found only in the ceNTS. The ceNTS was composed of round or oval-shaped, small neurons (14.7x8.7 micro m) containing sparse organelles and an irregularly shaped nucleus. The average number of axosomatic terminals was only 1.3 per section cut through the nucleolus. Most of them (92%) contained round vesicles and formed asymmetric synaptic contacts (Gray's type I), and a few (8%) contained pleomorphic vesicles and formed symmetric synaptic contacts (Gray's type II). All anterogradely labeled terminals contacted dendrites but not the neuronal somata. The labeled terminals were large (2.55+/-0.07 micro m) and exclusively Gray's type I. More than half of them (60%) contacted small dendrites (less than 1 micro m in diameter), and contained dense-cored vesicles. More than 40% of the labeled terminals contacted two to four dendrites, thus forming a synaptic glomerulus. Sometimes a labeled terminal that contacted an unlabeled terminal by an adherent junction was found within the glomerulus. The large terminals and these complex synaptic relations appeared to characterize the esophageal afferent projections in the ceNTS.

Afferent innervation patterns of the saccule in pigeons

NASA Technical Reports Server (NTRS)

Zakir, M.; Huss, D.; Dickman, J. D.

2003-01-01

The innervation patterns of vestibular saccular afferents were quantitatively investigated in pigeons using biotinylated dextran amine as a neural tracer and three-dimensional computer reconstruction. Type I hair cells were found throughout a large portion of the macula, with the highest density observed in the striola. Type II hair cells were located throughout the macula, with the highest density in the extrastriola. Three classes of afferent innervation patterns were observed, including calyx, dimorph, and bouton units, with 137 afferents being anatomically reconstructed and used for quantitative comparisons. Calyx afferents were located primarily in the striola, innervated a number of type I hair cells, and had small innervation areas. Most calyx afferent terminal fields were oriented parallel to the anterior-posterior axis and the morphological polarization reversal line. Dimorph afferents were located throughout the macula, contained fewer type I hair cells in a calyceal terminal than calyx afferents and had medium sized innervation areas. Bouton afferents were restricted to the extrastriola, with multi-branching fibers and large innervation areas. Most of the dimorph and bouton afferents had innervation fields that were oriented dorso-ventrally but were parallel to the neighboring reversal line. The organizational morphology of the saccule was found to be distinctly different from that of the avian utricle or lagena otolith organs and appears to represent a receptor organ undergoing evolutionary adaptation toward sensing linear motion in terrestrial and aerial species.

Monosynaptic convergence of chorda tympani and glossopharyngeal afferents onto ascending relay neurons in the nucleus of the solitary tract: A high-resolution confocal and correlative electron microscopy approach

PubMed Central

Corson, James A.; Erisir, Alev

2014-01-01

While physiological studies suggested convergence of chorda tympani and glossopharyngeal afferent axons onto single neurons of the rostral nucleus of the solitary tract (rNTS), anatomical evidence has been elusive. The current study uses high-magnification confocal microscopy to identify putative synaptic contacts from afferent fibers of the two nerves onto individual projection neurons. Imaged tissue is re-visualized with electron microscopy, confirming that overlapping fluorescent signals in confocal z-stacks accurately identify appositions between labeled terminal and dendrite pairs. Monte Carlo modeling reveals that the probability of overlapping fluorophores is stochastically unrelated to the density of afferent label suggesting that convergent innervation in the rNTS is selective rather than opportunistic. Putative synaptic contacts from each nerve are often compartmentalized onto dendrite segments of convergently innervated neurons. These results have important implications for orosensory processing in the rNTS, and the techniques presented here have applications in investigations of neural microcircuitry with an emphasis on innervation patterning. PMID:23640852

Thyroid hormone is required for pruning, functioning and long-term maintenance of afferent inner hair cell synapses

PubMed Central

Sundaresan, Srividya; Kong, Jee-Hyun; Fang, Qing; Salles, Felipe T.; Wangsawihardja, Felix; Ricci, Anthony J.; Mustapha, Mirna

2016-01-01

Functional maturation of afferent synaptic connections to inner hair cells (IHCs) involves pruning of excess synapses formed during development, as well as the strengthening and survival of the retained synapses. These events take place during the thyroid hormone (TH)-critical period of cochlear development, which is in the perinatal period for mice and in the third trimester for humans. Here, we used the hypothyroid Snell dwarf mouse (Pit1dw) as a model to study the role of TH in afferent type I synaptic refinement and functional maturation. We observed defects in afferent synaptic pruning and delays in calcium channel clustering in the IHCs of Pit1dw mice. Nevertheless, calcium currents and capacitance reached near normal levels in Pit1dw IHCs by the age of onset of hearing, despite the excess number of retained synapses. We restored normal synaptic pruning in Pit1dw IHCs by supplementing with TH from postnatal day (P)3 to P8, establishing this window as being critical for TH action on this process. Afferent terminals of older Pit1dw IHCs showed evidence of excitotoxic damage accompanied by a concomitant reduction in the levels of the glial glutamate transporter, GLAST. Our results indicate that a lack of TH during a critical period of inner ear development causes defects in pruning and long-term homeostatic maintenance of afferent synapses. PMID:26386265

Patterns of primary afferent depolarization of segmental and ascending intraspinal collaterals of single joint afferents in the cat.

PubMed

Rudomin, P; Lomelí, J

2007-01-01

We have examined in the anesthetized cat the threshold changes produced by sensory and supraspinal stimuli on intraspinal collaterals of single afferents from the posterior articular nerve (PAN). Forty-eight fibers were tested in the L3 segment, in or close to Clarke's column, and 70 fibers in the L6-L7 segments within the intermediate zone. Of these, 15 pairs of L3 and L6-L7 collaterals were from the same afferent. Antidromically activated fibers had conduction velocities between 23 and 74 m/s and peripheral thresholds between 1.1 and 4.7 times the threshold of the most excitable fibers (xT), most of them below 3 xT. PAN afferents were strongly depolarized by stimulation of muscle afferents and by cutaneous afferents, as well as by stimulation of the bulbar reticular formation and the midline raphe nuclei. Stimulation of muscle nerves (posterior biceps and semitendinosus, quadriceps) produced a larger PAD (primary afferent depolarization) in the L6-L7 than in the L3 terminations. Group II were more effective than group I muscle afferents. As with group I muscle afferents, the PAD elicited in PAN afferents by stimulation of muscle nerves could be inhibited by conditioning stimulation of cutaneous afferents. Stimulation of the cutaneous sural and superficial peroneal nerves increased the threshold of few terminations (i.e., produced primary afferent hyperpolarization, PAH) and reduced the threshold of many others, particularly of those tested in the L6-L7 segments. Yet, there was a substantial number of terminals where these conditioning stimuli had minor or no effects. Autogenetic stimulation of the PAN with trains of pulses increased the intraspinal threshold in 46% and reduced the threshold in 26% of fibers tested in the L6-L7 segments (no tests were made with trains of pulses on fibers ending in L3). These observations indicate that PAN afferents have a rather small autogenetic PAD, particularly if this is compared with the effects of heterogenetic stimulation. Therefore, the depression of the PAN intraspinal fields produced by autogenetic stimulation described by Rudomin et al. (Exp Brain Res DOI 10.1007/s00221-006-0600-x, 2006) may be ascribed to other mechanisms besides a GABAa PAD. It is suggested that the small or no autogenetic PAD displayed by the examined joint afferents prevents presynaptic filtering of their synaptic actions and preserves the original information generated in the periphery. This could be important for proper adjustment of limb position.

Functional recovery of anterior semicircular canal afferents following hair cell regeneration in birds

NASA Technical Reports Server (NTRS)

Boyle, Richard; Highstein, Stephen M.; Carey, John P.; Xu, Jinping

2002-01-01

Streptomycin sulfate (1.2 g/kg i.m.) was administered for 5 consecutive days to 5-7-day-old white Leghorn chicks; this causes damage to semicircular canal hair cells that ultimately regenerate to reform the sensory epithelium. During the recovery period, electrophysiological recordings were taken sequentially from anterior semicircular canal primary afferents using an indentation stimulus of the canal that has been shown to mimic rotational stimulation. Chicks were assigned to an early (14-18 days; n = 8), intermediate (28-34 days; n = 5), and late (38-58 days; n = 4) period based on days after treatment. Seven untreated chicks, 15-67 days old, provided control data. An absence of background and indent-induced discharge was the prominent feature of afferents in the early period: only "silent" afferents were encountered in 5/8 experiments. In several of these chicks, fascicles of afferent fibers were seen extending up to the epithelium that was void of hair cells, and intra- and extracellular biocytin labeling revealed afferent processes penetrating into the supporting cell layer of the crista. In 3/8 chicks 74 afferents could be characterized, and they significantly differed from controls (n = 130) by having a lower discharge rate and a negligible response to canal stimulation. In the intermediate period there was considerable variability in discharge properties of 121 afferents, but as a whole the number of "silent" fibers in the canal nerve diminished, the background rate increased, and a response to canal stimulation detected. Individually biocytin-labeled afferents had normal-appearing terminal specializations in the sensory epithelium by 28 days poststreptomycin. In the late period, afferents (n = 58) remained significantly different from controls in background discharge properties and response gain. The evidence suggests that a considerable amount of variability exists between chicks in the return of vestibular afferent function following ototoxic injury and that the secretory function of regenerating hair cells might become functional before their transducer function.

Pituitary adenylyl cyclase-activating polypeptide (PACAP) and its receptor (PAC1-R) are positioned to modulate afferent signaling in the cochlea.

PubMed

Drescher, M J; Drescher, D G; Khan, K M; Hatfield, J S; Ramakrishnan, N A; Abu-Hamdan, M D; Lemonnier, L A

2006-09-29

Pituitary adenylyl cyclase-activating polypeptide (PACAP), via its specific receptor pituitary adenylyl cyclase-activating polypeptide receptor 1 (PAC1-R), is known to have roles in neuromodulation and neuroprotection associated with glutamatergic and cholinergic neurotransmission, which, respectively, are believed to form the primary basis for afferent and efferent signaling in the organ of Corti. Previously, we identified transcripts for PACAP preprotein and multiple splice variants of its receptor, PAC1-R, in microdissected cochlear subfractions. In the present work, neural localizations of PACAP and PAC1-R within the organ of Corti and spiral ganglion were examined, defining sites of PACAP action. Immunolocalization of PACAP and PAC1-R in the organ of Corti and spiral ganglion was compared with immunolocalization of choline acetyltransferase (ChAT) and synaptophysin as efferent neuronal markers, and glutamate receptor 2/3 (GluR2/3) and neurofilament 200 as afferent neuronal markers, for each of the three cochlear turns. Brightfield microscopy giving morphological detail for individual immunolocalizations was followed by immunofluorescence detection of co-localizations. PACAP was found to be co-localized with ChAT in nerve fibers of the intraganglionic spiral bundle and beneath the inner and outer hair cells within the organ of Corti. Further, evidence was obtained that PACAP is expressed in type I afferent axons leaving the spiral ganglion en route to the auditory nerve, potentially serving as a neuromodulator in axonal terminals. In contrast to the efferent localization of PACAP within the organ of Corti, PAC1-R immunoreactivity was co-localized with afferent dendritic neuronal marker GluR2/3 in nerve fibers passing beneath and lateral to the inner hair cell and in fibers at supranuclear and basal sites on outer hair cells. Given the known association of PACAP with catecholaminergic neurotransmission in sympathoadrenal function, we also re-examined the issue of whether the organ of Corti receives adrenergic innervation. We now demonstrate the existence of nerve fibers within the organ of Corti which are immunoreactive for the adrenergic marker dopamine beta-hydroxylase (DBH). DBH immunoreactivity was particularly prominent in nerve fibers both at the base and near the cuticular plate of outer hair cells of the apical turn, extending to the non-sensory Hensen's cell region. Evidence was obtained for limited co-localization of DBH with PAC1-R and PACAP. In the process of this investigation, we obtained evidence that efferent and afferent nerve fibers, in addition to adrenergic nerve fibers, are present at supranuclear sites on outer hair cells and distributed within the non-sensory epithelium of the apical cochlear turn for rat, based upon immunoreactivity for the corresponding neuronal markers. Overall, PACAP is hypothesized to act within the organ of Corti as an efferent neuromodulator of afferent signaling via PAC1-R that is present on type I afferent dendrites, in position to afford protection from excitotoxicity. Additionally, PACAP/PAC1-R may modulate secretion of catecholamines from adrenergic terminals within the organ of Corti.

St. John’s Wort enhances the synaptic activity of the nucleus of the solitary tract

PubMed Central

Vance, Katie M.; Ribnicky, David M.; Hermann, Gerlinda E.; Rogers, Richard C.

2014-01-01

Objective St. John’s Wort extract, which is commonly used to treat depression, inhibits the reuptake of several neurotransmitters, including glutamate, serotonin, norepinephrine, and dopamine. Glutamatergic visceral vagal afferents synapse upon neurons of the solitary tract (NST); thus, we evaluated whether St. John’s Wort extract modulates glutamatergic neurotransmission within the NST. Materials and Methods We used live cell calcium imaging to evaluate whether St. John’s Wort and its isolated components hypericin and hyperforin increase the excitability of pre-labeled vagal afferent terminals synapsing upon the NST. We used voltage-clamp recordings of spontaneous miniature excitatory postsynaptic currents (mEPSCs) to evaluate whether St. John’s Wort alters glutamate release from vagal afferents onto NST neurons. Results Our imaging data show that St. John’s Wort (50 μg/mL) increased the intracellular calcium levels of stimulated vagal afferent terminals compared to the bath control. This increase in presynaptic vagal afferent calcium by the extract coincides with an increase in neurotransmitter release within the nucleus of the solitary tract, as the frequency of mEPSCs is significantly higher in the presence of the extract compared to the control. Finally, our imaging data show that hyperforin, a known component of St. John’s Wort extract, also significantly increases terminal calcium levels. Conclusion These data suggest that St. John’s Wort extract can significantly increase the probability of glutamate release from vagal afferents onto the NST by increasing presynaptic calcium. The in vitro vagal afferent synapse with NST neurons is an ideal model system to examine the mechanism of action of botanical agents on glutamatergic neurotransmission. PMID:24985104

Selective Expression of a Sodium Pump Isozyme by Cough Receptors and Evidence for Its Essential Role in Regulating Cough

PubMed Central

Mazzone, Stuart B.; Reynolds, Sandra M.; Mori, Nanako; Kollarik, Marian; Farmer, David G.; Myers, Allen C.

2009-01-01

We have identified a distinct subtype of airway vagal afferent nerve that plays an essential role in regulating the cough reflex. These afferents are exquisitely sensitive to punctate mechanical stimuli, acid, and decreases in extracellular chloride concentrations, but are insensitive to capsaicin, bradykinin, histamine, adenosine, serotonin, or changes in airway intraluminal pressures. In this study we used intravital imaging, retrograde neuronal tracing, and electrophysiological analyses to characterize the structural basis for their peculiar mechanical sensitivity and to further characterize the regulation of their excitability. In completing these experiments, we uncovered evidence for an essential role of an isozyme of Na+-K+ ATPase in regulating cough. These vagal sensory neurons arise bilaterally from the nodose ganglia and are selectively and brilliantly stained intravitally with the styryl dye FM2-10. Cough receptor terminations are confined and adherent to the extracellular matrix separating the airway epithelium and smooth muscle layers, a site of extensive remodeling in asthma and chronic obstructive pulmonary disease. The cough receptor terminals uniquely express the α3 subunit of Na+-K+ ATPase. Intravital staining of cough receptors by FM2-10, cough receptor excitability in vitro, and coughing in vivo are potently and selectively inhibited by the sodium pump inhibitor ouabain. These data provide the first detailed morphological description of the peripheral terminals of the sensory nerves regulating cough and identify a selective molecular target for their modulation. PMID:19864578

Nucleotide Signaling and Cutaneous Mechanisms of Pain Transduction

PubMed Central

Dussor, G.; Koerber, H.R.; Oaklander, AL; Rice, F.L.; Molliver, D.C.

2009-01-01

Sensory neurons that innervate the skin provide critical information about physical contact between the organism and the environment, including information about potentially-damaging stimuli that give rise to the sensation of pain. These afferents also contribute to the maintenance of tissue homeostasis, inflammation and wound healing, while sensitization of sensory afferents after injury results in painful hypersensitivity and protective behavior. In contrast to the traditional view of primary afferent terminals as the sole site of sensory transduction, recent reports have lead to the intriguing idea that cells of the skin play an active role in the transduction of sensory stimuli. The search for molecules that transduce different types of sensory stimuli (mechanical, heat, chemical) at the axon terminal has yielded a wide range of potential effectors, many of which are expressed by keratinocytes as well as neurons. Emerging evidence underscores the importance of nucleotide signaling through P2X ionotropic and P2Y metabotropic receptors in pain processing, and implicates nucleotide signaling as a critical form of communication between cells of the skin, immune cells and sensory neurons. It is of great interest to determine whether pathological changes in these mechanisms contribute to chronic pain in human disease states such as complex regional pain syndrome (CRPS). This review discusses recent advances in our understanding of communication mechanisms between cells of the skin and sensory axons in the transduction of sensory input leading to pain. PMID:19171165

Afferent Neural Feedback Overrides the Modulating Effects of Arousal, Hypercapnia and Hypoxemia on Neonatal Cardio-respiratory Control.

PubMed

Lumb, Kathleen J; Schneider, Jennifer M; Ibrahim, Thowfique; Rigaux, Anita; Hasan, Shabih U

2018-04-20

Evidence at whole animal, organ-system, and cellular and molecular levels suggests that afferent volume feedback is critical for establishment of adequate ventilation at birth. Due to the irreversible nature of vagal ablation studies to date, it was difficult to quantify the roles of afferent volume input, arousal and changes in blood gas tensions on neonatal respiratory control. During reversible perineural vagal block, profound apneas, and hypoxemia and hypercarbia were observed necessitating termination of perineural blockade. Respiratory depression and apneas were independent of the sleep states. We demonstrate that profound apneas and life-threatening respiratory failure in vagally denervated animals do not result from lack of arousal or hypoxemia. Change in sleep state and concomitant respiratory depression result from lack of afferent volume feedback, which appears to be critical for the maintenance of normal breathing patterns and adequate gas exchange during the early postnatal period. Afferent volume feedback plays a vital role in neonatal respiratory control. Mechanisms for the profound respiratory depression and life-threatening apneas observed in vagally denervated neonatal animals remain unclear. We investigated the roles of sleep states, hypoxic-hypercapnia and afferent volume feedback on respiratory depression using reversible perineural vagal block during early postnatal period. Seven lambs were instrumented during the first 48h of life to record/analyze sleep states, diaphragmatic electromyograph, arterial blood gas tensions, systemic arterial blood pressure and rectal temperature. Perineural cuffs were placed around the vagi to attain reversible blockade. Post-operatively, during the awake state, both vagi were blocked using 2% xylocaine for up to 30 minutes. Compared with baseline values, pHa, PaO 2 and SaO 2 decreased and PaCO 2 increased during perineural blockade (P < 0.05). Four of seven animals exhibited apneas of ≥20 sec requiring immediate termination of perineural blockade. Breathing rates decreased from the baseline value of 53 ± 12 to 24 ± 20 breaths/min during blockade despite an increased PaCO 2 (P < 0.001). Following blockade, breathing patterns returned to baseline values despite marked hypocapnia (PaCO 2 33 ± 3 torr; P = 0.03). Respiratory depression and apneas were independent of sleep states. This study provides the much needed physiologic evidence that profound apneas and life-threatening respiratory failure in vagally denervated animals do not result from lack of arousal or hypoxemia. Rather, change in sleep state and concomitant respiratory depression result from lack of afferent volume feedback, which appears to be critical for the maintenance of normal breathing patterns and adequate gas exchange during the early postnatal period. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Choline acetyltransferase immunoreactivity in the human vestibular end-organs.

PubMed

Ishiyama, A; Lopez, I; Wackym, P A

1994-10-01

Acetylcholine (ACh) is believed to play a major role in the efferent vestibular system in several animal models, however no information regarding the role of ACh in the human efferent vestibular system has been published. Post-embedding immunohistochemistry in a hydrophilic resin was used to investigate the choline acetyltransferase immunoreactivity (ChATi) and acetylcholinesterase (AChE) histochemistry in human vestibular end-organs. ChATi and AChE activity was found in numerous bouton-type terminals at the basal area of the vestibular hair cells. These terminals were found to contact type II vestibular hair cells and the afferent chalices surrounding type I hair cells. This study provides the first evidence that the human efferent vestibular axons and terminals are cholinergic.

Presynaptic control of transmission along the pathway mediating disynaptic reciprocal inhibition in the cat

PubMed Central

Enríquez-Denton, M; Nielsen, J; Perreault, M-C; Morita, H; Petersen, N; Hultborn, H

2000-01-01

In cat lumbar motoneurones, disynaptic inhibitory postsynaptic potentials (IPSPs) evoked by stimulation of antagonist motor nerves were depressed for at least 150 ms following conditioning stimulation of flexor (1.7-2 times threshold (T)) and ankle extensor (5T) nerves. The aim of the present study was to investigate the possibility that this depression is caused by presynaptic inhibitory mechanisms acting at the terminals of group I afferent fibres projecting to the Ia inhibitory interneurones and/or the terminals of these interneurones to the target motoneurones. Conditioning stimulation of flexor, but not ankle extensor, nerves evoked a depression of the monosynaptic Ia excitatory postsynaptic potentials (EPSPs) recorded intracellularly in Ia inhibitory interneurones. This depression lasted between 200 and 700 ms and was not accompanied by a depression of the monosynaptic EPSPs evoked by stimulation of descending pathways. These results suggest that flexor, but not ankle extensor, group I afferent fibres can modulate sensory transmission at the synapse between Ia afferent fibres and Ia inhibitory interneurones. Conditioning stimulation of flexor muscle nerves, extensor muscle nerves and cutaneous nerves produced a long-lasting increase in excitability of the terminals of the Ia inhibitory interneurones. The increase in the excitability of the terminals was not secondary to an electrotonic spread of synaptic excitation at the soma. Indeed, concomitant with the excitability increase of the terminals there were signs of synaptic inhibition in the soma. The unitary IPSPs induced in target motoneurones following the spike activity of single Ia inhibitory interneurones were depressed by conditioning stimulation of muscle and cutaneous nerves. Since the conditioning stimulation also evoked compound IPSPs in those motoneurones, a firm conclusion as to whether unitary IPSP depression involved presynaptic inhibitory mechanism of the terminals of the interneurones could not be reached. The possibility that the changes in excitability of the Ia interneuronal terminals reflect the presence of a presynaptic inhibitory mechanism similar to that operating at the terminals of the afferent fibres (presynaptic inhibition) is discussed.1. In cat lumbar motoneurones, disynaptic inhibitory postsynaptic potentials (IPSPs) evoked by stimulation of antagonist motor nerves were depressed for at least 150 ms following conditioning stimulation of flexor (1.7-2 times threshold (T)) and ankle extensor (5T) nerves. The aim of the present study was to investigate the possibility that this depression is caused by presynaptic inhibitory mechanisms acting at the terminals of group I afferent fibres projecting to the Ia inhibitory interneurones and/or the terminals of these interneurones to the target motoneurones. PMID:10922013

Withdrawal and restoration of central vagal afferents within the dorsal vagal complex following subdiaphragmatic vagotomy.

PubMed

Peters, James H; Gallaher, Zachary R; Ryu, Vitaly; Czaja, Krzysztof

2013-10-15

Vagotomy, a severing of the peripheral axons of the vagus nerve, has been extensively utilized to determine the role of vagal afferents in viscerosensory signaling. Vagotomy is also an unavoidable component of some bariatric surgeries. Although it is known that peripheral axons of the vagus nerve degenerate and then regenerate to a limited extent following vagotomy, very little is known about the response of central vagal afferents in the dorsal vagal complex to this type of damage. We tested the hypothesis that vagotomy results in the transient withdrawal of central vagal afferent terminals from their primary central target, the nucleus of the solitary tract (NTS). Sprague-Dawley rats underwent bilateral subdiaphragmatic vagotomy and were sacrificed 10, 30, or 60 days later. Plastic changes in vagal afferent fibers and synapses were investigated at the morphological and functional levels by using a combination of an anterograde tracer, synapse-specific markers, and patch-clamp electrophysiology in horizontal brain sections. Morphological data revealed that numbers of vagal afferent fibers and synapses in the NTS were significantly reduced 10 days following vagotomy and were restored to control levels by 30 days and 60 days, respectively. Electrophysiology revealed transient decreases in spontaneous glutamate release, glutamate release probability, and the number of primary afferent inputs. Our results demonstrate that subdiaphragmatic vagotomy triggers transient withdrawal and remodeling of central vagal afferent terminals in the NTS. The observed vagotomy-induced plasticity within this key feeding center of the brain may be partially responsible for the response of bariatric patients following gastric bypass surgery. Copyright © 2013 Wiley Periodicals, Inc.

Vagal Afferent Innervation of the Lower Esophageal Sphincter

PubMed Central

Powley, Terry L.; Baronowsky, Elizabeth A.; Gilbert, Jared M.; Hudson, Cherie N.; Martin, Felecia N.; Mason, Jacqueline K.; McAdams, Jennifer L.; Phillips, Robert J.

2013-01-01

To supply a fuller morphological characterization of the vagal afferents innervating the lower esophageal sphincter (LES), specifically to label vagal terminals in the tissues forming the LES in the gastroesophageal junction, the present experiment employed injections of dextran biotin into the nodose ganglia of rats. Four types of vagal afferents innervated the LES. Clasp and sling muscle fibers were directly and prominently innervated by intramuscular arrays (IMAs). Individual IMA terminals subtended about 16° of arc of the esophageal circumference, and, collectively, the terminal fields were distributed within the muscle ring to establish a 360° annulus of mechanoreceptors in the sphincter wall. 3D morphometry of the terminals established that, compared to sling muscle IMAs, clasp muscle IMAs had more extensive arbors and larger receptive fields. In addition, at the cardia, local myenteric ganglia between smooth muscle sheets and striated muscle bundles were innervated by intraganglionic laminar endings (IGLEs), in a pattern similar to the innervation of the myenteric plexus throughout the stomach and esophagus. Finally, as previously described, the principle bundle of sling muscle fibers that links LES sphincter tissue to the antropyloric region of the lesser curvature was innervated by exceptionally long IMAs as well as by unique web ending specializations at the distal attachment of the bundle. Overall, the specialized varieties of densely distributed vagal afferents innervating the LES underscore the conclusion that these sensory projections are critically involved in generating LES reflexes and may be promising targets for managing esophageal dysfunctions. PMID:23583280

Central projections and entries of capsaicin-sensitive muscle afferents.

PubMed

Della Torre, G; Lucchi, M L; Brunetti, O; Pettorossi, V E; Clavenzani, P; Bortolami, R

1996-03-25

The entry pathway and central distribution of A delta and C muscle afferents within the central nervous system (CNS) were investigated by combining electron microscopy and electrophysiological analysis after intramuscular injection of capsaicin. The drug was injected into the rat lateral gastrocnemius (LG) and extraocular (EO) muscles. The compound action potentials of LG nerve and the evoked field potentials recorded in semilunar ganglion showed an immediate and permanent reduction in A delta and C components. The morphological data revealed degenerating unmyelinated axons and terminals in the inner sublamina II and in the border of laminae I-II of the dorsal horn at L4-L5 and C1-C2 (subnucleus caudalis trigemini) spinal cord segments. Most degenerating terminals were the central bouton (C) of type I and II synaptic glomeruli. Furthermore, degenerating peripheral axonal endings (V2) presynaptic to normal C were found. Since V2 were previously found degenerated after cutting the oculomotor nerve (ON) or L4 ventral root, we conclude that some A delta and C afferents from LG and EO muscles entering the CNS by ON or ventral roots make axoaxonic synapses on other primary afferents to promote an afferent control of sensory input.

Synaptic and paracrine mechanisms at carotid body arterial chemoreceptors

PubMed Central

Nurse, Colin A

2014-01-01

Mammalian carotid bodies are the main peripheral arterial chemoreceptors, strategically located at the bifurcation of the common carotid artery. When stimulated these receptors initiate compensatory respiratory and cardiovascular reflexes to maintain homeostasis. Thus, in response to low oxygen (hypoxia) or increased CO2/H+ (acid hypercapnia), chemoreceptor type I cells depolarize and release excitatory neurotransmitters, such as ATP, which stimulate postsynaptic P2X2/3 receptors on afferent nerve terminals. The afferent discharge is shaped by autocrine and paracrine mechanisms involving both excitatory and inhibitory neuromodulators such as adenosine, serotonin (5-HT), GABA and dopamine. Recent evidence suggests that paracrine activation of P2Y2 receptors on adjacent glia-like type II cells may help boost the ATP signal via the opening of pannexin-1 channels. The presence of an inhibitory efferent innervation, mediated by release of nitric oxide, provides additional control of the afferent discharge. The broad array of neuromodulators and their receptors appears to endow the carotid body with a remarkable plasticity, most apparent during natural and pathophysiological conditions associated with chronic sustained and intermittent hypoxia. PMID:24665097

Current Status and Future Directions of Botulinum Neurotoxins for Targeting Pain Processing

PubMed Central

Pellett, Sabine; Yaksh, Tony L.; Ramachandran, Roshni

2015-01-01

Current evidence suggests that botulinum neurotoxins (BoNTs) A1 and B1, given locally into peripheral tissues such as skin, muscles, and joints, alter nociceptive processing otherwise initiated by inflammation or nerve injury in animal models and humans. Recent data indicate that such locally delivered BoNTs exert not only local action on sensory afferent terminals but undergo transport to central afferent cell bodies (dorsal root ganglia) and spinal dorsal horn terminals, where they cleave SNAREs and block transmitter release. Increasing evidence supports the possibility of a trans-synaptic movement to alter postsynaptic function in neuronal and possibly non-neuronal (glial) cells. The vast majority of these studies have been conducted on BoNT/A1 and BoNT/B1, the only two pharmaceutically developed variants. However, now over 40 different subtypes of botulinum neurotoxins (BoNTs) have been identified. By combining our existing and rapidly growing understanding of BoNT/A1 and /B1 in altering nociceptive processing with explorations of the specific characteristics of the various toxins from this family, we may be able to discover or design novel, effective, and long-lasting pain therapeutics. This review will focus on our current understanding of the molecular mechanisms whereby BoNTs alter pain processing, and future directions in the development of these agents as pain therapeutics. PMID:26556371

Botulinum toxin in Migraine: Role of transport in trigemino-somatic and trigemino-vascular afferents

PubMed Central

Roshni, Ramachandran; Carmen, Lam; Yaksh Tony, L

2015-01-01

Migraine secondary to meningeal input is referred to extracranial regions innervated by somatic afferents that project to homologous regions in the trigeminal nucleus caudalis (TNC). Reported efficacy of extracranial botulinum toxin (BoNT) in treating migraine is surprising since a local extracranial effect of BoNT cannot account for its effect upon meningeal input. We hypothesize that intradermal BoNT acts through central transport in somatic afferents. Anesthetized C57Bl/6 mice (male) received unilateral supraorbital (SO) injections of BoNT-B (1.5 U/40 μl) or saline. 3 days later, mice received ipsilateral (ipsi) -SO capsaicin (2.5 μg/30 μl) or meningeal capsaicin (4 μl of 1mg/ml). Pre-treatment with ipsi-SO BONT-B i) decreased nocicsponsive ipsilateral wiping behavior following ipsi-SO capsaicin; ii) produced cleavage of VAMP in the V1 region of ipsi-TG and in TG neurons showing WGA after SO injection; iii) reduced expression of c-fos in ipsi-TNC following ipsi-SO capsaicin; iv) reduced c-fos activation and NK-1 internalization in ipsi-TNC secondary to ipsi-meningeal capsaicin; vi) SO WGA did not label dural afferents. We conclude that BoNT-B is taken up by peripheral afferents and transported to central terminals where it inhibits transmitter release resulting in decreased activation of second order neurons. Further, this study supports the hypothesis that SO BoNT exerts a trans-synaptic action on either the second order neuron (which receives convergent input from the meningeal afferent) or the terminal/TG of the converging meningeal afferent. PMID:25958249

Central anatomy of individual rapidly adapting low-threshold mechanoreceptors innervating the "hairy" skin of newborn mice: early maturation of hair follicle afferents.

PubMed

Woodbury, C J; Ritter, A M; Koerber, H R

2001-07-30

Adult skin sensory neurons exhibit characteristic projection patterns in the dorsal horn of the spinal gray matter that are tightly correlated with modality. However, little is known about how these patterns come about during the ontogeny of the distinct subclasses of skin sensory neurons. To this end, we have developed an intact ex vivo somatosensory system preparation in neonatal mice, allowing single, physiologically identified cutaneous afferents to be iontophoretically injected with Neurobiotin for subsequent histological analyses. The present report, centered on rapidly adapting mechanoreceptors, represents the first study of the central projections of identified skin sensory neurons in neonatal animals. Cutaneous afferents exhibiting rapidly adapting responses to sustained natural stimuli were encountered as early as recordings were made. Well-stained representatives of coarse (tylotrich and guard) and fine-diameter (down) hair follicle afferents, along with a putative Pacinian corpuscle afferent, were recovered from 2-7-day-old neonates. All were characterized by narrow, uninflected somal action potentials and generally low mechanical thresholds, and many could be activated via deflection of recently erupted hairs. The central collaterals of hair follicle afferents formed recurrent, flame-shaped arbors that were essentially miniaturized replicas of their adult counterparts, with identical laminar terminations. The terminal arbors of down hair afferents, previously undescribed in rodents, were distinct and consistently occupied a more superficial position than tylotrich and guard hair afferents. Nevertheless, the former extended no higher than the middle of the incipient substantia gelatinosa, leaving a clear gap more dorsally. In all major respects, therefore, hair follicle afferents display the same laminar specificity in neonates as they do in adults. The widely held misperception that their collaterals extend exuberant projections into pain-specific regions of the dorsal horn during early postnatal life is shown to have multiple, deep-rooted underpinnings.

The spatiotemporal relationships between chondroitin sulfate proteoglycans and terminations of calcitonin gene related peptide and parvalbumin immunoreactive afferents in the spinal cord of mouse embryos.

PubMed

Wang, Liqing; Yu, Chao; Wang, Jun; Zhao, Hui; Chan, Sun-On

2017-08-10

Chondroitin sulfate (CS) proteoglycans (PGs) are a family of complex molecules in the extracellular matrix and cell surface that regulate axon growth and guidance during development of the central nervous system. In this study, the expression of CSPGs was investigated in the mouse spinal cord at late embryonic and neonatal stages using CS-56 antibody. CS immunoreactivity was observed abundantly in ventral regions of spinal cord of embryonic day (E) 15 embryos. At E16 to E18, CS expression spread dorsally, but never reached the superficial layers of the dorsal horn. This pattern was maintained until postnatal day 4, the latest stage examined. Antibodies against calcitonin gene related peptide (CGRP) and parvalbumin (PV) were employed to label primary afferents from nociceptors and proprioceptors, respectively. CGRP-immunoreactive fibers terminated in the superficial regions of the dorsal horn where CSPGs were weakly expressed, whereas PV-immunoreactive fibers were found in CSPG-rich regions in the ventral horn. Therefore, we conclude that CS expression is spatiotemporally regulated in the spinal cord, which correlates to the termination of sensory afferents. This pattern suggests a role of CSPGs on patterning afferents in the spinal cord, probably through a differential response of axons to these growth inhibitory molecules. Copyright © 2017 Elsevier B.V. All rights reserved.

Subcortical orientation biases explain orientation selectivity of visual cortical cells.

PubMed

Vidyasagar, Trichur R; Jayakumar, Jaikishan; Lloyd, Errol; Levichkina, Ekaterina V

2015-04-01

The primary visual cortex of carnivores and primates shows an orderly progression of domains of neurons that are selective to a particular orientation of visual stimuli such as bars and gratings. We recorded from single-thalamic afferent fibers that terminate in these domains to address the issue whether the orientation sensitivity of these fibers could form the basis of the remarkable orientation selectivity exhibited by most cortical cells. We first performed optical imaging of intrinsic signals to obtain a map of orientation domains on the dorsal aspect of the anaesthetized cat's area 17. After confirming using electrophysiological recordings the orientation preferences of single neurons within one or two domains in each animal, we pharmacologically silenced the cortex to leave only the afferent terminals active. The inactivation of cortical neurons was achieved by the superfusion of either kainic acid or muscimol. Responses of single geniculate afferents were then recorded by the use of high impedance electrodes. We found that the orientation preferences of the afferents matched closely with those of the cells in the orientation domains that they terminated in (Pearson's r = 0.633, n = 22, P = 0.002). This suggests a possible subcortical origin for cortical orientation selectivity. © 2015 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

Excitatory inputs to four types of spinocerebellar tract neurons in the cat and the rat thoraco-lumbar spinal cord

PubMed Central

Shrestha, Sony Shakya; Bannatyne, B Anne; Jankowska, Elzbieta; Hammar, Ingela; Nilsson, Elin; Maxwell, David J

2012-01-01

The cerebellum receives information from the hindlimbs through several populations of spinocerebellar tract neurons. Although the role of these neurons has been established in electrophysiological experiments, the relative contribution of afferent fibres and central neurons to their excitatory input has only been estimated approximately so far. Taking advantage of differences in the immunohistochemistry of glutamatergic terminals of peripheral afferents and of central neurons (with vesicular glutamate transporters VGLUT1 or VGLUT2, respectively), we compared sources of excitatory input to four populations of spinocerebellar neurons in the thoraco-lumbar spinal cord: dorsal spinocerebellar tract neurons located in Clarke's column (ccDSCT) and in the dorsal horn (dhDSCT) and ventral spinocerebellar tract (VSCT) neurons including spinal border (SB) neurons. This was done on 22 electrophysiologically identified intracellularly labelled neurons in cats and on 80 neurons labelled by retrograde transport of cholera toxin b subunit injected into the cerebellum of rats. In both species distribution of antibodies against VGLUT1 and VGLUT2 on SB neurons (which have dominating inhibitory input from limb muscles), revealed very few VGLUT1 contacts and remarkably high numbers of VGLUT2 contacts. In VSCT neurons with excitatory afferent input, the number of VGLUT1 contacts was relatively high although VGLUT2 contacts likewise dominated, while the proportions of VGLUT1 and VGLUT2 immunoreactive terminals were the reverse on the two populations of DSCT neurons. These findings provide morphological evidence that SB neurons principally receive excitatory inputs from central neurons and provide the cerebellum with information regarding central neuronal activity. PMID:22371473

Excitatory inputs to four types of spinocerebellar tract neurons in the cat and the rat thoraco-lumbar spinal cord.

PubMed

Shrestha, Sony Shakya; Bannatyne, B Anne; Jankowska, Elzbieta; Hammar, Ingela; Nilsson, Elin; Maxwell, David J

2012-04-01

The cerebellum receives information from the hindlimbs through several populations of spinocerebellar tract neurons. Although the role of these neurons has been established in electrophysiological experiments, the relative contribution of afferent fibres and central neurons to their excitatory input has only been estimated approximately so far. Taking advantage of differences in the immunohistochemistry of glutamatergic terminals of peripheral afferents and of central neurons (with vesicular glutamate transporters VGLUT1 or VGLUT2, respectively), we compared sources of excitatory input to four populations of spinocerebellar neurons in the thoraco-lumbar spinal cord: dorsal spinocerebellar tract neurons located in Clarke's column (ccDSCT) and in the dorsal horn (dhDSCT) and ventral spinocerebellar tract (VSCT) neurons including spinal border (SB) neurons. This was done on 22 electrophysiologically identified intracellularly labelled neurons in cats and on 80 neurons labelled by retrograde transport of cholera toxin b subunit injected into the cerebellum of rats. In both species distribution of antibodies against VGLUT1 and VGLUT2 on SB neurons (which have dominating inhibitory input from limb muscles), revealed very few VGLUT1 contacts and remarkably high numbers of VGLUT2 contacts. In VSCT neurons with excitatory afferent input, the number of VGLUT1 contacts was relatively high although VGLUT2 contacts likewise dominated, while the proportions of VGLUT1 and VGLUT2 immunoreactive terminals were the reverse on the two populations of DSCT neurons. These findings provide morphological evidence that SB neurons principally receive excitatory inputs from central neurons and provide the cerebellum with information regarding central neuronal activity.

Excitatory glutamate is essential for development and maintenance of the piloneural mechanoreceptor.

PubMed

Woo, Seung-Hyun; Baba, Yoshichika; Franco, Alexa M; Lumpkin, Ellen A; Owens, David M

2012-02-01

The piloneural collar in mammalian hairy skin comprises an intricate pattern of circumferential and longitudinal sensory afferents that innervate primary and secondary pelage hairs. The longitudinal afferents tightly associate with terminal Schwann cell processes to form encapsulated lanceolate nerve endings of rapidly adapting mechanoreceptors. The molecular basis for piloneural development, maintenance and function is poorly understood. Here, we show that Nefh-expressing glutamatergic neurons represent a major population of longitudinal and circumferential sensory afferents innervating the piloneural collar. Our findings using a VGLUT2 conditional-null mouse model indicate that glutamate is essential for innervation, patterning and differentiation of NMDAR(+) terminal Schwann cells during piloneural collar development. Similarly, treatment of adult mice with a selective NMDAR antagonist severely perturbed piloneural collar structure and reduced excitability of these mechanosensory neurons. Collectively, these results show that DRG-derived glutamate is essential for the proper development, maintenance and sensory function of the piloneural mechanoreceptor.

Role of central vagal 5-HT3 receptors in gastrointestinal physiology and pathophysiology

PubMed Central

Browning, Kirsteen N.

2015-01-01

Vagal neurocircuits are vitally important in the co-ordination and modulation of GI reflexes and homeostatic functions. 5-hydroxytryptamine (5-HT; serotonin) is critically important in the regulation of several of these autonomic gastrointestinal (GI) functions including motility, secretion and visceral sensitivity. While several 5-HT receptors are involved in these physiological responses, the ligand-gated 5-HT3 receptor appears intimately involved in gut-brain signaling, particularly via the afferent (sensory) vagus nerve. 5-HT is released from enterochromaffin cells in response to mechanical or chemical stimulation of the GI tract which leads to activation of 5-HT3 receptors on the terminals of vagal afferents. 5-HT3 receptors are also present on the soma of vagal afferent neurons, including GI vagal afferent neurons, where they can be activated by circulating 5-HT. The central terminals of vagal afferents also exhibit 5-HT3 receptors that function to increase glutamatergic synaptic transmission to second order neurons of the nucleus tractus solitarius within the brainstem. While activation of central brainstem 5-HT3 receptors modulates visceral functions, it is still unclear whether central vagal neurons, i.e., nucleus of the tractus solitarius (NTS) and dorsal motor nucleus of the vagus (DMV) neurons themselves also display functional 5-HT3 receptors. Thus, activation of 5-HT3 receptors may modulate the excitability and activity of gastrointestinal vagal afferents at multiple sites and may be involved in several physiological and pathophysiological conditions, including distention- and chemical-evoked vagal reflexes, nausea, and vomiting, as well as visceral hypersensitivity. PMID:26578870

TERMINAL ARBORS OF AXONS PROJECTING TO THE SOMATOSENSORY CORTEX OF THE ADULT RAT. 2. THE ALTERED MORPHOLOGY OF THALAMOCORTICAL AFFERENTS FOLLOWING NEONATAL INFRAORBITAL NERVE CUT (JOURNAL VERSION)

EPA Science Inventory

The organization of the whisker representation within the neocortex of the rat is dependent on an intact periphery during development. To further investigate how alterations in the cortical map arise the authors examined the organization of thalamocortical afferents to the whiske...

Evidence that protons act as neurotransmitters at vestibular hair cell-calyx afferent synapses.

PubMed

Highstein, Stephen M; Holstein, Gay R; Mann, Mary Anne; Rabbitt, Richard D

2014-04-08

Present data support the conclusion that protons serve as an important neurotransmitter to convey excitatory stimuli from inner ear type I vestibular hair cells to postsynaptic calyx nerve terminals. Time-resolved pH imaging revealed stimulus-evoked extrusion of protons from hair cells and a subsequent buildup of [H(+)] within the confined chalice-shaped synaptic cleft (ΔpH ∼ -0.2). Whole-cell voltage-clamp recordings revealed a concomitant nonquantal excitatory postsynaptic current in the calyx terminal that was causally modulated by cleft acidification. The time course of [H(+)] buildup limits the speed of this intercellular signaling mechanism, but for tonic signals such as gravity, protonergic transmission offers a significant metabolic advantage over quantal excitatory postsynaptic currents--an advantage that may have driven the proliferation of postsynaptic calyx terminals in the inner ear vestibular organs of contemporary amniotes.

Ionotropic and metabotropic receptor mediated airway sensory nerve activation.

PubMed

Lee, Min-Goo; Kollarik, Marian; Chuaychoo, Benjamas; Undem, Bradley J

2004-01-01

There are several receptors capable of inducing activating generator potentials in cough-associated afferent terminals in the airways. The chemical receptors leading to generator potentials can be subclassified into ionotropic and metabotropic types. An ionotropic receptor has an agonist-binding domain, and also serves directly as an ion channel that is opened upon binding of the agonist. Examples of ionotropic receptors found in airway sensory nerve terminals include receptors for serotonin (5-HT3 receptors), ATP (P2X receptors), acetylcholine (nicotinic receptors), receptors for capsaicin and related vanilloids (TRPV1 receptors), and acid receptors (acid sensing ion channels). Afferent nerve terminals can also be depolarized via activation of metabotropic or G-protein coupled receptors (GPCRs). Among the GPCRs that can lead to activation of airway afferent fibers include bradykinin B2 and adenosine A1 receptors. The signaling events leading to GPCR-mediated membrane depolarization are more complex than that seen with ionotropic receptors. The GPCR-mediated effects are thought to occur through classical second messenger systems such as activation of phospholipase C. This may lead to membrane depolarization through interaction with specific ionotropic receptors (such as TRPV1) and/or various types of calcium activated channels.

Morphological evidence for local microcircuits in rat vestibular maculae

NASA Technical Reports Server (NTRS)

Ross, M. D.

1997-01-01

Previous studies suggested that intramacular, unmyelinated segments of vestibular afferent nerve fibers and their large afferent endings (calyces) on type I hair cells branch. Many of the branches (processes) contain vesicles and are presynaptic to type II hair cells, other processes, intramacular nerve fibers, and calyces. This study used serial section transmission electron microscopy and three-dimensional reconstruction methods to document the origins and distributions of presynaptic processes of afferents in the medial part of the adult rat utricular macula. The ultrastructural research focused on presynaptic processes whose origin and termination could be observed in a single micrograph. Results showed that calyces had 1) vesiculated, spine-like processes that invaginated type I cells and 2) other, elongate processes that ended on type II cells pre- as well as postsynaptically. Intramacular, unmyelinated segments of afferent nerve fibers gave origin to branches that were presynaptic to type II cells, calyces, calyceal processes, and other nerve fibers in the macula. Synapses with type II cells occurred opposite subsynaptic cisternae (C synapses); all other synapses were asymmetric. Vesicles were pleomorphic but were differentially distributed according to process origin. Small, clear-centered vesicles, approximately 40-60 nm in diameter, predominated in processes originating from afferent nerve fibers and basal parts of calyces. Larger vesicles approximately 70-120 nm in diameter having approximately 40-80 nm electron-opaque cores were dominant in processes originating from the necks of calyces. Results are interpreted to indicate the existence of a complex system of intrinsic feedforward (postsynaptic)-feedback (presynaptic) connections in a network of direct and local microcircuits. The morphological findings support the concept that maculae dynamically preprocess linear acceleratory information before its transmission to the central nervous system.

Autoregulation and tubuloglomerular feedback in juxtamedullary glomerular arterioles.

PubMed

Casellas, D; Moore, L C

1990-03-01

Videometric measurements of changes in vessel lumen diameters were made to investigate autoregulatory and tubuloglomerular feedback (TGF) responses of early efferent arterioles (EA), mid-to-late afferent arterioles (MAA), and terminal, juxtaglomerular afferent arterioles (JAA) in rat juxtamedullary nephrons in vitro. High-contrast shadow-cast images of blood-perfused arterioles at the glomerular vascular pole were obtained with incident illumination and long-working-distance objectives fitted to a compound microscope. In response to an increase in blood perfusion pressure from 60 to 140 mmHg, strong autoregulatory vasoconstriction was observed in the MAA and JAA, with respective reductions in mean luminal diameter of 23 +/- 4 and 40 +/- 4% (mean +/- SE); EA diameter was unchanged. In response to TGF excitation by direct microinjection of Ringer solution into the cortical thick ascending limb segment near the macula densa, JAA luminal diameter decreased by 34 +/- 5%. The TGF responses were completely inhibited by the addition of 0.1 mM furosemide to the tubular injectate. Calcium channel blockade achieved by adding 1 microM nimodipine to the superfusate had no effect on early EA diameter but produced a blood pressure-dependent JAA and MAA vasodilation and complete inhibition of autoregulatory responses. These results provide direct evidence that the distal afferent arteriole in juxtamedullary nephrons is a major effector site for both renal autoregulation and tubuloglomerular feedback.

Ca2+ and calpain mediate capsaicin-induced ablation of axonal terminals expressing transient receptor potential vanilloid 1.

PubMed

Wang, Sheng; Wang, Sen; Asgar, Jamila; Joseph, John; Ro, Jin Y; Wei, Feng; Campbell, James N; Chung, Man-Kyo

2017-05-19

Capsaicin is an ingredient in spicy peppers that produces burning pain by activating transient receptor potential vanilloid 1 (TRPV1), a Ca 2+ -permeable ion channel in nociceptors. Capsaicin has also been used as an analgesic, and its topical administration is approved for the treatment of certain pain conditions. The mechanisms underlying capsaicin-induced analgesia likely involve reversible ablation of nociceptor terminals. However, the mechanisms underlying these effects are not well understood. To visualize TRPV1-lineage axons, a genetically engineered mouse model was used in which a fluorophore is expressed under the TRPV1 promoter. Using a combination of these TRPV1-lineage reporter mice and primary afferent cultures, we monitored capsaicin-induced effects on afferent terminals in real time. We found that Ca 2+ influx through TRPV1 is necessary for capsaicin-induced ablation of nociceptive terminals. Although capsaicin-induced mitochondrial Ca 2+ uptake was TRPV1-dependent, dissipation of the mitochondrial membrane potential, inhibition of the mitochondrial transition permeability pore, and scavengers of reactive oxygen species did not attenuate capsaicin-induced ablation. In contrast, MDL28170, an inhibitor of the Ca 2+ -dependent protease calpain, diminished ablation. Furthermore, overexpression of calpastatin, an endogenous inhibitor of calpain, or knockdown of calpain 2 also decreased ablation. Quantitative assessment of TRPV1-lineage afferents in the epidermis of the hind paws of the reporter mice showed that EGTA and MDL28170 diminished capsaicin-induced ablation. Moreover, MDL28170 prevented capsaicin-induced thermal hypoalgesia. These results suggest that TRPV1/Ca 2+ /calpain-dependent signaling plays a dominant role in capsaicin-induced ablation of nociceptive terminals and further our understanding of the molecular mechanisms underlying the effects of capsaicin on nociceptors. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Projections from the pontine nuclei proper and reticular tegmental nucleus onto the cerebellar cortex in the cat. An autoradiographic study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kawamura, K.; Hashikawa, T.

1981-09-20

After injections of 0.5 microliter of tritiated leucine and/or proline into various parts of the pontine nuclei proper or the pontine tegmental reticular nucleus (N.r.t.) of 34 cats, labeled terminals of pontocerebellar fibers were found in the cerebellar cortex. Fibers from the pontine nuclei and N.r.t. terminate as mossy fibers in the granular layer of the cerebellum, and no evidence is obtained of labeled fibers in the molecular layer. The pontocerebellar projection is, in general, bilateral with a contralateral preponderance, and a complex organization has been shown to exist in the cat. Clear evidence of divergence of this projection frommore » a small pontine area has been demonstrated. Thus, the dorsolateral nucleus has a heavy projection to lobule VII, besides modest projections to lobules VI, VIII, and IX, crus I and II, paraflocculus, and paramedian lobule. On the other hand, a particular cerebellar region receives afferent fibers from several pontine regions, confirming previous HRP studies. This is a convergent feature of the pontocerebellar projections. In addition, small adjoining areas within a pontine subdivision have different patterns of cerebellar projections, showing preferential sites of terminations. The cerebellar projection from the N.r.t. shows an essentially similar organization as the projection from the pontine nuclei proper, an apparent difference being only that the former is more extensive in the fields of termination than the latter. Some evidence for a parasagittal termination of pontocerebellar projections to the paramedian lobule has been found in this study.« less

Peripheral axotomy of the rat mandibular trigeminal nerve leads to an increase in VIP and decrease of other primary afferent neuropeptides in the spinal trigeminal nucleus.

PubMed

Atkinson, M E; Shehab, S A

1986-12-01

In the vasoactive intestinal polypeptide (VIP)-rich lumbosacral spinal cord, VIP increases at the expense of other neuropeptides after primary sensory nerve axotomy. This study was undertaken to ascertain whether similar changes occur in peripherally axotomised cranial sensory nerves. VIP immunoreactivity increased in the terminal region of the mandibular nerve in the trigeminal nucleus caudalis following unilateral section of the sensory root of the mandibular trigeminal nerve at the foramen orale. Other primary afferent neuropeptides (substance P, cholecystokinin and somatostatin) were depleted and fluoride-resistant acid phosphatase activity was abolished in the same circumscribed areas of the nucleus caudalis. The rise in VIP and depletion of other markers began 4 days postoperatively and was maximal by 10 days, these levels remaining unchanged up to 1 year postoperatively. VIP-immunoreactive cell bodies were absent from trigeminal ganglia from the unoperated side but small and medium cells stained intensely in the ganglia of the operated side after axotomy. These observations indicate that increase of VIP in sensory nerve terminals is a general phenomenon occurring in both cranial and spinal sensory terminal areas. The intense VIP immunoreactivity in axotomised trigeminal ganglia suggests that the increased levels of VIP in the nucleus caudalis are of peripheral origin, indicating a change in expression of neuropeptides within primary afferent neurons following peripheral axotomy.

Encoding of the cough reflex in anesthetized guinea pigs

PubMed Central

Mori, Nanako

2011-01-01

We have previously described the physiological and morphological properties of the cough receptors and their sites of termination in the airways and centrally in the nucleus tractus solitarius (nTS). In the present study, we have addressed the hypothesis that the primary central synapses of the cough receptors subserve an essential role in the encoding of cough. We found that cough requires sustained, high-frequency (≥8-Hz) afferent nerve activation. We also found evidence for processes that both facilitate (summation, sensitization) and inhibit the initiation of cough. Sensitization of cough occurs with repetitive subthreshold activation of the cough receptors or by coincident activation of C-fibers and/or nTS neurokinin receptor activation. Desensitization of cough evoked by repetitive and/or continuous afferent nerve activation has a rapid onset (<60 s) and does not differentiate between tussive stimuli, suggesting a central nervous system-dependent process. The cough reflex can also be actively inhibited upon activation of other airway afferent nerve subtypes, including slowly adapting receptors and pulmonary C-fibers. The sensitization and desensitization of cough are likely attributable to the prominent, primary, and unique role of N-methyl-d-aspartate receptor-dependent signaling at the central synapses of the cough receptors. These attributes may have direct relevance to the presentation of cough in disease and for the effectiveness of antitussive therapies. PMID:20926760

Central vagal sensory and motor connections: human embryonic and fetal development.

PubMed

Cheng, Gang; Zhou, Xiangtian; Qu, Jia; Ashwell, Ken W S; Paxinos, G

2004-07-30

The embryonic and fetal development of the nuclear components and pathways of vagal sensorimotor circuits in the human has been studied using Nissl staining and carbocyanine dye tracing techniques. Eight fetal brains ranging from 8 to 28 weeks of development had DiI (1,1'-dioctadecyl-3,3,3',3' tetramethylindocarbocyanine perchlorate) inserted into either the thoracic vagus nerve at the level of the sternal angle (two specimens of 8 and 9 weeks of gestation) or into vagal rootlets at the surface of the medulla (at all other ages), while a further five were used for study of cytoarchitectural development. The first central labeling resulting from peripheral application of DiI to the thoracic vagus nerve was seen at 8 weeks. By 9 weeks, labeled bipolar cells at the ventricular surface around the sulcus limitans (sl) were seen after DiI application to the thoracic vagus nerve. Subnuclear organization as revealed by both Nissl staining and carbocyanine dye tracing was found to be advanced at a relatively early fetal age, with afferent segregation in the medial Sol apparent at 13 weeks and subnuclear organization of efferent magnocellular divisions of dorsal motor nucleus of vagus nerve noticeable at the same stage. The results of the present study also confirm that vagal afferents are distributed to the dorsomedial subnuclei of the human nucleus of the solitary tract, with particular concentrations of afferent axons in the gelatinosus subnucleus. These vagal afferents appeared to have a restricted zone of termination from quite early in development (13 weeks) suggesting that there is no initial exuberance in the termination field of vagal afferents in the developing human nucleus of the solitary tract. On the other hand, the first suggestion of afferents invading 10N from the medial Sol was not seen until 20 weeks and was not well developed until 24 weeks, suggesting that direct monosynaptic connections between the sensory and effector components of the vagal sensorimotor complex do not develop until this age.

Cortical and subcortical afferents to the nucleus reticularis tegmenti pontis and basal pontine nuclei in the macaque monkey.

PubMed

Giolli, R A; Gregory, K M; Suzuki, D A; Blanks, R H; Lui, F; Betelak, K F

2001-01-01

Anatomical findings are presented that identify cortical and subcortical sources of afferents to the nucleus reticularis tegmenti pontis (NRTP) and basal pontine nuclei. Projections from the middle temporal visual area (MT), medial superior temporal visual area (MST), lateral intraparietal area (LIP), and areas 7a and 7b to the basal pontine nuclei were studied using 3H-leucine autoradiography. The results complemented a parallel study of retrograde neuronal labeling attributable to injecting WGA-HRP into NRTP and neighboring pontine nuclei. Small 3H-leucine injections confined to MT, MST, LIP, area 7a, or area 7b, produced multiple patches of pontine terminal label distributed as follows: (1) An injection within MT produced terminal label limited to the dorsolateral and lateral pontine nuclei. (2) Injections restricted to MST or LIP showed patches of terminal label in the dorsal, dorsolateral, lateral, and peduncular pontine nuclei. (3) Area 7a targets the dorsal, dorsolateral, lateral, peduncular, and ventral pontine nuclei, whereas area 7b projects, additionally, to the dorsomedial and paramedian pontine nuclei. Notably, no projections were seen to NRTP from any of these cortical areas. In contrast, injections made by other investigators into cortical areas anterior to the central sulcus revealed cerebrocortical afferents to NRTP, in addition to nuclei of the basal pontine gray. With our pontine WGA-HRP injections, retrograde neuronal labeling was observed over a large extent of the frontal cortex continuing onto the medial surface which included the lining of the cingulate sulcus and cingulate gyrus. Significant subcortical sources for afferents to the NRTP and basal pontine nuclei were the zona incerta, ventral mesencephalic tegmentum, dorsomedial hypothalamic area, rostral interstitial nucleus of the medial longitudinal fasciculus, red nucleus, and subthalamic nucleus. The combined anterograde and retrograde labeling data indicated that visuo-motor cortico-pontine pathways arising from parietal cortices target only the basal pontine gray, whereas the NRTP, together with select pontine nuclei, is a recipient of afferents from frontal cortical areas. The present findings implicate the existence of parallel direct and indirect cortico-pontine pathways from frontal motor-related cortices to NRTP and neighboring pontine nuclei.

Sustained neurochemical plasticity in central terminals of mouse DRG neurons following colitis.

PubMed

Benson, Jessica R; Xu, Jiameng; Moynes, Derek M; Lapointe, Tamia K; Altier, Christophe; Vanner, Stephen J; Lomax, Alan E

2014-05-01

Sensitization of dorsal root ganglia (DRG) neurons is an important mechanism underlying the expression of chronic abdominal pain caused by intestinal inflammation. Most studies have focused on changes in the peripheral terminals of DRG neurons in the inflamed intestine but recent evidence suggests that the sprouting of central nerve terminals in the dorsal horn is also important. Therefore, we examine the time course and reversibility of changes in the distribution of immunoreactivity for substance P (SP), a marker of the central terminals of DRG neurons, in the spinal cord during and following dextran sulphate sodium (DSS)-induced colitis in mice. Acute and chronic treatment with DSS significantly increased SP immunoreactivity in thoracic and lumbosacral spinal cord segments. This increase developed over several weeks and was evident in both the superficial laminae of the dorsal horn and in lamina X. These increases persisted for 5 weeks following cessation of both the acute and chronic models. The increase in SP immunoreactivity was not observed in segments of the cervical spinal cord, which were not innervated by the axons of colonic afferent neurons. DRG neurons dissociated following acute DSS-colitis exhibited increased neurite sprouting compared with neurons dissociated from control mice. These data suggest significant colitis-induced enhancements in neuropeptide expression in DRG neuron central terminals. Such neurotransmitter plasticity persists beyond the period of active inflammation and might contribute to a sustained increase in nociceptive signaling following the resolution of inflammation.

Expression of gastrin-releasing peptide by excitatory interneurons in the mouse superficial dorsal horn.

PubMed

Gutierrez-Mecinas, Maria; Watanabe, Masahiko; Todd, Andrew J

2014-12-11

Gastrin-releasing peptide (GRP) and its receptor have been shown to play an important role in the sensation of itch. However, although GRP immunoreactivity has been detected in the spinal dorsal horn, there is debate about whether this originates from primary afferents or local excitatory interneurons. We therefore examined the relation of GRP immunoreactivity to that seen with antibodies that label primary afferent or excitatory interneuron terminals. We tested the specificity of the GRP antibody by preincubating with peptides with which it could potentially cross-react. We also examined tissue from a mouse line in which enhanced green fluorescent protein (EGFP) is expressed under control of the GRP promoter. GRP immunoreactivity was seen in both primary afferent and non-primary glutamatergic axon terminals in the superficial dorsal horn. However, immunostaining was blocked by pre-incubation of the antibody with substance P, which is present at high levels in many nociceptive primary afferents. EGFP+ cells in the GRP-EGFP mouse did not express Pax2, and their axons contained the vesicular glutamate transporter 2 (VGLUT2), indicating that they are excitatory interneurons. In most cases, their axons were also GRP-immunoreactive. Multiple-labelling immunocytochemical studies indicated that these cells did not express either of the preprotachykinin peptides, and that they generally lacked protein kinase Cγ, which is expressed by a subset of the excitatory interneurons in this region. These results show that GRP is expressed by a distinct population of excitatory interneurons in laminae I-II that are likely to be involved in the itch pathway. They also suggest that the GRP immunoreactivity seen in primary afferents in previous studies may have resulted from cross-reaction of the GRP antibody with substance P or the closely related peptide neurokinin A.

Differential Structural Plasticity of Corticostriatal and Thalamostriatal Axo-Spinous Synapses in MPTP-Treated Parkinsonian Monkeys

PubMed Central

Villalba, Rosa M.; Smith, Yoland

2011-01-01

Striatal spine loss is a key pathological feature of Parkinson's disease (PD). Knowing that striatal glutamatergic afferents target dendritic spines, these data appear difficult to reconcile with evidence for an increased expression of the vesicular glutamate transporter 1 (vGluT1) in the striatum of PD patients and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys, as well as in some electrophysiological studies showing overactivity of the corticostriatal glutamatergic system in models of parkinsonism. To address the possibility that structural changes in glutamatergic afferents may underlie these discrepancies, we undertook an ultrastructural analysis of vGluT1-positive (i.e., corticostriatal) and vGluT2-positive (i.e., mostly thalamostriatal) axo-spinous glutamatergic synapses using a 3D electron microscopic approach in normal and MPTP-treated monkeys. Three main conclusions can be drawn: 1) spines contacted by vGluT1-containing terminals have larger volume and harbor significantly larger postsynaptic densities (PSDs) than those contacted by vGluT2-immunoreactive boutons; 2) a subset of vGluT2-, but not vGluT1-immunoreactive, terminals display a pattern of multisynaptic connectivity in normal and MPTP-treated monkeys; and 3) VGluT1- and vGluT2-positive axo-spinous synapses undergo ultrastructural changes (larger spine volume, larger PSDs, increased PSD perforations, larger presynaptic terminal) indicative of increased synaptic activity in parkinsonian animals. Furthermore, spines contacted by cortical terminals display an increased volume of their spine apparatus in MPTP-treated monkeys, suggesting an increased protein synthesis at corticostriatal synapses. These findings demonstrate that corticostriatal and thalamostriatal glutamatergic axo-spinous synapses display significantly different ultrastructural features, and that both systems undergo complex morphological changes that could underlie the pathophysiology of corticostriatal and thalamostriatal systems in PD. PMID:21280048

Interplay between mast cells, enterochromaffin cells, and sensory signaling in the aging human bowel.

PubMed

Yu, Y; Daly, D M; Adam, I J; Kitsanta, P; Hill, C J; Wild, J; Shorthouse, A; Grundy, D; Jiang, W

2016-10-01

Advanced age is associated with a reduction in clinical visceral pain perception. However, the underlying mechanisms remain largely unknown. Previous studies have suggested that an abnormal interplay between mast cells, enterochromaffin (EC) cells, and afferent nerves contribute to nociception in gastrointestinal disorders. The aim of this study was to investigate how aging affects afferent sensitivity and neuro-immune association in the human bowel. Mechanical and chemical sensitivity of human bowel afferents were examined by ex vivo afferent nerve recordings. Age-related changes in the density of mast cells, EC cells, sensory nerve terminals, and mast cell-nerve micro-anatomical association were investigated by histological and immune staining. Human afferents could be broadly classified into subpopulations displaying mechanical and chemical sensitivity, adaptation, chemo-sensitization, and recruitment. Interestingly human bowel afferent nerve sensitivity was attenuated with age. The density of substance P-immunoreactive (SP-IR) nerve varicosities was also reduced with age. In contrast, the density of ileal and colonic mucosal mast cells was increased with age, as was ileal EC cell number. An increased proportion of mast cells was found in close apposition to SP-IR nerves. Afferent sensitivity in human bowel was reduced with advancing age. Augmentation of mast cells and EC cell numbers and the mast cell-nerve association suggest a compensatory mechanism for sensory neurodegeneration. © 2016 The Authors. Neurogastroenterology & Motility Published by John Wiley & Sons Ltd.

Effects of ruthenium ions on the sensory terminal discharges of the frog muscle spindle.

PubMed

Ito, F; Fujitsuka, N; Komatsu, Y

1983-10-16

The presence of a mixed Na+-Ca2+ spike along the sensory terminal of the frog muscle spindle was verified. When the terminal was perfused with Ringer's solution containing 0.1-0.5 mM ruthenium red (RuR), the amplitude and duration of the spike were increased, occurring as a prolonged or a long-lasting depolarization of up to 20-30 s duration following individual afferent spikes evoked spontaneously or antidromically by electrical stimulation. In an isotonic TEA solution, the amplitude and duration of the afferent spikes were increased; however, no prolonged depolarization occurred. Adding 0.2 mM RuR to the TEA solution produced the prolonged and long-lasting depolarization. All responses disappeared in the presence of 3 microM TTX or Na+-free Ringer's solution. An impedance decrease along the terminal was observed during the prolonged or long-lasting depolarization. The prolonged depolarization was blocked by the addition of Ca2+-blockers; the afferent spikes remained. In preparations preincubated with 0.1 mM RuR, increasing CaCl2 in Ringer's solution from 0.2 mM, resulted in shortening of the duration of individual spikes with prolonged depolarization and in increase in the maximum rate of rise (MRR) of the spikes. Preincubation with higher concentrations of RuR produced higher sensitivities in the modifications of the duration and MRR to the change in [Ca2+]O. The responses were retained by adding RuR or RuCl3 to Ca2+-free Ringer's solution containing 0.1-5 mM EGTA, although all responses disappeared in Ca2+-free EGTA Ringer's solution. It is concluded that the RuR-induced prolonged response is produced by an influx of Na+.

Optogenetic Silencing of Nav1.8-Positive Afferents Alleviates Inflammatory and Neuropathic Pain123

PubMed Central

Daou, Ihab; Beaudry, Hélène; Ase, Ariel R.; Wieskopf, Jeffrey S.; Ribeiro-da-Silva, Alfredo; Mogil, Jeffrey S.

2016-01-01

Abstract We report a novel transgenic mouse model in which the terminals of peripheral nociceptors can be silenced optogenetically with high spatiotemporal precision, leading to the alleviation of inflammatory and neuropathic pain. Inhibitory archaerhodopsin-3 (Arch) proton pumps were delivered to Nav1.8+ primary afferents using the Nav1.8-Cre driver line. Arch expression covered both peptidergic and nonpeptidergic nociceptors and yellow light stimulation reliably blocked electrically induced action potentials in DRG neurons. Acute transdermal illumination of the hindpaws of Nav1.8-Arch+ mice significantly reduced mechanical allodynia under inflammatory conditions, while basal mechanical sensitivity was not affected by the optical stimulation. Arch-driven hyperpolarization of nociceptive terminals was sufficient to prevent channelrhodopsin-2 (ChR2)-mediated mechanical and thermal hypersensitivity in double-transgenic Nav1.8-ChR2+-Arch+mice. Furthermore, prolonged optical silencing of peripheral afferents in anesthetized Nav1.8-Arch+ mice led to poststimulation analgesia with a significant decrease in mechanical and thermal hypersensitivity under inflammatory and neuropathic conditions. These findings highlight the role of peripheral neuronal inputs in the onset and maintenance of pain hypersensitivity, demonstrate the plasticity of pain pathways even after sensitization has occurred, and support the involvement of Nav1.8+ afferents in both inflammatory and neuropathic pain. Together, we present a selective analgesic approach in which genetically identified subsets of peripheral sensory fibers can be remotely and optically inhibited with high temporal resolution, overcoming the compensatory limitations of genetic ablations. PMID:27022626

Evidence of a sensory processing unit in the mammalian macula

NASA Technical Reports Server (NTRS)

Chimento, T. C.; Ross, M. D.

1996-01-01

We cut serial sections through the medial part of the rat vestibular macula for transmission electron microscopic (TEM) examination, computer-assisted 3-D reconstruction, and compartmental modeling. The ultrastructural research showed that many primary vestibular neurons have an unmyelinated segment, often branched, that extends between the heminode (putative site of the spike initiation zone) and the expanded terminal(s) (calyx, calyces). These segments, termed the neuron branches, and the calyces frequently have spine-like processes of various dimensions with bouton endings that morphologically are afferent, efferent, or reciprocal to other macular neural elements. The major questions posed by this study were whether small details of morphology, such as the size and location of neuronal processes or synapses, could influence the output of a vestibular afferent, and whether a knowledge of morphological details could guide the selection of values for simulation parameters. The conclusions from our simulations are (1) values of 5.0 k omega cm2 for membrane resistivity and 1.0 nS for synaptic conductance yield simulations that best match published physiological results; (2) process morphology has little effect on orthodromic spread of depolarization from the head (bouton) to the spike initiation zone (SIZ); (3) process morphology has no effect on antidromic spread of depolarization to the process head; (4) synapses do not sum linearly; (5) synapses are electrically close to the SIZ; and (6) all whole-cell simulations should be run with an active SIZ.

Modulation of synaptic transmission from segmental afferents by spontaneous activity of dorsal horn spinal neurones in the cat.

PubMed

Manjarrez, E; Rojas-Piloni, J G; Jimenez, I; Rudomin, P

2000-12-01

We examined, in the anaesthetised cat, the influence of the neuronal ensembles producing spontaneous negative cord dorsum potentials (nCDPs) on segmental pathways mediating primary afferent depolarisation (PAD) of cutaneous and group I muscle afferents and on Ia monosynaptic activation of spinal motoneurones. The intraspinal distribution of the field potentials associated with the spontaneous nCDPs indicated that the neuronal ensembles involved in the generation of these potentials were located in the dorsal horn of lumbar segments, in the same region of termination of low-threshold cutaneous afferents. During the occurrence of spontaneous nCDPs, transmission from low-threshold cutaneous afferents to second order neurones in laminae III-VI, as well as transmission along pathways mediating PAD of cutaneous and Ib afferents, was facilitated. PAD of Ia afferents was instead inhibited. Monosynaptic reflexes of flexors and extensors were facilitated during the spontaneous nCDPs. The magnitude of the facilitation was proportional to the amplitude of the 'conditioning' spontaneous nCDPs. This led to a high positive correlation between amplitude fluctuations of spontaneous nCDPs and fluctuations of monosynaptic reflexes. Stimulation of low-threshold cutaneous afferents transiently reduced the probability of occurrence of spontaneous nCDPs as well as the fluctuations of monosynaptic reflexes. It is concluded that the spontaneous nCDPs were produced by the activation of a population of dorsal horn neurones that shared the same functional pathways and involved the same set of neurones as those responding monosynaptically to stimulation of large cutaneous afferents. The spontaneous activity of these neurones was probably the main cause of the fluctuations of the monosynaptic reflexes observed under anaesthesia and could provide a dynamic linkage between segmental sensory and motor pathways.

Inhibition of Parkinsonian tremor with cutaneous afferent evoked by transcutaneous electrical nerve stimulation.

PubMed

Hao, Man-Zhao; Xu, Shao-Qin; Hu, Zi-Xiang; Xu, Fu-Liang; Niu, Chuan-Xin M; Xiao, Qin; Lan, Ning

2017-07-14

Recent study suggests that tremor signals are transmitted by way of multi-synaptic corticospinal pathway. Neurophysiological studies have also demonstrated that cutaneous afferents exert potent inhibition to descending motor commands by way of spinal interneurons. We hypothesize in this study that cutaneous afferents could also affect the transmission of tremor signals, thus, inhibit tremor in patients with PD. We tested this hypothesis by activating cutaneous afferents in the dorsal hand skin innervated by superficial radial nerve using transcutaneous electrical nerve stimulation (TENS). Eight patients with PD having tremor dominant symptom were recruited to participate in this study using a consistent experimental protocol for tremor inhibition. Resting tremor and electromyogram (EMG) of muscles in the upper extremity of these subjects with PD were recorded, while surface stimulation was applied to the dorsal skin of the hand. Fifteen seconds of data were recorded for 5 s prior to, during and post stimulation. Power spectrum densities (PSDs) of tremor and EMG signals were computed for each data segment. The peak values of PSDs in three data segments were compared to detect evidence of tremor inhibition. At stimulation intensity from 1.5 to 1.75 times of radiating sensation threshold, apparent suppressions of tremor at wrist, forearm and upper arm and in the EMGs were observed immediately at the onset of stimulation. After termination of stimulation, tremor and rhythmic EMG bursts reemerged gradually. Statistical analysis of peak spectral amplitudes showed a significant difference in joint tremors and EMGs during and prior to stimulation in all 8 subjects with PD. The average percentage of suppression was 61.56% in tremor across all joints of all subjects, and 47.97% in EMG of all muscles. The suppression appeared to occur mainly in distal joints and muscles. There was a slight, but inconsistent effect on tremor frequency in the 8 patients with PD tested. Our results provide direct evidence that tremor in the upper extremity of patients with PD can be inhibited to a large extent with evoked cutaneous reflexes via surface stimulation of the dorsal hand skin area innervated by the superficial radial nerve.

Using vertebral movement and intact paraspinal muscles to determine the distribution of intrafusal fiber innervation of muscle spindle afferents in the anesthetized cat.

PubMed

Reed, William R; Cao, Dong-Yuan; Ge, Weiqing; Pickar, Joel G

2013-03-01

Increasing our knowledge regarding intrafusal fiber distribution and physiology of paraspinal proprioceptors may provide key insights regarding proprioceptive deficits in trunk control associated with low back pain and lead to more effective clinical intervention. The use of vertebral movement as a means to reliably stretch paraspinal muscles would greatly facilitate physiological study of paraspinal muscle proprioceptors where muscle tendon isolation is either very difficult or impossible. The effects of succinylcholine (SCh) on 194 muscle spindle afferents from lumbar longissimus or multifidus muscles in response to computer-controlled, ramp-and-hold movements of the L(6) vertebra were investigated in anesthetized cats. Paraspinal muscles were stretched by moving the L(6) vertebra 1.5-1.7 mm in the dorsal-ventral direction. Initial frequency (IF), dynamic difference (DD), their changes (∆) following SCh injection (100-400 μg kg(-1)), and post-SCh dynamic difference (SChDD) were measured. Muscle spindle intrafusal fiber terminations were classified as primary or secondary fibers as well as bag(1) (b(1)c), bag(2) (b(2)c), b(1)b(2)c, or chain (c) fibers. Intrafusal fiber subpopulations were distinguished using logarithmic transformation of SChDD and ∆IF distributions as established by previous investigators. Increases in DD indicate strength of b(1)c influence while increases in IF indicate strength of b(2)c influence. Out of 194 afferents, 46.9 % of afferents terminated on b(2)c fibers, 46.4 % on b(1)b(2)c fibers, 1 % on b(1)c fibers, and 5.7 % terminated on c fibers. Based on these intrafusal fiber subpopulation distributions, controlled vertebral movement can effectively substitute for direct tendon stretch and allow further investigation of paraspinal proprioceptors in this anatomically complex body region.

Calcitonin gene-related Peptide and choline acetyltransferase colocalization in the human vestibular periphery.

PubMed

Popper, Paul; Ishiyama, Akira; Lopez, Ivan; Wackym, Phillip A

2002-01-01

Within the vestibular system, calcitonin gene-related peptide (CGRP) has been localized in the efferent terminals and their brainstem neuronal cell bodies in several animal models. Presently, very few studies have verified these findings in the vestibular system in adult primates or humans. CGRP immunoreactivity (CGRPi) and its colocalization with choline acetyltransferase immunoreactivity (ChATi) in human vestibular end organs and Scarpa's ganglion were studied using polyclonal antibodies against CGRP and ChAT, at the light-microscopic level. The CGRPi axons ramified to produce numerous CGRPi terminals throughout the neurosensory epithelium of the maculae and cristae, primarily in the basal and midbasal areas. Numerous CGRPi efferent terminals made contact with both type II vestibular hair cells and the afferent chalices surrounding type I vestibular hair cells. All CGRP immunoreactive fibers also exhibited ChATi. As in the animal models, no CGRPi was found within Scarpa's ganglion. This study provides evidence for CGRPi in the human vestibular periphery and validates the biomedical relevance of the current animal models. Copyright 2002 S. Karger AG, Basel

Vagal sensory innervation of the gastric sling muscle and antral wall: implications for gastro-esophageal reflux disease?

PubMed

Powley, T L; Gilbert, J M; Baronowsky, E A; Billingsley, C N; Martin, F N; Phillips, R J

2012-10-01

The gastric sling muscle has not been investigated for possible sensory innervation, in spite of the key roles the structure plays in lower esophageal sphincter (LES) function and gastric physiology. Thus, the present experiment used tracing techniques to label vagal afferents and survey their projections in the lesser curvature. Sprague-Dawley rats received injections of dextran biotin into the nodose ganglia. Fourteen days postinjection, animals were euthanized and their stomachs were processed to visualize the vagal afferent innervation. In different cases, neurons, muscle cells, or interstitial cells of Cajal (ICC) were counterstained. The sling muscle is innervated throughout its length by vagal afferent intramuscular arrays (IMAs) associated with ICC. In addition, the distal antral attachment site of the sling muscle is innervated by a novel vagal afferent terminal specialization, an antral web ending. The muscle wall of the distal antrum is also innervated by conventional IMAs and intraganglionic laminar endings, the two types of mechanoreceptors found throughout stomach smooth muscle. The innervation of sling muscle by IMAs, putative stretch receptors, suggests that sling sensory feedback may generate vago-vagal or other reflexes with vagal afferent limbs. The restricted distribution of afferent web endings near the antral attachments of sling fibers suggests the possibility of specialized mechanoreceptor functions linking antral and pyloric activity to the operation of the LES. Dysfunctional sling afferents could generate LES motor disturbances, or normative compensatory sensory feedback from the muscle could compromise therapies targeting only effectors. © 2012 Blackwell Publishing Ltd.

Quantitative changes of GABA-immunoreactive cells in the hindlimb representation of the rat somatosensory cortex after 14-day hindlimb unloading by tail suspension

NASA Technical Reports Server (NTRS)

D'Amelio, F.; Fox, R. A.; Wu, L. C.; Daunton, N. G.

1996-01-01

The present study was aimed at evaluating quantitatively gamma-aminobutyric acid (GABA) immunoreactivity in the hindlimb representation of the rat somatosensory cortex after 14 days of hindlimb unloading by tail suspension. A reduction in the number of GABA-immunoreactive cells with respect to the control animals was observed in layer Va and Vb. GABA-containing terminals were also reduced in the same layers, particularly those terminals surrounding the soma and apical dendrites of pyramidal cells in layer Vb. On the basis of previous morphological and behavioral studies of the neuromuscular system of hindlimb-suspended animals, it is suggested that the unloading due to hindlimb suspension alters afferent signaling and feedback information from intramuscular receptors to the cerebral cortex due to modifications in the reflex organization of hindlimb muscle groups. We propose that the reduction in immunoreactivity of local circuit GABAergic neurons and terminals is an expression of changes in their modulatory activity to compensate for the alterations in the afferent information.

Three-dimensional analysis of vestibular efferent neurons innervating semicircular canals of the gerbil

NASA Technical Reports Server (NTRS)

Purcell, I. M.; Perachio, A. A.

1997-01-01

Anterograde labeling techniques were used to examine peripheral innervation patterns of vestibular efferent neurons in the crista ampullares of the gerbil. Vestibular efferent neurons were labeled by extracellular injections of biocytin or biotinylated dextran amine into the contralateral or ipsilateral dorsal subgroup of efferent cell bodies (group e) located dorsolateral to the facial nerve genu. Anterogradely labeled efferent terminal field varicosities consist mainly of boutons en passant with fewer of the terminal type. The bouton swellings are located predominately in apposition to the basolateral borders of the afferent calyces and type II hair cells, but several boutons were identified close to the hair cell apical border on both types. Three-dimensional reconstruction and morphological analysis of the terminal fields from these cells located in the sensory neuroepithelium of the anterior, horizontal, and posterior cristae were performed. We show that efferent neurons densely innervate each end organ in widespread terminal fields. Subepithelial bifurcations of parent axons were minimal, with extensive collateralization occurring after the axons penetrated the basement membrane of the neuroepithelium. Axonal branching ranged between the 6th and 27th orders and terminal field collecting area far exceeds that of the peripheral terminals of primary afferent neurons. The terminal fields of the efferent neurons display three morphologically heterogeneous types: central, peripheral, and planum. All cell types possess terminal fields displaying a high degree of anisotropy with orientations typically parallel to or within +/-45 degrees of the longitudinal axis if the crista. Terminal fields of the central and planum zones predominately project medially toward the transverse axis from the more laterally located penetration of the basement membrane by the parent axon. Peripheral zone terminal fields extend predominately toward the planum semilunatum. The innervation areas of efferent terminal fields display a trend from smallest to largest for the central, peripheral, and planum types, respectively. Neurons that innervate the central zone of the crista do not extend into the peripheral or planum regions. Conversely, those neurons with terminal fields in the peripheral or planum regions do not innervate the central zone of the sensory neuroepithelium. The central zone of the crista is innervated preferentially by efferent neurons with cell bodies located in the ipsilateral group e. The peripheral and planum zones of the crista are innervated preferentially by efferent neurons with cell bodies located in the contralateral group e. A model incorporating our anatomic observations is presented describing an ipsilateral closed-loop feedback between ipsilateral efferent neurons and the periphery and an open-loop feed-forward innervation from contralateral efferent neurons. A possible role for the vestibular efferent neurons in the modulation of semicircular canal afferent response dynamics is proposed.

Implications for bidirectional signaling between afferent nerves and urothelial cells-ICI-RS 2014.

PubMed

Kanai, Anthony; Fry, Christopher; Ikeda, Youko; Kullmann, Florenta Aura; Parsons, Brian; Birder, Lori

2016-02-01

To present a synopsis of the presentations and discussions from Think Tank I, "Implications for afferent-urothelial bidirectional communication" of the 2014 International Consultation on Incontinence-Research Society (ICI-RS) meeting in Bristol, UK. The participants presented what is new, currently understood or still unknown on afferent-urothelial signaling mechanisms. New avenues of research and experimental methodologies that are or could be employed were presented and discussed. It is clear that afferent-urothelial interactions are integral to the regulation of normal bladder function and that its disruption can have detrimental consequences. The urothelium is capable of releasing numerous signaling factors that can affect sensory neurons innervating the suburothelium. However, the understanding of how factors released from urothelial cells and afferent nerve terminals regulate one another is incomplete. Utilization of techniques such as viruses that genetically encode Ca(2+) sensors, based on calmodulin and green fluorescent protein, has helped to address the cellular mechanisms involved. Additionally, the epithelial-neuronal interactions in the urethra may also play a significant role in lower urinary tract regulation and merit further investigation. The signaling capabilities of the urothelium and afferent nerves are well documented, yet how these signals are integrated to regulate bladder function is unclear. There is unquestionably a need for expanded methodologies to further our understanding of lower urinary tract sensory mechanisms and their contribution to various pathologies. © 2016 Wiley Periodicals, Inc.

Presynaptic and postsynaptic effects of local cathodal DC polarization within the spinal cord in anaesthetized animal preparations

PubMed Central

Bolzoni, F; Jankowska, E

2015-01-01

The present study aimed to compare presynaptic and postsynaptic actions of direct current polarization in the spinal cord, focusing on DC effects on primary afferents and motoneurons. To reduce the directly affected spinal cord region, a weak polarizing direct current (0.1–0.3 μA) was applied locally in deeply anaesthetized cats and rats; within the hindlimb motor nuclei in the caudal lumbar segments, or in the dorsal horn within the terminal projection area of low threshold skin afferents. Changes in the excitability of primary afferents activated by intraspinal stimuli (20–50 μA) were estimated using increases or decreases in compound action potentials recorded from the dorsal roots or peripheral nerves as their measure. Changes in the postsynaptic actions of the afferents were assessed from intracellularly recorded monosynaptic EPSPs in hindlimb motoneurons and monosynaptic extracellular field potentials (evoked by group Ia afferents in motor nuclei, or by low threshold cutaneous afferents in the dorsal horn). The excitability of motoneurons activated by intraspinal stimuli was assessed using intracellular records or motoneuronal discharges recorded from a ventral root or a muscle nerve. Cathodal polarization was found to affect motoneurons and afferents providing input to them to a different extent. The excitability of both was markedly increased during DC application, although post-polarization facilitation was found to involve presynaptic afferents and some of their postsynaptic actions, but only negligibly motoneurons themselves. Taken together, these results indicate that long-lasting post-polarization facilitation of spinal activity induced by locally applied cathodal current primarily reflects the facilitation of synaptic transmission. PMID:25416625

Role of presynaptic inputs to proprioceptive afferents in tuning sensorimotor pathways of an insect joint control network.

PubMed

Sauer, A E; Büschges, A; Stein, W

1997-04-01

The femur-tibia (FT) joint of insects is governed by a neuronal network that controls activity in tibial motoneurons by processing sensory information about tibial position and movement provided by afferents of the femoral chordotonal organ (fCO). We show that central arborizations of fCO afferents receive presynaptic depolarizing synaptic inputs. With an average resting potential of -71.9 +/- 3.72 mV (n = 10), the reversal potential of these potentials is on average -62.8 +/- 2.3 mV (n = 5). These synaptic potentials occur either spontaneously or are related to movements at the fCO. They are thus induced by signals from other fCO afferents. Therefore, the synaptic inputs to fCO afferents are specific and depend on the sensitivity of the individual afferent affected. These potentials reduce the amplitude of concurrent afferent action potentials. Bath application of picrotoxin, a noncompetitive blocker of chloride ion channels, blocks these potentials, which indicates that they are mediated by chloride ions. From these results, it is concluded that these are inhibitory synaptic potentials generated in the central terminals of fCO afferents. Pharmacologic removal of these potentials affects the tuning of the complete FT control system. Following removal, the dependence of the FT control loop on the tibia position increases relative to the dependency on the velocity of tibia movements. This is due to changes in the relative weighting of the position and velocity signals in the parallel interneuronal pathways from the fCO onto tibial motoneurons. Consequently, the FT joint is no longer able to perform twig mimesis (i.e., catalepsy), which is known to rely on a low position compared to the high-velocity dependency of the FT control system.

Afferent projections to the deep mesencephalic nucleus in the rat

DOE Office of Scientific and Technical Information (OSTI.GOV)

Veazey, R.B.; Severin, C.M.

1982-01-10

Afferent projections to the deep mesencephalic nucleus (DMN) of the rat were demonstrated with axonal transport techniques. Potential sources for projections to the DMN were first identified by injecting the nucleus with HRP and examining the cervical spinal cord, brain stem, and cortex for retrogradely labeled neurons. Areas consistently labeled were then injected with a tritiated radioisotope, the tissue processed for autoradiography, and the DMN examined for anterograde labeling. Afferent projections to the medial and/or lateral parts of the DMN were found to originate from a number of spinal, bulbar, and cortical centers. Rostral brain centers projecting to both medialmore » and lateral parts of the DMN include the ipsilateral motor and somatosensory cortex, the entopeduncular nucleus, and zona incerta. at the level of the midbrain, the ipsilateral substantia nigra and contralateral DMN likewise project to the DMN. Furthermore, the ipsilateral superior colliculus projects to the DMN, involving mainly the lateral part of the nucleus. Afferents from caudal centers include bilateral projections from the sensory nucleus of the trigeminal complex and the nucleus medulla oblongata centralis, as well as from the contralateral dentate nucleus. The projections from the trigeminal complex and nucleus medullae oblongatae centralis terminate in the intermediate and medial parts of the DMN, whereas projections from the contralateral dentate nucleus terminate mainly in its lateral part. In general, the afferent connections of the DMN arise from diverse areas of the brain. Although most of these projections distribute throughout the entire extent of the DMN, some of them project mainly to either medial or lateral parts of the nucleus, thus suggesting that the organization of the DMN is comparable, at least in part, to that of the reticular formation of the pons and medulla, a region in which hodological differences between medial and lateral subdivisions are known to exist.« less

Vagal Sensory Innervation of the Gastric Sling Muscle and Antral Wall: Implications for GERD?

PubMed Central

Powley, Terry L.; Gilbert, Jared M.; Baronowsky, Elizabeth A.; Billingsley, Cherie N.; Martin, Felecia N.; Phillips, Robert J.

2012-01-01

Background The gastric sling muscle has not been investigated for possible sensory innervation, in spite of the key roles the structure plays in lower esophageal sphincter (LES) function and gastric physiology. Thus, the present experiment used tracing techniques to label vagal afferents and survey their projections in the lesser curvature. Methods Sprague Dawley rats received injections of dextran biotin into the nodose ganglia. Fourteen days post-injection, animals were euthanized and their stomachs were processed to visualize the vagal afferent innervation. In different cases, neurons, muscle cells, or interstitial cells of Cajal were counterstained. Key Results The sling muscle is innervated throughout its length by vagal afferent intramuscular arrays (IMAs) associated with interstitial cells of Cajal. In addition, the distal antral attachment site of the sling muscle is innervated by a novel vagal afferent terminal specialization, an antral web ending. The muscle wall of the distal antrum is also innervated by conventional IMAs and intraganglionic laminar endings (IGLEs), the two types of mechanoreceptors found throughout stomach smooth muscle. Conclusions & Inferences The innervation of sling muscle by IMAs, putative stretch receptors, suggests that sling sensory feedback may generate vago-vagal or other reflexes with vagal afferent limbs. The restricted distribution of afferent web endings near the antral attachments of sling fibers suggests the possibility of specialized mechanoreceptor functions linking antral and pyloric activity to the operation of the LES. Dysfunctional sling afferents could generate LES motor disturbances, or normative compensatory sensory feedback from the muscle could compromise therapies targeting only effectors. PMID:22925069

Bidirectional modulation of windup by NMDA receptors in the rat spinal trigeminal nucleus.

PubMed

Woda, Alain; Blanc, Olivier; Voisin, Daniel L; Coste, Jérôme; Molat, Jean-Louis; Luccarini, Philippe

2004-04-01

Activation of afferent nociceptive pathways is subject to activity-dependent plasticity, which may manifest as windup, a progressive increase in the response of dorsal horn nociceptive neurons to repeated stimuli. At the cellular level, N-methyl-d-aspartate (NMDA) receptor activation by glutamate released from nociceptive C-afferent terminals is currently thought to generate windup. Most of the wide dynamic range nociceptive neurons that display windup, however, do not receive direct C-fibre input. It is thus unknown where the NMDA mechanisms for windup operate. Here, using the Sprague-Dawley rat trigeminal system as a model, we anatomically identify a subpopulation of interneurons that relay nociceptive information from the superficial dorsal horn where C-fibres terminate, to downstream wide dynamic range nociceptive neurons. Using in vivo electrophysiological recordings, we show that at the end of this pathway, windup was reduced (24 +/- 6%, n = 7) by the NMDA receptor antagonist AP-5 (2.0 fmol) and enhanced (62 +/- 19%, n = 12) by NMDA (1 nmol). In contrast, microinjections of AP-5 (1.0 fmol) within the superficial laminae increased windup (83 +/- 44%, n = 9), whereas NMDA dose dependently decreased windup (n = 19). These results indicate that NMDA receptor function at the segmental level depends on their precise location in nociceptive neural networks. While some NMDA receptors actually amplify pain information, the new evidence for NMDA dependent inhibition of windup we show here indicates that, simultaneously, others act in the opposite direction. Working together, the two mechanisms may provide a fine tuning of gain in pain.

Transfer characteristics of the hair cell's afferent synapse

NASA Astrophysics Data System (ADS)

Keen, Erica C.; Hudspeth, A. J.

2006-04-01

The sense of hearing depends on fast, finely graded neurotransmission at the ribbon synapses connecting hair cells to afferent nerve fibers. The processing that occurs at this first chemical synapse in the auditory pathway determines the quality and extent of the information conveyed to the central nervous system. Knowledge of the synapse's input-output function is therefore essential for understanding how auditory stimuli are encoded. To investigate the transfer function at the hair cell's synapse, we developed a preparation of the bullfrog's amphibian papilla. In the portion of this receptor organ representing stimuli of 400-800 Hz, each afferent nerve fiber forms several synaptic terminals onto one to three hair cells. By performing simultaneous voltage-clamp recordings from presynaptic hair cells and postsynaptic afferent fibers, we established that the rate of evoked vesicle release, as determined from the average postsynaptic current, depends linearly on the amplitude of the presynaptic Ca2+ current. This result implies that, for receptor potentials in the physiological range, the hair cell's synapse transmits information with high fidelity. auditory system | exocytosis | glutamate | ribbon synapse | synaptic vesicle

BDNF released during neuropathic pain potentiates NMDA receptors in primary afferent terminals

PubMed Central

Chen, Wenling; Walwyn, Wendy; Ennes, Helena S.; Kim, Hyeyoung; McRoberts, James A.; Marvizón, Juan Carlos G.

2014-01-01

NMDA receptors in primary afferent terminals can contribute to hyperalgesia by increasing neurotransmitter release. In rats and mice, we found that the ability of intrathecal NMDA to induce neurokinin 1 receptor (NK1R) internalization (a measure of substance P release) required a previous injection of BDNF. Selective knock-down of NMDA receptors in primary afferents decreased NMDA-induced NK1R internalization, confirming the presynaptic location of these receptors. The effect of BDNF was mediated by tropomyosin-related kinase B (trkB) receptors and not p75 neurotrophin receptors (p75NTR), because it was not produced by proBDNF and was inhibited by the trkB antagonist ANA-12 but not by the p75NTR inhibitor TAT-Pep5. These effects are probably mediated through the truncated form of the trkB receptor as there is little expression of full-length trkB in dorsal root ganglion (DRG) neurons. Src family kinase inhibitors blocked the effect of BDNF, suggesting that trkB receptors promote the activation of these NMDA receptors by Src family kinase phosphorylation. Western blots of cultured DRG neurons revealed that BDNF increased Tyr1472 phosphorylation of the NR2B subunit of the NMDA receptor, known to have a potentiating effect. Patch-clamp recordings showed that BDNF, but not proBDNF, increased NMDA receptor currents in cultured DRG neurons. NMDA-induced NK1R internalization was also enabled in a neuropathic pain model or by activating dorsal horn microglia with lipopolysaccharide. These effects were decreased by a BDNF scavenger, a trkB receptor antagonist and an Src family kinase inhibitor, indicating that BDNF released by microglia potentiates NMDA receptors in primary afferents during neuropathic pain. PMID:24611998

Distribution of Vesicular Glutamate Transporter 2 (VGluT2) in the Primary Visual Cortex of the Macaque and Human

PubMed Central

Garcia-Marin, Virginia; Ahmed, Tunazzina H.; Afzal, Yasmeen C.; Hawken, Michael J.

2014-01-01

The majority of thalamic terminals in V1 arise from lateral geniculate nucleus (LGN) afferents. Thalamic afferent terminals are preferentially labeled by an isoform of the vesicular glutamate transporter, VGluT2. The goal of our study was to determine the distribution of VGluT2-ir puncta in macaque and human visual cortex. First, we investigated the distribution of VGluT2-ir puncta in all layers of macaque monkey primary visual cortex (V1), and found a very close correspondence between the known distribution of LGN afferents from previous studies and the distribution of VGluT2-immunoreactive (-ir) puncta. There was also a close correspondence between cytochrome oxidase density and VGluT2-ir puncta distribution. After validating the correspondence in macaque, we made a comparative study in human V1. In many aspects, the distribution of VGluT2-ir puncta in human was qualitatively similar to that of the macaque: high densities in layer 4C, patches of VGluT2-ir puncta in the supragranular layer (2/3), lower but clear distribution in layers 1 and 6, and very few puncta in layers 5 and 4B. However, there were also important differences between macaques and humans. In layer 4A of human, there was a sparse distribution of VGluT2-ir puncta, whereas in macaque, there was a dense distribution with the characteristic honeycomb organization. The results suggest important changes in the pattern of cortical VGluT2 immunostaining that may be related to evolutionary differences in the cortical organization of LGN afferents between Old World monkeys and humans. PMID:22684983

Synaptic-like vesicles and candidate transduction channels in mechanosensory terminals

PubMed Central

Bewick, Guy S

2015-01-01

This article summarises progress to date over an exciting and very enjoyable first 15 years of collaboration with Bob Banks. Our collaboration began when I contacted him with (to me) an unexpected observation that a dye used to mark recycling synaptic vesicle membrane at efferent terminals also labelled muscle spindle afferent terminals. This observation led to the re-discovery of a system of small clear vesicles present in all vertebrate primary mechanosensory nerve terminals. These synaptic-like vesicles (SLVs) have been, and continue to be, the major focus of our work. This article describes our characterisation of the properties and functional significance of these SLVs, combining our complementary skills: Bob’s technical expertise and encyclopaedic knowledge of mechanosensation with my experience of synaptic vesicles and the development of the styryl pyridinium dyes, of which the most widely used is FM1-43. On the way we have found that SLVs seem to be part of a constitutive glutamate secretory system necessary to maintain the stretch-sensitivity of spindle endings. The glutamate activates a highly unusual glutamate receptor linked to phospholipase D activation, which we have termed the PLD-mGluR. It has a totally distinct pharmacology first described in the hippocampus nearly 20 years ago but, like the SLVs that were first described over 50 years ago, has since been little researched. Yet, our evidence and literature searches suggest this glutamate/SLV/PLD-mGluR system is a ubiquitous feature of mechanosensory endings and, at least for spindles, is essential for maintaining mechanosensory function. This article summarises how this system integrates with the classical model of mechanosensitive channels in spindles and other mechanosensory nerve terminals, including hair follicle afferents and baroreceptors controlling blood pressure. Finally, in this time when there is an imperative to show translational relevance, I describe how this fascinating system might actually be a useful therapeutic drug target for clinical conditions such as hypertension and muscle spasticity. This has been a fascinating 15-year journey in collaboration with Bob who, as well as having an astute scientific mind, is also a great enthusiast, motivator and friend. I hope this exciting and enjoyable journey will continue well into the future. PMID:26179025

Immunocytochemical localization of glutamic acid decarboxylase (GAD) and substance P in neural areas mediating motion-induced emesis: Effects of vagal stimulation on GAD immunoreactivity

NASA Technical Reports Server (NTRS)

Damelio, F.; Gibbs, M. A.; Mehler, W. R.; Daunton, Nancy G.; Fox, Robert A.

1991-01-01

Immunocytochemical methods were employed to localize the neurotransmitter amino acid gamma-aminobutyric acid (GABA) by means of its biosynthetic enzyme glutamic acid decarboxylase (GAD) and the neuropeptide substance P in the area postrema (AP), area subpostrema (ASP), nucleus of the tractus solitarius (NTS), and gelatinous nucleus (GEL). In addition, electrical stimulation was applied to the night vagus nerve at the cervical level to assess the effects on GAD-immunoreactivity (GAR-IR). GAD-IR terminals and fibers were observed in the AP, ASP, NTS, and GEL. They showed pronounced density at the level of the ASP and gradual decrease towards the solitary complex. Nerve cells were not labelled in our preparations. Ultrastructural studies showed symmetric or asymmetric synaptic contracts between labelled terminals and non-immunoreactive dendrites, axons, or neurons. Some of the labelled terminals contained both clear- and dense-core vesicles. Our preliminary findings, after electrical stimulation of the vagus nerve, revealed a bilateral decrease of GAD-IR that was particularly evident at the level of the ASP. SP-immunoreactive (SP-IR) terminals and fibers showed varying densities in the AP, ASP, NTS, and GEL. In our preparations, the lateral sub-division of the NTS showed the greatest accumulation. The ASP showed medium density of immunoreactive varicosities and terminals and the AP and GEL displayed scattered varicose axon terminals. The electron microscopy revealed that all immunoreactive terminals contained clear-core vesicles which make symmetric or asymmetric synaptic contact with unlabelled dendrites. It is suggested that the GABAergic terminals might correspond to vagal afferent projections and that GAD/GABA and substance P might be co-localized in the same terminal allowing the possibility of a regulated release of the transmitters in relation to demands.

Complex impairment of IA muscle proprioceptors following traumatic or neurotoxic injury.

PubMed

Vincent, Jacob A; Nardelli, Paul; Gabriel, Hanna M; Deardorff, Adam S; Cope, Timothy C

2015-08-01

The health of primary sensory afferents supplying muscle has to be a first consideration in assessing deficits in proprioception and related motor functions. Here we discuss the role of a particular proprioceptor, the IA muscle spindle proprioceptor in causing movement disorders in response to either regeneration of a sectioned peripheral nerve or damage from neurotoxic chemotherapy. For each condition, there is a single preferred and widely repeated explanation for disability of movements associated with proprioceptive function. We present a mix of published and preliminary findings from our laboratory, largely from in vivo electrophysiological study of treated rats to demonstrate newly discovered IA afferent defects that seem likely to make important contributions to movement disorders. First, we argue that reconnection of regenerated IA afferents with inappropriate targets, although often repeated as the reason for lost stretch-reflex contraction, is not a complete explanation. We present evidence that despite successful recovery of stretch-evoked sensory signaling, peripherally regenerated IA afferents retract synapses made with motoneurons in the spinal cord. Second, we point to evidence that movement disability suffered by human subjects months after discontinuation of oxaliplatin (OX) chemotherapy for some is not accompanied by peripheral neuropathy, which is the acknowledged primary cause of disability. Our studies of OX-treated rats suggest a novel additional explanation in showing the loss of sustained repetitive firing of IA afferents during static muscle stretch. Newly extended investigation reproduces this effect in normal rats with drugs that block Na(+) channels apparently involved in encoding static IA afferent firing. Overall, these findings highlight multiplicity in IA afferent deficits that must be taken into account in understanding proprioceptive disability, and that present new avenues and possible advantages for developing effective treatment. Extending the study of IA afferent deficits yielded the additional benefit of elucidating normal processes in IA afferent mechanosensory function. © 2015 Anatomical Society.

Ulex europaeus agglutinin-I binding to dental primary afferent projections in the spinal trigeminal complex combined with double immunolabeling of substance P and GABA elements using peroxidase and colloidal gold.

PubMed

Matthews, M A; Hoffmann, K D; Hernandez, T V

1989-01-01

Ulex europaeus agglutinin I (UEA-I) is a plant lectin with an affinity for L-fucosyl residues in the chains of lactoseries oligosaccharides associated with medium- and smaller-diameter dorsal root ganglion neurons and their axonal processes. These enter Lissauer's tract and terminate within the superficial laminae of the spinal cord overlapping projections known to have a nociceptive function. This implies that the surface coatings of neuronal membranes may have a relationship with functional modalities. The present investigation further examined this concept by studying a neuronal projection with a nociceptive function to determine whether fucosyl-lactoseries residues were incorporated in its primary afferent terminals. Transganglionic transport of horseradish peroxidase (HRP) following injection into tooth pulp chambers was employed to demonstrate dental pulp terminals in the trigeminal spinal complex, while peroxidase and fluorescent tags were used concomitantly to stain for UEA-I. Double immunolabeling for substance P (SP) and gamma-aminobutyric acid (GABA) using peroxidase and colloidal gold allowed a comparison of the distribution of a known excitatory nociceptive transmitter with that of UEA-I binding in specific subnuclei. Synaptic interrelationships between UEA-I positive dental pulp primary afferent inputs and specific inhibitory terminals were also examined. SP immunoreactivity occurred in laminae I and outer lamina II (IIo) of subnucleus caudalis (Vc) and in the ventrolateral and lateral marginal region of the caudal half of subnucleus interpolaris (Vi), including the periobex area in which Vi is slightly overlapped on its lateral aspect by cellular elements of Vc. The adjacent interstitial nucleus (IN) also showed an intense immunoreactivity for this peptide antibody. UEA-I binding displayed a similar distribution pattern in both Vc and Vi, but extended into lamina IIi and the superficial part of Lamina III in Vc. Dental pulp terminals were found to have a comparable distribution; however, many extended into the dorsal portion of the caudal half of Vi and the ventromedial quadrant of rostral Vi. Electron-microscopic analysis showed that transganglionically labeled dental pulp terminals contained ovoid, complex membrane-bound vacuoles laden with transported HRP. The preterminal axon and synaptic membranes of those dental pulp terminals located in zones of Vc and Vi displaying an affinity for UEA-I were usually characterized by a patchy, electron-dense coating of the peroxidase tag. SP was demonstrated ultrastructurally with Protein-A colloidal gold (3-nm particles), whereas GABA immunoreactivity was revealed by the avidin-biotin-peroxidase method.(ABSTRACT TRUNCATED AT 400 WORDS)

Drivers of the primate thalamus

PubMed Central

Rovó, Zita; Ulbert, István; Acsády, László

2012-01-01

The activity of thalamocortical neurons is largely determined by giant excitatory terminals, called drivers. These afferents may arise from neocortex or from subcortical centers; however their exact distribution, segregation or putative absence in given thalamic nuclei are unknown. To unravel the nucleus-specific composition of drivers, we mapped the entire macaque thalamus utilizing vesicular glutamate transporters 1 and 2 to label cortical and subcortical afferents, respectively. Large thalamic territories were innervated exclusively either by giant vGLUT2- or vGLUT1-positive boutons. Co-distribution of drivers with different origin was not abundant. In several thalamic regions, no giant terminals of any type could be detected at light microscopic level. Electron microscopic observation of these territories revealed either the complete absence of large multisynaptic excitatory terminals (basal ganglia-recipient nuclei) or the presence of both vGLUT1- and vGLUT2-positive terminals, which were significantly smaller than their giant counterparts (intralaminar nuclei, medial pulvinar). In the basal ganglia-recipient thalamus, giant inhibitory terminals replaced the excitatory driver inputs. The pulvinar and the mediodorsal nucleus displayed subnuclear heterogeneity in their driver assemblies. These results show that distinct thalamic territories can be under pure subcortical or cortical control; however there is significant variability in the composition of major excitatory inputs in several thalamic regions. Since thalamic information transfer depends on the origin and complexity of the excitatory inputs, this suggests that the computations performed by individual thalamic regions display considerable variability. Finally, the map of driver distribution may help to resolve the morphological basis of human diseases involving different parts of the thalamus. PMID:23223308

Afferent connections of nervus facialis and nervus glossopharyngeus in the pigeon (Columba livia) and their role in feeding behavior.

PubMed

Dubbeldam, J L

1984-01-01

The afferent connections of the facial nerve and glossopharyngeal nerve in the pigeon have been studied with the Fink-Heimer I method after ganglion lesions. The nucleus ventrolateralis anterior of the solitary complex and an indistinct cell group S VII medial to the nucleus interpolaris of the descending trigeminal tract are the terminal fields for facial afferents. The n. ventrolateralis anterior also receives an important projection from the distal glossopharyngeal ganglion. Other projection areas of this ganglion are the n. presulcalis , n. centralis anterior, n. intermedius anterior and the parasolitary nucleus. Both ganglia have only ipsilateral projections. A lesion in the jugular ganglion complex causes degeneration throughout the ipsilateral solitary complex, in the contralateral n. commissuralis and n. centralis posterior and in the n. cuneatus externus. The lack of a substantial contribution to the trigeminal system is ascribed to the absence of mechanoreceptors in the tongue. The implications for the organization of neuronal pathways related to the feeding behavior are discussed.

Neurotrophin trafficking by anterograde transport.

PubMed

Altar, C A; DiStefano, P S

1998-10-01

The ever-unfolding biology of NGF is consistent with a target-derived retrograde mode of action in peripheral and central neurons. However, another member of the neurotrophin family, brain-derived neurotrophic factor (BDNF), is present within nerve terminals in certain regions of the brain and PNS that do not contain the corresponding mRNA. Recent studies have shown that the endogenous neurotrophins, BDNF and neurotrophin-3 (NT-3), are transported anterogradely by central and peripheral neurons. The supply of BDNF by afferents is consistent with their presynaptic synthesis, vesicular storage, release and postsynaptic actions. Anterograde axonal transport provides an 'afferent supply' of BDNF and NT-3 to neurons and target tissues, where they function as trophic factors and as neurotransmitters.

Cortical presynaptic control of dorsal horn C-afferents in the rat.

PubMed

Moreno-López, Yunuen; Pérez-Sánchez, Jimena; Martínez-Lorenzana, Guadalupe; Condés-Lara, Miguel; Rojas-Piloni, Gerardo

2013-01-01

Lamina 5 sensorimotor cortex pyramidal neurons project to the spinal cord, participating in the modulation of several modalities of information transmission. A well-studied mechanism by which the corticospinal projection modulates sensory information is primary afferent depolarization, which has been characterized in fast muscular and cutaneous, but not in slow-conducting nociceptive skin afferents. Here we investigated whether the inhibition of nociceptive sensory information, produced by activation of the sensorimotor cortex, involves a direct presynaptic modulation of C primary afferents. In anaesthetized male Wistar rats, we analyzed the effects of sensorimotor cortex activation on post tetanic potentiation (PTP) and the paired pulse ratio (PPR) of dorsal horn field potentials evoked by C-fiber stimulation in the sural (SU) and sciatic (SC) nerves. We also explored the time course of the excitability changes in nociceptive afferents produced by cortical stimulation. We observed that the development of PTP was completely blocked when C-fiber tetanic stimulation was paired with cortex stimulation. In addition, sensorimotor cortex activation by topical administration of bicuculline (BIC) produced a reduction in the amplitude of C-fiber responses, as well as an increase in the PPR. Furthermore, increases in the intraspinal excitability of slow-conducting fiber terminals, produced by sensorimotor cortex stimulation, were indicative of primary afferent depolarization. Topical administration of BIC in the spinal cord blocked the inhibition of C-fiber neuronal responses produced by cortical stimulation. Dorsal horn neurons responding to sensorimotor cortex stimulation also exhibited a peripheral receptive field and responded to stimulation of fast cutaneous myelinated fibers. Our results suggest that corticospinal inhibition of nociceptive responses is due in part to a modulation of the excitability of primary C-fibers by means of GABAergic inhibitory interneurons.

Cortical Presynaptic Control of Dorsal Horn C–Afferents in the Rat

PubMed Central

Martínez-Lorenzana, Guadalupe; Condés-Lara, Miguel; Rojas-Piloni, Gerardo

2013-01-01

Lamina 5 sensorimotor cortex pyramidal neurons project to the spinal cord, participating in the modulation of several modalities of information transmission. A well-studied mechanism by which the corticospinal projection modulates sensory information is primary afferent depolarization, which has been characterized in fast muscular and cutaneous, but not in slow-conducting nociceptive skin afferents. Here we investigated whether the inhibition of nociceptive sensory information, produced by activation of the sensorimotor cortex, involves a direct presynaptic modulation of C primary afferents. In anaesthetized male Wistar rats, we analyzed the effects of sensorimotor cortex activation on post tetanic potentiation (PTP) and the paired pulse ratio (PPR) of dorsal horn field potentials evoked by C–fiber stimulation in the sural (SU) and sciatic (SC) nerves. We also explored the time course of the excitability changes in nociceptive afferents produced by cortical stimulation. We observed that the development of PTP was completely blocked when C-fiber tetanic stimulation was paired with cortex stimulation. In addition, sensorimotor cortex activation by topical administration of bicuculline (BIC) produced a reduction in the amplitude of C–fiber responses, as well as an increase in the PPR. Furthermore, increases in the intraspinal excitability of slow-conducting fiber terminals, produced by sensorimotor cortex stimulation, were indicative of primary afferent depolarization. Topical administration of BIC in the spinal cord blocked the inhibition of C–fiber neuronal responses produced by cortical stimulation. Dorsal horn neurons responding to sensorimotor cortex stimulation also exhibited a peripheral receptive field and responded to stimulation of fast cutaneous myelinated fibers. Our results suggest that corticospinal inhibition of nociceptive responses is due in part to a modulation of the excitability of primary C–fibers by means of GABAergic inhibitory interneurons. PMID:23935924

Presynaptic Inhibition of Diverse Afferents to the Locus Coeruleus by Kappa Opiate Receptors: a Novel Mechanism for Regulating the Central Norepinephrine System

PubMed Central

Kreibich, Arati S.; Reyes, Beverly A. S.; Curtis, Andre L.; Ecke, Laurel; Chavkin, Charles; Van Bockstaele, Elisabeth J.; Valentino, Rita J.

2008-01-01

The norepinephrine nucleus, locus coeruleus (LC), is activated by diverse stimuli and modulates arousal and behavioral strategies in response to these stimuli through its divergent efferent system. Afferents communicating information to the LC include excitatory amino acids (EAA), corticotropin-releasing factor (CRF) and endogenous opioids acting at μ-opiate receptors. As the LC is also innervated by the endogenous κ-opiate receptor (κ-OR) ligand, dynorphin, and expresses κ-ORs, this study investigated κ-OR regulation of LC neuronal activity in rat. Immunoelectron microscopy revealed a prominent localization of κ-ORs in axon terminals in the LC that also contained either the vesicular glutamate transporter or CRF. Microinfusion of the κ-OR agonist, U50488, into the LC did not alter LC spontaneous discharge but attenuated phasic discharge evoked by stimuli that engage EAA afferents to the LC, including sciatic nerve stimulation and auditory stimuli and the tonic activation associated with opiate withdrawal. Inhibitory effects of the κ-OR agonist were not restricted to EAA afferents, as U50488 also attenuated tonic LC activation by hypotensive stress, an effect mediated by CRF afferents. Together, these results indicate that κ-ORs are poised to presynaptically inhibit diverse afferent signaling to the LC. This is a novel and potentially powerful means of regulating the LC-NE system that can impact on forebrain processing of stimuli and the organization of behavioral strategies in response to environmental stimuli. The results implicate κ-ORs as a novel target for alleviating symptoms of opiate withdrawal, stress-related disorders or disorders characterized by abnormal sensory responses, such as autism. PMID:18562623

Presynaptic inhibition of diverse afferents to the locus ceruleus by kappa-opiate receptors: a novel mechanism for regulating the central norepinephrine system.

PubMed

Kreibich, Arati; Reyes, Beverly A S; Curtis, Andre L; Ecke, Laurel; Chavkin, Charles; Van Bockstaele, Elisabeth J; Valentino, Rita J

2008-06-18

The norepinephrine nucleus, locus ceruleus (LC), is activated by diverse stimuli and modulates arousal and behavioral strategies in response to these stimuli through its divergent efferent system. Afferents communicating information to the LC include excitatory amino acids (EAAs), corticotropin-releasing factor (CRF), and endogenous opioids acting at mu-opiate receptors. Because the LC is also innervated by the endogenous kappa-opiate receptor (kappa-OR) ligand dynorphin and expresses kappa-ORs, this study investigated kappa-OR regulation of LC neuronal activity in rat. Immunoelectron microscopy revealed a prominent localization of kappa-ORs in axon terminals in the LC that also contained either the vesicular glutamate transporter or CRF. Microinfusion of the kappa-OR agonist (trans)-3,4-dichloro-N-methyl-N-[2-1-pyrrolidinyl)-cyclo-hexyl] benzeneacetamide (U50488) into the LC did not alter LC spontaneous discharge but attenuated phasic discharge evoked by stimuli that engage EAA afferents to the LC, including sciatic nerve stimulation and auditory stimuli and the tonic activation associated with opiate withdrawal. Inhibitory effects of the kappa-OR agonist were not restricted to EAA afferents, as U50488 also attenuated tonic LC activation by hypotensive stress, an effect mediated by CRF afferents. Together, these results indicate that kappa-ORs are poised to presynaptically inhibit diverse afferent signaling to the LC. This is a novel and potentially powerful means of regulating the LC-norepinephrine system that can impact on forebrain processing of stimuli and the organization of behavioral strategies in response to environmental stimuli. The results implicate kappa-ORs as a novel target for alleviating symptoms of opiate withdrawal, stress-related disorders, or disorders characterized by abnormal sensory responses, such as autism.

Static γ-motoneurones couple group Ia and II afferents of single muscle spindles in anaesthetised and decerebrate cats

PubMed Central

Gladden, M H; Matsuzaki, H

2002-01-01

Ideas about the functions of static γ-motoneurones are based on the responses of primary and secondary endings to electrical stimulation of single static γ-axons, usually at high frequencies. We compared these effects with the actions of spontaneously active γ-motoneurones. In anaesthetised cats, afferents and efferents were recorded in intramuscular nerve branches to single muscle spindles. The occurrence of γ-spikes, identified by a spike shape recognition system, was linked to video-taped contractions of type-identified intrafusal fibres in the dissected muscle spindles. When some static γ-motoneurones were active at low frequency (< 15 Hz) they coupled the firing of group Ia and II afferents. Activity of other static γ-motoneurones which tensed the intrafusal fibres appeared to enhance this effect. Under these conditions the secondary ending responded at shorter latency than the primary ending. In another series of experiments on decerebrate cats, responses of primary and secondary endings of single muscle spindles to activation of γ-motoneurones by natural stimuli were compared with their responses to electrical stimulation of single γ-axons supplying the same spindle. Electrical stimulation mimicked the natural actions of γ-motoneurones on either the primary or the secondary ending, but not on both together. However, γ-activity evoked by natural stimuli coupled the firing of afferents with the muscle at constant length, and also when it was stretched. Analysis showed that the timing and tightness of this coupling determined the degree of summation of excitatory postsynaptic potentials (EPSPs) evoked by each afferent in α-motoneurones and interneurones contacted by terminals of both endings, and thus the degree of facilitation of reflex actions of group II afferents. PMID:12181298

Loss of neurotrophin-3 from smooth muscle disrupts vagal gastrointestinal afferent signaling and satiation

PubMed Central

Biddinger, Jessica E.; Baquet, Zachary C.; Jones, Kevin R.; McAdams, Jennifer

2013-01-01

A large proportion of vagal afferents are dependent on neurotrophin-3 (NT-3) for survival. NT-3 is expressed in developing gastrointestinal (GI) smooth muscle, a tissue densely innervated by vagal mechanoreceptors, and thus could regulate their survival. We genetically ablated NT-3 from developing GI smooth muscle and examined the pattern of loss of NT-3 expression in the GI tract and whether this loss altered vagal afferent signaling or feeding behavior. Meal-induced c-Fos activation was reduced in the solitary tract nucleus and area postrema in mice with a smooth muscle-specific NT-3 knockout (SM-NT-3KO) compared with controls, suggesting a decrease in vagal afferent signaling. Daily food intake and body weight of SM-NT-3KO mice and controls were similar. Meal pattern analysis revealed that mutants, however, had increases in average and total daily meal duration compared with controls. Mutants maintained normal meal size by decreasing eating rate compared with controls. Although microstructural analysis did not reveal a decrease in the rate of decay of eating in SM-NT-3KO mice, they ate continuously during the 30-min meal, whereas controls terminated feeding after 22 min. This led to a 74% increase in first daily meal size of SM-NT-3KO mice compared with controls. The increases in meal duration and first meal size of SM-NT-3KO mice are consistent with reduced satiation signaling by vagal afferents. This is the first demonstration of a role for GI NT-3 in short-term controls of feeding, most likely involving effects on development of vagal GI afferents that regulate satiation. PMID:24068045

Parkinson subtype-specific Granger-causal coupling and coherence frequency in the subthalamic area.

PubMed

Florin, Esther; Pfeifer, Johannes; Visser-Vandewalle, Veerle; Schnitzler, Alfons; Timmermann, Lars

2016-09-22

Previous work on Parkinson's disease (PD) has indicated a predominantly afferent coupling between affected arm muscle activity and electrophysiological activity within the subthalamic nucleus (STN). So far, no information is available indicating which frequency components drive the afferent information flow in PD patients. Non-directional coupling e.g. by measuring coherence is primarily established in the beta band as well as at tremor frequency. Based on previous evidence it is likely that different subtypes of the disease are associated with different connectivity patterns. Therefore, we determined coherence and causality between local field potentials (LFPs) in the STN and surface electromyograms (EMGs) from the contralateral arm in 18 akinetic-rigid (AR) PD patients and 8 tremor-dominant (TD) PD patients. During the intraoperative recording, patients were asked to lift their forearm contralateral to the recording side. Significantly more afferent connections were detected for the TD patients for tremor-periods and non-tremor-periods combined as well as for only tremor periods. Within the STN 74% and 63% of the afferent connections are associated with coherence from 4-8Hz and 8-12Hz, respectively. However, when considering only tremor-periods significantly more afferent than efferent connections were associated with coherence from 12 to 20Hz across all recording heights. No difference between efferent and afferent connections is seen in the frequency range from 4 to 12Hz for all recording heights. For the AR patients, no significant difference in afferent and efferent connections within the STN was found for the different frequency bands. Still, for the AR patients dorsal of the STN significantly more afferent than efferent connections were associated with coherence in the frequency range from 12 to 16Hz. These results provide further evidence for the differential pathological oscillations and pathways present in AR and TD Parkinson patients. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

Enterocyte-afferent nerve interactions in dietary fat sensing.

PubMed

Mansouri, A; Langhans, W

2014-09-01

The central nervous system (CNS) constantly monitors nutrient availability in the body and, in particular, in the gastrointestinal (GI) tract to regulate nutrient and energy homeostasis. Extrinsic parasympathetic and sympathetic nerves are crucial for CNS nutrient sensing in the GI tract. These extrinsic afferent nerves detect the nature and amount of nutrients present in the GI tract and relay the information to the brain, which controls energy intake and expenditure accordingly. Dietary fat and fatty acids are sensed through various direct and indirect mechanisms. These sensing processes involve the binding of fatty acids to specific G protein-coupled receptors expressed either on the afferent nerve fibres or on the surface of enteroendocrine cells that release gut peptides, which themselves can modulate afferent nerve activity through their cognate receptors or have endocrine effects directly on the brain. Further dietary fat sensing mechanisms that are related to enterocyte fat handling and metabolism involve the release of several possible chemical mediators such as fatty acid ethanolamides or apolipoprotein A-IV. We here present evidence for yet another mechanism that may be based on ketone bodies resulting from enterocyte oxidation of dietary fat-derived fatty acids. The presently available evidence suggests that sympathetic rather than vagal afferents are involved, but further experiments are necessary to critically examine this concept. © 2014 John Wiley & Sons Ltd.

Inhibition of muscle spindle afferent activity during masseter muscle fatigue in the rat.

PubMed

Brunetti, Orazio; Della Torre, Giovannella; Lucchi, Maria Luisa; Chiocchetti, Roberto; Bortolami, Ruggero; Pettorossi, Vito Enrico

2003-09-01

The influence of muscle fatigue on the jaw-closing muscle spindle activity has been investigated by analyzing: (1) the field potentials evoked in the trigeminal motor nucleus (Vmot) by trigeminal mesencephalic nucleus (Vmes) stimulation, (2) the orthodromic and antidromic responses evoked in the Vmes by stimulation of the peripheral and central axons of the muscle proprioceptive afferents, and (3) the extracellular unitary discharge of masseter muscle spindles recorded in the Vmes. The masseter muscle was fatigued by prolonged tetanic masseter nerve electrical stimulation. Pre- and postsynaptic components of the potentials evoked in the Vmot showed a significant reduction in amplitude following muscle fatigue. Orthodromic and antidromic potentials recorded in the Vmes also showed a similar amplitude decrease. Furthermore, muscle fatigue caused a decrease of the discharge frequency of masseter muscle spindle afferents in most of the examined units. The inhibition of the potential amplitude and discharge frequency was strictly correlated with the extent of muscle fatigue and was mediated by the group III and IV afferent muscle fibers activated by fatigue. In fact, the inhibitory effect was abolished by capsaicin injection in the masseter muscle that provokes selective degeneration of small afferent muscle fibers containing neurokinins. We concluded that fatigue signals originating from the muscle and traveling through capsaicin-sensitive fibers are able to diminish the proprioceptive input by a central presynaptic influence. In the second part of the study, we examined the central projection of the masseter small afferents sensitive to capsaicin at the electron-microscopic level. Fiber degeneration was induced by injecting capsaicin into the masseter muscle. Degenerating terminals were found on the soma and stem process in Vmes and on the dendritic tree of neurons in Vmot. This suggests that small muscle afferents may influence the muscle spindle activity through direct synapses on somata in Vmes and on dendrites of neurons in Vmot.

Hydrogen peroxide preferentially activates capsaicin-sensitive high threshold afferents via TRPA1 channels in the guinea pig bladder.

PubMed

Nicholas, S; Yuan, S Y; Brookes, S J H; Spencer, N J; Zagorodnyuk, V P

2017-01-01

There is increasing evidence suggesting that ROS play a major pathological role in bladder dysfunction induced by bladder inflammation and/or obstruction. The aim of this study was to determine the effect of H 2 O 2 on different types of bladder afferents and its mechanism of action on sensory neurons in the guinea pig bladder. 'Close-to-target' single unit extracellular recordings were made from fine branches of pelvic nerves entering the guinea pig bladder, in flat sheet preparations, in vitro. H 2 O 2 (300-1000 μM) preferentially and potently activated capsaicin-sensitive high threshold afferents but not low threshold stretch-sensitive afferents, which were only activated by significantly higher concentrations of hydrogen peroxide. The TRPV1 channel agonist, capsaicin, excited 86% of high threshold afferents. The TRPA1 channel agonist, allyl isothiocyanate and the TRPM8 channel agonist, icilin activated 72% and 47% of capsaicin-sensitive high threshold afferents respectively. The TRPA1 channel antagonist, HC-030031, but not the TRPV1 channel antagonist, capsazepine or the TRPM8 channel antagonist, N-(2-aminoethyl)-N-[[3-methoxy-4-(phenylmethoxy)phenyl]methyl]thiophene-2-carboxamide, significantly inhibited the H 2 O 2 -induced activation of high threshold afferents. Dimethylthiourea and deferoxamine did not significantly change the effect of H 2 O 2 on high threshold afferents. The findings show that H 2 O 2 , in the concentration range detected in inflammation or reperfusion after ischaemia, evoked long-lasting activation of the majority of capsaicin-sensitive high threshold afferents, but not low threshold stretch-sensitive afferents. The data suggest that the TRPA1 channels located on these capsaicin-sensitive afferent fibres are probable targets of ROS released during oxidative stress. © 2016 The British Pharmacological Society.

Morphologically mixed chemical-electrical synapses formed by primary afferents in rodent vestibular nuclei as revealed by immunofluorescence detection of connexin36 and vesicular glutamate transporter-1

PubMed Central

Nagy, James I.; Bautista, Wendy; Blakley, Brian; Rash, John E.

2013-01-01

Axon terminals forming mixed chemical/electrical synapses in the lateral vestibular nucleus of rat were described over forty years ago. Because gap junctions formed by connexins are the morphological correlate of electrical synapses, and with demonstrations of widespread expression of the gap junction protein connexin36 (Cx36) in neurons, we investigated the distribution and cellular localization of electrical synapses in the adult and developing rodent vestibular nuclear complex, using immunofluorescence detection of Cx36 as a marker for these synapses. In addition, we examined Cx36 localization in relation to that of the nerve terminal marker vesicular glutamate transporter-1 (vglut-1). An abundance of immunolabelling for Cx36 in the form of Cx36-puncta was found in each of the four major vestibular nuclei of adult rat and mouse. Immunolabelling was associated with somata and initial dendrites of medium and large neurons, and was absent in vestibular nuclei of Cx36 knockout mice. Cx36-puncta were seen either dispersed or aggregated into clusters on the surface of neurons, and were never found to occur intracellularly. Nearly all Cx36-puncta were localized to large nerve terminals immunolabelled for vglut-1. These terminals and their associated Cx36-puncta were substantially depleted after labyrinthectomy. Developmentally, labelling for Cx36 was already present in the vestibular nuclei at postnatal day 5, where it was only partially co-localized with vglut-1, and did not become fully associated with vglut-1-positive terminals until postnatal day 20 to 25. The results show that vglut-1-positive primary afferent nerve terminals form mixed synapses throughout the vestibular nuclear complex, that the gap junction component of these synapses contain Cx36, that multiple Cx36-containing gap junctions are associated with individual vglut-1 terminals and that the development of these mixed synapses is protracted over several postnatal weeks. PMID:23912039

Functional significance of M-type potassium channels in nociceptive cutaneous sensory endings

PubMed Central

Passmore, Gayle M.; Reilly, Joanne M.; Thakur, Matthew; Keasberry, Vanessa N.; Marsh, Stephen J.; Dickenson, Anthony H.; Brown, David A.

2012-01-01

M-channels carry slowly activating potassium currents that regulate excitability in a variety of central and peripheral neurons. Functional M-channels and their Kv7 channel correlates are expressed throughout the somatosensory nervous system where they may play an important role in controlling sensory nerve activity. Here we show that Kv7.2 immunoreactivity is expressed in the peripheral terminals of nociceptive primary afferents. Electrophysiological recordings from single afferents in vitro showed that block of M-channels by 3 μM XE991 sensitized Aδ- but not C-fibers to noxious heat stimulation and induced spontaneous, ongoing activity at 32°C in many Aδ-fibers. These observations were extended in vivo: intraplantar injection of XE991 selectively enhanced the response of deep dorsal horn (DH) neurons to peripheral mid-range mechanical and higher range thermal stimuli, consistent with a selective effect on Aδ-fiber peripheral terminals. These results demonstrate an important physiological role of M-channels in controlling nociceptive Aδ-fiber responses and provide a rationale for the nocifensive behaviors that arise following intraplantar injection of the M-channel blocker XE991. PMID:22593734

Afferent fibers and sensory ganglion cells within the oculomotor nerve in some mammals and man. II. Electrophysiological investigations.

PubMed

Manni, E; Bortolami, R; Pettorossi, V E; Lucchi, M L; Callegari, E

1978-01-01

The main aim of the present study was to localize with electrophysiological techniques the central projections and terminations of the aberrant trigeminal fibres contained in the oculomotor nerve of the lamb. After severing a trigeminal root, single-shock electrical stimulation of the trigeminal axons present in the central stump of the ipsilateral oculomotor nerve evoked field potentials in the area of, i) the subnucleus gelatinosus of the nucleus caudalis trigemini at the level of C1-C2; ii) the main sensory trigeminal nucleus; iii) the descending trigeminal nucleus and tract; iv) the adjacent reticular formation. Units whose discharge rate was influenced by such a stimulation were also found in the same territories. These regions actually exhibited degenerations after cutting an oculomotor nerve. We conclude, therefore, that the trigeminal fibres which leave the Vth nerve at the level of the cavernous sinus and enter the brain stem through the IIIrd nerve, end in the same structures which receive the terminations of the afferent fibres entering the brain stem through the sensory trigeminal root.

Evidence for glutamatergic mechanisms in the vagal sensory pathway initiating cardiorespiratory reflexes in the shorthorn sculpin Myoxocephalus scorpius.

PubMed

Sundin, L; Turesson, J; Taylor, E W

2003-03-01

Glutamate is a major neurotransmitter of chemoreceptor and baroreceptor afferent pathways in mammals and therefore plays a central role in the development of cardiorespiratory reflexes. In fish, the gills are the major sites of these receptors, and, consequently, the terminal field (sensory area) of their afferents (glossopharyngus and vagus) in the medulla must be an important site for the integration of chemoreceptor and baroreceptor signals. This investigation explored whether fish have glutamatergic mechanisms in the vagal sensory area (Xs) that could be involved in the generation of cardiorespiratory reflexes. The locations of the vagal sensory and motor (Xm) areas in the medulla were established by the orthograde and retrograde axonal transport of the neural tract tracer Fast Blue following its injection into the ganglion nodosum. Glutamate was then microinjected into identified sites within the Xs in an attempt to mimic chemoreceptor- and baroreceptor-induced reflexes commonly observed in fish. By necessity, the brain injections were performed on anaesthetised animals that were fixed by 'eye bars' in a recirculating water system. Blood pressure and heart rate were measured using an arterial cannula positioned in the afferent branchial artery of the 3rd gill arch, and ventilation was measured by impedance probes sutured onto the operculum. Unilateral injection of glutamate (40-100 nl, 10 mmol l(-1)) into the Xs caused marked cardiorespiratory changes. Injection (0.1-0.3 mm deep) in different rostrocaudal, medial-lateral positions induced a bradycardia, either increased or decreased blood pressure, ventilation frequency and amplitude and, sometimes, an initial apnea. Often these responses occurred simultaneously in various different combinations but, occasionally, they appeared singly, suggesting specific projections into the Xs for each cardiorespiratory variable and local determination of the modality of the response. Response patterns related to chemoreceptor reflex activation were predominantly located rostral of obex, whereas patterns related to baroreceptor reflex activation were more caudal, around obex. The glutamate-induced bradycardia was N-methyl-D-aspartate (NMDA) receptor dependent and atropine sensitive. Taken together, our data provide evidence that glutamate is a putative player in the central integration of chemoreceptor and baroreceptor information in fish.

Stimulation of proteinase-activated receptor 2 excites jejunal afferent nerves in anaesthetised rats

PubMed Central

Kirkup, Anthony J; Jiang, Wen; Bunnett, Nigel W; Grundy, David

2003-01-01

Proteinase-activated receptor 2 (PAR2) is a receptor for mast cell tryptase and trypsins and might participate in brain-gut communication. However, evidence that PAR2 activation can lead to afferent impulse generation is lacking. To address this issue, we examined the sensitivity of jejunal afferent nerves to a hexapeptide agonist of PAR2, SLIGRL-NH2, and the modulation of the resulting response to treatment with drugs and vagotomy. Multiunit recordings of jejunal afferent activity were made using extracellular recording techniques in anaesthetised male rats. SLIGRL-NH2 (0.001–1 mg kg−1, I.V.) increased jejunal afferent firing and intrajejunal pressure. The reverse peptide sequence (1 mg kg−1, I.V.), which does not stimulate PAR2, was inactive. Naproxen (10 mg kg−1, I.V.), but not a cocktail of ω-conotoxins GVIA and SVIB (each at 25 μg kg−1, I.V.), curtailed both the afferent response and the intrajejunal pressure rise elicited by the PAR2 agonist. Although neither treatment modulated the peak magnitude of the afferent firing, they each altered the intestinal motor response, unmasking an initial inhibitory component. Nifedipine (1 mg kg−1, I.V.) reduced the peak magnitude of the afferent nerve discharge and abolished the initial rise in intrajejunal pressure produced by SLIGRL-NH2. Vagotomy did not significantly influence the magnitude of the afferent response to the PAR2 agonist, which involves a contribution from capsaicin-sensitive fibres. In conclusion, intravenous administration of SLIGRL-NH2 evokes complex activation of predominantly spinally projecting extrinsic intestinal afferent nerves, an effect that involves both direct and indirect mechanisms. PMID:14561839

Cerebellar afferents originating from the medullary reticular formation that are different from mossy, climbing or monoaminergic fibers in the rat.

PubMed

Luo, Yuanjun; Sugihara, Izumi

2014-05-30

Integration of cortical Purkinje cell inputs and brain stem inputs is essential in generating cerebellar outputs to the cerebellar nuclei (CN). Currently, collaterals of climbing and mossy fiber axons, noradrenergic, serotoninergic and cholinergic axons, and collaterals of rubrospinal axons are known to innervate the CN from the brain stem. We investigated whether other afferents to the CN from the medulla exist in the rat. Retrograde labeling revealed the presence of neurons that project to the CN but not to the cerebellar cortex in the median reticular formation in the rostrodorsal medulla (tentatively named 'caudal raphe interpositus area', CRI). Anterograde tracer injection into the CRI labeled abundant axonal terminals in the CN, mainly in the ventral parvocellular part of the posterior interposed and lateral nucleus. Axonal reconstruction showed that a single CRI axon projected to the CN with 170-1086 varicosities, more broadly and densely than collaterals of a mossy or climbing fiber axon. CRI axons had no or a few collaterals that projected to the granular and Purkinje cell layers of the cerebellar cortex with some small terminals, indicating that these axons are different from mossy fiber axons. CRI axons also had collaterals that projected to the medial vestibular nucleus and an ascending branch that was not reconstructed. The location of the CRI, electron microscopic observations, and immunostaining results all indicated that CRI axons are not monoaminergic. We conclude that CRI axons form a type of afferent projection to the CN that is different from mossy, climbing or monoaminergic fibers. Copyright © 2014 Elsevier B.V. All rights reserved.

Plasticity of gastrointestinal vagal afferent satiety signals.

PubMed

Page, A J; Kentish, S J

2017-05-01

The vagal link between the gastrointestinal tract and the central nervous system (CNS) has numerous vital functions for maintaining homeostasis. The regulation of energy balance is one which is attracting more and more attention due to the potential for exploiting peripheral hormonal targets as treatments for conditions such as obesity. While physiologically, this system is well tuned and demonstrated to be effective in the regulation of both local function and promoting/terminating food intake the neural connection represents a susceptible pathway for disruption in various disease states. Numerous studies have revealed that obesity in particularly is associated with an array of modifications in vagal afferent function from changes in expression of signaling molecules to altered activation mechanics. In general, these changes in vagal afferent function in obesity further promote food intake instead of the more desirable reduction in food intake. It is essential to gain a comprehensive understanding of the mechanisms responsible for these detrimental effects before we can establish more effective pharmacotherapies or lifestyle strategies for the treatment of obesity and the maintenance of weight loss. © 2016 John Wiley & Sons Ltd.

Hydrogen peroxide preferentially activates capsaicin‐sensitive high threshold afferents via TRPA1 channels in the guinea pig bladder

PubMed Central

Nicholas, S; Yuan, S Y; Brookes, S J H; Spencer, N J

2016-01-01

Background and Purpose There is increasing evidence suggesting that ROS play a major pathological role in bladder dysfunction induced by bladder inflammation and/or obstruction. The aim of this study was to determine the effect of H2O2 on different types of bladder afferents and its mechanism of action on sensory neurons in the guinea pig bladder. Experimental Approach ‘Close‐to‐target’ single unit extracellular recordings were made from fine branches of pelvic nerves entering the guinea pig bladder, in flat sheet preparations, in vitro. Key Results H2O2 (300–1000 μM) preferentially and potently activated capsaicin‐sensitive high threshold afferents but not low threshold stretch‐sensitive afferents, which were only activated by significantly higher concentrations of hydrogen peroxide. The TRPV1 channel agonist, capsaicin, excited 86% of high threshold afferents. The TRPA1 channel agonist, allyl isothiocyanate and the TRPM8 channel agonist, icilin activated 72% and 47% of capsaicin‐sensitive high threshold afferents respectively. The TRPA1 channel antagonist, HC‐030031, but not the TRPV1 channel antagonist, capsazepine or the TRPM8 channel antagonist, N‐(2‐aminoethyl)‐N‐[[3‐methoxy‐4‐(phenylmethoxy)phenyl]methyl]thiophene‐2‐carboxamide, significantly inhibited the H2O2‐induced activation of high threshold afferents. Dimethylthiourea and deferoxamine did not significantly change the effect of H2O2 on high threshold afferents. Conclusions and Implications The findings show that H2O2, in the concentration range detected in inflammation or reperfusion after ischaemia, evoked long‐lasting activation of the majority of capsaicin‐sensitive high threshold afferents, but not low threshold stretch‐sensitive afferents. The data suggest that the TRPA1 channels located on these capsaicin‐sensitive afferent fibres are probable targets of ROS released during oxidative stress. PMID:27792844

Evidence for a vagal pathophysiology for bulimia nervosa and the accompanying depressive symptoms.

PubMed

Faris, Patricia L; Eckert, Elke D; Kim, Suck-Won; Meller, William H; Pardo, Jose V; Goodale, Robert L; Hartman, Boyd K

2006-05-01

The bilateral vagus nerves (Cranial X) provide both afferent and efferent connections between the viscera and the caudal medulla. The afferent branches increasingly are being recognized as providing significant input to the central nervous system for modulation of complex behaviors. In this paper, we review evidence from our laboratory that increases in vagal afferent activity are involved in perpetuating binge-eating and vomiting in bulimia nervosa. Preliminary findings are also presented which suggest that a subgroup of depressions may have a similar pathophysiology. Two main approaches were used to study the role of vagal afferents. Ondansetron (ONDAN), a 5-HT3 antagonist, was used as a pharmacological tool for inhibiting or reducing vagal afferent neurotransmission. Second, somatic pain detection thresholds were assessed for monitoring a physiological process known to be modulated by vagal afferents, including the gastric branches involved in meal termination and satiety. High levels of vagal activity result in an increase in pain detection thresholds. Depressive symptoms were assessed using the Beck Depression Inventory (BDI). Positron Emission Tomography (PET) was used to identify higher cortical brain areas activated by vagal stimulation produced by proximal gastric distention in normal eating subjects. Double-blind treatment of severe bulimia nervosa subjects with ONDAN resulted in a rapid and significant decrease in binge-eating and vomiting compared to placebo controls. The decrease in abnormal eating episodes was accompanied by a return of normal satiety. Pain detection thresholds measured weekly over the course of the treatment protocol were found to dynamically fluctuate in association with bulimic episodes. Thresholds were the most elevated during periods of short-term abstinence from the behaviors, suggesting that not engaging in a binge/vomit episode is accompanied by an increase in vagal activity. ONDAN also resulted in abolition of the fluctuations in pain thresholds. Depressive symptoms in these subjects also were reduced by ONDAN. Like pain thresholds, depressive symptoms varied dynamically with the bulimic behaviors, with BDI scores increasing (more depressed) as more time elapsed since the last bulimic episode. PET studies indicated that mechanical distention of the stomach with a balloon (a non-nutritive stimulus) was associated with the activation of several brain loci, including those associated with vagal activation (parabrachial nucleus), emotive aspects of eating (lateral inferior frontal and orbitofrontal), and depressive symptoms (anterior cingulate). The results of the ONDAN study in bulimia nervosa subjects suggest that cyclic increases in vagal activity drive the urge to binge-eat and vomit. The alterations in vagal firing patterns are possibly a physiological adaptation to the high levels of vagal stimulation initially provided by voluntarily binge-eating and vomiting for weight control. The depressive symptoms that occur in association with the urge to binge-eat are also likely due to the cyclic increase in vagal activity. This suggestion is supported by the reduction of depressive symptoms during ONDAN treatment in bulimia subjects and PET imaging studies in normal eating subjects showing that brain loci classically involved in depression are activated by vagal stimulation administered by mechanical gastric distention. In normal eating individuals, depressions accompanying visceral diseases may also be vagally mediated. Ondansetron and other drugs known to modulate vagal activity may be helpful in treating depressions of this origin.

Innervation of the mammalian esophagus.

PubMed

Neuhuber, Winfried L; Raab, Marion; Berthoud, Hans-Rudolf; Wörl, Jürgen

2006-01-01

Understanding the innervation of the esophagus is a prerequisite for successful treatment of a variety of disorders, e.g., dysphagia, achalasia, gastroesophageal reflux disease (GERD) and non-cardiac chest pain. Although, at first glance, functions of the esophagus are relatively simple, their neuronal control is considerably complex. Vagal motor neurons of the nucleus ambiguus and preganglionic neurons of the dorsal motor nucleus innervate striated and smooth muscle, respectively. Myenteric neurons represent the interface between the dorsal motor nucleus and smooth muscle but they are also involved in striated muscle innervation. Intraganglionic laminar endings (IGLEs) represent mechanosensory vagal afferent terminals. They also establish intricate connections with enteric neurons. Afferent information is implemented by the swallowing central pattern generator in the brainstem, which generates and coordinates deglutitive activity in both striated and smooth esophageal muscle and orchestrates esophageal sphincters as well as gastric adaptive relaxation. Disturbed excitation/inhibition balance in the lower esophageal sphincter results in motility disorders, e.g., achalasia and GERD. Loss of mechanosensory afferents disrupts adaptation of deglutitive motor programs to bolus variables, eventually leading to megaesophagus. Both spinal and vagal afferents appear to contribute to painful sensations, e.g., non-cardiac chest pain. Extrinsic and intrinsic neurons may be involved in intramural reflexes using acetylcholine, nitric oxide, substance P, CGRP and glutamate as main transmitters. In addition, other molecules, e.g., ATP, GABA and probably also inflammatory cytokines, may modulate these neuronal functions.

Chemoarchitecture and afferent connections of the "olfactostriatum": a specialized vomeronasal structure within the basal ganglia of snakes.

PubMed

Martinez-Marcos, Alino; Ubeda-Bañon, Isabel; Lanuza, Enrique; Halpern, Mimi

2005-01-01

The olfactostriatum, a portion of the striatal complex of snakes, is the major tertiary vomeronasal structure in the ophidian brain, receiving substantial afferents from the nucleus sphericus, the primary target of accessory olfactory bulb efferents. In the present study, we have characterized the olfactostriatum of garter snakes (Thamnophis sirtalis) on the basis of chemoarchitecture (distribution of serotonin, neuropeptide Y and tyrosine hydroxylase) and hodology (afferent connections). The olfactostriatum is densely immunoreactive for serotonin and neuropeptide Y and shows moderate-to-weak immunoreactivity for tyrosine hydroxylase. In addition to afferents from the nucleus sphericus, the olfactostriatum receives inputs from the dorsal and lateral cortices, nucleus of the accessory olfactory tract, external and dorsolateral amygdalae, dorsomedial thalamic nucleus, ventral tegmental area and raphe nuclei. Double labeling experiments demonstrated that the distribution of serotonin and neuropeptide Y in this area almost completely overlaps the terminal field of projections from the nucleus sphericus. Also, serotonergic and dopaminergic innervation of the olfactostriatum likely arise, respectively, from the raphe nuclei and the ventral tegmental area, whereas local circuit neurons originate the neuropeptide Y immunoreactivity. These results indicate that the olfactostriatum of snakes could be a portion of the nucleus accumbens, with features characteristic of the accumbens shell, devoted to processing vomeronasal information. Comparative data suggest that a similar structure is present in the ventral striatum of amphibians and mammals.

Modulation of experimental arthritis by vagal sensory and central brain stimulation.

PubMed

Bassi, Gabriel Shimizu; Dias, Daniel Penteado Martins; Franchin, Marcelo; Talbot, Jhimmy; Reis, Daniel Gustavo; Menezes, Gustavo Batista; Castania, Jaci Airton; Garcia-Cairasco, Norberto; Resstel, Leonardo Barbosa Moraes; Salgado, Helio Cesar; Cunha, Fernando Queiróz; Cunha, Thiago Mattar; Ulloa, Luis; Kanashiro, Alexandre

2017-08-01

Articular inflammation is a major clinical burden in multiple inflammatory diseases, especially in rheumatoid arthritis. Biological anti-rheumatic drug therapies are expensive and increase the risk of systemic immunosuppression, infections, and malignancies. Here, we report that vagus nerve stimulation controls arthritic joint inflammation by inducing local regulation of innate immune response. Most of the previous studies of neuromodulation focused on vagal regulation of inflammation via the efferent peripheral pathway toward the viscera. Here, we report that vagal stimulation modulates arthritic joint inflammation through a novel "afferent" pathway mediated by the locus coeruleus (LC) of the central nervous system. Afferent vagal stimulation activates two sympatho-excitatory brain areas: the paraventricular hypothalamic nucleus (PVN) and the LC. The integrity of the LC, but not that of the PVN, is critical for vagal control of arthritic joint inflammation. Afferent vagal stimulation suppresses articular inflammation in the ipsilateral, but not in the contralateral knee to the hemispheric LC lesion. Central stimulation is followed by subsequent activation of joint sympathetic nerve terminals inducing articular norepinephrine release. Selective adrenergic beta-blockers prevent the effects of articular norepinephrine and thereby abrogate vagal control of arthritic joint inflammation. These results reveals a novel neuro-immune brain map with afferent vagal signals controlling side-specific articular inflammation through specific inflammatory-processing brain centers and joint sympathetic innervations. Copyright © 2017 Elsevier Inc. All rights reserved.

Activation of normal and inflamed fine articular afferent units by serotonin.

PubMed

Herbert, M K; Schmidt, R F

1992-07-01

In cats anesthetized with alpha-chloralose, extracellular recordings were made from fine afferent units belonging to the medial articular nerve (MAN) of the knee joint. The excitatory and sensitizing effects on articular afferents of serotonin (5-HT) applied intra-arterially close to the joint were examined. The joints were either normal or an experimental arthritis had been induced some hours before the recording session. Bolus injections of 1.35-135 micrograms 5-HT excited about 43% of group III (CV: 2.5-20 m/sec) and 73% of group IV units (CV: less than 2.5 m/sec) from normal joints. The latency was usually between 10 and 30 sec, and the duration and size of the responses were dose-dependent. Fast group III units (CV: greater than 16 m/sec) and group II units (CV: greater than 20 m/sec) were never excited by 5-HT. Repetitive administration led to pronounced tachyphylaxis of the 5-HT response. Inflammation induced an enhanced sensitivity of group III articular afferent units to close intra-arterial application of 5-HT. In particular the total duration of each response was considerably prolonged (4-10 min against 1-2 min under normal conditions). At the same time the tachyphylaxis seen under normal conditions was greatly reduced. In contrast, group IV articular afferent units did not become sensitized to 5-HT in the course of inflammation. In normal joints 5-HT did not sensitize fine afferent units for movement-induced responses. However, after inflammation, a distinct sensitization to such movements by 5-HT application could be observed both in group III and group IV fiber ranges. The sensitization had a short time course not exceeding 7 min. The tonic component of the movement-induced response was more enhanced than the phasic one. The bolus application of 5-HT led to temporary vasoconstriction of the knee joint vessels. This vasoconstriction was especially pronounced in inflamed joints and impeded the access of subsequently applied substances to the terminal regions of the afferent units under observation. It is concluded that the present results support the notion that 5-HT may participate in the mediation of pain from inflamed tissue such as an arthritic joint by exciting and sensitizing fine afferent units. During inflammation group III units are particularly sensitive to 5-HT and, thus, may carry the bulk of the 5-HT-induced nociceptive messages.

Effect of a muscle relaxant, chlorphenesin carbamate, on the spinal neurons of rats.

PubMed

Kurachi, M; Aihara, H

1984-09-01

The effects of chlorphenesin carbamate (CPC) and mephenesin on spinal neurons were investigated in spinal rats. CPC (50 mg/kg i.v.) inhibited the mono-(MSR) and poly-synaptic reflex (PSR), the latter being more susceptible than the former to CPC depression. Mephenesin also inhibited MSR and PSR, though the effects were short in duration. CPC had no effect on the dorsal root potential evoked by the stimulation of the dorsal root, while mephenesin reduced the dorsal root-dorsal root reflex. The excitability of motoneuron was reduced by the administration of CPC or mephenesin. The excitability of primary afferent terminal was unchanged by CPC, while it was inhibited by mephenesin. Neither CPC nor mephenesin influenced the field potential evoked by the dorsal root stimulation. Both CPC and mephenesin had no effect on the synaptic recovery. These results suggest that both CPC and mephenesin inhibit the firing of motoneurons by stabilizing the neuronal membrane, while mephenesin additionally suppresses the dorsal root reflex and the excitability of the primary afferent terminal. These inhibitory actions of CPC on spinal activities may contribute, at least partly, to its muscle relaxing action.

Evidence against high pressure, arterial baroreceptors in the abdominal viscera of cats.

PubMed

Martin, S E; Longhurst, J C

1986-12-01

The abdominal viscera of cats have been postulated to contain a site of cardiovascular regulation. In particular, a baroreceptive function has been ascribed to splanchnic afferent nerves. We wished to determine whether afferents with a cardiac-rhythmic discharge functioned as arterial baroreceptors. Nineteen afferents with a cardiac rhythmic discharge were studied. All afferents were A fibers, whose endings were located in either the pancreas, mesentery, or porta hepatis region. We examined their characteristics of discharge with regard to changes in mean pressure, pulse pressure, and dP/dt of the arterial pulse. Hemodynamic alterations were achieved by intravenous administration of isoproterenol, norepinephrine, or phenylephrine and by occlusion of the descending thoracic aorta. After isoproterenol, increases in nerve activity occurred when pulse pressure and dP/dt were increased but while mean pressure was decreasing, indicating that mean pressure was not the stimulus for discharge of these afferents. Additionally, under similar hemodynamic conditions, afferents did not demonstrate reproducible patterns of activity. The afferents generally discharged with one impulse per cardiac cycle, rarely with two to three impulses per cycle. None demonstrated a bursting pattern even when arterial blood pressure was quite elevated. The spontaneous pattern of discharge changed frequently, often after the viscera were repositioned, and sometimes remained even after complete occlusion of the aorta. The data indicate that these visceral afferents do not respond as high pressure, arterial baroreceptors. All afferents adapted extremely rapidly and exhibited a low gain (0.02 +/- 0.00 impulses X s-1 X mmHg-1), indicating that these fibers would be ineffective in signaling physiologically significant changes in hemodynamic variables. The data from this study do not support the existence of baroreceptors in the abdominal viscera of cats.

Dopaminergic modulation of the voltage-gated sodium current in the cochlear afferent neurons of the rat.

PubMed

Valdés-Baizabal, Catalina; Soto, Enrique; Vega, Rosario

2015-01-01

The cochlear inner hair cells synapse onto type I afferent terminal dendrites, constituting the main afferent pathway for auditory information flow. This pathway receives central control input from the lateral olivocochlear efferent neurons that release various neurotransmitters, among which dopamine (DA) plays a salient role. DA receptors activation exert a protective role in the over activation of the afferent glutamatergic synapses, which occurs when an animal is exposed to intense sound stimuli or during hypoxic events. However, the mechanism of action of DA at the cellular level is still not completely understood. In this work, we studied the actions of DA and its receptor agonists and antagonists on the voltage-gated sodium current (INa) in isolated cochlear afferent neurons of the rat to define the mechanisms of dopaminergic control of the afferent input in the cochlear pathway. Experiments were performed using the voltage and current clamp techniques in the whole-cell configuration in primary cultures of cochlear spiral ganglion neurons (SGNs). Recordings of the INa showed that DA receptor activation induced a significant inhibition of the peak current amplitude, leading to a significant decrease in cell excitability. Inhibition of the INa was produced by a phosphorylation of the sodium channels as shown by the use of phosphatase inhibitor that produced an inhibition analogous to that caused by DA receptor activation. Use of specific agonists and antagonists showed that inhibitory action of DA was mediated both by activation of D1- and D2-like DA receptors. The action of the D1- and D2-like receptors was shown to be mediated by a Gαs/AC/cAMP/PKA and Gαq/PLC/PKC pathways respectively. These results showed that DA receptor activation constitutes a significant modulatory input to SGNs, effectively modulating their excitability and information flow in the auditory pathway.

Dysbindin-1 is reduced in intrinsic, glutamatergic terminals of the hippocampal formation in schizophrenia

PubMed Central

Talbot, Konrad; Eidem, Wess L.; Tinsley, Caroline L.; Benson, Matthew A.; Thompson, Edward W.; Smith, Rachel J.; Hahn, Chang-Gyu; Siegel, Steven J.; Trojanowski, John Q.; Gur, Raquel E.; Blake, Derek J.; Arnold, Steven E.

2004-01-01

Eleven studies now report significant associations between schizophrenia and certain haplotypes of single-nucleotide polymorphisms in the gene encoding dysbindin-1 at 6p22.3. Dysbindin-1 is best known as dystrobrevin-binding protein 1 (DTNBP1) and may thus be associated with the dystrophin glycoprotein complex found at certain postsynaptic sites in the brain. Contrary to expectations, however, we found that when compared to matched, nonpsychiatric controls, 73–93% of cases in two schizophrenia populations displayed presynaptic dysbindin-1 reductions averaging 18–42% (P = 0.027–0.0001) at hippocampal formation sites lacking neuronal dystrobrevin (i.e., β-dystrobrevin). The reductions, which were not observed in the anterior cingulate of the same schizophrenia cases, occurred specifically in terminal fields of intrinsic, glutamatergic afferents of the subiculum, the hippocampus proper, and especially the inner molecular layer of the dentate gyrus (DGiml). An inversely correlated increase in vesicular glutamate transporter-1 (VGluT-1) occurred in DGiml of the same schizophrenia cases. Those changes occurred without evidence of axon terminal loss or neuroleptic effects on dysbindin-1 or VGluT-1. Our findings indicate that presynaptic dysbindin-1 reductions independent of the dystrophin glycoprotein complex are frequent in schizophrenia and are related to glutamatergic alterations in intrinsic hippocampal formation connections. Such changes may contribute to the cognitive deficits common in schizophrenia. PMID:15124027

Dysbindin-1 is reduced in intrinsic, glutamatergic terminals of the hippocampal formation in schizophrenia.

PubMed

Talbot, Konrad; Eidem, Wess L; Tinsley, Caroline L; Benson, Matthew A; Thompson, Edward W; Smith, Rachel J; Hahn, Chang-Gyu; Siegel, Steven J; Trojanowski, John Q; Gur, Raquel E; Blake, Derek J; Arnold, Steven E

2004-05-01

Eleven studies now report significant associations between schizophrenia and certain haplotypes of single-nucleotide polymorphisms in the gene encoding dysbindin-1 at 6p22.3. Dysbindin-1 is best known as dystrobrevin-binding protein 1 (DTNBP1) and may thus be associated with the dystrophin glycoprotein complex found at certain postsynaptic sites in the brain. Contrary to expectations, however, we found that when compared to matched, nonpsychiatric controls, 73-93% of cases in two schizophrenia populations displayed presynaptic dysbindin-1 reductions averaging 18-42% (P = 0.027-0.0001) at hippocampal formation sites lacking neuronal dystrobrevin (i.e., beta-dystrobrevin). The reductions, which were not observed in the anterior cingulate of the same schizophrenia cases, occurred specifically in terminal fields of intrinsic, glutamatergic afferents of the subiculum, the hippocampus proper, and especially the inner molecular layer of the dentate gyrus (DGiml). An inversely correlated increase in vesicular glutamate transporter-1 (VGluT-1) occurred in DGiml of the same schizophrenia cases. Those changes occurred without evidence of axon terminal loss or neuroleptic effects on dysbindin-1 or VGluT-1. Our findings indicate that presynaptic dysbindin-1 reductions independent of the dystrophin glycoprotein complex are frequent in schizophrenia and are related to glutamatergic alterations in intrinsic hippocampal formation connections. Such changes may contribute to the cognitive deficits common in schizophrenia.

Mu-opioid receptors in nociceptive afferents produce a sustained suppression of hyperalgesia in chronic pain.

PubMed

Severino, Amie; Chen, Wenling; Hakimian, Joshua K; Kieffer, Brigitte L; Gaveriaux-Ruff, Claire; Walwyn, Wendy; Marvizon, Juan Carlos

2018-04-17

The latent sensitization model of chronic pain reveals that recovery from some types of long-term hyperalgesia is an altered state in which nociceptive sensitization persists but is suppressed by the ongoing activity of analgesic receptors such as µ-opioid receptors (MORs). To determine whether these MORs are the ones present in nociceptive afferents, we bred mice expressing Cre-recombinase under the Nav1.8 channel promoter (Nav1.8cre) with MOR-floxed mice (flMOR). These Nav1.8cre/flMOR mice had reduced MOR expression in primary afferents, as revealed by quantitative PCR, in situ hybridization and immunofluorescence colocalization with the neuropeptide CGRP. We then studied the recovery from chronic pain of these mice and their flMOR littermates. When Nav1.8cre/flMOR mice were injected in the paw with complete Freund's adjuvant they developed mechanical hyperalgesia that persisted for over two months, whereas the responses of flMOR mice returned to baseline after three weeks. We then used the inverse agonist naltrexone to assess ongoing MOR activity. Naltrexone produced a robust reinstatement of hyperalgesia in control flMOR mice, but produced no effect in the Nav1.8/flMOR males and a weak reinstatement of hyperalgesia in Nav1.8/flMOR females. Naltrexone also reinstated swelling of the hind paw in flMOR mice and female Nav1.8cre/flMOR mice, but not male Nav1.8cre/flMOR mice. The MOR agonist DAMGO inhibited substance P release in flMOR mice but not Nav1.8cre/flMOR mice, demonstrating a loss of MOR function at the central terminals of primary afferents. We conclude that MORs in nociceptive afferents mediate an ongoing suppression of hyperalgesia to produce remission from chronic pain.

Perception of stochastically undersampled sound waveforms: a model of auditory deafferentation

PubMed Central

Lopez-Poveda, Enrique A.; Barrios, Pablo

2013-01-01

Auditory deafferentation, or permanent loss of auditory nerve afferent terminals, occurs after noise overexposure and aging and may accompany many forms of hearing loss. It could cause significant auditory impairment but is undetected by regular clinical tests and so its effects on perception are poorly understood. Here, we hypothesize and test a neural mechanism by which deafferentation could deteriorate perception. The basic idea is that the spike train produced by each auditory afferent resembles a stochastically digitized version of the sound waveform and that the quality of the waveform representation in the whole nerve depends on the number of aggregated spike trains or auditory afferents. We reason that because spikes occur stochastically in time with a higher probability for high- than for low-intensity sounds, more afferents would be required for the nerve to faithfully encode high-frequency or low-intensity waveform features than low-frequency or high-intensity features. Deafferentation would thus degrade the encoding of these features. We further reason that due to the stochastic nature of nerve firing, the degradation would be greater in noise than in quiet. This hypothesis is tested using a vocoder. Sounds were filtered through ten adjacent frequency bands. For the signal in each band, multiple stochastically subsampled copies were obtained to roughly mimic different stochastic representations of that signal conveyed by different auditory afferents innervating a given cochlear region. These copies were then aggregated to obtain an acoustic stimulus. Tone detection and speech identification tests were performed by young, normal-hearing listeners using different numbers of stochastic samplers per frequency band in the vocoder. Results support the hypothesis that stochastic undersampling of the sound waveform, inspired by deafferentation, impairs speech perception in noise more than in quiet, consistent with auditory aging effects. PMID:23882176

The expression of vesicular glutamate transporters VGLUT1 and VGLUT2 in neurochemically defined axonal populations in the rat spinal cord with emphasis on the dorsal horn.

PubMed

Todd, A J; Hughes, D I; Polgár, E; Nagy, G G; Mackie, M; Ottersen, O P; Maxwell, D J

2003-01-01

Two vesicular glutamate transporters, VGLUT1 and VGLUT2, have recently been identified, and it has been reported that they are expressed by largely nonoverlapping populations of glutamatergic neurons in the brain. We have used immunocytochemistry with antibodies against both transporters, together with markers for various populations of spinal neurons, in an attempt to identify glutamatergic interneurons in the dorsal horn of the mid-lumbar spinal cord of the rat. The great majority (94-100%) of nonprimary axonal boutons that contained somatostatin, substance P or neurotensin, as well as 85% of those that contained enkephalin, were VGLUT2-immunoreactive, which suggests that most dorsal horn neurons that synthesize these peptides are glutamatergic. In support of this, we found that most somatostatin- and enkephalin-containing boutons (including somatostatin-immunoreactive boutons that lacked calcitonin gene-related peptide and were therefore probably derived from local interneurons) formed synapses at which AMPA receptors were present. We also investigated VGLUT expression in central terminals of primary afferents. Myelinated afferents were identified with cholera toxin B subunit; most of those in lamina I were VGLUT2-immunoreactive, whereas all those in deeper laminae were VGLUT1-immunoreactive, and some (in laminae III-VI) appeared to contain both transporters. However, peptidergic primary afferents that contained substance P or somatostatin (most of which are unmyelinated), as well as nonpeptidergic C fibres (identified with Bandeiraea simplicifolia isolectin B4) showed low levels of VGLUT2-immunoreactivity, or were not immunoreactive with either VGLUT antibody. As all primary afferents are thought to be glutamatergic, this raises the possibility that unmyelinated afferents, most of which are nociceptors, express a different vesicular glutamate transporter.

The synaptic terminations of certain midbrain-olivary fibers in the opossum.

PubMed

King, J S; Hamos, J E; Maley, B E

1978-11-15

The nuclear origin and distribution of midbrain-olivary fibers has been described in a previous study utilizing axonal transport techniques (Linauts and Martin, '78a). The present report extends their results to the electron microscopic level and details the postsynaptic distribution of such fibers. Lesions within the ventral periaqueductal grey and adjacent tegmentum, the red nucleus or the nucleus subparafascicularis result in electron dense axon terminals within the olive at survival times of 48, 72 and 96 hours. At 72 hours, many degenerating presynaptic profiles shrink, become irregular in shape and are totally or partially surrounded by glial processes. The principal olivary nucleus contains the majority of these profiles. However, the subparafascicular terminals are more abundant in the rostral and intermediate parts of the medial accessory nucleus and the rubral terminals are concentrated within the dorsal lamella of the principal nucleus. The nuclear location of the degenerating terminals was determined by examination of 1 micrometer plastic sections cut in the transverse plane from each block face prior to thin sectioning. Degenerating terminals were counted in three cases, one from each of the three lesion sites described above. When taken together these cases show that just over 50% of the degenerating terminals are presynaptic to spiny appendages and are located within the synaptic clusters (glomeruli) described previously (King, '76). The percentage of degenerating terminals in the glomeruli increases to 70% when the lesion is in the ventral periaqueductal grey and adjacent tegmentum. The remaining degenerating terminals contact dendritic shafts outside the astrocytic boundaries of the synaptic clusters. The synpatic vesicle populations within the degenerating terminals vary with the location of the lesion. Lesions in the ventral periaqueductal grey and the adjacent tegmentum result in the degeneration of terminals with either clear spherical vesicles or endings with both clear spherical vesicles and a variable number of large dense core vesicles. In contrast, the primary degenerative changes that occur after destruction of the red nucleus or the nucleus subparafascicularis are in terminals with clear spherical vesicles. When the synaptic complex was present in the plane of section, regardless of the site of the lesion, the degenerating terminals could be classified as Gray's type I. Thus, we have demonstrated that afferents from the mesencephalon terminate within synpatic clusters located in the principal and medial accessory (part A) subnuclei of the inferior olive. Although the mesencephalic afferents have multiple origins (Linauts and Martin, '78a), many of their synaptic terminals contact spiny appendages within the synaptic clusters. This postsynaptic site also receives cerebellar terminals (King et al., '76). The origin of presynaptic profiles within the synaptic clusters that contain clear pleomorphlic vesicles is yet to be determined.

Functional Organization of Cutaneous and Muscle Afferent Synapses onto Immature Spinal Lamina I Projection Neurons

PubMed Central

Li, Jie

2017-01-01

It is well established that sensory afferents innervating muscle are more effective at inducing hyperexcitability within spinal cord circuits compared with skin afferents, which likely contributes to the higher prevalence of chronic musculoskeletal pain compared with pain of cutaneous origin. However, the mechanisms underlying these differences in central nociceptive signaling remain incompletely understood, as nothing is known about how superficial dorsal horn neurons process sensory input from muscle versus skin at the synaptic level. Using a novel ex vivo spinal cord preparation, here we identify the functional organization of muscle and cutaneous afferent synapses onto immature rat lamina I spino-parabrachial neurons, which serve as a major source of nociceptive transmission to the brain. Stimulation of the gastrocnemius nerve and sural nerve revealed significant convergence of muscle and cutaneous afferent synaptic input onto individual projection neurons. Muscle afferents displayed a higher probability of glutamate release, although short-term synaptic plasticity was similar between the groups. Importantly, muscle afferent synapses exhibited greater relative expression of Ca2+-permeable AMPARs compared with cutaneous inputs. In addition, the prevalence and magnitude of spike timing-dependent long-term potentiation were significantly higher at muscle afferent synapses, where it required Ca2+-permeable AMPAR activation. Collectively, these results provide the first evidence for afferent-specific properties of glutamatergic transmission within the superficial dorsal horn. A larger propensity for activity-dependent strengthening at muscle afferent synapses onto developing spinal projection neurons could contribute to the enhanced ability of these sensory inputs to sensitize central nociceptive networks and thereby evoke persistent pain in children following injury. SIGNIFICANCE STATEMENT The neurobiological mechanisms underlying the high prevalence of chronic musculoskeletal pain remain poorly understood, in part because little is known about why sensory neurons innervating muscle appear more capable of sensitizing nociceptive pathways in the CNS compared with skin afferents. The present study identifies, for the first time, the functional properties of muscle and cutaneous afferent synapses onto immature lamina I projection neurons, which convey nociceptive information to the brain. Despite many similarities, an enhanced relative expression of Ca2+-permeable AMPA receptors at muscle afferent synapses drives greater LTP following repetitive stimulation. A preferential ability of the dorsal horn synaptic network to amplify nociceptive input arising from muscle is predicted to favor the generation of musculoskeletal pain following injury. PMID:28069928

Dopaminergic Presynaptic Modulation of Nigral Afferents: Its Role in the Generation of Recurrent Bursting in Substantia Nigra Pars Reticulata Neurons

PubMed Central

de Jesús Aceves, José; Rueda-Orozco, Pavel E.; Hernández, Ricardo; Plata, Víctor; Ibañez-Sandoval, Osvaldo; Galarraga, Elvira; Bargas, José

2011-01-01

Previous work has shown the functions associated with activation of dopamine presynaptic receptors in some substantia nigra pars reticulata (SNr) afferents: (i) striatonigral terminals (direct pathway) posses presynaptic dopamine D1-class receptors whose action is to enhance inhibitory postsynaptic currents (IPSCs) and GABA transmission. (ii) Subthalamonigral terminals posses D1- and D2-class receptors where D1-class receptor activation enhances and D2-class receptor activation decreases excitatory postsynaptic currents. Here we report that pallidonigral afferents posses D2-class receptors (D3 and D4 types) that decrease inhibitory synaptic transmission via presynaptic modulation. No action of D1-class agonists was found on pallidonigral synapses. In contrast, administration of D1-receptor antagonists greatly decreased striatonigral IPSCs in the same preparation, suggesting that tonic dopamine levels help in maintaining the function of the striatonigral (direct) pathway. When both D3 and D4 type receptors were blocked, pallidonigral IPSCs increased in amplitude while striatonigral connections had no significant change, suggesting that tonic dopamine levels are repressing a powerful inhibition conveyed by pallidonigral synapses (a branch of the indirect pathway). We then blocked both D1- and D2-class receptors to acutely decrease direct pathway (striatonigral) and enhance indirect pathways (subthalamonigral and pallidonigral) synaptic force. The result was that most SNr projection neurons entered a recurrent bursting firing mode similar to that observed during Parkinsonism in both patients and animal models. These results raise the question as to whether the lack of dopamine in basal ganglia output nuclei is enough to generate some pathological signs of Parkinsonism. PMID:21347219

Effect of peripheral nerve injury on receptive fields of cells in the cat spinal cord.

PubMed

Devor, M; Wall, P D

1981-06-20

When the sciatic and saphenous nerves are cut and ligated in adult cats, the immediate effect is the production of a completely anesthetic foot and a region in medial lumbar dorsal horn where almost all cells have lost their natural receptive fields (RFs). Beginning at about 1 week and maturing by 4 weeks, some 40% of cells in the medial dorsal horn gain a novel RF on proximal skin, that is, upper and lower leg, thigh, lower back, or perineum. This new RF is supplied by intact proximal nerves and not by sciatic and saphenous nerve fibers that sprouted in the periphery. During the period of switching of RFs from distal to proximal skin there was no gross atrophy of dorsal horn grey matter and no Fink-Heimer stainable degeneration of central arbors and terminals of peripherally axotomized afferents. In intact animals medial dorsal horn cells showed no sign of response to mechanical stimulation of proximal skin. RFs of some of the cells had spontaneous variations in size and sensitivity, but these were not nearly sufficient to explain the large shifts observed after chronic nerve section. Tetanic electrical stimulation of skin or peripheral nerves often caused RFs to shrink, but never to expand. Although natural stimuli of proximal skin would not excite medial dorsal horn cells in intact or acutely deafferented animals, it was found that electrical stimulation of proximal nerves did excite many of these cells, often at short latencies. In the discussion we justify our working hypothesis that the appearance of novel RFs is due to the strengthening or unmasking of normally present but ineffective afferent terminals, rather than to long-distance sprouting of new afferent arbors within the spinal cord.

Amyloid-β expression in retrosplenial cortex of 3xTg-AD mice: relationship to cholinergic axonal afferents from medial septum

PubMed Central

Robertson, Richard T.; Baratta, Janie; Yu, Jen; LaFerla, Frank M.

2009-01-01

Triple transgenic (3xTg-AD) mice harboring the presenilin 1, amyloid precursor protein, and tau transgenes (Oddo et al., 2003) display prominent levels of amyloid-beta (Aβ) immunoreactivity in forebrain regions. The Aβ immunoreactivity is first seen intracellularly in neurons and later as extracellular plaque deposits. The present study examined Aβ immunoreactivity that occurs in layer III of the granular division of retrosplenial cortex (RSg). This pattern of Aβ immunoreactivity in layer III of RSg develops relatively late, and is seen in animals older than 14 mo. The appearance of the Aβ immunoreactivity is similar to an axonal terminal field and thus may offer a unique opportunity to study the relationship between afferent projections and the formation of Aβ deposits. Axonal tract tracing techniques demonstrated that the pattern of axon terminal labeling in layer III of RSg, following placement of DiI in medial septum, is remarkably similar to the pattern of cholinergic axons in RSg, as detected by acetylcholinesterase histochemical staining, choline acetyltransferase immunoreactivity, or p75 receptor immunoreactivity; this pattern also is strikingly similar to the band of Aβ immunoreactivity. In animals sustaining early damage to the medial septal nucleus (prior to the advent of Aβ immunoreactivity), the band of Aβ in layer III of RSg does not develop; the corresponding band of cholinergic markers also is eliminated. In older animals (after the appearance of the Aβ immunoreactivity) damage to cholinergic afferents by electrolytic lesions, immunotoxin lesions, or cutting the cingulate bundle, result in a rapid loss of the cholinergic markers and a slower reduction of Aβ immunoreactivity. These results suggest that the septal cholinergic axonal projections transport Aβ or APP to layer III of RSg. PMID:19772895

The big CGRP flood - sources, sinks and signalling sites in the trigeminovascular system.

PubMed

Messlinger, Karl

2018-03-12

Calcitonin gene-related peptide (CGRP) has long been a focus of migraine research, since it turned out that inhibition of CGRP or CGRP receptors by antagonists or monoclonal IgG antibodies was therapeutic in frequent and chronic migraine. This contribution deals with the questions, from which sites CGRP is released, where it is drained and where it acts to cause its headache proliferating effects in the trigeminovascular system. The available literature suggests that the bulk of CGRP is released from trigeminal afferents both in meningeal tissues and at the first synapse in the spinal trigeminal nucleus. CGRP may be drained off into three different compartments, the venous blood plasma, the cerebrospinal fluid and possibly the glymphatic system. CGRP receptors in peripheral tissues are located on arterial vessel walls, mononuclear immune cells and possibly Schwann cells; within the trigeminal ganglion they are located on neurons and glial cells; in the spinal trigeminal nucleus they can be found on central terminals of trigeminal afferents. All these structures are potential signalling sites for CGRP, where CGRP mediates arterial vasodilatation but not direct activation of trigeminal afferents. In the spinal trigeminal nucleus a facilitating effect on synaptic transmission seems likely. In the trigeminal ganglion CGRP is thought to initiate long-term changes including cross-signalling between neurons and glial cells based on gene expression. In this way, CGRP may upregulate the production of receptor proteins and pro-nociceptive molecules. CGRP and other big molecules cannot easily pass the blood-brain barrier. These molecules may act in the trigeminal ganglion to influence the production of pronociceptive substances and receptors, which are transported along the central terminals into the spinal trigeminal nucleus. In this way peripherally acting therapeutics can have a central antinociceptive effect.

Effects of microgravity on muscle and cerebral cortex: a suggested interaction

NASA Astrophysics Data System (ADS)

D'Amelio, F.; Fox, R. A.; Wu, L. C.; Daunton, N. G.; Corcoran, M. L.

The ``slow'' antigravity muscle adductor longus was studied in rats after 14 days of spaceflight (SF). The techniques employed included standard methods for light microscopy, neural cell adhesion molecule (N-CAM) immunocytochemistry and electron microscopy. Light and electron microscopy revealed myofiber atrophy, segmental necrosis and regenerative myofibers. Regenerative myofibers were N-CAM immunoreactive (N-CAM-IR). The neuromuscular junctions showed axon terminals with a decrease or absence of synaptic vesicles, degenerative changes, vacant axonal spaces and changes suggestive of axonal sprouting. No alterations of muscle spindles was seen either by light or electron microscopy. These observations suggest that muscle regeneration and denervation and synaptic remodeling at the level of the neuromuscular junction may take place during spaceflight. In a separate study, GABA immunoreactivity (GABA-IR) was evaluated at the level of the hindlimb representation of the rat somatosensory cortex after 14 days of hindlimb unloading by tail suspension (``simulated'' microgravity). A reduction in number of GABA-immunoreactive cells with respect to the control animals was observed in layer Va and Vb. GABA-IR terminals were also reduced in the same layers, particularly those terminals surrounding the soma and apical dendrites of pyramidal cells in layer Vb. On the basis of previous morphological and behavioral studies of the neuromuscular system after spaceflight and hindlimb suspension it is suggested that after limb unloading there are alterations of afferent signaling and feedback information from intramuscular receptors to the cerebral cortex due to modifications in the reflex organization of hindlimb muscle groups. We propose that the changes observed in GABA immunoreactivity of cells and terminals is an expression of changes in their modulatory activity to compensate for the alterations in the afferent information.

Functional support of glutamate as a vestibular hair cell transmitter in an amniote

NASA Technical Reports Server (NTRS)

Cochran, S. L.; Correia, M. J.

1995-01-01

Although hair cells in the cochlea and in the vestibular endorgans of anamniotes are thought to release glutamate or a similar compound as their transmitter, there is little evidence in amniotes (which, unlike anamniotes, possess both type I and II hair cells) as to the nature of the hair cell transmitters in the vestibular labyrinth. We have recorded extracellularly from single semicircular canal afferents in the turtle labyrinth maintained in vitro and have bath-applied a number of transmitter agonists and antagonists to relate the effects of these substances to the actions of the endogenous transmitter substances. Both glutamate and aspartate strongly excite the afferents while GABA and carbachol have negligible or weak effects. In contrast to its lack of effect on afferent activity in some anamniotes, N-methyl-D-aspartate (NMDA) was also found to excite these afferents. Kynurenic acid reversibly reduced the resting firing rates of the afferents and the increases in firing due to the application of glutamate and aspartate. These findings provide preliminary support for the hypothesis that glutamate (or a related compound) is also a vestibular hair cell transmitter in amniotes.

Physiological basis of tingling paresthesia evoked by hydroxy-alpha-sanshool.

PubMed

Lennertz, Richard C; Tsunozaki, Makoto; Bautista, Diana M; Stucky, Cheryl L

2010-03-24

Hydroxy-alpha-sanshool, the active ingredient in plants of the prickly ash plant family, induces robust tingling paresthesia by activating a subset of somatosensory neurons. However, the subtypes and physiological function of sanshool-sensitive neurons remain unknown. Here we use the ex vivo skin-nerve preparation to examine the pattern and intensity with which the sensory terminals of cutaneous neurons respond to hydroxy-alpha-sanshool. We found that sanshool excites virtually all D-hair afferents, a distinct subset of ultrasensitive light-touch receptors in the skin and targets novel populations of Abeta and C fiber nerve afferents. Thus, sanshool provides a novel pharmacological tool for discriminating functional subtypes of cutaneous mechanoreceptors. The identification of sanshool-sensitive fibers represents an essential first step in identifying the cellular and molecular mechanisms underlying tingling paresthesia that accompanies peripheral neuropathy and injury.

Physiological basis of tingling paresthesia evoked by hydroxy-α-sanshool

PubMed Central

Lennertz, Richard C; Tsunozaki, Makoto; Bautista, Diana M; Stucky, Cheryl L

2010-01-01

Hydroxy-α-sanshool, the active ingredient in plants of the prickly ash plant family, induces robust tingling paresthesia by activating a subset of somatosensory neurons. However, the subtypes and physiological function of sanshool-sensitive neurons remain unknown. Here we use the ex vivo skin-nerve preparation to examine the pattern and intensity with which the sensory terminals of cutaneous neurons respond to hydroxy-α-sanshool. We found that sanshool excites virtually all D-hair afferents, a distinct subset of ultra-sensitive light touch receptors in the skin, and targets novel populations of Aβ and C-fiber nerve afferents. Thus, sanshool provides a novel pharmacological tool for discriminating functional subtypes of cutaneous mechanoreceptors. The identification of sanshool-sensitive fibers represents an essential first step in identifying the cellular and molecular mechanisms underlying tingling paresthesia that accompanies peripheral neuropathy and injury. PMID:20335471

Effects of long-term bed rest on H-reflex and motor evoked potential in lower leg muscles during standing.

PubMed

Yamanaka, K; Yamamoto, S; Nakazawa, K; Yano, H; Suzuki, Y; Fukunaga, T

1999-07-01

Maximal H-reflex amplitude (Hmax) compared with maximal M-response (Mmax) has been generally used to assess the efficacy of the monosynaptic transmission from Ia afferents to alpha motoneurons in spinal cord. In previous studies, it has been demonstrated that H-reflex in soleus muscle (SOL) is inhibited during free standing due to an increase in presynaptic inhibition of the Ia afferent terminals to SOL motoneurones (Katz et al. 1988, Koceja et al. 1993). Transcranial magnetic stimulation (TMS) of human motor cortex excites the corticospinal system monosynapticaly connecting to spinal alpha motoneurones. However, it is not clear whether or not the motor evoked potentials (MEPs) in SOL and tibialis anterior (TA) muscles induced by TMS are modulated during standing (Ackermann et al. 1991, Lavoie et al. 1995). Considering that postural control functions change with exposure to weightlessness, we supposed that the excitability of SOL and TA spinal motoneurons from Ia afferents and/or corticospinal tracts during free standing would change after long-term bed rest (BR). The aim of this study was to investigate the effect of BR on H-reflex and MEP in SOL and TA during free standing.

The primary vestibular projection to the cerebellar cortex in the pigeon (Columba livia)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schwarz, I.E.; Schwarz, D.W.

1983-06-01

The cerebellar cortex of the pigeon receiving direct vestibular afferents was delineated by anterograde transport of (/sup 3/H)-amino acids injected into the vestibular nerve. Labelled mossy fiber rosettes in the granular layer were concentrated in lobule X (nodulus) and to a lesser extent, in the ventral portion of lobule IXd (uvula and paraflocculus). A few solitary labelled rosettes were also found in more dorsal portions of lobule IX, as well as in the anterior lobe between lobule II and IV. The lingula remained unlabelled. Discrete injections of (/sup 3/H)-leucine into the cristae of each of the three semicircular canals ormore » the utricular macula yielded a similar distribution of fewer labelled rosettes. A few primary mossy fiber terminals labelled after cochlear injections are attributed to afferents from the lagenar macula. Since effective diffusion of label from the injection site was excluded by controls, it is concluded that projection of individual canal and macula nerves to the vestibulocerebellar cortex is not topographically separated. It is proposed that this extensive convergence of various afferents is required by the cerebellum to compute precise and directionally specific control signals during head rotation in all conceivable planes.« less

Unravelling the Mystery of Capsaicin: A Tool to Understand and Treat Pain

PubMed Central

Brock, Christina; Olesen, Anne Estrup; Andresen, Trine; Nilsson, Matias; Dickenson, Anthony H.

2012-01-01

A large number of pharmacological studies have used capsaicin as a tool to activate many physiological systems, with an emphasis on pain research but also including functions such as the cardiovascular system, the respiratory system, and the urinary tract. Understanding the actions of capsaicin led to the discovery its receptor, transient receptor potential (TRP) vanilloid subfamily member 1 (TRPV1), part of the superfamily of TRP receptors, sensing external events. This receptor is found on key fine sensory afferents, and so the use of capsaicin to selectively activate pain afferents has been exploited in animal studies, human psychophysics, and imaging studies. Its effects depend on the dose and route of administration and may include sensitization, desensitization, withdrawal of afferent nerve terminals, or even overt death of afferent fibers. The ability of capsaicin to generate central hypersensitivity has been valuable in understanding the consequences and mechanisms behind enhanced central processing of pain. In addition, capsaicin has been used as a therapeutic agent when applied topically, and antagonists of the TRPV1 receptor have been developed. Overall, the numerous uses for capsaicin are clear; hence, the rationale of this review is to bring together and discuss the different types of studies that exploit these actions to shed light upon capsaicin working both as a tool to understand pain but also as a treatment for chronic pain. This review will discuss the various actions of capsaicin and how it lends itself to these different purposes. PMID:23023032

Potential self-regulatory mechanisms of yoga for psychological health

PubMed Central

Gard, Tim; Noggle, Jessica J.; Park, Crystal L.; Vago, David R.; Wilson, Angela

2014-01-01

Research suggesting the beneficial effects of yoga on myriad aspects of psychological health has proliferated in recent years, yet there is currently no overarching framework by which to understand yoga’s potential beneficial effects. Here we provide a theoretical framework and systems-based network model of yoga that focuses on integration of top-down and bottom-up forms of self-regulation. We begin by contextualizing yoga in historical and contemporary settings, and then detail how specific components of yoga practice may affect cognitive, emotional, behavioral, and autonomic output under stress through an emphasis on interoception and bottom-up input, resulting in physical and psychological health. The model describes yoga practice as a comprehensive skillset of synergistic process tools that facilitate bidirectional feedback and integration between high- and low-level brain networks, and afferent and re-afferent input from interoceptive processes (somatosensory, viscerosensory, chemosensory). From a predictive coding perspective we propose a shift to perceptual inference for stress modulation and optimal self-regulation. We describe how the processes that sub-serve self-regulation become more automatized and efficient over time and practice, requiring less effort to initiate when necessary and terminate more rapidly when no longer needed. To support our proposed model, we present the available evidence for yoga affecting self-regulatory pathways, integrating existing constructs from behavior theory and cognitive neuroscience with emerging yoga and meditation research. This paper is intended to guide future basic and clinical research, specifically targeting areas of development in the treatment of stress-mediated psychological disorders. PMID:25368562

Tempol prevents altered K(+) channel regulation of afferent arteriolar tone in diabetic rat kidney.

PubMed

Troncoso Brindeiro, Carmen M; Lane, Pascale H; Carmines, Pamela K

2012-03-01

Experiments were performed to test the hypothesis that oxidative stress underlies the enhanced tonic dilator impact of inward-rectifier K(+) channels on renal afferent arterioles of rats with streptozotocin-induced diabetes mellitus. Sham and diabetic rats were left untreated or provided Tempol in their drinking water for 26±1 days, after which afferent arteriolar lumen diameter and its responsiveness to K(+) channel blockade were measured using the in vitro blood-perfused juxtamedullary nephron technique. Afferent diameter averaged 19.4±0.8 μm in sham rats and 24.4±0.8 μm in diabetic rats (P<0.05). The decrease in diameter evoked by Ba(2+) (inward-rectifier K(+) channel blocker) was 3 times greater in diabetic rats than in sham rats. Glibenclamide (K(ATP) channel blocker) and tertiapin-Q (Kir1.1/Kir3.x channel blocker) decreased afferent diameter in diabetic rats but had no effect on arterioles from sham rats. Chronic Tempol treatment prevented diabetes mellitus-induced increases in both renal vascular dihydroethidium staining and baseline afferent arteriolar diameter. Moreover, Tempol prevented the exaggeration of afferent arteriolar responses to Ba(2+), tertiapin-Q, and glibenclamide otherwise evident in diabetic rats. Preglomerular microvascular smooth muscle cells expressed mRNA encoding Kir1.1, Kir2.1, and Kir6.1. Neither diabetes mellitus nor Tempol altered Kir1.1, Kir2.1, Kir6.1, or SUR2B protein levels in renal cortical microvessels. To the extent that the effects of Tempol reflect its antioxidant actions, our observations indicate that oxidative stress contributes to the exaggerated impact of Kir1.1, Kir2.1, and K(ATP) channels on afferent arteriolar tone during diabetes mellitus and that this phenomenon involves posttranslational modulation of channel function.

Effects of canal plugging on the vestibuloocular reflex and vestibular nerve discharge during passive and active head rotations.

PubMed

Sadeghi, Soroush G; Goldberg, Jay M; Minor, Lloyd B; Cullen, Kathleen E

2009-11-01

Mechanical occlusion (plugging) of the slender ducts of semicircular canals has been used in the clinic as well as in basic vestibular research. Here, we investigated the effect of canal plugging in two macaque monkeys on the horizontal vestibuloocular reflex (VOR) and the responses of vestibular-nerve afferents during passive head rotations. Afferent responses to active head movements were also studied. The horizontal VOR gain decreased after plugging to <0.1 for frequencies <2 Hz but rose to about 0.6 as frequency was increased to 15 Hz. Afferents innervating plugged horizontal canals had response sensitivities that increased with the frequency of passive rotations from <0.01 (spikes/s)/( degrees/s) at 0.5 Hz to values of about 0.2 and 0.5 (spikes/s)/( degrees/s) at 8 Hz for regular and irregular afferents, respectively (<50% of responses in controls). An increase in phase lead was also noted following plugging in afferent discharge, but not in the VOR. Because the phase discrepancy between the VOR and afferent discharge is much larger than that seen in control animals, this suggests that central adaptation shapes VOR dynamics following plugging. The effect of canal plugging on afferent responses can be modeled as an increase in stiffness and a reduction in the dominant time constant and gain in the transfer function describing canal dynamics. Responses were also evident during active head rotations, consistent with the frequency content of these movements. We conclude that canal plugging in macaques is effective only at frequencies <2 Hz. At higher frequencies, afferents show significant responses, with a nearly 90 degrees phase lead, such that they encode near-rotational acceleration. Our results demonstrate that afferents innervating plugged canals respond robustly during voluntary movements, a finding that has implications for understanding the effects of canal plugging in clinical practice.

Effects of Canal Plugging on the Vestibuloocular Reflex and Vestibular Nerve Discharge During Passive and Active Head Rotations

PubMed Central

Sadeghi, Soroush G.; Goldberg, Jay M.; Minor, Lloyd B.

2009-01-01

Mechanical occlusion (plugging) of the slender ducts of semicircular canals has been used in the clinic as well as in basic vestibular research. Here, we investigated the effect of canal plugging in two macaque monkeys on the horizontal vestibuloocular reflex (VOR) and the responses of vestibular-nerve afferents during passive head rotations. Afferent responses to active head movements were also studied. The horizontal VOR gain decreased after plugging to <0.1 for frequencies <2 Hz but rose to about 0.6 as frequency was increased to 15 Hz. Afferents innervating plugged horizontal canals had response sensitivities that increased with the frequency of passive rotations from <0.01 (spikes/s)/(°/s) at 0.5 Hz to values of about 0.2 and 0.5 (spikes/s)/(°/s) at 8 Hz for regular and irregular afferents, respectively (<50% of responses in controls). An increase in phase lead was also noted following plugging in afferent discharge, but not in the VOR. Because the phase discrepancy between the VOR and afferent discharge is much larger than that seen in control animals, this suggests that central adaptation shapes VOR dynamics following plugging. The effect of canal plugging on afferent responses can be modeled as an increase in stiffness and a reduction in the dominant time constant and gain in the transfer function describing canal dynamics. Responses were also evident during active head rotations, consistent with the frequency content of these movements. We conclude that canal plugging in macaques is effective only at frequencies <2 Hz. At higher frequencies, afferents show significant responses, with a nearly 90° phase lead, such that they encode near-rotational acceleration. Our results demonstrate that afferents innervating plugged canals respond robustly during voluntary movements, a finding that has implications for understanding the effects of canal plugging in clinical practice. PMID:19726724

Changes in monkey horizontal semicircular canal afferent responses after spaceflight

NASA Technical Reports Server (NTRS)

Correia, M. J.; Perachio, A. A.; Dickman, J. D.; Kozlovskaia, I. B.; Sirota, M. G.; Iakushin, S. B.; Beloozerova, I. N.

1992-01-01

Extracellular responses from single horizontal semicircular canal afferents in two rhesus monkeys were studied after recovery from a 14-day biosatellite (Cosmos 2044) orbital spaceflight. On the 1st postflight day, the mean gain for 9 different horizontal canal afferents, tested using one or several different passive yaw rotation waveforms, was nearly twice that for 20 horizontal canal afferents similarly tested during preflight and postflight control studies. Adaptation of the afferent response to passive yaw rotation on the 1st postflight day was also greater. These results suggest that at least one component of the vestibular end organ (the semicircular canals) is transiently modified after exposure to 14 days of microgravity. It is unclear whether the changes are secondary to other effects of microgravity, such as calcium loss, or an adaptive response. If the response is adaptive, then this report is the first evidence that the response of the vestibular end organ may be modified (presumably by the central nervous system via efferent connections) after prolonged unusual vestibular stimulation. If this is the case, the sites of plasticity of vestibular responses may not be exclusively within central nervous system vestibular structures, as previously believed.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sekizawa, Shin-ichi, E-mail: ssekizawa@ucdavis.ed; Bechtold, Andrea G.; Tham, Rick C.

Allergic airway diseases in children are a common and a growing health problem. Changes in the central nervous system (CNS) have been implicated in contributing to some of the symptoms. We hypothesized that airway allergic diseases are associated with altered histamine H3 receptor expression in the nucleus tractus solitarius (NTS) and caudal spinal trigeminal nucleus, where lung/airway and nasal sensory afferents terminate, respectively. Immunohistochemistry for histamine H3 receptors was performed on brainstem sections containing the NTS and the caudal spinal trigeminal nucleus from 6- and 12-month-old rhesus monkeys who had been exposed for 5 months to house dust mite allergenmore » (HDMA) + O{sub 3} or to filtered air (FA). While histamine H3 receptors were found exclusively in astrocytes in the caudal spinal trigeminal nucleus, they were localized to both neuronal terminals and processes in the NTS. HDMA + O{sub 3} exposure significantly decreased histamine H3 receptor immunoreactivity in the NTS at 6 months and in the caudal spinal trigeminal nucleus at 12 months of age. In conclusion, exposing young primates to HDMA + O{sub 3} changed histamine H3 receptor expression in CNS pathways involving lung and nasal afferent nerves in an age-related manner. Histamine H3 receptors may be a therapeutic target for allergic asthma and rhinitis in children.« less

Neural readaptation to earth s gravity following exposure to microgravity

NASA Astrophysics Data System (ADS)

Boyle, R.; Highstein, S.; Mensinger, A.

Vertebrates possess hair cell otolith organs of the inner ear, the utricule and saccule, that transduce inertial force due to head translation and head tilt relative to gravitational vertical, and transform the vector sum of the imposing accelerations into a neural code carried by the afferent nerve fibers. This code is combined in the central vestibular pathways with motion signals obtained from the semicircular canals and other sensory modalities to compute a cent ral representation of the body in space called the gravitoinertial vector. Thus the central nervous system resolves the ambiguity of gravity and self-motion and thereby maintains balance and equilibrium under varying conditions. Exposure to microgravity imposes an extreme condition to which the organism must adapt. Space travelers often experience disorientation during the first few days in microgravity, called Space Adaptation Syndrome. From the earliest manned missions it was evident that adjustments to the microgravity environment in-flight and upon return to Earth's 1g occur. We studied the neural readaptation to Earth's 1g using electrophysiological techniques to measure the response characteristics of utricular nerve afferents in fish upon return from an exposure to microgravity. Following a 9 (STS-95) and 15 (STS-90) day exposure to microgravity aboard two NASA shuttle orbital flights, single afferent recording experiments were conducted in four toadfish, Opsanus tau, to characterize the afferent response properties to gravito inertial accelerations and compare them to- afferent responses of control animals similarly tested. Six recording sessions were made sequentially 10-117 hrs postflight. Afferent responses to translational accelerations and head tilts were detected in the earliest sessions. The most striking result is the occurrence of hypersensitive afferents, having extremely high response sensitivity to minor displacements such as < 0.5 mm displacement at 0.006g, within the first day postflight. After about 30 hrs the afferent response properties of flight and control fish were similar. The reduced gravitational acceleration in orbit apparently resulted in a temporary up-regulation of the sensitivity of utricular afferents. The time course of return to normal afferent sensitivity parallels the decrease in vestibular disorientation in astronauts following return from space. (Supported by NASA, NIH and NASDA)

Parallel processing of afferent olfactory sensory information

PubMed Central

Vaaga, Christopher E.

2016-01-01

Key points The functional synaptic connectivity between olfactory receptor neurons and principal cells within the olfactory bulb is not well understood.One view suggests that mitral cells, the primary output neuron of the olfactory bulb, are solely activated by feedforward excitation.Using focal, single glomerular stimulation, we demonstrate that mitral cells receive direct, monosynaptic input from olfactory receptor neurons.Compared to external tufted cells, mitral cells have a prolonged afferent‐evoked EPSC, which serves to amplify the synaptic input.The properties of presynaptic glutamate release from olfactory receptor neurons are similar between mitral and external tufted cells.Our data suggest that afferent input enters the olfactory bulb in a parallel fashion. Abstract Primary olfactory receptor neurons terminate in anatomically and functionally discrete cortical modules known as olfactory bulb glomeruli. The synaptic connectivity and postsynaptic responses of mitral and external tufted cells within the glomerulus may involve both direct and indirect components. For example, it has been suggested that sensory input to mitral cells is indirect through feedforward excitation from external tufted cells. We also observed feedforward excitation of mitral cells with weak stimulation of the olfactory nerve layer; however, focal stimulation of an axon bundle entering an individual glomerulus revealed that mitral cells receive monosynaptic afferent inputs. Although external tufted cells had a 4.1‐fold larger peak EPSC amplitude, integration of the evoked currents showed that the synaptic charge was 5‐fold larger in mitral cells, reflecting the prolonged response in mitral cells. Presynaptic afferents onto mitral and external tufted cells had similar quantal amplitude and release probability, suggesting that the larger peak EPSC in external tufted cells was the result of more synaptic contacts. The results of the present study indicate that the monosynaptic afferent input to mitral cells depends on the strength of odorant stimulation. The enhanced spiking that we observed in response to brief afferent input provides a mechanism for amplifying sensory information and contrasts with the transient response in external tufted cells. These parallel input paths may have discrete functions in processing olfactory sensory input. PMID:27377344

Zonal variations in K+ currents in vestibular crista calyx terminals

PubMed Central

Meredith, Frances L.

2014-01-01

We developed a rodent crista slice to investigate regional variations in electrophysiological properties of vestibular afferent terminals. Thin transverse slices of the gerbil crista ampullaris were made and electrical properties of calyx terminals in central zones (CZ) and peripheral zones (PZ) compared with whole cell patch clamp. Spontaneous action potential firing was observed in 25% of current-clamp recordings and was either regular or irregular in both zones. Firing was abolished when extracellular choline replaced Na+ but persisted when hair cell mechanotransduction channels or calyx AMPA receptors were blocked. This suggests that ion channels intrinsic to the calyx can generate spontaneous firing. In response to depolarizing voltage steps, outward K+ currents were observed at potentials above −60 mV. K+ currents in PZ calyces showed significantly more inactivation than currents in CZ calyces. Underlying K+ channel populations contributing to these differences were investigated. The KCNQ channel blocker XE991 dihydrochloride blocked a slowly activating, sustained outward current in both PZ and CZ calyces, indicating the presence of KCNQ channels. Mean reduction was greatest in PZ calyces. XE991 also reduced action potential firing frequency in CZ and PZ calyces and broadened mean action potential width. The K+ channel blocker 4-aminopyridine (10–50 μM) blocked rapidly activating, moderately inactivating currents that were more prevalent in PZ calyces. α-Dendrotoxin, a selective blocker of KV1 channels, reduced outward currents in CZ calyces but not in PZ calyces. Regional variations in K+ conductances may contribute to different firing responses in calyx afferents. PMID:25343781

Zonal variations in K+ currents in vestibular crista calyx terminals.

PubMed

Meredith, Frances L; Rennie, Katherine J

2015-01-01

We developed a rodent crista slice to investigate regional variations in electrophysiological properties of vestibular afferent terminals. Thin transverse slices of the gerbil crista ampullaris were made and electrical properties of calyx terminals in central zones (CZ) and peripheral zones (PZ) compared with whole cell patch clamp. Spontaneous action potential firing was observed in 25% of current-clamp recordings and was either regular or irregular in both zones. Firing was abolished when extracellular choline replaced Na(+) but persisted when hair cell mechanotransduction channels or calyx AMPA receptors were blocked. This suggests that ion channels intrinsic to the calyx can generate spontaneous firing. In response to depolarizing voltage steps, outward K(+) currents were observed at potentials above -60 mV. K(+) currents in PZ calyces showed significantly more inactivation than currents in CZ calyces. Underlying K(+) channel populations contributing to these differences were investigated. The KCNQ channel blocker XE991 dihydrochloride blocked a slowly activating, sustained outward current in both PZ and CZ calyces, indicating the presence of KCNQ channels. Mean reduction was greatest in PZ calyces. XE991 also reduced action potential firing frequency in CZ and PZ calyces and broadened mean action potential width. The K(+) channel blocker 4-aminopyridine (10-50 μM) blocked rapidly activating, moderately inactivating currents that were more prevalent in PZ calyces. α-Dendrotoxin, a selective blocker of KV1 channels, reduced outward currents in CZ calyces but not in PZ calyces. Regional variations in K(+) conductances may contribute to different firing responses in calyx afferents. Copyright © 2015 the American Physiological Society.

Differential effects of C- and N-terminal substance P metabolites on the release of amino acid neurotransmitters from the spinal cord: potential role in nociception.

PubMed

Skilling, S R; Smullin, D H; Larson, A A

1990-04-01

Extensive evidence implicates Substance P [SP(1-11)] as a primary afferent neurotransmitter or modulator of nociceptive information, and there is increasing evidence that the excitatory amino acids aspartate (Asp) and glutamate (Glu) may also act as nociceptive neurotransmitters. We have previously demonstrated that nociceptive stimulation (metatarsal injection of formalin) caused a tetrodotoxin (TTX)-sensitive release of Asp and a TTX-insensitive release of Glu from the dorsal spinal cord. We have also shown release of Asp and Glu following the direct infusion of SP(1-11), suggesting that formalin-induced Asp or Glu changes could be secondary to an initial release of SP(1-11). In contrast to nociception, pretreatment with TTX, reported here, had no effect on the SP(1-11)-induced release of Asp, suggesting a presynaptic mechanism. Behavioral experiments, in both our laboratory, and others, now suggest that the N-terminal products of SP metabolism play a distinct role in the modulation of SP(1-11) nociception, possibly through an interaction with an opiate receptor. To test the hypothesis that N- and C-terminal fragments of SP produce opposite effects on biochemical events potentially involved in nociception, we compared the effects of infusion of the N-terminal metabolite SP(1-7) and the C-terminal metabolite SP(5-11) on changes in the ECF concentration of amino acids in the spinal cord as a measure of their apparent release, using microdialysis. Intradiaylsate infusion of SP(5-11) increased the release of Asp, Glu, asparagine (Asn), glycine (Gly), and taurine (Tau). The changes in Asp, Glu, and Tau were similar in direction and magnitude to changes produced by SP(1-11) or formalin injection, further supporting the hypothesis that the C-terminal is responsible for the nociceptive effects of SP(1-11). In contrast, infusion of SP(1-7) significantly decreased the release of Asn, Tau, Glu, and Gly. This inhibition of amino acid release is consistent with the hypothesis that N-terminal metabolites produce opposite effects to those of C-terminal metabolites of SP(1-11). The decreases in Glu, Asn, Gly, and Tau following SP(1-7) infusion were significantly reduced by i.p. or intradialysate naloxone. Systemic naloxone had no significant effects on the SP(5-11)-induced amino acid changes; however, it did inhibit the SP(1-11)-induced increase in Asp and Glu. Intradialysate naloxone had no effect on the SP(1-11)-induced increases.(ABSTRACT TRUNCATED AT 400 WORDS)

Emerging Role of Spinal Cord TRPV1 in Pain Exacerbation

PubMed Central

Choi, Seung-In; Lim, Ji Yeon; Yoo, Sungjae; Kim, Hyun; Hwang, Sun Wook

2016-01-01

TRPV1 is well known as a sensor ion channel that transduces a potentially harmful environment into electrical depolarization of the peripheral terminal of the nociceptive primary afferents. Although TRPV1 is also expressed in central regions of the nervous system, its roles in the area remain unclear. A series of recent reports on the spinal cord synapses have provided evidence that TRPV1 plays an important role in synaptic transmission in the pain pathway. Particularly, in pathologic pain states, TRPV1 in the central terminal of sensory neurons and interneurons is suggested to commonly contribute to pain exacerbation. These observations may lead to insights regarding novel synaptic mechanisms revealing veiled roles of spinal cord TRPV1 and may offer another opportunity to modulate pathological pain by controlling TRPV1. In this review, we introduce historical perspectives of this view and details of the recent promising results. We also focus on extended issues and unsolved problems to fully understand the role of TRPV1 in pathological pain. Together with recent findings, further efforts for fine analysis of TRPV1's plastic roles in pain synapses at different levels in the central nervous system will promote a better understanding of pathologic pain mechanisms and assist in developing novel analgesic strategies. PMID:26885404

Decreased afferent excitability contributes to synaptic depression during high-frequency stimulation in hippocampal area CA1

PubMed Central

Kim, Eunyoung; Owen, Benjamin; Holmes, William R.

2012-01-01

Long-term potentiation (LTP) is often induced experimentally by continuous high-frequency afferent stimulation (HFS), typically at 100 Hz for 1 s. Induction of LTP requires postsynaptic depolarization and voltage-dependent calcium influx. Induction is more effective if the same number of stimuli are given as a series of short bursts rather than as continuous HFS, in part because excitatory postsynaptic potentials (EPSPs) become strongly depressed during HFS, reducing postsynaptic depolarization. In this study, we examined mechanisms of EPSP depression during HFS in area CA1 of rat hippocampal brain slices. We tested for presynaptic terminal vesicle depletion by examining minimal stimulation-evoked excitatory postsynaptic currents (EPSCs) during 100-Hz HFS. While transmission failures increased, consistent with vesicle depletion, EPSC latencies also increased during HFS, suggesting a decrease in afferent excitability. Extracellular recordings of Schaffer collateral fiber volleys confirmed a decrease in afferent excitability, with decreased fiber volley amplitudes and increased latencies during HFS. To determine the mechanism responsible for fiber volley changes, we recorded antidromic action potentials in single CA3 pyramidal neurons evoked by stimulating Schaffer collateral axons. During HFS, individual action potentials decreased in amplitude and increased in latency, and these changes were accompanied by a large increase in the probability of action potential failure. Time derivative and phase-plane analyses indicated decreases in both axon initial segment and somato-dendritic components of CA3 neuron action potentials. Our results indicate that decreased presynaptic axon excitability contributes to depression of excitatory synaptic transmission during HFS at synapses between Schaffer collaterals and CA1 pyramidal neurons. PMID:22773781

Serotonergic transmission at Merkel discs: modulation by exogenously applied chemical messengers and involvement of Ih currents.

PubMed

Chang, Weipang; Kanda, Hirosato; Ikeda, Ryo; Ling, Jennifer; Gu, Jianguo G

2017-05-01

The Merkel disc is a main type of tactile end organ consisting of Merkel cells and Aβ-afferent endings that responds to tactile stimulation with slowly adapting type 1 (SA1) afferent impulses. Our recent study has shown that Merkel discs in whisker hair follicles are serotonergic synapses using endogenous serotonin to transmit tactile signals from Merkel cells to Aβ-afferent endings. In this study, we hypothesize that tactile sensitivity of Merkel discs can be modulated by chemical messengers. We tested this hypothesis by determining whether and how SA1 responses of mouse whisker hair follicles may be affected by exogenously applied chemical messengers. We found that SA1 responses were potentiated by serotonin at low concentration (10 μM) but almost completely occluded by serotonin at high concentration (2 mM). In contrast, SA1 responses were not significantly affected by ATP and its metabolically stable analog α,β-methylene-ATP, glutamate, γ-aminobutyric acid (GABA), and histamine. SA1 responses were also not affected by antagonists for P2X receptors, ionotropic glutamate receptors, and ionotropic GABA and glycine receptors. Whole-cell patch-clamp recordings reconfirm the presence of both ionotropic and metabotropic 5-HT receptors on afferent neurons and their terminals innervating whisker hair follicles. All whisker afferent neurons expressed hyperpolarization-activated inward currents (I h ), which are potentiated by serotonin through the activation of metabotropic 5-HT receptors. Taken together, the findings substantiate the serotonergic mechanism of tactile transmission at Merkel discs and identify the involvement of I h currents in postsynaptic excitatory actions of serotonin. In addition, the findings do not favor any significant involvement of ATP, glutamate, histamine, GABA, or glycine in tactile transmission at the Merkel discs of whisker hair follicles. © 2017 International Society for Neurochemistry.

Cationic influences upon synaptic transmission at the hair cell-afferent fiber synapse of the frog

NASA Technical Reports Server (NTRS)

Cochran, S. L.

1995-01-01

The concentrations of inorganic cations (K+, Na+, and Ca2+) bathing the isolated frog labyrinth were varied in order to assess their role in influencing and mediating synaptic transmission at the hair cell-afferent fiber synapse. Experiments employed intracellular recordings of synaptic activity from VIIIth nerve afferents. Recordings were digitized continuously at 50 kHz, and excitatory postsynaptic potentials were detected and parameters quantified by computer algorithms. Particular attention was focused on cationic effects upon excitatory postsynaptic potential frequency of occurrence and excitatory postsynaptic potential amplitude, in order to discriminate between pre- and postsynaptic actions. Because the small size of afferents preclude long term stable recordings, alterations in cationic concentrations were applied transiently and their peak effects on synaptic activity were assessed. Increases in extracellular K+ concentration of a few millimolar produced a large increase in the frequency of occurrence of excitatory postsynaptic potentials with little change in amplitude, indicating that release of transmitter from the hair cell is tightly coupled to its membrane potential. Increasing extracellular Na+ concentration resulted in an increase in excitatory postsynaptic potential amplitude with no significant change in excitatory postsynaptic potential frequency of occurrence, suggesting that the transmitter-gated subsynaptic channel conducts Na+ ions. Decreases in extracellular Ca2+ concentration had little effect upon excitatory postsynaptic potential frequency, but increased excitatory postsynaptic potential frequency and amplitude. These findings suggest that at higher concentrations Ca2+ act presynaptically to prevent transmitter release and postsynaptically to prevent Na+ influx during the generation of the excitatory postsynaptic potential. The influences of these ions on synaptic activity at this synapse are remarkably similar to those reported at the vertebrate neuromuscular junction. The major differences between these two synapses are the neurotransmitters and the higher resting release rate and higher sensitivity of release to increased K+ concentrations of the hair cells over that of motor nerve terminals. These differences reflect the functional roles of the two synapses: the motor nerve terminal response in an all-or-nothing signal consequent from action potential invasion, while the hair cell releases transmitter in a graded fashion, proportionate to the extent of stereocilial deflection. Despite these differences between the two junctions, the similar actions of these elemental cations upon synaptic function at each implies that these ions may participate similarly in the operations of other synapses, independent of the neurotransmitter type.(ABSTRACT TRUNCATED AT 400 WORDS).

Abnormal afferent nerve endings in the soft palatal mucosa of sleep apnoics and habitual snorers.

PubMed

Friberg, D; Gazelius, B; Hökfelt, T; Nordlander, B

1997-07-23

Habitual snoring precedes obstructive sleep apnea (OSA), but the pathophysiological mechanisms behind progression are still unclear. The patency of upper airways depends on a reflexogen mechanism reacting on negative intrapharyngeal pressure at inspiration, probably mediated by mucosal receptors, i.e., via afferent nerve endings. Such nerves contain a specific nerve protein, protein-gene product 9.5 (PGP 9.5) and in some cases substance P (SP) and calcitonin gene-related (CGRP). Biopsies of the soft palatial mucosa were obtained from non-smoking men ten OSA patients, 11 habitual snorers and 11 non-snoring controls. The specimens were immunohistochemically analyzed for PGP 9.5, SP and CGRP. As compared to controls, an increased number of PGP-, SP- and CGRP-immunoreactive nerves were demonstrated in the mucosa in 9/10 OSA patients and 4/11 snorers, in addition to varicose nerve endings in the papillae and epithelium. Using double staining methodology, it could be shown that SP- and CGRP-like immunoreactivities (LIs) often coexisted in these fibres, as did CGRP- and PGP 9.5-LIs. The increased density in sensory nerve terminals are interpreted to indicate an afferent nerve lesion. Our results support the hypothesis of a progressive neurogenic lesion as a contributory factor to the collapse of upper airways during sleep in OSA patients.

Plasticity of synaptic connections in sensory-motor pathways of the adult locust flight system.

PubMed

Wolf, H; Büschges, A

1997-09-01

We investigated possible roles of retrograde signals and competitive interactions in the lesion-induced reorganization of synaptic contacts in the locust CNS. Neuronal plasticity is elicited in the adult flight system by removal of afferents from the tegula, a mechanoreceptor organ at the base of the wing. We severed one hindwing organ and studied the resulting rearrangement of synaptic contacts between flight interneurons and afferent neurons from the remaining three tegulae (2 forewing, 1 hindwing). This was done by electric stimulation of afferents and intracellular recording from interneurons (and occasionally motoneurons). Two to three weeks after unilateral tegula lesion, connections between tegula afferents and flight interneurons were altered in the following way. 1) Axons from the forewing tegula on the operated side had established new synaptic contacts with metathoracic elevator interneurons. In addition, the amplitude of compound excitatory postsynaptic potentials elicited by electric stimulation was increased, indicating that a larger number of afferents connected to any given interneuron. 2) On the side contralateral to the lesion, connectivity between axons from the forewing tegula and elevator interneurons was decreased. 3) The efficacy of the (remaining) hindwing afferents appeared to be increased with regard to both synaptic transmission to interneurons and impact on flight motor pattern. 4) Flight motoneurons, which are normally restricted to the ipsilateral hemiganglion, sprouted across the ganglion midline after unilateral tegula removal and apparently established new synaptic contacts with tegula afferents on that side. The changes on the operated side are interpreted as occupation of synaptic space vacated on the interneurons by the severed hindwing afferents. On the contralateral side, the changes in synaptic contact must be elicited by retrograde signals from bilaterally arborizing flight interneurons, because tegula projections remain strictly ipsilateral. The pattern of changes suggests competitive interactions between forewing and hindwing afferents. The present investigation thus presents evidence that the CNS of the mature locust is capable of extensive synaptic rearrangement in response to injury and indicates for the first time the action of retrograde signals from interneurons.

Combined Changes in Chloride Regulation and Neuronal Excitability Enable Primary Afferent Depolarization to Elicit Spiking without Compromising its Inhibitory Effects

PubMed Central

2016-01-01

The central terminals of primary afferent fibers experience depolarization upon activation of GABAA receptors (GABAAR) because their intracellular chloride concentration is maintained above electrochemical equilibrium. Primary afferent depolarization (PAD) normally mediates inhibition via sodium channel inactivation and shunting but can evoke spikes under certain conditions. Antidromic (centrifugal) conduction of these spikes may contribute to neurogenic inflammation while orthodromic (centripetal) conduction could contribute to pain in the case of nociceptive fibers. PAD-induced spiking is assumed to override presynaptic inhibition. Using computer simulations and dynamic clamp experiments, we sought to identify which biophysical changes are required to enable PAD-induced spiking and whether those changes necessarily compromise PAD-mediated inhibition. According to computational modeling, a depolarizing shift in GABA reversal potential (EGABA) and increased intrinsic excitability (manifest as altered spike initiation properties) were necessary for PAD-induced spiking, whereas increased GABAAR conductance density (ḡGABA) had mixed effects. We tested our predictions experimentally by using dynamic clamp to insert virtual GABAAR conductances with different EGABA and kinetics into acutely dissociated dorsal root ganglion (DRG) neuron somata. Comparable experiments in central axon terminals are prohibitively difficult but the biophysical requirements for PAD-induced spiking are arguably similar in soma and axon. Neurons from naïve (i.e. uninjured) rats were compared before and after pharmacological manipulation of intrinsic excitability, and against neurons from nerve-injured rats. Experimental data confirmed that, in most neurons, both predicted changes were necessary to yield PAD-induced spiking. Importantly, such changes did not prevent PAD from inhibiting other spiking or from blocking spike propagation. In fact, since the high value of ḡGABA required for PAD-induced spiking still mediates strong inhibition, we conclude that PAD-induced spiking does not represent failure of presynaptic inhibition. Instead, diminished PAD caused by reduction of ḡGABA poses a greater risk to presynaptic inhibition and the sensory processing that relies upon it. PMID:27835641

Formalin-induced behavioural hypersensitivity and neuronal hyperexcitability are mediated by rapid protein synthesis at the spinal level

PubMed Central

Asante, Curtis O; Wallace, Victoria C; Dickenson, Anthony H

2009-01-01

Background The mammalian target of rapamycin (mTOR) is a key regulator of mRNA translation whose action can be inhibited by the drug rapamycin. Forms of long-term plasticity require protein synthesis and evidence indicates that mRNA in dendrites, axon terminals and cell bodies is essential for long-term synaptic plasticity. Specific to pain, shifts in pain thresholds and responsiveness are an expression of neuronal plasticity and this likely contributes to persistent pain. We investigated this by inhibiting the activity of mTOR with rapamycin at the spinal level, of rats that were subjected to the formalin test, using both behavioural and electrophysiological techniques. Results For in vivo electrophysiology, Sprague Dawley rats were fully anaesthetised and single-unit extracellular recordings were obtained from lamina V wide dynamic range (WDR) dorsal horn spinal neurones at the region where input is received from the hind paw. Neuronal responses from naive rats showed that rapamycin-sensitive pathways were important in nociceptive-specific C-fibre mediated transmission onto WDR neurones as well mechanically-evoked responses since rapamycin was effective in attenuating these measures. Formalin solution was injected into the hind paw prior to which, rapamycin or vehicle was applied directly onto the exposed spinal cord. When rapamycin was applied to the spinal cord prior to hind paw formalin injection, there was a significant attenuation of the prolonged second phase of the formalin test, which comprises continuing afferent input to the spinal cord, neuronal hyperexcitability and an activated descending facilitatory drive from the brainstem acting on spinal neurones. In accordance with electrophysiological data, behavioural studies showed that rapamycin attenuated behavioural hypersensitivity elicited by formalin injection into the hind paw. Conclusion We conclude that mTOR has a role in maintaining persistent pain states via mRNA translation and thus protein synthesis. We hypothesise that mTOR may be activated by excitatory neurotransmitter release acting on sensory afferent terminals as well as dorsal horn spinal neurones, which may be further amplified by descending facilitatory systems originating from higher centres in the brain. PMID:19500426

Distribution of TTX-sensitive voltage-gated sodium channels in primary sensory endings of mammalian muscle spindles.

PubMed

Carrasco, Dario I; Vincent, Jacob A; Cope, Timothy C

2017-04-01

Knowledge of the molecular mechanisms underlying signaling of mechanical stimuli by muscle spindles remains incomplete. In particular, the ionic conductances that sustain tonic firing during static muscle stretch are unknown. We hypothesized that tonic firing by spindle afferents depends on sodium persistent inward current (INaP) and tested for the necessary presence of the appropriate voltage-gated sodium (NaV) channels in primary sensory endings. The NaV 1.6 isoform was selected for both its capacity to produce INaP and for its presence in other mechanosensors that fire tonically. The present study shows that NaV 1.6 immunoreactivity (IR) is concentrated in heminodes, presumably where tonic firing is generated, and we were surprised to find NaV 1.6 IR strongly expressed also in the sensory terminals, where mechanotransduction occurs. This spatial pattern of NaV 1.6 IR distribution was consistent for three mammalian species (rat, cat, and mouse), as was tonic firing by primary spindle afferents. These findings meet some of the conditions needed to establish participation of INaP in tonic firing by primary sensory endings. The study was extended to two additional NaV isoforms, selected for their sensitivity to TTX, excluding TTX-resistant NaV channels, which alone are insufficient to support firing by primary spindle endings. Positive immunoreactivity was found for NaV 1.1 , predominantly in sensory terminals together with NaV 1.6 and for NaV 1.7 , mainly in preterminal axons. Differential distribution in primary sensory endings suggests specialized roles for these three NaV isoforms in the process of mechanosensory signaling by muscle spindles. NEW & NOTEWORTHY The molecular mechanisms underlying mechanosensory signaling responsible for proprioceptive functions are not completely elucidated. This study provides the first evidence that voltage-gated sodium channels (NaVs) are expressed in the spindle primary sensory ending, where NaVs are found at every site involved in transduction or encoding of muscle stretch. We propose that NaVs contribute to multiple steps in sensory signaling by muscle spindles as it does in other types of slowly adapting sensory neurons. Copyright © 2017 the American Physiological Society.

Tectonigral Projections in the Primate: A Pathway for Pre-Attentive Sensory Input to Midbrain Dopaminergic Neurons

PubMed Central

May, Paul J.; McHaffie, John G.; Stanford, Terrence R.; Jiang, Huai; Costello, M. Gabriela; Coizet, Veronique; Hayes, Lauren M.; Haber, Suzanne N.; Redgrave, Peter

2010-01-01

Much of the evidence linking the short-latency phasic signaling of midbrain dopaminergic neurons with reward-prediction errors used in learning and habit formation comes from recording the visual responses of monkey dopaminergic neurons. However, the information encoded by dopaminergic neuron activity is constrained by the qualities of the afferent visual signals made available to these cells. Recent evidence from rats and cats indicates the primary source of this visual input originates subcortically, via a direct tectonigral projection. The present anatomical study sought to establish whether a direct tectonigral projection is a significant feature of the primate brain. Injections of anterograde tracers into the superior colliculus of macaque monkeys labelled terminal arbors throughout the substantia nigra, with the densest terminations in the dorsal tier. Labelled boutons were found in close association (possibly indicative of synaptic contact) with ventral midbrain neurons staining positively for the dopaminergic marker tyrosine hydroxylase. Injections of retrograde tracer confined to the macaque substantia nigra retrogradely labelled small to medium sized neurons in the intermediate and deep layers of the superior colliculus. Together, these data indicate that a direct tectonigral projection is also a feature of the monkey brain, and therefore likely to have been conserved throughout mammalian evolution. Insofar as the superior colliculus is configured to detect unpredicted, biologically salient, sensory events, it may be safer to regard the phasic responses of midbrain dopaminergic neurons as ‘sensory prediction errors’ rather than ‘reward prediction errors’, in which case, dopamine-based theories of reinforcement learning will require revision. PMID:19175405

The function of metabotropic glutamate receptors in thalamus and cortex.

PubMed

Sherman, S Murray

2014-04-01

Metabotropic glutamate receptors (mGluRs) are found throughout thalamus and cortex and are clearly important to circuit behavior in both structures, and so considering only participation of ionotropic glutamate receptors (e.g., [R,S]-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid [AMPA] and N-methyl-d-aspartate receptors [NMDA] receptors) in glutamatergic processing would be an unfortunate oversimplification. These mGluRs are found both postsynaptically, on target cells of glutamatergic afferents, and presynaptically, on various synaptic terminals themselves, and when activated, they produce prolonged effects lasting at least hundreds of msec to several sec and perhaps longer. Two main types exist: activation of group I mGluRs causes postsynaptic depolarization, and group II, hyperpolarization. Both types are implicated in synaptic plasticity, both short term and long term. Their evident importance in functioning of thalamus and cortex makes it critical to develop a better understanding of how these receptors are normally activated, especially because they also seem implicated in a wide range of neurological and cognitive pathologies.

The Function of Metabotropic Glutamate Receptors in Thalamus and Cortex

PubMed Central

Sherman, S. Murray

2016-01-01

Metabotropic glutamate receptors (mGluRs) are found throughout thalamus and cortex and are clearly important to circuit behavior in both structures, and so considering only participation of ionotropic glutamate receptors (e.g., [R,S]-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid [AMPA] and N-methyl-d-aspartate receptors [NMDA] receptors) in glutamatergic processing would be an unfortunate oversimplification. These mGluRs are found both postsynaptically, on target cells of glutamatergic afferents, and presynaptically, on various synaptic terminals themselves, and when activated, they produce prolonged effects lasting at least hundreds of msec to several sec and perhaps longer. Two main types exist: activation of group I mGluRs causes postsynaptic depolarization, and group II, hyperpolarization. Both types are implicated in synaptic plasticity, both short term and long term. Their evident importance in functioning of thalamus and cortex makes it critical to develop a better understanding of how these receptors are normally activated, especially because they also seem implicated in a wide range of neurological and cognitive pathologies. PMID:23459618

The Increased Sensitivity of Irregular Peripheral Canal and Otolith Vestibular Afferents Optimizes their Encoding of Natural Stimuli

PubMed Central

Schneider, Adam D.; Jamali, Mohsen; Carriot, Jerome; Chacron, Maurice J.

2015-01-01

Efficient processing of incoming sensory input is essential for an organism's survival. A growing body of evidence suggests that sensory systems have developed coding strategies that are constrained by the statistics of the natural environment. Consequently, it is necessary to first characterize neural responses to natural stimuli to uncover the coding strategies used by a given sensory system. Here we report for the first time the statistics of vestibular rotational and translational stimuli experienced by rhesus monkeys during natural (e.g., walking, grooming) behaviors. We find that these stimuli can reach intensities as high as 1500 deg/s and 8 G. Recordings from afferents during naturalistic rotational and linear motion further revealed strongly nonlinear responses in the form of rectification and saturation, which could not be accurately predicted by traditional linear models of vestibular processing. Accordingly, we used linear–nonlinear cascade models and found that these could accurately predict responses to naturalistic stimuli. Finally, we tested whether the statistics of natural vestibular signals constrain the neural coding strategies used by peripheral afferents. We found that both irregular otolith and semicircular canal afferents, because of their higher sensitivities, were more optimized for processing natural vestibular stimuli as compared with their regular counterparts. Our results therefore provide the first evidence supporting the hypothesis that the neural coding strategies used by the vestibular system are matched to the statistics of natural stimuli. PMID:25855169

Laminar patterns of geniculocortical projection in the cat.

PubMed

LeVay, S; Gilbert, C D

1976-08-20

The cortical afferents from individual laminae of the dorsal lateral geniculate nucleus (LGN) were studied using both light and electron microscope autoradiography. In area 17, the A geniculate laminae (A and A1) had two main bands of projection, one extending from the bottom of IVc to the deepest cells in layer III, and one in layer VI. The C geniculate laminae projected in two dense bands to the upper and lower borders of layer IV, thus bracketing the A laminae projection, though with some overlap. In addition, the C laminae projected to the superficial half of layer I, which the A laminae did not. Conversely, while the A laminae projected to layer VI, the C laminae did not. The two sets of laminae also showed differences in the areas to which they projected. The A geniculate laminae projected to areas 17 and 18, whereas the C geniculate laminae had a more extensive projection, including areas 17, 18, 19 and other areas on the suprasylvian gyrus. The laminar organization of the projection to area 18 was similar to that found in area 17. At the electron microscopic level the geniculate terminals were found to make Gray's type 1 synapses, for the most part onto dendritic spines. Labeled terminals were found in all the projection bands seen in the light microscope. The implications of these findings on the connectivity of cells in layer IV are discussed. The presence of labeled terminals in layer VI, which contains the cells of origin of the corticogeniculate pathway, suggests that the recurrent loop to the LGN is mediated monosynaptically. Finally, the afferents from each geniculate lamina were found to be segregated into patches, about 500 mum wide, which probably form the anatomical basis for ocular dominance columns.

Comparison of projection neurons in the pontine nuclei and the nucleus reticularis tegmenti pontis of the rat.

PubMed

Schwarz, C; Thier, P

1996-12-16

Dendritic features of identified projection neurons in two precerebellar nuclei, the pontine nuclei (PN) and the nucleus reticularis tegmenti pontis (NRTP) were established by using a combination of retrograde tracing (injection of fluorogold or rhodamine labelled latex micro-spheres into the cerebellum) with subsequent intracellular filling (lucifer yellow) in fixed slices of pontine brainstem. A multivariate analysis revealed that parameters selected to characterize the dendritic tree such as size of dendritic field, number of branching points, and length of terminal dendrites did not deviate significantly between different regions of the PN and the NRTP. On the other hand, projection neurons in ventral regions of the PN were characterized by an irregular coverage of their distal dendrites by appendages while those in the dorsal PN and the NRTP were virtually devoid of them. The NRTP, dorsal, and medial PN tended to display larger somata and more primary dendrites than ventral regions of the PN. These differences, however, do not allow the differentiation of projection neurons within the PN from those in the NRTP. They rather reflect a dorso-ventral gradient ignoring the border between the nuclei. Accordingly, a cluster analysis did not differentiate distinct types of projection neurons within the total sample. In both nuclei, multiple linear regression analysis revealed that the size of dendritic fields was strongly correlated with the length of terminal dendrites while it did not depend on other parameters of the dendritic field. Thus, larger dendritic fields seem not to be accompanied by a higher complexity but rather may be used to extend the reach of a projection neuron within the arrangement of afferent terminals. We suggest that these similarities within dendritic properties in PN and NRTP projection neurons reflect similar processing of afferent information in both precerebellar nuclei.

Differential synaptic plasticity of the corticostriatal and thalamostriatal systems in an MPTP-treated monkey model of parkinsonism.

PubMed

Raju, Dinesh V; Ahern, Todd H; Shah, Deep J; Wright, Terrence M; Standaert, David G; Hall, Randy A; Smith, Yoland

2008-04-01

Two cardinal features of Parkinson's disease (PD) pathophysiology are a loss of glutamatergic synapses paradoxically accompanied by an increased glutamatergic transmission to the striatum. The exact substrate of this increased glutamatergic drive remains unclear. The striatum receives glutamatergic inputs from the thalamus and the cerebral cortex. Using vesicular glutamate transporters (vGluTs) 1 and 2 as markers of the corticostriatal and thalamostriatal afferents, respectively, we examined changes in the synaptology and relative prevalence of striatal glutamatergic inputs in methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys using electron microscopic immunoperoxidase and confocal immunofluorescence methods. Our findings demonstrate that the prevalence of vGluT1-containing terminals is significantly increased in the striatum of MPTP-treated monkeys (51.9 +/- 3.5% to 66.5 +/- 3.4% total glutamatergic boutons), without any significant change in the pattern of synaptic connectivity; more than 95% of vGluT1-immunolabeled terminals formed axo-spinous synapses in both conditions. In contrast, the prevalence of vGluT2-immunoreactive terminals did not change after MPTP treatment (21.7 +/- 1.3% vs. 21.6 +/- 1.2% total glutamatergic boutons). However, a substantial increase in the ratio of axo-spinous to axo-dendritic synapses formed by vGluT2-immunoreactive terminals was found in the pre-caudate and post-putamen striatal regions of MPTP-treated monkeys, suggesting a certain degree of synaptic reorganization of the thalamostriatal system in parkinsonism. About 20% of putative glutamatergic terminals did not show immunoreactivity in striatal tissue immunostained for both vGluT1 and vGluT2, suggesting the expression of another vGluT in these boutons. These findings provide striking evidence that suggests a differential degree of plasticity of the corticostriatal and thalamostriatal system in PD.

Mechanisms of efferent-mediated responses in the turtle posterior crista.

PubMed

Holt, Joseph C; Lysakowski, Anna; Goldberg, Jay M

2006-12-20

To study the cellular mechanisms of efferent actions, we recorded from vestibular-nerve afferents close to the turtle posterior crista while efferent fibers were electrically stimulated. Efferent-mediated responses were obtained from calyx-bearing (CD, calyx and dimorphic) afferents and from bouton (B) afferents distinguished by their neuroepithelial locations into BT units near the torus and BM units at intermediate sites. The spike discharge of CD units is strongly excited by efferent stimulation, whereas BT and BM units are inhibited, with BM units also showing a postinhibitory excitation. Synaptic activity was recorded intracellularly after spikes were blocked. Responses of BT/BM units to single efferent shocks consist of a brief depolarization followed by a prolonged hyperpolarization. Both components reflect variations in hair-cell quantal release rates and are eliminated by pharmacological antagonists of alpha9/alpha10 nicotinic receptors. Blocking calcium-dependent SK potassium channels converts the biphasic response into a prolonged depolarization. Results can be explained, as in other hair-cell systems, by the sequential activation of alpha9/alpha10 and SK channels. In BM units, the postinhibitory excitation is based on an increased rate of hair-cell quanta and depends on the preceding inhibition. There is, in addition, an efferent-mediated, direct depolarization of BT/BM and CD fibers. In CD units, it is the exclusive efferent response. Nicotinic antagonists have different effects on hair-cell efferent actions and on the direct depolarization of CD and BT/BM units. Ultrastructural studies, besides confirming the efferent innervation of type II hair cells and calyx endings, show that turtle efferents commonly contact afferent boutons terminating on type II hair cells.

The new vestibular stimuli: sound and vibration-anatomical, physiological and clinical evidence.

PubMed

Curthoys, Ian S

2017-04-01

The classical view of the otoliths-as flat plates of fairly uniform receptors activated by linear acceleration dragging on otoconia and so deflecting the receptor hair bundles-has been replaced by new anatomical and physiological evidence which shows that the maculae are much more complex. There is anatomical spatial differentiation across the macula in terms of receptor types, hair bundle heights, stiffness and attachment to the overlying otolithic membrane. This anatomical spatial differentiation corresponds to the neural spatial differentiation of response dynamics from the receptors and afferents from different regions of the otolithic maculae. Specifically, receptors in a specialized band of cells, the striola, are predominantly type I receptors, with short, stiff hair bundles and looser attachment to the overlying otoconial membrane than extrastriolar receptors. At the striola the hair bundles project into holes in the otolithic membrane, allowing for fluid displacement to deflect the hair bundles and activate the cell. This review shows the anatomical and physiological evidence supporting the hypothesis that fluid displacement, generated by sound or vibration, deflects the short stiff hair bundles of type I receptors at the striola, resulting in neural activation of the irregular afferents innervating them. So these afferents are activated by sound or vibration and show phase-locking to individual cycles of the sound or vibration stimulus up to frequencies above 2000 Hz, underpinning the use of sound and vibration for clinical tests of vestibular function.

Glucagon-like peptide 1 interacts with ghrelin and leptin to regulate glucose metabolism and food intake through vagal afferent neuron signaling.

PubMed

Ronveaux, Charlotte C; Tomé, Daniel; Raybould, Helen E

2015-04-01

Emerging evidence has suggested a possible physiologic role for peripheral glucagon-like peptide 1 (GLP-1) in regulating glucose metabolism and food intake. The likely site of action of GLP-1 is on vagal afferent neurons (VANs). The vagal afferent pathway is the major neural pathway by which information about ingested nutrients reaches the central nervous system and influences feeding behavior. Peripheral GLP-1 acts on VANs to inhibit food intake. The mechanism of the GLP-1 receptor (GLP-1R) is unlike other gut-derived receptors; GLP-1Rs change their cellular localization according to feeding status rather than their protein concentrations. It is possible that several gut peptides are involved in mediating GLP-1R translocation. The mechanism of peripheral GLP-1R translocation still needs to be elucidated. We review data supporting the role of peripheral GLP-1 acting on VANs in influencing glucose homeostasis and feeding behavior. We highlight evidence demonstrating that GLP-1 interacts with ghrelin and leptin to induce satiation. Our aim was to understand the mechanism of peripheral GLP-1 in the development of noninvasive antiobesity treatments. © 2015 American Society for Nutrition.

Response of soleus Ia afferents to vibration in the presence of the tonic vibration reflex in the decerebrate cat.

PubMed

Clark, F J; Matthews, P B; Muir, R B

1981-02-01

1. Micro-electrode recordings were made from single Ia afferents in the intact nerve to the soleus muscle in the decerebrate cat while the muscle was developing a tonic vibration reflex. This was done in order to test how effectively the afferents were excited by the vibration, and to see if any insecurity in driving might be related to tremor.2. When the amplitude of vibration was 50 mum, and the tonic vibration reflex was reasonably well developed (> 1 N of active tension) all but one of forty-four Ia afferents were driven 1:1 by the vibration. Most were still driven by 30 mum vibration. The vibration, consisting of a train of discrete pulses at 150 Hz, was applied longitudinally in combination with a stretch of 1 mm to make the muscle taut.3. If the reflex was poorly developed (active tension < 1 N) the driving was on average less secure. However, fourteen of eighteen afferents then studied were still driven 1:1 by 50 mum vibration. The lower level of excitation by vibration was thought to be due to a deficiency of spontaneous fusimotor activity, because stroking the cat's tail or other similar gentle manipulation led each of the three misbehaving afferents so tested to be driven securely by 50 mum vibration; at the same time the reflex tension increased.4. Additional, indirect evidence favouring widespread security of Ia driving by 50 mum vibration in the presence of the reflex was obtained by modulating the amplitude of the 150 Hz vibration with a 7-10 Hz square wave and detecting any tension fluctuations at that frequency by spectral analysis. Small degrees of modulation (e.g. < 10%) produced little if any effect, although larger depths of modulation had a powerful action.5. When the amplitude of vibration was reduced to permit insecure driving but still to elicit a reflex response, the fluctuations in Ia firing pattern were unlike those previously seen in the de-efferented muscle. Spectral analysis showed that these firing fluctuations bore a general similarity to the tremor in the same preparation, but measurement of coherence demonstrated that the tremor and Ia firing were not well related. This was probably because individual Ia afferents were primarily influenced by local factors, and provides further evidence against the tremor of this preparation being attributable to the action of the stretch reflex.

Response of soleus Ia afferents to vibration in the presence of the tonic vibration reflex in the decerebrate cat

PubMed Central

Clark, F. J.; Matthews, P. B. C.; Muir, R. B.

1981-01-01

1. Micro-electrode recordings were made from single Ia afferents in the intact nerve to the soleus muscle in the decerebrate cat while the muscle was developing a tonic vibration reflex. This was done in order to test how effectively the afferents were excited by the vibration, and to see if any insecurity in driving might be related to tremor. 2. When the amplitude of vibration was 50 μm, and the tonic vibration reflex was reasonably well developed (> 1 N of active tension) all but one of forty-four Ia afferents were driven 1:1 by the vibration. Most were still driven by 30 μm vibration. The vibration, consisting of a train of discrete pulses at 150 Hz, was applied longitudinally in combination with a stretch of 1 mm to make the muscle taut. 3. If the reflex was poorly developed (active tension < 1 N) the driving was on average less secure. However, fourteen of eighteen afferents then studied were still driven 1:1 by 50 μm vibration. The lower level of excitation by vibration was thought to be due to a deficiency of spontaneous fusimotor activity, because stroking the cat's tail or other similar gentle manipulation led each of the three misbehaving afferents so tested to be driven securely by 50 μm vibration; at the same time the reflex tension increased. 4. Additional, indirect evidence favouring widespread security of Ia driving by 50 μm vibration in the presence of the reflex was obtained by modulating the amplitude of the 150 Hz vibration with a 7-10 Hz square wave and detecting any tension fluctuations at that frequency by spectral analysis. Small degrees of modulation (e.g. < 10%) produced little if any effect, although larger depths of modulation had a powerful action. 5. When the amplitude of vibration was reduced to permit insecure driving but still to elicit a reflex response, the fluctuations in Ia firing pattern were unlike those previously seen in the de-efferented muscle. Spectral analysis showed that these firing fluctuations bore a general similarity to the tremor in the same preparation, but measurement of coherence demonstrated that the tremor and Ia firing were not well related. This was probably because individual Ia afferents were primarily influenced by local factors, and provides further evidence against the tremor of this preparation being attributable to the action of the stretch reflex. PMID:7264987

Spectral integration in primary auditory cortex attributable to temporally precise convergence of thalamocortical and intracortical input.

PubMed

Happel, Max F K; Jeschke, Marcus; Ohl, Frank W

2010-08-18

Primary sensory cortex integrates sensory information from afferent feedforward thalamocortical projection systems and convergent intracortical microcircuits. Both input systems have been demonstrated to provide different aspects of sensory information. Here we have used high-density recordings of laminar current source density (CSD) distributions in primary auditory cortex of Mongolian gerbils in combination with pharmacological silencing of cortical activity and analysis of the residual CSD, to dissociate the feedforward thalamocortical contribution and the intracortical contribution to spectral integration. We found a temporally highly precise integration of both types of inputs when the stimulation frequency was in close spectral neighborhood of the best frequency of the measurement site, in which the overlap between both inputs is maximal. Local intracortical connections provide both directly feedforward excitatory and modulatory input from adjacent cortical sites, which determine how concurrent afferent inputs are integrated. Through separate excitatory horizontal projections, terminating in cortical layers II/III, information about stimulus energy in greater spectral distance is provided even over long cortical distances. These projections effectively broaden spectral tuning width. Based on these data, we suggest a mechanism of spectral integration in primary auditory cortex that is based on temporally precise interactions of afferent thalamocortical inputs and different short- and long-range intracortical networks. The proposed conceptual framework allows integration of different and partly controversial anatomical and physiological models of spectral integration in the literature.

Psychoactive bacteria Lactobacillus rhamnosus (JB-1) elicits rapid frequency facilitation in vagal afferents.

PubMed

Perez-Burgos, Azucena; Wang, Bingxian; Mao, Yu-Kang; Mistry, Bhavik; McVey Neufeld, Karen-Anne; Bienenstock, John; Kunze, Wolfgang

2013-01-15

Mounting evidence supports the influence of the gut microbiome on the local enteric nervous system and its effects on brain chemistry and relevant behavior. Vagal afferents are involved in some of these effects. We previously showed that ingestion of the probiotic bacterium Lactobacillus rhamnosus (JB-1) caused extensive neurochemical changes in the brain and behavior that were abrogated by prior vagotomy. Because information can be transmitted to the brain via primary afferents encoded as neuronal spike trains, our goal was to record those induced by JB-1 in vagal afferents in the mesenteric nerve bundle and thus determine the nature of the signals sent to the brain. Male Swiss Webster mice jejunal segments were cannulated ex vivo, and serosal and luminal compartments were perfused separately. Bacteria were added intraluminally. We found no evidence for translocation of labeled bacteria across the epithelium during the experiment. We recorded extracellular multi- and single-unit neuronal activity with glass suction pipettes. Within minutes of application, JB-1 increased the constitutive single- and multiunit firing rate of the mesenteric nerve bundle, but Lactobacillus salivarius (a negative control) or media alone were ineffective. JB-1 significantly augmented multiunit discharge responses to an intraluminal distension pressure of 31 hPa. Prior subdiaphragmatic vagotomy abolished all of the JB-1-evoked effects. This detailed exploration of the neuronal spike firing that encodes behavioral signaling to the brain may be useful to identify effective psychoactive bacteria and thereby offer an alternative new perspective in the field of psychiatry and comorbid conditions.

[Myofibroblasts and afferent signalling in the urinary bladder. A concept].

PubMed

Neuhaus, J; Scholler, U; Freick, K; Schwalenberg, T; Heinrich, M; Horn, L C; Stolzenburg, J U

2008-09-01

Afferent signal transduction in the urinary bladder is still not clearly understood. An increasing body of evidence supports the view of complex interactions between urothelium, suburothelial myofibroblasts, and sensory nerves. Bladder tissue from tumour patients was used in this study. Methods included confocal immunofluorescence, polymerase chain reaction, calcium imaging, and fluorescence recovery after photobleaching (FRAP).Myofibroblasts express muscarinic and purinergic receptors. They show constitutive spontaneous activity in calcium imaging, which completely depends on extracellular calcium. Stimulation with carbachol and ATP-evoked intracellular calcium transients also depend on extracellular calcium. The intensive coupling between the cells is significantly diminished by incubation with TGF-beta 1. Myofibroblasts form an important cellular element within the afferent signalling of the urinary bladder. They possess all features required to take part in the complex interactions with urothelial cells and sensory nerves. Modulation of their function by cytokines may provide a pathomechanism for bladder dysfunction.

Ultrastructural localization of ChAT-like immunoreactivity in the human vestibular periphery.

PubMed

Kong, W J; Hussl, B; Thumfart, W F; Schrott-Fischer, A

1998-05-01

Acetylcholine (ACh) has long been considered a neurotransmitter candidate in the efferent vestibular system of mammals. Recently, choline acetyltransferase (ChAT), the synthesizing enzyme for ACh, was immunocytochemically localized in all five end-organs of the rat vestibule (Kong et al. (1994) Hear. Res. 75, 192-200). However, there is little information in the literature concerning the cholinergic innervation in the vestibular periphery of man. In the present study the ultrastructural localization of the ChAT-like immunoreactivity in the human vestibular periphery was investigated in order to reveal the cholinergic innervation in the human vestibular end-organs. A modified method of pre-embedding immunoelectron microscopy was applied. It was found that the ChAT-like immunoreactivity was located in the bouton-type vesiculated nerve terminals in the vestibular neurosensory epithelia of man. These ChAT-like immunostained nerve terminals make synaptic contacts either with afferent chalices surrounding type I vestibular sensory hair cells, or with type II vestibular sensory hair cells. These results show that the ChAT-like immunoreactivity in the human vestibular periphery is confined to the efferent vestibular system. The ChAT-containing efferents innervate both type I hair cells and type II hair cells, making postsynaptic and presynaptic contacts, respectively. This study presents evidence that ACh is a neurotransmitter candidate in the efferent vestibular system of man.

Immunomodulation of afferent neurons in guinea-pig isolated airway.

PubMed

Riccio, M M; Myers, A C; Undem, B J

1996-03-01

1. The trachea, larynx and main bronchi with the right vagus nerve and nodose ganglion were isolated from guinea-pigs passively immunized 24 h previously with serum containing anti-ovalbumin antibody. 2. The airways were placed in one compartment of a Perspex chamber for recording of isometric tension while the nodose ganglion and attached vagus nerve were pulled into another compartment. Action potentials arriving from single airway afferent nerve endings were monitored extracellularly using a glass microelectrode positioned near neuronal cell bodies in the ganglion. Mechanosensitivity of the nerve endings was quantified using calibrated von Frey filaments immediately before and after exposure to antigen (10 micrograms ml-1 ovalbumin). 3. Ten endings responded to the force exerted by the lowest filament (0.078 mN) and were not further investigated. In airways from thirteen immunized guinea-pigs, the mechanical sensitivity of A delta afferent fibres (conduction velocity = 4.3 +/- 0.6 m s-1) was enhanced 4.1 +/- 0.9-fold following airway exposure to antigen (P < 0.005). Mechanical sensitivities of afferent fibres (conduction velocity = 4.3 +/- 0.6 m s-1) from non-immunized control guinea-pig airways were unaffected by antigen (n = 13). 4. Antigen did not overtly cause action potential generation except in one instance when the receptive field was located over the smooth muscle. This ending also responded to methacholine suggesting that spatial changes in the receptive field, induced by muscle contraction, were responsible for the activation. 5. The mediators responsible for these effects are unknown, although histamine, prostaglandins, leukotrienes and tachykinins do not appear to be essential. The increase in mechanical responsiveness was not associated with the smooth muscle contraction since leukotriene C4, histamine and tachykinins, which all caused a similar contraction to antigen, did not affect mechanical thresholds. Moreover, the antigen-induced increases in excitability persisted beyond the duration of the smooth muscle contraction. 6. These results demonstrate that antigen-antibody-mediated inflammatory processes may enhance the excitability of vagal afferent nerve terminals projecting from the airway and thus may contribute to the pathophysiology of allergic airway diseases.

Optogenetic versus electrical stimulation of dopamine terminals in the nucleus accumbens reveals local modulation of presynaptic release

PubMed Central

Melchior, James R.; Ferris, Mark J.; Stuber, Garret D.; Riddle, David R.; Jones, Sara R.

2015-01-01

The nucleus accumbens is highly heterogeneous, integrating regionally distinct afferent projections and accumbal interneurons, resulting in diverse local microenvironments. Dopamine (DA) neuron terminals similarly express a heterogeneous collection of terminal receptors that modulate DA signaling. Cyclic voltammetry is often used to probe DA terminal dynamics in brain slice preparations; however, this method traditionally requires electrical stimulation to induce DA release. Electrical stimulation excites all of the neuronal processes in the stimulation field, potentially introducing simultaneous, multi-synaptic modulation of DA terminal release. We used optogenetics to selectively stimulate DA terminals and used voltammetry to compare DA responses from electrical and optical stimulation of the same area of tissue around a recording electrode. We found that with multiple pulse stimulation trains, optically stimulated DA release increasingly exceeded that of electrical stimulation. Furthermore, electrical stimulation produced inhibition of DA release across longer duration stimulations. The GABAB antagonist, CGP 55845, increased electrically stimulated DA release significantly more than light stimulated release. The nicotinic acetylcholine receptor antagonist, dihydro-β-erythroidine hydrobromide, inhibited single pulse electrically stimulated DA release while having no effect on optically stimulated DA release. Our results demonstrate that electrical stimulation introduces local multi-synaptic modulation of DA release that is absent with optogenetically targeted stimulation. PMID:26011081

Locomotor training improves premotoneuronal control after chronic spinal cord injury.

PubMed

Knikou, Maria; Mummidisetty, Chaithanya K

2014-06-01

Spinal inhibition is significantly reduced after spinal cord injury (SCI) in humans. In this work, we examined if locomotor training can improve spinal inhibition exerted at a presynaptic level. Sixteen people with chronic SCI received an average of 45 training sessions, 5 days/wk, 1 h/day. The soleus H-reflex depression in response to low-frequency stimulation, presynaptic inhibition of soleus Ia afferent terminals following stimulation of the common peroneal nerve, and bilateral EMG recovery patterns were assessed before and after locomotor training. The soleus H reflexes evoked at 1.0, 0.33, 0.20, 0.14, and 0.11 Hz were normalized to the H reflex evoked at 0.09 Hz. Conditioned H reflexes were normalized to the associated unconditioned H reflex evoked with subjects seated, while during stepping both H reflexes were normalized to the maximal M wave evoked after the test H reflex at each bin of the step cycle. Locomotor training potentiated homosynaptic depression in all participants regardless the type of the SCI. Presynaptic facilitation of soleus Ia afferents remained unaltered in motor complete SCI patients. In motor incomplete SCIs, locomotor training either reduced presynaptic facilitation or replaced presynaptic facilitation with presynaptic inhibition at rest. During stepping, presynaptic inhibition was modulated in a phase-dependent manner. Locomotor training changed the amplitude of locomotor EMG excitability, promoted intralimb and interlimb coordination, and altered cocontraction between knee and ankle antagonistic muscles differently in the more impaired leg compared with the less impaired leg. The results provide strong evidence that locomotor training improves premotoneuronal control after SCI in humans at rest and during walking. Copyright © 2014 the American Physiological Society.

The RNA binding and transport proteins staufen and fragile X mental retardation protein are expressed by rat primary afferent neurons and localize to peripheral and central axons.

PubMed

Price, T J; Flores, C M; Cervero, F; Hargreaves, K M

2006-09-15

Neuronal proteins have been traditionally viewed as being derived solely from the soma; however, accumulating evidence indicates that dendritic and axonal sites are capable of a more autonomous role in terms of new protein synthesis. Such extra-somal translation allows for more rapid, on-demand regulation of neuronal structure and function than would otherwise be possible. While mechanisms of dendritic RNA transport have been elucidated, it remains unclear how RNA is trafficked into the axon for this purpose. Primary afferent neurons of the dorsal root (DRG) and trigeminal (TG) ganglia have among the longest axons in the neuraxis and such axonal protein synthesis would be advantageous, given the greater time involved for protein trafficking to occur via axonal transport. Therefore, we hypothesized that these primary sensory neurons might express proteins involved in RNA transport. Rat DRG and TG neurons expressed staufen (stau) 1 and 2 (detected at the mRNA level) and stau2 and fragile x mental retardation protein (FMRP; detected at the protein level). Stau2 mRNA was also detected in human TG neurons. Stau2 and FMRP protein were localized to the sciatic nerve and dorsal roots by immunohistochemistry and to dorsal roots by Western blot. Stau2 and FMRP immunoreactivities colocalized with transient receptor potential channel type 1 immunoreactivity in sensory axons of the sciatic nerve and dorsal root, suggesting that these proteins are being transported into the peripheral and central terminals of nociceptive sensory axons. Based on these findings, we propose that stau2 and FMRP proteins are attractive candidates to subserve RNA transport in sensory neurons, linking somal transcriptional events to axonal translation.

THE RNA BINDING AND TRANSPORT PROTEINS STAUFEN AND FRAGILE X MENTAL RETARDATION PROTEIN ARE EXPRESSED BY RAT PRIMARY AFFERENT NEURONS AND LOCALIZE TO PERIPHERAL AND CENTRAL AXONS

PubMed Central

PRICE, T. J.; FLORES, C. M.; CERVERO, F.; HARGREAVES, K. M.

2007-01-01

Neuronal proteins have been traditionally viewed as being derived solely from the soma; however, accumulating evidence indicates that dendritic and axonal sites are capable of a more autonomous role in terms of new protein synthesis. Such extra-somal translation allows for more rapid, on-demand regulation of neuronal structure and function than would otherwise be possible. While mechanisms of dendritic RNA transport have been elucidated, it remains unclear how RNA is trafficked into the axon for this purpose. Primary afferent neurons of the dorsal root (DRG) and trigeminal (TG) ganglia have among the longest axons in the neuraxis and such axonal protein synthesis would be advantageous, given the greater time involved for protein trafficking to occur via axonal transport. Therefore, we hypothesized that these primary sensory neurons might express proteins involved in RNA transport. Rat DRG and TG neurons expressed staufen (stau) 1 and 2 (detected at the mRNA level) and stau2 and fragile × mental retardation protein (FMRP; detected at the protein level). Stau2 mRNA was also detected in human TG neurons. Stau2 and FMRP protein were localized to the sciatic nerve and dorsal roots by immunohistochemistry and to dorsal roots by Western blot. Stau2 and FMRP immunoreactivities colocalized with transient receptor potential channel type 1 immunoreactivity in sensory axons of the sciatic nerve and dorsal root, suggesting that these proteins are being transported into the peripheral and central terminals of nociceptive sensory axons. Based on these findings, we propose that stau2 and FMRP proteins are attractive candidates to subserve RNA transport in sensory neurons, linking somal transcriptional events to axonal translation. PMID:16809002

The concept of peripheral modulation of bladder sensation

PubMed Central

Eastham, Jane E; Gillespie, James I

2013-01-01

It is recognized that, as the bladder fills, there is a corresponding increase in sensation. This awareness of the volume in the bladder is then used in a complex decision making process to determine if there is a need to void. It is also part of everyday experience that, when the bladder is full and sensations strong, these sensations can be suppressed and the desire to void postponed. The obvious explanation for such altered perceptions is that they occur centrally. However, this may not be the only mechanism. There are data to suggest that descending neural influences and local factors might regulate the sensitivity of the systems within the bladder wall generating afferent activity. Specifically, evidence is accumulating to suggest that the motor-sensory system within the bladder wall is influenced in this way. The motor-sensory system, first described over 100 years ago, appears to be a key component in the afferent outflow, the afferent “noise,” generated within the bladder wall. However, the presence and possible importance of this complex system in the generation of bladder sensation has been overlooked in recent years. As the bladder fills the motor activity increases, driven by cholinergic inputs and modulated, possibly, by sympathetic inputs. In this way information on bladder volume can be transmitted to the CNS. It can be argued that the ability to alter the sensitivity of the mechanisms generating the motor component of this motor-sensory system represents a possible indirect way to influence afferent activity and so the perception of bladder volume centrally. Furthermore, it is emerging that the apparent modulation of sensation by drugs to alleviate the symptoms of overactive bladder (OAB), the anti-cholinergics and the new generation of drugs the β3 sympathomimetics, may be the result of their ability to modulate the motor component of the motor sensory system. The possibility of controlling sensation, physiologically and pharmacologically, by influencing afferent firing at its point of origin is a “new” concept in bladder physiology. It is one that deserves careful consideration as it might have wider implications for our understanding of bladder pathology and in the development of new therapeutic drugs. In this overview, evidence for the concept peripheral modulation of bladder afferent outflow is explored. PMID:23917648

Microbiome Heterogeneity Characterizing Intestinal Tissue and Inflammatory Bowel Disease Phenotype.

PubMed

Tyler, Andrea D; Kirsch, Richard; Milgrom, Raquel; Stempak, Joanne M; Kabakchiev, Boyko; Silverberg, Mark S

2016-04-01

Inflammatory bowel disease has been associated with differential abundance of numerous organisms when compared to healthy controls (HCs); however, few studies have investigated variability in the microbiome across intestinal locations and how this variability might be related to disease location and phenotype. In this study, we have analyzed the microbiome of a large cohort of individuals recruited at Mount Sinai Hospital in Toronto, Canada. Biopsies were taken from subjects with Crohn's disease, ulcerative colitis, and HC, and also individuals having undergone ileal pouch-anal anastomosis for treatment of ulcerative colitis or familial adenomatous polyposis. Microbial 16S rRNA was sequenced using the Illumina MiSeq platform. We observed a great deal of variability in the microbiome characterizing different sampling locations. Samples from pouch and afferent limb were comparable in microbial composition. When comparing sigmoid and terminal ileum samples, more differences were observed. The greatest number of differentially abundant microbes was observed when comparing either pouch or afferent limb samples to sigmoid or terminal ileum. Despite these differences, we were able to observe modest microbial variability between inflammatory bowel disease phenotypes and HCs, even when controlling for sampling location and additional experimental factors. Most detected associations were observed between HCs and Crohn's disease, with decreases in specific genera in the families Ruminococcaceae and Lachnospiraceae characterizing tissue samples from individuals with Crohn's disease. This study highlights important considerations when analyzing the composition of the microbiome and also provides useful insight into differences in the microbiome characterizing these seemingly related phenotypes.

Cholinergic Axons in the Rat Ventral Tegmental Area Synapse Preferentially onto Mesoaccumbens Dopamine Neurons

PubMed Central

Omelchenko, Natalia; Sesack, Susan R.

2008-01-01

Cholinergic afferents to the ventral tegmental area (VTA) contribute substantially to the regulation of motivated behaviors and the rewarding properties of nicotine. These actions are believed to involve connections with dopamine (DA) neurons projecting to the nucleus accumbens (NAc). However, this direct synaptic link has never been investigated, nor is it known whether cholinergic inputs innervate other populations of DA and GABA neurons, including those projecting to the prefrontal cortex (PFC). We addressed these questions using electron microscopic analysis of retrograde tract-tracing and immunocytochemistry for the vesicular acetylcholine transporter (VAChT) and for tyrosine hydroxylase (TH) and GABA. In tissue labeled for TH, VAChT+ terminals frequently synapsed onto DA mesoaccumbens neurons but only seldom contacted DA mesoprefrontal cells. In tissue labeled for GABA, one third of VAChT+ terminals innervated GABA-labeled dendrites, including both mesoaccumbens and mesoprefrontal populations. VAChT+ synapses onto DA and mesoaccumbens neurons were more commonly of the asymmetric (presumed excitatory) morphological type, whereas VAChT+ synapses onto GABA cells were more frequently symmetric (presumed inhibitory or modulatory). These findings suggest that cholinergic inputs to the VTA mediate complex synaptic actions, with a major portion of this effect likely to involve an excitatory influence on DA mesoaccumbens neurons. As such, the results suggest that natural and drug rewards operating through cholinergic afferents to the VTA have a direct synaptic link to the mesoaccumbens DA neurons that modulate approach behaviors. PMID:16385486

Afferent fibres from pulmonary arterial baroreceptors in the left cardiac sympathetic nerve of the cat

PubMed Central

Nishi, K.; Sakanashi, M.; Takenaka, F.

1974-01-01

1. Afferent discharges were recorded from the left cardiac sympathetic nerve or the third sympathetic ramus communicans of anaesthetized cats. Twenty-one single units with baroreceptor activity were obtained. 2. The receptors of each unit were localized to the extrapulmonary part of the pulmonary artery, determined by direct mechanical probing of the wall of the pulmonary artery after death of the animals. Conduction velocity of the fibres ranged from 2·5 to 15·7 m/sec. 3. Afferent discharges occurred irregularly under artificial ventilation. The impulse activity was increased when pulmonary arterial pressure was raised by an intravenous infusion of Locke solution, or by occlusion of lung roots, and decreased by bleeding the animal from the femoral artery. 4. Above a threshold pressure, discharges occurred synchronously with the systolic pressure pulse in the pulmonary artery. A progressive further rise in pressure did not produce an increase in the number of impulses per heart beat. Occlusion of lung roots initially elicited a burst of discharges but the number of impulses for each cardiac cycle gradually decreased. 5. The receptors responded to repetitive mechanical stimuli up to a frequency of 10/sec, but failed to respond to stimuli delivered at 20/sec. 6. The results provide further evidence for the presence of afferent fibres in the cardiac sympathetic nerve. These afferent fibres are likely to provide the spinal cord with specific information only on transient changes in pulmonary arterial pressure. PMID:4850456

Selective damage to cochlear efferents by the choline neurotoxin ethylcholine mustard aziridinium ion (AF64A) in the chinchilla.

PubMed

Smith, D W; Mount, R J; Callahan, J W

1989-10-01

The cholinotoxin ethylcholine mustard aziridinium ion (AF64A) was diluted in artificial perilymph to concentrations ranging from 10-100 microM, injected unilaterally into the bulla of chinchillas, and allowed to passively diffuse across the round window membrane. Following 21-day survival, the animals were sacrificed and ears removed and embedded in epoxy for histological evaluation under both light and transmission electron microscopy. At 10 microM concentration, selective degeneration of efferent fibers was observed in the efferent terminals on outer hair cells (OHC), tunnel radial fibers, tunnel spiral bundle, and the inner spiral bundle. Serial sections of the middle turn of an animal at 10 microM concentrations showed normal efferent terminals on approximately 50% of OHCs. At the higher concentrations non-specific damage was seen in OHCs, afferents, and some supporting cells. These data suggest that low doses AF64A produces selective damage to cochlear efferent terminals and fibers in the chinchilla.

Cardiorespiratory activity of C-terminal pentapeptide of substance P in anaesthetized rats.

PubMed

Wojciechowski, Piotr; Szereda-Przestaszewska, Małgorzata; Lipkowski, Andrzej Wojciech

2016-11-01

Experiments were performed in anaesthetized, spontaneously breathing rats to: (1) analyse the respiratory and cardiovascular effects of C-terminal fragment of substance P (AWL2077) as referred to those exerted by the parent undecapeptide, (2) determine the involvement of lung vagal afferents to these responses. Each peptide was injected intravenously at a dose of 0.3μmol/kg into neurally intact or midcervically vagotomized rats. Administration of both compounds decreased tidal volume, minute ventilation, mean arterial blood pressure and heart rate, showing stimulatory (SP) and depressive (AWL2077) effects on the rate of breathing. Midcervical vagotomy reversed (post-SP) and precluded (post-AWL2077) respiratory rate responses and eliminated bradycardia evoked by both peptides. These findings indicate that the examined C-terminal pentapeptide was convergent with, but less potent than substance P in central depression of tidal volume and displayed divergence in the peripheral effect on respiratory timing. Copyright © 2016 Elsevier B.V. All rights reserved.

Vagotomy attenuates brain cytokines and sleep induced by peripherally administered tumor necrosis factor-α and lipopolysaccharide in mice.

PubMed

Zielinski, Mark R; Dunbrasky, Danielle L; Taishi, Ping; Souza, Gianne; Krueger, James M

2013-08-01

Systemic tumor necrosis factor-α (TNF-α) is linked to sleep and sleep altering pathologies in humans. Evidence from animals indicates that systemic and brain TNF-α have a role in regulating sleep. In animals, TNF-α or lipopolysaccharide (LPS) enhance brain pro-inflammatory cytokine expression and sleep after central or peripheral administration. Vagotomy blocks enhanced sleep induced by systemic TNF-α and LPS in rats, suggesting that vagal afferent stimulation by TNF-α enhances pro-inflammatory cytokines in sleep-related brain areas. However, the effects of systemic TNF-α on brain cytokine expression and mouse sleep remain unknown. We investigated the role of vagal afferents on brain cytokines and sleep after systemically applied TNF-α or LPS in mice. Spontaneous sleep was similar in vagotomized and sham-operated controls. Vagotomy attenuated TNF-α- and LPS-enhanced non-rapid eye movement sleep (NREMS); these effects were more evident after lower doses of these substances. Vagotomy did not affect rapid eye movement sleep responses to these substances. NREMS electroencephalogram delta power (0.5-4 Hz range) was suppressed after peripheral TNF-α or LPS injections, although vagotomy did not affect these responses. Compared to sham-operated controls, vagotomy did not affect liver cytokines. However, vagotomy attenuated interleukin-1 beta (IL-1β) and TNF-α mRNA brain levels after TNF-α, but not after LPS, compared to the sham-operated controls. We conclude that vagal afferents mediate peripheral TNF-α-induced brain TNF-α and IL-1β mRNA expressions to affect sleep. We also conclude that vagal afferents alter sleep induced by peripheral pro-inflammatory stimuli in mice similar to those occurring in other species.

Identification of the visceral pain pathway activated by noxious colorectal distension in mice.

PubMed

Kyloh, Melinda; Nicholas, Sarah; Zagorodnyuk, Vladimir P; Brookes, Simon J; Spencer, Nick J

2011-01-01

In patients with irritable bowel syndrome, visceral pain is evoked more readily following distension of the colorectum. However, the identity of extrinsic afferent nerve pathway that detects and transmits visceral pain from the colorectum to the spinal cord is unclear. In this study, we identified which extrinsic nerve pathway(s) underlies nociception from the colorectum to the spinal cord of rodents. Electromyogram recordings were made from the transverse oblique abdominal muscles in anesthetized wild type (C57BL/6) mice and acute noxious intraluminal distension stimuli (100-120 mmHg) were applied to the terminal 15 mm of colorectum to activate visceromotor responses (VMRs). Lesioning the lumbar colonic nerves in vivo had no detectable effect on the VMRs evoked by colorectal distension. Also, lesions applied to the right or left hypogastric nerves failed to reduce VMRs. However, lesions applied to both left and right branches of the rectal nerves abolished VMRs, regardless of whether the lumbar colonic or hypogastric nerves were severed. Electrical stimulation applied to either the lumbar colonic or hypogastric nerves in vivo, failed to elicit a VMR. In contrast, electrical stimulation (2-5 Hz, 0.4 ms, 60 V) applied to the rectum reliably elicited VMRs, which were abolished by selective lesioning of the rectal nerves. DiI retrograde labeling from the colorectum (injection sites 9-15 mm from the anus, measured in unstretched preparations) labeled sensory neurons primarily in dorsal root ganglia (DRG) of the lumbosacral region of the spinal cord (L6-S1). In contrast, injection of DiI into the mid to proximal colon (injection sites 30-75 mm from the anus, measured in unstretched preparations) labeled sensory neurons in DRG primarily of the lower thoracic level (T6-L2) of the spinal cord. The visceral pain pathway activated by acute noxious distension of the terminal 15 mm of mouse colorectum is transmitted predominantly, if not solely, through rectal/pelvic afferent nerve fibers to the spinal cord. The sensory neurons of this spinal afferent pathway lie primarily in the lumbosacral region of the spinal cord, between L6 and S1.

Method of euthanasia affects amygdala plasticity in horizontal brain slices from mice.

PubMed

Kulisch, C; Eckers, N; Albrecht, D

2011-10-15

An important consideration in any terminal experiment is the method used for euthanizing animals. Although the prime consideration is that the method is humane, some methods can have a dramatic impact on experimental outcomes. The standard inhalant anesthetic for experiments in brain slices is isoflurane, which replaced the flammable ethers used in the pioneer days of surgery. To our knowledge, there are no data available evaluating the effects of the method of euthanasia on plasticity changes in brain slices. Here, we compare the magnitude of long-term potentiation (LTP) and long-term depression (LTD) in the lateral nucleus of the amygdala (LA) after euthanasia following either ether or isoflurane anesthesia, as well as in mice decapitated without anesthesia. We found no differences in input-output curves using different methods of euthanasia. The LTP magnitude did not differ between ether and normal isoflurane anesthesia. After deep isoflurane anesthesia LTP induced by high frequency stimulation of cortical or intranuclear afferents was significantly reduced compared to ether anesthesia. In contrast to ether anesthesia and decapitation without anesthesia, the low frequency stimulation of cortical afferents induced a reliable LA-LTD after deep isoflurane anesthesia. Low frequency stimulation of intranuclear afferents only caused LTD after pretreatment with ether anesthesia. The results demonstrate that the method of euthanasia can influence brain plasticity for hours at least in the interface chamber. Therefore, the method of euthanasia is an important consideration when brain plasticity will be evaluated. Copyright © 2011 Elsevier B.V. All rights reserved.

Microneurography as a tool in clinical neurophysiology to investigate peripheral neural traffic in humans.

PubMed

Mano, Tadaaki; Iwase, Satoshi; Toma, Shinobu

2006-11-01

Microneurography is a method using metal microelectrodes to investigate directly identified neural traffic in myelinated as well as unmyelinated efferent and afferent nerves leading to and coming from muscle and skin in human peripheral nerves in situ. The present paper reviews how this technique has been used in clinical neurophysiology to elucidate the neural mechanisms of autonomic regulation, motor control and sensory functions in humans under physiological and pathological conditions. Microneurography is particularly important to investigate efferent and afferent neural traffic in unmyelinated C fibers. The recording of efferent discharges in postganglionic sympathetic C efferent fibers innervating muscle and skin (muscle sympathetic nerve activity; MSNA and skin sympathetic nerve activity; SSNA) provides direct information about neural control of autonomic effector organs including blood vessels and sweat glands. Sympathetic microneurography has become a potent tool to reveal neural functions and dysfunctions concerning blood pressure control and thermoregulation. This recording has been used not only in wake conditions but also in sleep to investigate changes in sympathetic neural traffic during sleep and sleep-related events such as sleep apnea. The same recording was also successfully carried out by astronauts during spaceflight. Recordings of afferent discharges from muscle mechanoreceptors have been used to understand the mechanisms of motor control. Muscle spindle afferent information is particularly important for the control of fine precise movements. It may also play important roles to predict behavior outcomes during learning of a motor task. Recordings of discharges in myelinated afferent fibers from skin mechanoreceptors have provided not only objective information about mechanoreceptive cutaneous sensation but also the roles of these signals in fine motor control. Unmyelinated mechanoreceptive afferent discharges from hairy skin seem to be important to convey cutaneous sensation to the central structures related to emotion. Recordings of afferent discharges in thin myelinated and unmyelinated fibers from nociceptors in muscle and skin have been used to provide information concerning pain. Recordings of afferent discharges of different types of cutaneous C-nociceptors identified by marking method have become an important tool to reveal the neural mechanisms of cutaneous sensations such as an itch. No direct microneurographic evidence has been so far proved regarding the effects of sympathoexcitation on sensitization of muscle and skin sensory receptors at least in healthy humans.

Differential localization of vesicular glutamate transporters and peptides in corneal afferents to trigeminal nucleus caudalis.

PubMed

Hegarty, Deborah M; Tonsfeldt, Karen; Hermes, Sam M; Helfand, Helen; Aicher, Sue A

2010-09-01

Trigeminal afferents convey nociceptive information from the corneal surface of the eye to the trigeminal subnucleus caudalis (Vc). Trigeminal afferents, like other nociceptors, are thought to use glutamate and neuropeptides as neurotransmitters. The current studies examined whether corneal afferents contain both neuropeptides and vesicular glutamate transporters. Corneal afferents to the Vc were identified by using cholera toxin B (CTb). Corneal afferents project in two clusters to the rostral and caudal borders of the Vc, regions that contain functionally distinct nociceptive neurons. Thus, corneal afferents projecting to these two regions were examined separately. Dual immunocytochemical studies combined CTb with either calcitonin gene-related peptide (CGRP), substance P (SP), vesicular glutamate transporter 1 (VGluT1), or VGluT2. Corneal afferents were more likely to contain CGRP than SP, and corneal afferents projecting to the rostral region were more likely to contain CGRP than afferents projecting caudally. Overall, corneal afferents were equally likely to contain VGluT1 or VGluT2. Together, 61% of corneal afferents contained either VGluT1 or VGluT2, suggesting that some afferents lack a VGluT. Caudal corneal afferents were more likely to contain VGluT2 than VGluT1, whereas rostral corneal afferents were more likely to contain VGluT1 than VGluT2. Triple-labeling studies combining CTb, CGRP, and VGluT2 showed that very few corneal afferents contain both CGRP and VGluT2, caudally (1%) and rostrally (2%). These results suggest that most corneal afferents contain a peptide or a VGluT, but rarely both. Our results are consistent with a growing literature suggesting that glutamatergic and peptidergic sensory afferents may be distinct populations.

Different role of TTX-sensitive voltage-gated sodium channel (NaV 1) subtypes in action potential initiation and conduction in vagal airway nociceptors.

PubMed

Kollarik, M; Sun, H; Herbstsomer, R A; Ru, F; Kocmalova, M; Meeker, S N; Undem, B J

2018-04-15

The action potential initiation in the nerve terminals and its subsequent conduction along the axons of afferent nerves are not necessarily dependent on the same voltage-gated sodium channel (Na V 1) subunits. The action potential initiation in jugular C-fibres within airway tissues is not blocked by TTX; nonetheless, conduction of action potentials along the vagal axons of these nerves is often dependent on TTX-sensitive channels. This is not the case for nodose airway Aδ-fibres and C-fibres, where both action potential initiation and conduction is abolished by TTX or selective Na V 1.7 blockers. The difference between the initiation of action potentials within the airways vs. conduction along the axons should be considered when developing Na V 1 blocking drugs for topical application to the respiratory tract. The action potential (AP) initiation in the nerve terminals and its subsequent AP conduction along the axons do not necessarily depend on the same subtypes of voltage-gated sodium channels (Na V 1s). We evaluated the role of TTX-sensitive and TTX-resistant Na V 1s in vagal afferent nociceptor nerves derived from jugular and nodose ganglia innervating the respiratory system. Single cell RT-PCR was performed on vagal afferent neurons retrogradely labelled from the guinea pig trachea. Almost all of the jugular neurons expressed the TTX-sensitive channel Na V 1.7 along with TTX-resistant Na V 1.8 and Na V 1.9. Tracheal nodose neurons also expressed Na V 1.7 but, less frequently, Na V 1.8 and Na V 1.9. Na V 1.6 were expressed in ∼40% of the jugular and 25% of nodose tracheal neurons. Other Na V 1 α subunits were only rarely expressed. Single fibre recordings were made from the vagal nodose and jugular nerve fibres innervating the trachea or lung in the isolated perfused vagally-innervated preparations that allowed for selective drug delivery to the nerve terminal compartment (AP initiation) or to the desheathed vagus nerve (AP conduction). AP initiation in jugular C-fibres was unaffected by TTX, although it was inhibited by Na V 1.8 blocker (PF-01247324) and abolished by combination of TTX and PF-01247324. However, AP conduction in the majority of jugular C-fibres was abolished by TTX. By contrast, both AP initiation and conduction in nodose nociceptors was abolished by TTX or selective Na V 1.7 blockers. Distinction between the effect of a drug with respect to inhibiting AP in the nerve terminals within the airways vs. at conduction sites along the vagus nerve is relevant to therapeutic strategies involving inhaled Na V 1 blocking drugs. © 2018 The Authors. The Journal of Physiology © 2018 The Physiological Society.

Anatomic evidence for peripheral neural processing in mammalian graviceptors

NASA Technical Reports Server (NTRS)

Ross, M. D.

1985-01-01

Ultrastructural study of utricular and saccular maculas demonstrates that their innervation patterns are complex. There is a clustering of type I and type II hair cells based upon a sharing of afferents, a system of efferent-type beaded fibers that is of intramacular (mostly calyceal) origin, and a plexus-like arrangement of afferents and efferents at many sites in the neuroepithelium. Results suggest that information concerning linear acceleration is processed peripherally, beginning at the hair cell level, before being sent to the central nervous system. The findings may supply a structural basis for peripheral adaptation to a constant stimulus, and for lateral inhibition to improve signal relative to noise.

Complement reduction impairs the febrile response of guinea pigs to endotoxin.

PubMed

Sehic, E; Li, S; Ungar, A L; Blatteis, C M

1998-06-01

Although it is generally believed that circulating exogenous pyrogens [e.g., lipopolysaccharides (LPS)] induce fever via the mediation of endogenous pyrogens (EP) such as cytokines, the first of these, tumor necrosis factor-alpha, is usually not detectable in blood until at least 30 min after intravenous administration of LPS, whereas the febrile rise begins within 15 min after its administration. Moreover, although abundant evidence indicates that circulating LPS is cleared primarily by liver macrophages [Kupffer cells (KC)], these do not secrete EP in immediate response. This would imply that other factors, presumably evoked earlier than EP, may mediate the onset of the febrile response to intravenous LPS. It is well known that blood-borne LPS very rapidly activates the intravascular complement (C) system, some components of which in turn stimulate the quick release into blood of various substances that have roles in the acute inflammatory reaction. KC contain receptors for C components and are in close contact with afferent vagal terminals in the liver; the involvement of hepatic vagal afferents in LPS-induced fever has recently been shown. In this study, we tested the hypothesis that the initiation of fever by intravenous LPS involves, sequentially, the C system and KC. To test this postulated mechanism, we measured directly the levels of prostaglandin E2 (PGE2) in the interstitial fluid of the preoptic anterior hypothalamus (POA), the presumptive site of the fever-producing controller, of conscious guinea pigs over their entire febrile course, before and after C depletion by cobra venom factor (CVF) and before and after elimination of KC by gadolinium chloride (GdCl3). CVF and GdCl3 pretreatment each individually attenuated the first of the biphasic core temperature (Tc) rises after intravenous LPS, inverted the second into a Tc fall, and greatly reduced the usual fever-associated increase in POA PGE2. We conclude, therefore, that C activation may indeed be pivotal in the induction of fever by intravenous LPS and that substance(s) generated presumably by KC in almost immediate reaction to the presence of LPS and/or C may transmit pyrogenic signals via hepatic vagal afferents to the POA, where they rapidly induce the production of PGE2 and, hence, fever.

Glutamate synaptic inputs to ventral tegmental area neurons in the rat derive primarily from subcortical sources.

PubMed

Omelchenko, N; Sesack, S R

2007-05-25

Dopamine and GABA neurons in the ventral tegmental area project to the nucleus accumbens and prefrontal cortex and modulate locomotor and reward behaviors as well as cognitive and affective processes. Both midbrain cell types receive synapses from glutamate afferents that provide an essential control of behaviorally-linked activity patterns, although the sources of glutamate inputs have not yet been completely characterized. We used antibodies against the vesicular glutamate transporter subtypes 1 and 2 (VGlut1 and VGlut2) to investigate the morphology and synaptic organization of axons containing these proteins as putative markers of glutamate afferents from cortical versus subcortical sites, respectively, in rats. We also characterized the ventral tegmental area cell populations receiving VGlut1+ or VGlut2+ synapses according to their transmitter phenotype (dopamine or GABA) and major projection target (nucleus accumbens or prefrontal cortex). By light and electron microscopic examination, VGlut2+ as opposed to VGlut1+ axon terminals were more numerous, had a larger average size, synapsed more proximally, and were more likely to form convergent synapses onto the same target. Both axon types formed predominantly asymmetric synapses, although VGlut2+ terminals more often formed synapses with symmetric morphology. No absolute selectivity was observed for VGlut1+ or VGlut2+ axons to target any particular cell population. However, the synapses onto mesoaccumbens neurons more often involved VGlut2+ terminals, whereas mesoprefrontal neurons received relatively equal synaptic inputs from VGlut1+ and VGlut2+ profiles. The distinct morphological features of VGlut1 and VGlut2 positive axons suggest that glutamate inputs from presumed cortical and subcortical sources, respectively, differ in the nature and intensity of their physiological actions on midbrain neurons. More specifically, our findings imply that subcortical glutamate inputs to the ventral tegmental area expressing VGlut2 predominate over cortical sources of excitation expressing VGlut1 and are more likely to drive the behaviorally-linked bursts in dopamine cells that signal future expectancy or attentional shifting.

Spinal N-methyl-D-aspartate receptors and nociception-evoked release of primary afferent substance P.

PubMed

Nazarian, A; Gu, G; Gracias, N G; Wilkinson, K; Hua, X Y; Vasko, M R; Yaksh, T L

2008-03-03

Dorsal horn N-methyl-D-aspartate (NMDA) receptors contribute significantly to spinal nociceptive processing through an effect postsynaptic to non-primary glutamatergic axons, and perhaps presynaptic to the primary afferent terminals. The present study sought to examine the regulatory effects of NMDA receptors on primary afferent release of substance P (SP), as measured by neurokinin 1 receptor (NK1r) internalization in the spinal dorsal horn of rats. The effects of intrathecal NMDA alone or in combination with D-serine (a glycine site agonist) were initially examined on basal levels of NK1r internalization. NMDA alone or when co-administered with D-serine failed to induce NK1r internalization, whereas activation of spinal TRPV1 receptors by capsaicin resulted in a notable NK1r internalization. To determine whether NMDA receptor activation could potentiate NK1r internalization or pain behavior induced by a peripheral noxious stimulus, intrathecal NMDA was given prior to an intraplantar injection of formalin. NMDA did not alter the formalin-induced NK1r internalization nor did it enhance the formalin paw flinching behavior. To further characterize the effects of presynaptic NMDA receptors, the NMDA antagonists DL-2-amino-5-phosphonopentanoic acid (AP-5) and MK-801 were intrathecally administered to assess their regulatory effects on formalin-induced NK1r internalization and pain behavior. AP-5 had no effect on formalin-induced NK1r internalization, whereas MK-801 produced only a modest reduction. Both antagonists, however, reduced the formalin paw flinching behavior. In subsequent in vitro experiments, perfusion of NMDA in spinal cord slice preparations did not evoke basal release of SP or calcitonin gene-related peptide (CGRP). Likewise, perfusion of NMDA did not enhance capsaicin-evoked release of the two peptides. These results suggest that presynaptic NMDA receptors in the spinal cord play little if any role on the primary afferent release of SP.

Urothelial Tight Junction Barrier Dysfunction Sensitizes Bladder Afferents

PubMed Central

Rued, Anna C.; Taiclet, Stefanie N.; Birder, Lori A.; Kullmann, F. Aura

2017-01-01

Abstract Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic voiding disorder that presents with pain in the urinary bladder and surrounding pelvic region. A growing body of evidence suggests that an increase in the permeability of the urothelium, the epithelial barrier that lines the interior of the bladder, contributes to the symptoms of IC/BPS. To examine the consequence of increased urothelial permeability on pelvic pain and afferent excitability, we overexpressed in the urothelium claudin 2 (Cldn2), a tight junction (TJ)-associated protein whose message is significantly upregulated in biopsies of IC/BPS patients. Consistent with the presence of bladder-derived pain, rats overexpressing Cldn2 showed hypersensitivity to von Frey filaments applied to the pelvic region. Overexpression of Cldn2 increased the expression of c-Fos and promoted the activation of ERK1/2 in spinal cord segments receiving bladder input, which we conceive is the result of noxious stimulation of afferent pathways. To determine whether the mechanical allodynia observed in rats with reduced urothelial barrier function results from altered afferent activity, we examined the firing of acutely isolated bladder sensory neurons. In patch-clamp recordings, about 30% of the bladder sensory neurons from rats transduced with Cldn2, but not controls transduced with GFP, displayed spontaneous activity. Furthermore, bladder sensory neurons with tetrodotoxin-sensitive (TTX-S) action potentials from rats transduced with Cldn2 showed hyperexcitability in response to suprathreshold electrical stimulation. These findings suggest that as a result of a leaky urothelium, the diffusion of urinary solutes through the urothelial barrier sensitizes bladders afferents, promoting voiding at low filling volumes and pain. PMID:28560313

Amino terminus of substance P potentiates kainic acid-induced activity in the mouse spinal cord.

PubMed

Larson, A A; Sun, X

1992-12-01

Sensitization to the behavioral effects produced by repeated injections of kainic acid (KA) into the mouse spinal cord area has been previously shown to be abolished by pretreatment with capsaicin, a neurotoxin of substance P (SP)-containing primary afferent C-fibers. While SP has a variety of well characterized biological actions that are mediated by interactions of its COOH terminus with neurokinin receptors, more recently we have characterized an amino-terminally directed SP binding site. The present studies were initiated to determine whether behavioral sensitization to repeated injections of intrathecally administered KA is mediated by the COOH or NH2 terminal of SP. In the present studies, pretreatment with SP(1-7), an NH2-terminal fragment of SP, but not SP(5-11), a COOH-terminal fragment, potentiated KA-induced behavioral activity in mice. Pretreatment with [D-Pro2,D-Phe7]SP(1-7), an inhibitor of SP NH2-terminal binding, blocked the potentiative effect of SP(1-7) as well as the sensitization to repeated injections of KA. In contrast, [D-Pro2,D-Trp7,9]SP, a neurokinin antagonist, had little effect on behavioral sensitization to KA. The present study suggests that SP has an important modulatory role on excitatory amino acid activity in the spinal cord that is mediated by an action of the NH2 terminal of SP at a non-neurokinin receptor.

A comparative analysis of the encapsulated end-organs of mammalian skeletal muscles and of their sensory nerve endings.

PubMed

Banks, R W; Hulliger, M; Saed, H H; Stacey, M J

2009-06-01

The encapsulated sensory endings of mammalian skeletal muscles are all mechanoreceptors. At the most basic functional level they serve as length sensors (muscle spindle primary and secondary endings), tension sensors (tendon organs), and pressure or vibration sensors (lamellated corpuscles). At a higher functional level, the differing roles of individual muscles in, for example, postural adjustment and locomotion might be expected to be reflected in characteristic complements of the various end-organs, their sensory endings and afferent nerve fibres. This has previously been demonstrated with regard to the number of muscle-spindle capsules; however, information on the other types of end-organ, as well as the complements of primary and secondary endings of the spindles themselves, is sporadic and inconclusive regarding their comparative provision in different muscles. Our general conclusion that muscle-specific variability in the provision of encapsulated sensory endings does exist demonstrates the necessity for the acquisition of more data of this type if we are to understand the underlying adaptive relationships between motor control and the structure and function of skeletal muscle. The present quantitative and comparative analysis of encapsulated muscle afferents is based on teased, silver-impregnated preparations. We begin with a statistical analysis of the number and distribution of muscle-spindle afferents in hind-limb muscles of the cat, particularly tenuissimus. We show that: (i) taking account of the necessity for at least one primary ending to be present, muscles differ significantly in the mean number of additional afferents per spindle capsule; (ii) the frequency of occurrence of spindles with different sensory complements is consistent with a stochastic, rather than deterministic, developmental process; and (iii) notwithstanding the previous finding, there is a differential distribution of spindles intramuscularly such that the more complex ones tend to be located closer to the main divisions of the nerve. Next, based on a sample of tendon organs from several hind-foot muscles of the cat, we demonstrate the existence in at least a large proportion of tendon organs of a structural substrate to account for multiple spike-initiation sites and pacemaker switching, namely the distribution of sensory terminals supplied by the different first-order branches of the Ib afferent to separate, parallel, tendinous compartments of individual tendon organs. We then show that the numbers of spindles, tendon organs and paciniform corpuscles vary independently in a sample of (mainly) hind-foot muscles of the cat. Grouping muscles by anatomical region in the cat indicated the existence of a gradual proximo-distal decline in the overall average size of the afferent complement of muscle spindles from axial through hind limb to intrinsic foot muscles, but with considerable muscle-specific variability. Finally, we present some comparative data on muscle-spindle afferent complements of rat, rabbit and guinea pig, one particularly notable feature being the high incidence of multiple primary endings in the rat.

Interganglionic segregation of distinct vagal afferent fibre phenotypes in guinea-pig airways.

PubMed Central

Ricco, M M; Kummer, W; Biglari, B; Myers, A C; Undem, B J

1996-01-01

1. The present study addressed the hypothesis that jugular and nodose vagal ganglia contain the somata of functionally and anatomically distinct airway afferent fibres. 2. Anatomical investigations were performed by injecting guinea-pig airways with the neuronal tracer Fast Blue. The animals were killed 7 days later, and the ganglia were removed and immunostained with antisera against substance P (SP) and neurofilament protein (NF). In the nodose ganglion, NF-immunoreactive neurones accounted for about 98% of the Fast Blue-labelled cells while in the jugular ganglion they accounted for approximately 48%. SP and NF immunoreactivity was never (n = 100) observed in the same cell suggesting that the antisera labelled distinct populations. 3. Electrophysiological investigations were performed using an in vitro guinea-pig tracheal and bronchial preparation with intact afferent vagal pathways, including nodose and jugular ganglia. Action potentials arriving from single airway afferent nerve endings were monitored extracellularly using a glass microelectrode positioned near neuronal cell bodies in either ganglion. 4. The nodose ganglion contained the somata of mainly fast-conducting tracheal A delta fibres whereas the jugular ganglion contained equal numbers of C fibre and A delta fibre tracheal afferent somata. The nodose A delta neurones adapted rapidly to mechanical stimulation, had relatively low mechanical thresholds, were not activated by capsaicin and adapted rapidly to a hyperosmotic stimulus. By contrast, jugular A delta and C fibres adapted slowly to mechanical stimulation, were often activated by capsaicin, had higher mechanical thresholds and displayed a slow adaptation to a hyperosmotic stimulus. 5. The anatomical, physiological and pharmacological data provide evidence to support the contention that the vagal ganglionic source of the fibre supplying the airways ultimately dictates its neurochemical and physiological phenotype. Images Figure 1 PMID:8910234

Saccule contribution to immediate early gene induction in the gerbil brainstem with posterior canal galvanic or hypergravity stimulation

NASA Technical Reports Server (NTRS)

Marshburn, T. H.; Kaufman, G. D.; Purcell, I. M.; Perachio, A. A.

1997-01-01

Immunolabeling patterns of the immediate early gene-related protein Fos in the gerbil brainstem were studied following stimulation of the sacculus by both hypergravity and galvanic stimulation. Head-restrained, alert animals were exposed to a prolonged (1 h) inertial vector of 2 G (19.6 m/s2) head acceleration directed in a dorso-ventral head axis to maximally stimulate the sacculus. Fos-defined immunoreactivity was quantified, and the results compared to a control group. The hypergravity stimulus produced Fos immunolabeling in the dorsomedial cell column (dmcc) of the inferior olive independently of other subnuclei. Similar dmcc labeling was induced by a 30 min galvanic stimulus of up to -100 microA applied through a stimulating electrode placed unilaterally on the bony labyrinth overlying the posterior canal (PC). The pattern of vestibular afferent firing activity induced by this galvanic stimulus was quantified in anesthetized gerbils by simultaneously recording from Scarpa's ganglion. Only saccular and PC afferent neurons exhibited increases in average firing rates of 200-300%, suggesting a pattern of current spread involving only PC and saccular afferent neurons at this level of stimulation. These results suggest that alteration in saccular afferent firing rates are sufficient to induce Fos-defined genomic activation of the dmcc, and lend further evidence to the existence of a functional vestibulo-olivary-cerebellar pathway of adaptation to novel gravito-inertial environments.

The renal nerves in chronic heart failure: efferent and afferent mechanisms

PubMed Central

Schiller, Alicia M.; Pellegrino, Peter R.; Zucker, Irving H.

2015-01-01

The function of the renal nerves has been an area of scientific and medical interest for many years. The recent advent of a minimally invasive catheter-based method of renal denervation has renewed excitement in understanding the afferent and efferent actions of the renal nerves in multiple diseases. While hypertension has been the focus of much this work, less attention has been given to the role of the renal nerves in the development of chronic heart failure (CHF). Recent studies from our laboratory and those of others implicate an essential role for the renal nerves in the development and progression of CHF. Using a rabbit tachycardia model of CHF and surgical unilateral renal denervation, we provide evidence for both renal efferent and afferent mechanisms in the pathogenesis of CHF. Renal denervation prevented the decrease in renal blood flow observed in CHF while also preventing increases in Angiotensin-II receptor protein in the microvasculature of the renal cortex. Renal denervation in CHF also reduced physiological markers of autonomic dysfunction including an improvement in arterial baroreflex function, heart rate variability, and decreased resting cardiac sympathetic tone. Taken together, the renal sympathetic nerves are necessary in the pathogenesis of CHF via both efferent and afferent mechanisms. Additional investigation is warranted to fully understand the role of these nerves and their role as a therapeutic target in CHF. PMID:26300788

Sensing of blood pressure increase by transient receptor potential vanilloid 1 receptors on baroreceptors.

PubMed

Sun, Hao; Li, De-Pei; Chen, Shao-Rui; Hittelman, Walter N; Pan, Hui-Lin

2009-12-01

The arterial baroreceptor is critically involved in the autonomic regulation of homoeostasis. The transient receptor potential vanilloid 1 (TRPV1) receptor is expressed on both somatic and visceral sensory neurons. Here, we examined the TRPV1 innervation of baroreceptive pathways and its functional significance in the baroreflex. Resiniferatoxin (RTX), an ultrapotent analog of capsaicin, was used to ablate TRPV1-expressing afferent neurons and fibers in adult rats. Immunofluorescence labeling revealed that TRPV1 immunoreactivity was present on nerve fibers and terminals in the adventitia of the ascending aorta and aortic arch, the nodose ganglion neurons, and afferent fibers in the solitary tract of the brainstem. RTX treatment eliminated TRPV1 immunoreactivities in the aorta, nodose ganglion, and solitary tract. Renal sympathetic nerve activity, blood pressure, and heart rate were recorded in anesthetized rats. The baroreflex was triggered by lowering and raising blood pressure through intravenous infusion of sodium nitroprusside and phenylephrine, respectively. Inhibition of sympathetic nerve activity and heart rate by the phenylephrine-induced increase in blood pressure was largely impaired in RTX-treated rats. The maximum gain of the baroreflex function was significantly lower in RTX-treated than vehicle-treated rats. Furthermore, blocking of TRPV1 receptors significantly blunted the baroreflex and decreased the maximum gain of baroreflex function in the high blood pressure range. Our findings provide important new information that TRPV1 is expressed along the entire baroreceptive afferent pathway. TRPV1 receptors expressed on baroreceptive nerve endings can function as mechanoreceptors to detect the increase in blood pressure and maintain the homoeostasis.

Sensing of Blood Pressure Increase by Transient Receptor Potential Vanilloid 1 Receptors on Baroreceptors

PubMed Central

Sun, Hao; Li, De-Pei; Chen, Shao-Rui; Hittelman, Walter N.

2009-01-01

The arterial baroreceptor is critically involved in the autonomic regulation of homoeostasis. The transient receptor potential vanilloid 1 (TRPV1) receptor is expressed on both somatic and visceral sensory neurons. Here, we examined the TRPV1 innervation of baroreceptive pathways and its functional significance in the baroreflex. Resiniferatoxin (RTX), an ultrapotent analog of capsaicin, was used to ablate TRPV1-expressing afferent neurons and fibers in adult rats. Immunofluorescence labeling revealed that TRPV1 immunoreactivity was present on nerve fibers and terminals in the adventitia of the ascending aorta and aortic arch, the nodose ganglion neurons, and afferent fibers in the solitary tract of the brainstem. RTX treatment eliminated TRPV1 immunoreactivities in the aorta, nodose ganglion, and solitary tract. Renal sympathetic nerve activity, blood pressure, and heart rate were recorded in anesthetized rats. The baroreflex was triggered by lowering and raising blood pressure through intravenous infusion of sodium nitroprusside and phenylephrine, respectively. Inhibition of sympathetic nerve activity and heart rate by the phenylephrine-induced increase in blood pressure was largely impaired in RTX-treated rats. The maximum gain of the baroreflex function was significantly lower in RTX-treated than vehicle-treated rats. Furthermore, blocking of TRPV1 receptors significantly blunted the baroreflex and decreased the maximum gain of baroreflex function in the high blood pressure range. Our findings provide important new information that TRPV1 is expressed along the entire baroreceptive afferent pathway. TRPV1 receptors expressed on baroreceptive nerve endings can function as mechanoreceptors to detect the increase in blood pressure and maintain the homoeostasis. PMID:19726694

Hypergravity exposure decreases gamma-aminobutyric acid immunoreactivity in axon terminals contacting pyramidal cells in the rat somatosensory cortex: a quantitative immunocytochemical image analysis

NASA Technical Reports Server (NTRS)

D'Amelio, F.; Wu, L. C.; Fox, R. A.; Daunton, N. G.; Corcoran, M. L.; Polyakov, I.

1998-01-01

Quantitative evaluation of gamma-aminobutyric acid immunoreactivity (GABA-IR) in the hindlimb representation of the rat somatosensory cortex after 14 days of exposure to hypergravity (hyper-G) was conducted by using computer-assisted image processing. The area of GABA-IR axosomatic terminals apposed to pyramidal cells of cortical layer V was reduced in rats exposed to hyper-G compared with control rats, which were exposed either to rotation alone or to vivarium conditions. Based on previous immunocytochemical and behavioral studies, we suggest that this reduction is due to changes in sensory feedback information from muscle receptors. Consequently, priorities for muscle recruitment are altered at the cortical level, and a new pattern of muscle activity is thus generated. It is proposed that the reduction observed in GABA-IR of the terminal area around pyramidal neurons is the immunocytochemical expression of changes in the activity of GABAergic cells that participate in reprogramming motor outputs to achieve effective movement control in response to alterations in the afferent information.

Dynamic neuroanatomy at subcellular resolution in the zebrafish.

PubMed

Faucherre, Adèle; López-Schier, Hernán

2014-01-01

Genetic means to visualize and manipulate neuronal circuits in the intact animal have revolutionized neurobiology. "Dynamic neuroanatomy" defines a range of approaches aimed at quantifying the architecture or subcellular organization of neurons over time during their development, regeneration, or degeneration. A general feature of these approaches is their reliance on the optical isolation of defined neurons in toto by genetically expressing markers in one or few cells. Here we use the afferent neurons of the lateral line as an example to describe a simple method for the dynamic neuroanatomical study of axon terminals in the zebrafish by laser-scanning confocal microscopy.

The nucleus of the optic tract (NOT) and the dorsal terminal nucleus (DTN) of opossums (Didelphis marsupialis aurita).

PubMed

Vargas, C D; Volchan, E; Nasi, J P; Bernardes, R F; Rocha-Miranda, C E

1996-01-01

Wheat germ agglutinin conjugated to horseradish peroxidase (WGA-HRP) was injected unilaterally into the pretectocollicular region of opossums (Didelphis marsupialis aurita), primarily to investigate the existence of a commissural subcortical pathway but also to reveal afferents and efferents of the nucleus of the optic tract (NOT) and dorsal terminal nucleus (DTN) in this species. Labelled cells and terminals were observed in the contralateral NOT-DTN. Furthermore, HRP was injected bilaterally in the region of the inferior olive (IO) to verify if the distribution of labelled cells in the NOT-DTN overlapped the region of commissural labelled cells. The two subpopulations of retrogradely labelled cells coincided, being distributed within the retinal terminal field attributed to the NOT-DTN, as revealed by contralateral eye injections of HRP. The commissural cells were located slightly more ventral than the olivary cells in the optic tract. The pretectocollicular WGA-HRP injections also labelled cells and terminals bilaterally in the lateral terminal nucleus (LTN), interstitial nucleus of the superior fasciculus, posterior fibers (INSFp), ventral lateral geniculate nucleus (vLGN), and superior colliculus (SC) and ipsilaterally in the medial terminal nucleus (MTN). In addition, further caudally, labelled cells and terminals were observed bilaterally in the nuclei prepositus hypoglossi (PH) and in the medial (MVN) and lateral (LVN) vestibular nuclei. Labelled terminals were found in the ipsilateral nucleus reticularis tegmenti pontis (NRTP) and in the IO with ipsilateral predominance. This study allowed an anatomical delimitation of the NOT-DTN in this opossum species, as defined by the olivary and commissural subpopulations, as well as a hodological evaluation of this region. The existence of some common anatomical aspects with other mammalian species is discussed.

Expression of the transient receptor potential channels TRPV1, TRPA1 and TRPM8 in mouse trigeminal primary afferent neurons innervating the dura

PubMed Central

2012-01-01

Background Migraine and other headache disorders affect a large percentage of the population and cause debilitating pain. Activation and sensitization of the trigeminal primary afferent neurons innervating the dura and cerebral vessels is a crucial step in the “headache circuit”. Many dural afferent neurons respond to algesic and inflammatory agents. Given the clear role of the transient receptor potential (TRP) family of channels in both sensing chemical stimulants and mediating inflammatory pain, we investigated the expression of TRP channels in dural afferent neurons. Methods We used two fluorescent tracers to retrogradely label dural afferent neurons in adult mice and quantified the abundance of peptidergic and non-peptidergic neuron populations using calcitonin gene-related peptide immunoreactivity (CGRP-ir) and isolectin B4 (IB4) binding as markers, respectively. Using immunohistochemistry, we compared the expression of TRPV1 and TRPA1 channels in dural afferent neurons with the expression in total trigeminal ganglion (TG) neurons. To examine the distribution of TRPM8 channels, we labeled dural afferent neurons in mice expressing farnesylated enhanced green fluorescent protein (EGFPf) from a TRPM8 locus. We used nearest-neighbor measurement to predict the spatial association between dural afferent neurons and neurons expressing TRPA1 or TRPM8 channels in the TG. Results and conclusions We report that the size of dural afferent neurons is significantly larger than that of total TG neurons and facial skin afferents. Approximately 40% of dural afferent neurons exhibit IB4 binding. Surprisingly, the percentage of dural afferent neurons containing CGRP-ir is significantly lower than those of total TG neurons and facial skin afferents. Both TRPV1 and TRPA1 channels are expressed in dural afferent neurons. Furthermore, nearest-neighbor measurement indicates that TRPA1-expressing neurons are clustered around a subset of dural afferent neurons. Interestingly, TRPM8-expressing neurons are virtually absent in the dural afferent population, nor do these neurons cluster around dural afferent neurons. Taken together, our results suggest that TRPV1 and TRPA1 but not TRPM8 channels likely contribute to the excitation of dural afferent neurons and the subsequent activation of the headache circuit. These results provide an anatomical basis for understanding further the functional significance of TRP channels in headache pathophysiology. PMID:22971321

Functional evidence for the rapid desensitization of 5-HT(3) receptors on vagal afferents mediating the Bezold-Jarisch reflex

NASA Technical Reports Server (NTRS)

Whalen, E. J.; Johnson, A. K.; Lewis, S. J.

2000-01-01

The aim of this study was to determine whether 5-hydroxytryptamine (5-HT)(3) receptors on cardiopulmonary afferents mediating the Bezold-Jarisch reflex (BJR) desensitize upon repeated exposure to selective agonists. BJR-mediated falls in heart rate, diastolic arterial blood pressure and cardiac output elicited by the 5-HT(3)-receptor agonists, phenylbiguanide (100 microg/kg, i.v.) or 2-methyl-5-HT (100 microg/kg, i.v.), progressively diminished upon repeated injection in conscious rats. The BJR responses elicited by 5-HT (40 microg/kg, i.v.) were markedly reduced in rats which had received the above injections of phenylbiguanide or 2-methyl-5-HT whereas the BJR responses elicited by L-S-nitrosocysteine (10 micromol/kg, i.v.) were similar before and after the injections of the 5-HT(3) receptor agonists. These findings suggest that tachyphylaxis to 5-HT(3) receptor agonists may be due to the desensitization of 5-HT(3) receptors on cardiopulmonary afferents rather than the impairment of the central or peripheral processing of the BJR.

Deep tissue afferents, but not cutaneous afferents, mediate transcutaneous electrical nerve stimulation-Induced antihyperalgesia.

PubMed

Radhakrishnan, Rajan; Sluka, Kathleen A

2005-10-01

In this study we investigated the involvement of cutaneous versus knee joint afferents in the antihyperalgesia produced by transcutaneous electrical nerve stimulation (TENS) by differentially blocking primary afferents with local anesthetics. Hyperalgesia was induced in rats by inflaming one knee joint with 3% kaolin-carrageenan and assessed by measuring paw withdrawal latency to heat before and 4 hours after injection. Skin surrounding the inflamed knee joint was anesthetized using an anesthetic cream (EMLA). Low (4 Hz) or high (100 Hz) frequency TENS was then applied to the anesthetized skin. In another group, 2% lidocaine gel was injected into the inflamed knee joint, and low or high frequency TENS was applied. Control experiments were done using vehicles. In control and EMLA groups, both low and high frequency TENS completely reversed hyperalgesia. However, injection of lidocaine into the knee joint prevented antihyperalgesia produced by both low and high frequency TENS. Recordings of cord dorsum potentials showed that both low and high frequency TENS at sensory intensity activates only large diameter afferent fibers. Increasing intensity to twice the motor threshold recruits Adelta afferent fibers. Furthermore, application of EMLA cream to the skin reduces the amplitude of the cord dorsum potential by 40% to 70% for both high and low frequency TENS, confirming a loss of large diameter primary afferent input after EMLA is applied to the skin. Thus, inactivation of joint afferents, but not cutaneous afferents, prevents the antihyperalgesia effects of TENS. We conclude that large diameter primary afferent fibers from deep tissue are required and that activation of cutaneous afferents is not sufficient for TENS-induced antihyperalgesia. Transcutaneous electrical nerve stimulation (TENS) is an accepted clinical modality used for pain relief. It is generally believed that TENS analgesia is caused mainly by cutaneous afferent activation. In this study by differentially blocking cutaneous and deep tissue primary afferents, we show that the activation of large diameter primary afferents from deep somatic tissues, and not cutaneous afferents, are pivotal in causing TENS analgesia.

Neurochemical diversity of afferent neurons that transduce sensory signals from dog ventricular myocardium

PubMed Central

Hoover, Donald B.; Shepherd, Angela V.; Southerland, E. Marie; Armour, J. Andrew; Ardell, Jeffrey L.

2008-01-01

While much is known about the influence of ventricular afferent neurons on cardiovascular function in the dog, identification of the neurochemicals transmitting cardiac afferent signals to central neurons is lacking. Accordingly, we identified ventricular afferent neurons in canine dorsal root ganglia (DRG) and nodose ganglia by retrograde labeling after injecting horseradish peroxidase (HRP) into the anterior right and left ventricles. Primary antibodies from three host species were used in immunohistochemical experiments to simultaneously evaluate afferent somata for the presence of HRP and markers for two neurotransmitters. Only a small percentage (2%) of afferent somata were labeled with HRP. About half of the HRP-identified ventricular afferent neurons in T3 DRG also stained for substance P (SP), calcitonin gene-related peptide (CGRP), or neuronal nitric oxide synthase (nNOS), either alone or with two markers colocalized. Ventricular afferent neurons and the general population of T3 DRG neurons showed the same labeling profiles; CGRP (alone or colocalized with SP) being the most common (30–40% of ventricular afferent somata in T3 DRG). About 30% of the ventricular afferent neurons in T2 DRG displayed CGRP immunoreactivity and binding of the putative nociceptive marker IB4. Ventricular afferent neurons of the nodose ganglia were distinct from those in the DRG by having smaller size and lacking immunoreactivity for SP, CGRP, and nNOS. These findings suggest that ventricular sensory information is transferred to the central nervous system by relatively small populations of vagal and spinal afferent neurons and that spinal afferents use a variety of neurotransmitters. PMID:18558516

Neurochemical diversity of afferent neurons that transduce sensory signals from dog ventricular myocardium.

PubMed

Hoover, Donald B; Shepherd, Angela V; Southerland, E Marie; Armour, J Andrew; Ardell, Jeffrey L

2008-08-18

While much is known about the influence of ventricular afferent neurons on cardiovascular function in the dog, identification of the neurochemicals transmitting cardiac afferent signals to central neurons is lacking. Accordingly, we identified ventricular afferent neurons in canine dorsal root ganglia (DRG) and nodose ganglia by retrograde labeling after injecting horseradish peroxidase (HRP) into the anterior right and left ventricles. Primary antibodies from three host species were used in immunohistochemical experiments to simultaneously evaluate afferent somata for the presence of HRP and markers for two neurotransmitters. Only a small percentage (2%) of afferent somata were labeled with HRP. About half of the HRP-identified ventricular afferent neurons in T(3) DRG also stained for substance P (SP), calcitonin gene-related peptide (CGRP), or neuronal nitric oxide synthase (nNOS), either alone or with two markers colocalized. Ventricular afferent neurons and the general population of T(3) DRG neurons showed the same labeling profiles; CGRP (alone or colocalized with SP) being the most common (30-40% of ventricular afferent somata in T(3) DRG). About 30% of the ventricular afferent neurons in T(2) DRG displayed CGRP immunoreactivity and binding of the putative nociceptive marker IB(4). Ventricular afferent neurons of the nodose ganglia were distinct from those in the DRG by having smaller size and lacking immunoreactivity for SP, CGRP, and nNOS. These findings suggest that ventricular sensory information is transferred to the central nervous system by relatively small populations of vagal and spinal afferent neurons and that spinal afferents use a variety of neurotransmitters.

Human cerebral cortex Cajal-Retzius neuron: development, structure and function. A Golgi study.

PubMed

Marín-Padilla, Miguel

2015-01-01

The development, morphology and possible functional activity of the Cajal-Retzius cell of the developing human cerebral cortex are explored herein. The C-RC, of extracortical origin, is the essential neuron of the neocortex first lamina. It receives inputs from afferent fibers that reach the first lamina early in development. Although the origin and function of these original afferent fibers remain unknown, their target is the first lamina sole neuron: the C-RC. This neuron orchestrates the arrival, size and stratification of all pyramidal neurons (of ependymal origin) of the neocortex gray matter. Its axonic terminals spread radially and horizontally throughout the entirety of the first lamina establishing contacts with the dendritic terminals of all gray matter pyramidal cells regardless of size, location and/or eventual functional roles. While the neuron axonic terminals spread radially and horizontally throughout the first lamina, the neuronal' body undergoes progressive developmental dilution and locating any of them in the adult brain become quite difficult. The neuron bodies are probably retained in the older regions of the neocortex while their axonic collaterals will spread throughout its more recent ones and eventually will extend to great majority of the cortical surface. The neocortex first lamina evolution and composition and that of the C-RC are intertwined and mutually interdependent. It is not possible to understand the C-RC evolving morphology without understanding that of the first lamina. The first lamina composition and its structural and functional organizations obtained with different staining methods may be utterly different. These differences have added unnecessary confusion about its nature. The essential emptiness observed in hematoxylin and eosin preparations (most commonly used) contrast sharply with the concentration of dendrites (the cortex' largest) obtained using special (MAP-2) stain for dendrites. Only Golgi preparations demonstrate the numerous dendritic and axonic terminals that compose the first lamina basic structure. High power microscopic views of Golgi preparations demonstrate the intimate anatomical and functional interrelationships among dendritic and axonic terminals as well as synaptic contacts between them. The C-RC' essential morphology does not changes but it is progressively modified by the first lamina increase in thickness and in number of terminal dendrites and their subsequent maturation. This neuron variable morphologic appearance has been the source of controversy. Its morphology depends on the first lamina thickness that may be quite variable among different mammals. In rodents (most commonly used experimental mammal), the first lamina thickness, number and horizontal expansion of dendrites is but a fraction of those in humans. This differences are reflected in the C-RC' morphology among mammals (including humans) and should not be thought as representing new types of neurons.

Vestibular afferent responses to linear accelerations in the alert squirrel monkey

NASA Technical Reports Server (NTRS)

Somps, Christopher J.; Schor, Robert H.; Tomko, David L.

1994-01-01

The spontaneous activity of 40 otolith afferents and 44 canal afferents was recorded in 4 alert, intact squirrel monkeys. Polarization vectors and response properties of otolith afferents were determined during static re-orientations relative to gravity and during Earth-horizontal, sinusoidal, linear oscillations. Canal afferents were tested for sensitivity to linear accelerations. For regular otolith afferents, a significant correlation between upright discharge rate and sensitivity to dynamic acceleration in the horizontal plane was observed. This correlation was not present in irregular units. The sensitivity of otolith afferents to both static tilts and dynamic linear acceleration was much greater in irregularly discharging units than in regularly discharging units. The spontaneous activity and static and dynamic response properties of regularly discharging otolith afferents were similar to those reported in barbiturate-anesthetized squirrel monkeys. Irregular afferents also had similar dynamic response properties when compared to anesthetized monkeys. However, this sample of irregular afferents in alert animals had higher resting discharge rates and greater sensitivity to static tilts. The majority of otolith polarization vectors were oriented near the horizontal in the plane of the utricular maculae; however, directions of maximum sensitivity were different during dynamic and static testing. Canal afferents were not sensitive to static tilts or linear oscillations of the head.

The firing characteristics of foot sole cutaneous mechanoreceptor afferents in response to vibration stimuli.

PubMed

Strzalkowski, Nicholas D J; Ali, R Ayesha; Bent, Leah R

2017-10-01

Single unit microneurography was used to record the firing characteristics of the four classes of foot sole cutaneous afferents [fast and slowly adapting type I and II (FAI, FAII, SAI, and SAII)] in response to sinusoidal vibratory stimuli. Frequency (3-250 Hz) and amplitude (0.001-2 mm) combinations were applied to afferent receptive fields through a 6-mm diameter probe. The impulses per cycle, defined as the number of action potentials evoked per vibration sine wave, were measured over 1 s of vibration at each frequency-amplitude combination tested. Afferent entrainment threshold (lowest amplitude at which an afferent could entrain 1:1 to the vibration frequency) and afferent firing threshold (minimum amplitude for which impulses per cycle was greater than zero) were then obtained for each frequency. Increases in vibration frequency are generally associated with decreases in expected impulses per cycle ( P < 0.001), but each foot sole afferent class appears uniquely tuned to vibration stimuli. FAII afferents tended to have the lowest entrainment and firing thresholds ( P < 0.001 for both); however, these afferents seem to be sensitive across frequency. In contrast to FAII afferents, SAI and SAII afferents tended to demonstrate optimal entrainment to frequencies below 20 Hz and FAI afferents faithfully encoded frequencies between 8 and 60 Hz. Contrary to the selective activation of distinct afferent classes in the hand, application of class-specific frequencies in the foot sole is confounded due to the high sensitivity of FAII afferents. These findings may aid in the development of sensorimotor control models or the design of balance enhancement interventions. NEW & NOTEWORTHY Our work provides a mechanistic look at the capacity of foot sole cutaneous afferents to respond to vibration of varying frequency and amplitude. We found that foot sole afferent classes are uniquely tuned to vibration stimuli; however, unlike in the hand, they cannot be independently activated by class-specific frequencies. Viewing the foot sole as a sensory structure, the present findings may aid in the refinement of sensorimotor control models and design of balance enhancement interventions. Copyright © 2017 the American Physiological Society.

UNMYELINATED FIBERS OF THE ANTERIOR ETHMOIDAL NERVE IN THE RAT CO-LOCALIZE WITH NEURONS IN THE MEDULLARY DORSAL HORN AND VENTROLATERAL MEDULLA ACTIVATED BY NASAL STIMULATION

PubMed Central

Hollandsworth, Michael P.; DiNovo, Karyn M.; McCulloch, Paul F.

2009-01-01

The anterior ethmoidal nerve (AEN) innervates the nasal passages and external nares, and serves as the afferent limb of the nasopharyngeal and diving responses. However, although 65% of the AEN is composed of unmyelinated fibers, it has not been determined whether this afferent signal is carried by unmyelinated or myelinated fibers. We used the transganglionic tracers WGA-HRP, IB4-HRP, and CTB-HRP to trace the central projections of the AEN of the rat. Interpretation of the labeling patterns suggests that AEN unmyelinated fibers project primarily to the ventral tip of the ipsilateral medullary dorsal horn (MDH) at the level of the area postrema. Other unmyelinated projections were to the ventral paratrigeminal nucleus and ventrolateral medulla, specifically the Bötzinger and RVLM/C1 regions. Myelinated AEN fibers projected to the ventral paratrigeminal and mesencephalic trigeminal nuclei. Stimulating the nasal passages of urethane-anesthetized rats with ammonia vapors produced the nasopharyngeal response that included apnea, bradycardia and an increase in arterial blood pressure. Central projections of the AEN co-localized with neurons within both MDH and RVLM/C1 that were activated by nasal stimulation. Within the ventral MDH the density of AEN terminal projections positively correlated with the rostral-caudal location of activated neurons, especially at and just caudal to the obex. We conclude that unmyelinated AEN terminal projections are involved in the activation of neurons in the MDH and ventrolateral medulla that participate in the nasopharyngeal response in the rat. We also found that IB4-HRP was a much less robust tracer than WGA-HRP. PMID:19732757

Cannabinoid CB1 receptor facilitation of substance P release in the rat spinal cord, measured as neurokinin 1 receptor internalization

PubMed Central

Zhang, Guohua; Chen, Wenling; Lao, Lijun; Marvizón, Juan Carlos G.

2010-01-01

The contribution of CB1 receptors in the spinal cord to cannabinoid analgesia is still unclear. The objective of this study was to investigate the effect of CB1 receptors on substance P release from primary afferent terminals in the spinal cord. Substance P release was measured as NK1 receptor internalization in lamina I neurons. It was induced in spinal cord slices by dorsal root stimulation and in live rats by a noxious stimulus. In spinal cord slices, the CB1 receptor antagonists AM251, AM281 and rimonabant partially but potently inhibited NK1 receptor internalization induced by electrical stimulation of the dorsal root. This was due to an inhibition of substance P release and not of NK1 receptor internalization itself, because AM251 and AM281 did not inhibit NK1 receptor internalization induced by exogenous substance P. The CB1 receptor agonist ACEA increased NK1 receptor internalization evoked by dorsal root stimulation. The effects of AM251 and ACEA cancelled each other. In vivo, AM251 injected intrathecally decreased NK1 receptor internalization in spinal segments L5 and L6 induced by noxious hind paw clamp. Intrathecal AM251 also produced analgesia to radiant heat stimulation of the paw. The inhibition by AM251 of NK1 receptor internalization was reversed by antagonists of μ-opioid and GABAB receptors. This indicates that CB1 receptors facilitate substance P release by inhibiting the release of GABA and opioids next to primary afferent terminals, producing disinhibition. This results in a pronociceptive effect of CB1 receptors in the spinal cord. PMID:20074214

Migraine, vertigo and migrainous vertigo: Links between vestibular and pain mechanisms.

PubMed

Balaban, Carey D

2011-01-01

This review develops the hypothesis that co-morbid balance disorders and migraine can be understood as additive effects of processing afferent vestibular and pain information in pre-parabrachial and pre-thalamic pathways, that have consequences on cortical mechanisms influencing perception, interoception and affect. There are remarkable parallel neurochemical phenotypes for inner ear and trigeminal ganglion cells and these afferent channels appear to converge in shared central pathways for vestibular and nociceptive information processing. These pathways share expression of receptors targeted by anti-migraine drugs. New evidence is also presented regarding the distribution of serotonin receptors in the planum semilunatum of the primate cristae ampullaris, which may indicate involvement of inner ear ionic homeostatic mechanisms in audiovestibular symptoms that can accompany migraine.

The intrinsic organization of the vestibular complex: evidence for internuclear connectivity.

PubMed

Rubertone, J A; Mehler, W R; Cox, G E

1983-03-14

The HRP anterograde and retrograde labeling techniques provide evidence for extensive internuclear connectivity within the vestibular complex. Specifically: (1) the superior vestibular nucleus is topographically and reciprocally related to the spinal (spr) and medial vestibular nuclei (mv); (2) the lateral vestibular nucleus (lv) is reciprocally related to the mv, and (3) the lv receives afferent fibers from the spv but does not reciprocate this input.

Advances in the understanding of cluster headache.

PubMed

Leone, Massimo; Proietti Cecchini, Alberto

2017-02-01

Cluster headache is the worst primary headache form; it occurs in paroxysmal excruciatingly severe unilateral head pain attacks usually grouped in cluster periods. The familial occurrence of the disease indicates a genetic component but a gene abnormality is yet to be disclosed. Activation of trigeminal afferents and cranial parasympathetic efferents, the so-called trigemino-parasympathetic reflex, can explain pain and accompanying oculo-facial autonomic phenomena. In particular, pain in cluster headache is attributed, at least in part, to the increased CGRP plasma levels released by activated trigeminal system. Posterior hypothalamus was hypothesized to be the cluster generator activating the trigemino-parasympathetic reflex. Efficacy of monoclonal antibodies against CRGP is under investigation in randomized clinical trials. Areas covered: This paper will focus on main findings contributing to consider cluster headache as a neurovascular disorder with an origin from within the brain. Expert commentary: Accumulated evidence with hypothalamic stimulation in cluster headache patients indicate that posterior hypothalamus terminates rather than triggers the attacks. More extensive studies on the genetics of cluster headache are necessary to disclose anomalies behind the increased familial risk of the disease. Results from ongoing clinical trials in cluster headache sufferers using monoclonal antibodies against CGRP will open soon a new era.

Afferent thermosensory function in relapsing-remitting multiple sclerosis following exercise-induced increases in body temperature.

PubMed

Filingeri, Davide; Chaseling, Georgia; Hoang, Phu; Barnett, Michael; Davis, Scott L; Jay, Ollie

2017-08-01

What is the central question of this study? Between 60 and 80% of multiple sclerosis (MS) patients experience transient worsening of symptoms with increased body temperature (heat sensitivity). As sensory abnormalities are common in MS, we asked whether afferent thermosensory function is altered in MS following exercise-induced increases in body temperature. What is the main finding and its importance? Increases in body temperature of as little as ∼0.4°C were sufficient to decrease cold, but not warm, skin thermosensitivity (∼10%) in MS, across a wider temperature range than in age-matched healthy individuals. These findings provide new evidence on the impact of heat sensitivity on afferent function in MS, which could be useful for clinical evaluation of this neurological disease. In multiple sclerosis (MS), increases in body temperature result in transient worsening of clinical symptoms (heat sensitivity or Uhthoff's phenomenon). Although the impact of heat sensitivity on efferent physiological function has been investigated, the effects of heat stress on afferent sensory function in MS are unknown. Hence, we quantified afferent thermosensory function in MS following exercise-induced increases in body temperature with a new quantitative sensory test. Eight relapsing-remitting MS patients (three men and five women; 51.4 ± 9.1 years of age; Expanded Disability Status Scale score 2.8 ± 1.1) and eight age-matched control (CTR) subjects (five men and three women; 47.4 ± 9.1 years of age) rated the perceived magnitude of two cold (26 and 22°C) and two warm stimuli (34 and 38°C) applied to the dorsum of the hand before and after 30 min cycling in the heat (30°C air; 30% relative humidity). Exercise produced similar increases in mean body temperature in MS [+0.39°C (95% CI: +0.21, +0.53) P = 0.001] and CTR subjects [+0.41°C (95% CI: +0.25, +0.58) P = 0.001]. These changes were sufficient to decrease thermosensitivity significantly to all cold [26°C stimulus, -9.1% (95% CI: -17.0, -1.5), P = 0.006; 22°C stimulus, -10.6% (95% CI: -17.3, -3.7), P = 0.027], but not warm, stimuli in MS. Contrariwise, CTR subjects showed sensitivity reductions to colder stimuli only [22°C stimulus, -9.7% (95% CI: -16.4, -3.1), P = 0.011]. The observation that reductions in thermal sensitivity in MS were confined to the myelinated cold-sensitive pathway and extended across a wider (including milder and colder) temperature range than what is observed in CTR subjects provides new evidence on the impact of rising body temperature on afferent neural function in MS. Also, our findings support the use of our new approach to investigate afferent sensory function in MS during heat stress. © 2017 The Authors. Experimental Physiology © 2017 The Physiological Society.

An Analysis of Entorhinal Cortex Projections to the Dentate Gyrus, Hippocampus, and Subiculum of the Neonatal Macaque Monkey

PubMed Central

Amaral, David G.; Kondo, Hideki; Lavenex, Pierre

2015-01-01

The entorhinal cortex is the primary interface between the hippocampal formation and neocortical sources of sensory information. Although much is known about the cells of origin, termination patterns, and topography of the entorhinal projections to other fields of the adult hippocampal formation, very little is known about the development of these pathways, particularly in the human or nonhuman primate. We have carried out experiments in which the anterograde tracers 3H-amino acids, biotinylated dextran amine, and Phaseolus vulgaris leucoagglutinin were injected into the entorhinal cortex in 2-week-old rhesus monkeys (Macaca mulatta). We found that the three fiber bundles originating from the entorhinal cortex (the perforant path, the alvear pathway, and the commissural connection) are all established by 2 weeks of age. Fundamental features of the laminar and topographic distribution of these pathways are also similar to those in adults. There is evidence, however, that some of these projections may be more extensive in the neonate than in the mature brain. The homotopic commissural projections from the entorhinal cortex, for example, originate from a larger region within the entorhinal cortex and terminate much more densely in layer I of the contralateral entorhinal cortex than in the adult. These findings indicate that the overall topographical organization of the main cortical afferent pathways to the dentate gyrus and hippocampus are established by birth. These findings add to the growing body of literature on the development of the primate hippocampal formation and will facilitate further investigations on the development of episodic memory. PMID:24122645

Cutaneous afferents mediating the cutaneous silent period in the upper limbs: evidences for a role of low-threshold sensory fibres.

PubMed

Serrao, M; Parisi, L; Pierelli, F; Rossi, P

2001-11-01

To evaluate the contribution of the low-threshold afferents to the production of the cutaneous silent period (CSP) in the upper limbs. The CSP was studied in 10 healthy adults and 4 patients with Friedreich's ataxia. The following neurophysiological aspects were studied: (a) relationship between sensory threshold (ST), sensory action potential (SAP) amplitude and CSP parameters; (b) habituation and recovery cycle of the CSP at different stimulus intensities (2xST and 8xST); (c) pattern of responses in distal and proximal muscles at different stimulus intensities (2xST and 8xST). (a) The CSP occurred at low intensities (1xST and 2xST) and increased abruptly between 3.5xST and 4xST (corresponding to the pain threshold). The SAP amplitude was saturated before CSP saturation. In the patients with Friedreich's ataxia, the CSP appeared only at higher stimulus intensities (6xST-8xST). (b) The CSP evoked at 2xST showed a fast habituation and slow recovery cycle whereas the opposite behaviour was found at 8xST. (c) Low-threshold stimuli induced an inhibitory response restricted to the distal muscles. High-intensity stimulation produced an electromyographic suppression, significantly increasing from proximal to distal muscles. Our findings support the notion that low-threshold afferents participate in the production of the CSP in the upper limbs. The different afferents may activate different central neural networks with separate functional significance.

OnabotulinumtoxinA significantly attenuates bladder afferent nerve firing and inhibits ATP release from the urothelium.

PubMed

Collins, Valerie M; Daly, Donna M; Liaskos, Marina; McKay, Neil G; Sellers, Donna; Chapple, Christopher; Grundy, David

2013-11-01

To investigate the direct effect of onabotulinumtoxinA (OnaBotA) on bladder afferent nerve activity and release of ATP and acetylcholine (ACh) from the urothelium. Bladder afferent nerve activity was recorded using an in vitro mouse preparation enabling simultaneous recordings of afferent nerve firing and intravesical pressure during bladder distension. Intraluminal and extraluminal ATP, ACh, and nitric oxide (NO) release were measured using the luciferin-luciferase and Amplex(®) Red assays (Molecular Probes, Carlsbad, CA, USA), and fluorometric assay kit, respectively. OnaBotA (2U), was applied intraluminally, during bladder distension, and its effect was monitored for 2 h after application. Whole-nerve activity was analysed to classify the single afferent units responding to physiological (low-threshold [LT] afferent <15 mmHg) and supra-physiological (high-threshold [HT] afferent >15 mmHg) distension pressures. Bladder distension evoked reproducible pressure-dependent increases in afferent nerve firing. After exposure to OnaBotA, both LT and HT afferent units were significantly attenuated. OnaBotA also significantly inhibited ATP release from the urothelium and increased NO release. These data indicate that OnaBotA attenuates the bladder afferent nerves involved in micturition and bladder sensation, suggesting that OnaBotA may exert its clinical effects on urinary urgency and the other symptoms of overactive bladder syndrome through its marked effect on afferent nerves. © 2013 The Authors. BJU International © 2013 BJU International.

Xenin Augments Duodenal Anion Secretion via Activation of Afferent Neural Pathways

PubMed Central

Kaji, Izumi; Akiba, Yasutada; Kato, Ikuo; Maruta, Koji; Kuwahara, Atsukazu

2017-01-01

Xenin-25, a neurotensin (NT)-related anorexigenic gut hormone generated mostly in the duodenal mucosa, is believed to increase the rate of duodenal ion secretion, because xenin-induced diarrhea is not present after Roux-en-Y gastric bypass surgery. Because the local effects of xenin on duodenal ion secretion have remained uninvestigated, we thus examined the neural pathways underlying xenin-induced duodenal anion secretion. Intravenous infusion of xenin-8, a bioactive C-terminal fragment of xenin-25, dose dependently increased the rate of duodenal HCO3− secretion in perfused duodenal loops of anesthetized rats. Xenin was immunolocalized to a subset of enteroendocrine cells in the rat duodenum. The mRNA of the xenin/NT receptor 1 (NTS1) was predominantly expressed in the enteric plexus, nodose and dorsal root ganglia, and in the lamina propria rather than in the epithelium. The serosal application of xenin-8 or xenin-25 rapidly and transiently increased short-circuit current in Ussing-chambered mucosa-submucosa preparations in a concentration-dependent manner in the duodenum and jejunum, but less so in the ileum and colon. The selective antagonist for NTS1, substance P (SP) receptor (NK1), or 5-hydroxytryptamine (5-HT)3, but not NTS2, inhibited the responses to xenin. Xenin-evoked Cl- secretion was reduced by tetrodotoxin (TTX) or capsaicin-pretreatment, and abolished by the inhibitor of TTX-resistant sodium channel Nav1.8 in combination with TTX, suggesting that peripheral xenin augments duodenal HCO3− and Cl− secretion through NTS1 activation on intrinsic and extrinsic afferent nerves, followed by release of SP and 5-HT. Afferent nerve activation by postprandial, peripherally released xenin may account for its secretory effects in the duodenum. PMID:28115552

Regulation of Spinal Substance P Release by Intrathecal Calcium Channel Blockade

PubMed Central

Takasusuki, Toshifumi; Yaksh, Tony L.

2012-01-01

Background We investigated the role of different voltage sensitive calcium channels expressed at presynaptic afferent terminals in substance P release and on nociceptive behavior evoked by intraplantar formalin by examining the effects of intrathecally delivered N- (ziconotide), T- (mibefradil) and L-type voltage sensitive calcium channels blockers (diltiazem and verapamil). Methods Rats received intrathecal pretreatment with saline or doses of morphine, ziconotide, mibefradil, diltiazem or verapamil. The effect of these injections upon flinching evoked by intraplantar formalin (5%, 50μl) was quantified. To assess substance P release, the incidence of neurokinin 1 receptor internalization in the ipsilateral and contralateral lamina I was determined in immunofluorescent stained tissues. Results Intrathecal morphine (20μg), ziconotide (0.3, 0.6 and 1μg), mibefradil (100μg, but not 50μg), diltiazem (500μg, but not 300μg) and verapamil (200μg, but not 50 and 100μg) reduced paw flinching in phase 2 as compared to vehicle control (P < 0.05), with no effect upon phase 1. Ziconotide (0.3, 0.6 and 1μg) and morphine (20μg) significantly inhibited neurokinin 1 receptor internalization (P < 0.05), but mibefradil, diltiazem and verapamil at the highest doses had no effect. Conclusion These results emphasize the role in vivo of N-, but not T- and L-type voltage sensitive calcium channels in mediating the stimulus evoked substance P release from small primary afferents and suggest that T- and L-type voltage sensitive calcium channels blockers exert antihyperalgesic effects by an action on other populations of afferents or mechanisms involving post synaptic excitability. PMID:21577088

Excitatory and inhibitory innervation of the mouse orofacial motor nuclei: A stereological study.

PubMed

Faunes, Macarena; Oñate-Ponce, Alejandro; Fernández-Collemann, Sara; Henny, Pablo

2016-03-01

Neurons in the trigeminal (Mo5), facial (Mo7), ambiguus (Amb), and hypoglossal (Mo12) motor nuclei innervate jaw, facial, pharynx/larynx/esophagus, and tongue muscles, respectively. They are essential for movements subserving feeding, exploration of the environment, and social communication. These neurons are largely controlled by sensory afferents and premotor neurons of the reticular formation, where central pattern generator circuits controlling orofacial movements are located. To provide a description of the orofacial nuclei of the adult mouse and to ascertain the influence of excitatory and inhibitory afferents upon them, we used stereology to estimate the number of motoneurons as well as of varicosities immunopositive for glutamate (VGluT1+, VGluT2+) and GABA/glycine (known as VIAAT+ or VGAT+) vesicular transporters in the Mo5, Mo7, Amb, and Mo12. Mo5, Mo7, Amb, and Mo12 contain ∼1,000, ∼3,000, ∼600, and ∼1,700 cells, respectively. VGluT1+, VGluT2+, and VIAAT+ varicosities respectively represent: 28%, 41%, and 31% in Mo5; 2%, 49%, and 49% in Mo7; 12%, 42%, and 46% in Amb; and 4%, 54%, and 42% in Mo12. The Mo5 jaw-closing subdivision shows the highest VGluT1+ innervation. Noticeably, the VGluT2+ and VIAAT+ varicosity density in Mo7 is 5-fold higher than in Mo5 and 10-fold higher than in Amb and Mo12. The high density of terminals in Mo7 likely reflects the convergence and integration of numerous inputs to motoneurons subserving the wide range of complex behaviors to which this nucleus contributes. Also, somatic versus neuropil location of varicosities suggests that most of these afferents are integrated in the dendritic trees of Mo7 neurons. © 2015 Wiley Periodicals, Inc.

High glucose increases action potential firing of catecholamine neurons in the nucleus of the solitary tract by increasing spontaneous glutamate inputs.

PubMed

Roberts, Brandon L; Zhu, Mingyan; Zhao, Huan; Dillon, Crystal; Appleyard, Suzanne M

2017-09-01

Glucose is a crucial substrate essential for cell survival and function. Changes in glucose levels impact neuronal activity and glucose deprivation increases feeding. Several brain regions have been shown to respond to glucoprivation, including the nucleus of the solitary tract (NTS) in the brain stem. The NTS is the primary site in the brain that receives visceral afferent information from the gastrointestinal tract. The catecholaminergic (CA) subpopulation within the NTS modulates many homeostatic functions including cardiovascular reflexes, respiration, food intake, arousal, and stress. However, it is not known if they respond to changes in glucose. Here we determined whether NTS-CA neurons respond to changes in glucose concentration and the mechanism involved. We found that decreasing glucose concentrations from 5 mM to 2 mM to 1 mM, significantly decreased action potential firing in a cell-attached preparation, whereas increasing it back to 5 mM increased the firing rate. This effect was dependent on glutamate release from afferent terminals and required presynaptic 5-HT 3 Rs. Decreasing the glucose concentration also decreased both basal and 5-HT 3 R agonist-induced increase in the frequency of spontaneous glutamate inputs onto NTS-CA neurons. Low glucose also blunted 5-HT-induced inward currents in nodose ganglia neurons, which are the cell bodies of vagal afferents. The effect of low glucose in both nodose ganglia cells and in NTS slices was mimicked by the glucokinase inhibitor glucosamine. This study suggests that NTS-CA neurons are glucosensing through a presynaptic mechanism that is dependent on vagal glutamate release, 5-HT 3 R activity, and glucokinase. Copyright © 2017 the American Physiological Society.

Functional role of peripheral opioid receptors in the regulation of cardiac spinal afferent nerve activity during myocardial ischemia

PubMed Central

Longhurst, John C.

2013-01-01

Thinly myelinated Aδ-fiber and unmyelinated C-fiber cardiac sympathetic (spinal) sensory nerve fibers are activated during myocardial ischemia to transmit the sensation of angina pectoris. Although recent observations showed that myocardial ischemia increases the concentrations of opioid peptides and that the stimulation of peripheral opioid receptors inhibits chemically induced visceral and somatic nociception, the role of opioids in cardiac spinal afferent signaling during myocardial ischemia has not been studied. The present study tested the hypothesis that peripheral opioid receptors modulate cardiac spinal afferent nerve activity during myocardial ischemia by suppressing the responses of cardiac afferent nerve to ischemic mediators like bradykinin and extracellular ATP. The nerve activity of single unit cardiac afferents was recorded from the left sympathetic chain (T2–T5) in anesthetized cats. Forty-three ischemically sensitive afferent nerves (conduction velocity: 0.32–3.90 m/s) with receptive fields in the left and right ventricles were identified. The responses of these afferent nerves to repeat ischemia or ischemic mediators were further studied in the following protocols. First, epicardial administration of naloxone (8 μmol), a nonselective opioid receptor antagonist, enhanced the responses of eight cardiac afferent nerves to recurrent myocardial ischemia by 62%, whereas epicardial application of vehicle (PBS) did not alter the responses of seven other cardiac afferent nerves to ischemia. Second, naloxone applied to the epicardial surface facilitated the responses of seven cardiac afferent nerves to epicardial ATP by 76%. Third, administration of naloxone enhanced the responses of seven other afferent nerves to bradykinin by 85%. In contrast, in the absence of naloxone, cardiac afferent nerves consistently responded to repeated application of ATP (n = 7) or bradykinin (n = 7). These data suggest that peripheral opioid peptides suppress the responses of cardiac sympathetic afferent nerves to myocardial ischemia and ischemic mediators like ATP and bradykinin. PMID:23645463

[Immunocytochemical study of cholinergic innervation in the neurosensory epithelia of human vestibule].

PubMed

Kong, W; Hussl, B; Schrott-Fischer, A

1998-02-01

To investigate the cholinergic innervation of the neurosensory epithelia of human vestibule. A modified preembedding immunostaining technique for immunoelectronmicroscopy was applied to this study. A polyclonal antibody to choline acetyltransferase (ChAT) was used as the marker of cholinergic fibers. ChAT-immunoreactive products were restricted to the nerve fibers and terminals which were rich in synaptic vesicles. The ChAT-immunoreactive fibers synaps with afferent chalice as well as with type II sensory hair cells. This study demonstrates that cholinergic fibers innervate the neurosensory epithelia of human vestible. The cholinergic fibers of human vestibular sensory epithelia belong to the vestibular efferent system.

Afferent Nerve Regulation of Bladder Function in Health and Disease

PubMed Central

de Groat, William C.; Yoshimura, Naoki

2012-01-01

The afferent innervation of the urinary bladder consists primarily of small myelinated (Aδ) and unmyelinated (C-fiber) axons that respond to chemical and mechanical stimuli. Immunochemical studies indicate that bladder afferent neurons synthesize several putative neurotransmitters, including neuropeptides, glutamic acid, aspartic acid, and nitric oxide. The afferent neurons also express various types of receptors and ion channels, including transient receptor potential channels, purinergic, muscarinic, endothelin, neurotrophic factor, and estrogen receptors. Patch-clamp recordings in dissociated bladder afferent neurons and recordings of bladder afferent nerve activity have revealed that activation of many of these receptors enhances neuronal excitability. Afferent nerves can respond to chemicals present in urine as well as chemicals released in the bladder wall from nerves, smooth muscle, inflammatory cells, and epithelial cells lining the bladder lumen. Pathological conditions alter the chemical and electrical properties of bladder afferent pathways, leading to urinary urgency, increased voiding frequency, nocturia, urinary incontinence, and pain. Neurotrophic factors have been implicated in the pathophysiological mechanisms underlying the sensitization of bladder afferent nerves. Neurotoxins such as capsaicin, resiniferatoxin, and botulinum neurotoxin that target sensory nerves are useful in treating disorders of the lower urinary tract. PMID:19655106

Electrophysiological property and chemical sensitivity of primary afferent neurons that innervate rat whisker hair follicles.

PubMed

Ikeda, Ryo; Gu, Jianguo

2016-01-01

Whisker hair follicles are sensory organs that sense touch and perform tactile discrimination in animals, and they are sites where sensory impulses are initiated when whisker hairs touch an object. The sensory signals are then conveyed by whisker afferent fibers to the brain for sensory perception. Electrophysiological property and chemical sensitivity of whisker afferent fibers, important factors affecting whisker sensory processing, are largely not known. In the present study, we performed patch-clamp recordings from pre-identified whisker afferent neurons in whole-mount trigeminal ganglion preparations and characterized their electrophysiological property and sensitivity to ATP, serotonin and glutamate. Of 97 whisker afferent neurons examined, 67% of them are found to be large-sized (diameter ≥45 µm) cells and 33% of them are medium- to small-sized (diameter <45 µm) cells. Almost every large-sized whisker afferent neuron fires a single action potential but many (40%) small/medium-sized whisker afferent neurons fire multiple action potentials in response to prolonged stepwise depolarization. Other electrophysiological properties including resting membrane potential, action potential threshold, and membrane input resistance are also significantly different between large-sized and small/medium-sized whisker afferent neurons. Most large-sized and many small/medium-sized whisker afferent neurons are sensitive to ATP and/or serotonin, and ATP and/or serotonin could evoke strong inward currents in these cells. In contrast, few whisker afferent neurons are sensitive to glutamate. Our results raise a possibility that ATP and/or serotonin may be chemical messengers involving sensory signaling for different types of rat whisker afferent fibers.

Effects of omega-conotoxin GVIA on the activation of capsaicin-sensitive afferent sensory nerves in guinea pig airway tissues.

PubMed

Morimoto, H; Matsuda, A; Ohori, M; Fujii, T

1996-06-01

We examined the effects of Ca2+ channel antagonists on various respiratory reactions induced by the activation of capsaicin-sensitive afferent sensory nerves. Intravenous (i.v.) injection of the N-type Ca2+ channel antagonist omega-conotoxin GVIA (CgTX) (1-20 micrograms/kg) dose-dependently inhibited capsaicin-induced guinea pig bronchoconstriction, whereas i.v. administration of the L-type antagonist nicardipine (100 micrograms/kg), the P-type antagonist omega-agatoxin IVA (AgaTX) (20 micrograms/kg) or the OPQ family-type antagonist omega-conotoxin MVIIC (CmTX) (20 micrograms/kg) had no effect. However, CgTX (20 micrograms/kg) failed to inhibit substance P-induced guinea pig bronchoconstriction. CgTX (20 micrograms/kg) significantly inhibited cigarette smoke-induced guinea pig tracheal plasma extravasation, but not the substance P-induced reaction. CgTX also reduced electrical field stimulation-induced guinea pig bronchial smooth muscle contraction (0.01-10 microM) and capsaicin-induced substance P-like immunoreactivity release from guinea pig lung (0.14 microM). This evidence suggests that N-type Ca2+ channels modulate tachykinin release from capsaicin-sensitive afferent sensory nerve endings in guinea pig airway tissue.

Monosynaptic Ia projections from intrinsic hand muscles to forearm motoneurones in humans.

PubMed

Marchand-Pauvert, V; Nicolas, G; Pierrot-Deseilligny, E

2000-05-15

Heteronymous Ia excitatory projections from intrinsic hand muscles to human forearm motoneurones (MNs) were investigated. Changes in firing probability of single motor units (MUs) in the flexor carpi radialis (FCR), flexor carpi ulnaris (FCU), flexor digitorum superficialis (FDS), extensor carpi radialis (ECR), extensor carpi ulnaris (ECU) and extensor digitorum communis (EDC) were studied after electrical stimuli were applied to the median and ulnar nerve at wrist level and to the corresponding homonymous nerve at elbow level. Homonymous facilitation, occurring at the same latency as the H reflex, and therefore attributed to monosynaptic Ia EPSPs, was found in all the sampled units. In many MUs an early facilitation was also evoked by heteronymous low-threshold afferents from intrinsic hand muscles. The low threshold (between 0.5 and 0.6 times motor threshold (MT)) and the inability of a pure cutaneous stimulation to reproduce this effect indicate that it is due to stimulation of group I muscle afferents. Evidence for a similar central delay (monosynaptic) in heteronymous as in homonymous pathways was accepted when the difference in latencies of the homonymous and heteronymous peaks did not differ from the estimated supplementary afferent conduction time from wrist to elbow level by more than 0.5 ms (conduction velocity in the fastest Ia afferents between wrist and elbow levels being equal to 69 m s-1). A statistically significant heteronymous monosynaptic Ia excitation from intrinsic hand muscles supplied by both median and ulnar nerves was found in MUs belonging to all forearm motor nuclei tested (although not in ECU MUs after ulnar stimulation). It was, however, more often found in flexors than in extensors, in wrist than in finger muscles and in muscles operating in the radial than in the ulnar side. It is argued that the connections of Ia afferents from intrinsic hand muscles to forearm MNs, which are stronger and more widely distributed than in the cat, might be used to provide a support to the hand during manipulatory movements.

Role of the vagus nerve in the development and treatment of diet‐induced obesity

PubMed Central

2016-01-01

Abstract This review highlights evidence for a role of the vagus nerve in the development of obesity and how targeting the vagus nerve with neuromodulation or pharmacology can be used as a therapeutic treatment of obesity. The vagus nerve innervating the gut plays an important role in controlling metabolism. It communicates peripheral information about the volume and type of nutrients between the gut and the brain. Depending on the nutritional status, vagal afferent neurons express two different neurochemical phenotypes that can inhibit or stimulate food intake. Chronic ingestion of calorie‐rich diets reduces sensitivity of vagal afferent neurons to peripheral signals and their constitutive expression of orexigenic receptors and neuropeptides. This disruption of vagal afferent signalling is sufficient to drive hyperphagia and obesity. Furthermore neuromodulation of the vagus nerve can be used in the treatment of obesity. Although the mechanisms are poorly understood, vagal nerve stimulation prevents weight gain in response to a high‐fat diet. In small clinical studies, in patients with depression or epilepsy, vagal nerve stimulation has been demonstrated to promote weight loss. Vagal blockade, which inhibits the vagus nerve, results in significant weight loss. Vagal blockade is proposed to inhibit aberrant orexigenic signals arising in obesity as a putative mechanism of vagal blockade‐induced weight loss. Approaches and molecular targets to develop future pharmacotherapy targeted to the vagus nerve for the treatment of obesity are proposed. In conclusion there is strong evidence that the vagus nerve is involved in the development of obesity and it is proving to be an attractive target for the treatment of obesity. PMID:26959077

Do we understand how botulinum toxin works and have we optimized the way it is administered to the bladder? ICI-RS 2014.

PubMed

Apostolidis, Apostolos; Rahnama'i, Mohammad S; Fry, Christopher; Dmochowski, Roger; Sahai, Arun

2016-02-01

The use of botulinum toxin A (BoNT/A) is commonplace now in the management of refractory overactive bladder and neurogenic detrusor overactivity (NDO). Despite one formulation now having a license, the full mechanism of action is not fully understood. Furthermore practice varies worldwide in the way the toxin is delivered to the bladder. At the ICI-RS 2014 Meeting in Bristol, UK a Think Tank session was conducted on the topic of "Do we understand how botulinum toxin works and have we optimized the way it is administered to the bladder?" This manuscript reflects the Think Tank's summary and opinion. An overview of the existing evidence and consensus regarding mechanism of action and practical aspects of BoNT/A administration was presented. Further avenues of potential research were suggested. BoNT/A effect in the bladder is complex with likely effects on both efferent and afferent nerves. The site of action is controversial with the relative contribution of the detrusor as opposed to the suburothelial effects remaining unclear and open to further studying. The classical concept of prevention of acetylcholine release in the bladder is not supported by a wealth of evidence on neurotransmitters although co-localization studies have suggested cholinergic nerves are the most affected by BoNT/A. There is more robust evidence for effects on the purinergic system and afferent desensitization and emerging evidence for central effects. A variety of technique studies were presented. OnabotlinumtoxinA has recently been studied in large phase III trials and with this there is a standardized injection technique which is trigone-sparing. The evidence for altering location of injection is mixed with some studies suggesting less voiding dysfunction in bladder base injections alone but others suggesting location of injection does not affect outcomes. Early pilot data and evidence of instillation either with electromotive drug administration (EMDA) or in liposomes were also presented as an alternative to injections. The mechanism of action of BoNT/A in the bladder is complex and not fully understood. There is emerging support for its role on afferent mechanisms. The technical aspects of the injection procedure have been standardized to a certain extent but further study is required in larger scale studies to assess minimizing voiding dysfunction, improving tolerability, and assessing alternatives to injections. © 2016 Wiley Periodicals, Inc.

Metabolic changes in deafferented central neurons of an insect, Acheta domesticus. I. Effects upon amino acid uptake and incorporation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Meyer, M.R.; Edwards, J.S.

1982-11-01

Chronic cercal deafferentation of the terminal ganglion in developing crickets (Acheta domesticus), which is known to suppress normal development of giant interneuron dendritic arborizations is shown here to reduce (/sup 3/H)leucine uptake and incorporation into ganglion proteins. Short term deafferentation of adult crickets, in contrast, does not depress amino acid uptake and incorporation significantly. Following unilateral long term deafferentation of the terminal ganglion, a comparison was made of the (/sup 3/H)leucine incorporation into primary dendritic processes and somata of deafferented and normally innervated medial giant interneurons (MGIs) within the same ganglion by means of quantitative autoradiography. Grain densities within dendritesmore » of deafferented MGIs were significantly lower than in paired control MGIs' grain densities within somata of deafferented MGIs also were reduced, although the effects of deafferentation were less pronounced in somata than in target dendrites. These results imply a specific influence of afferent innervation on protein metabolism during growth and development of target postsynaptic elements.« less

Drosophila SLC22A transporter is a memory suppressor gene that influences cholinergic neurotransmission to the mushroom bodies

PubMed Central

Gai, Yunchao; Liu, Ze; Cervantes-Sandoval, Isaac; Davis, Ronald L.

2016-01-01

SUMMARY The mechanisms that constrain memory formation are of special interest because they provide insights into the brain’s memory management systems and potential avenues for correcting cognitive disorders. RNAi knockdown in the Drosophila mushroom body neurons (MBn) of a newly discovered memory suppressor gene, Solute Carrier DmSLC22A, a member of the organic cation transporter family, enhances olfactory memory expression, while overexpression inhibits it. The protein localizes to the dendrites of the MBn, surrounding the presynaptic terminals of cholinergic afferent fibers from projection neurons (Pn). Cell-based expression assays show that this plasma membrane protein transports cholinergic compounds with the highest affinity among several in vitro substrates. Feeding flies choline or inhibiting acetylcholinesterase in Pn enhances memory; an effect blocked by overexpression of the transporter in the MBn. The data argue that DmSLC22A is a memory suppressor protein that limits memory formation by helping to terminate cholinergic neurotransmission at the Pn:MBn synapse. PMID:27146270

Resting Afferent Renal Nerve Discharge and Renal Inflammation: Elucidating the Role of Afferent and Efferent Renal Nerves in Deoxycorticosterone Acetate Salt Hypertension.

PubMed

Banek, Christopher T; Knuepfer, Mark M; Foss, Jason D; Fiege, Jessica K; Asirvatham-Jeyaraj, Ninitha; Van Helden, Dusty; Shimizu, Yoji; Osborn, John W

2016-12-01

Renal sympathetic denervation (RDNx) has emerged as a novel therapy for hypertension; however, the therapeutic mechanisms remain unclear. Efferent renal sympathetic nerve activity has recently been implicated in trafficking renal inflammatory immune cells and inflammatory chemokine and cytokine release. Several of these inflammatory mediators are known to activate or sensitize afferent nerves. This study aimed to elucidate the roles of efferent and afferent renal nerves in renal inflammation and hypertension in the deoxycorticosterone acetate (DOCA) salt rat model. Uninephrectomized male Sprague-Dawley rats (275-300 g) underwent afferent-selective RDNx (n=10), total RDNx (n=10), or Sham (n=10) and were instrumented for the measurement of mean arterial pressure and heart rate by radiotelemetry. Rats received 100-mg DOCA (SC) and 0.9% saline for 21 days. Resting afferent renal nerve activity in DOCA and vehicle animals was measured after the treatment protocol. Renal tissue inflammation was assessed by renal cytokine content and T-cell infiltration and activation. Resting afferent renal nerve activity, expressed as a percent of peak afferent nerve activity, was substantially increased in DOCA than in vehicle (35.8±4.4 versus 15.3±2.8 %Amax). The DOCA-Sham hypertension (132±12 mm Hg) was attenuated by ≈50% in both total RDNx (111±8 mm Hg) and afferent-selective RDNx (117±5 mm Hg) groups. Renal inflammation induced by DOCA salt was attenuated by total RDNx and unaffected by afferent-selective RDNx. These data suggest that afferent renal nerve activity may mediate the hypertensive response to DOCA salt, but inflammation may be mediated primarily by efferent renal sympathetic nerve activity. Also, resting afferent renal nerve activity is elevated in DOCA salt rats, which may highlight a crucial neural mechanism in the development and maintenance of hypertension. © 2016 American Heart Association, Inc.

Undiscovered role of endogenous thromboxane A2 in activation of cardiac sympathetic afferents during ischaemia

PubMed Central

Fu, Liang-Wu; Guo, Zhi-Ling; Longhurst, John C

2008-01-01

Myocardial ischaemia activates blood platelets, which in turn stimulate cardiac sympathetic afferents, leading to chest pain and sympathoexcitatory reflex cardiovascular responses. Previous studies have shown that activated platelets stimulate ischaemically sensitive cardiac sympathetic afferents, and that thromboxane A2 (TxA2) is one of the mediators released from activated platelets during myocardial ischaemia. The present study tested the hypothesis that endogenous TxA2 stimulates cardiac afferents during ischaemia through direct activation of TxA2 (TP) receptors coupled with the phospholipase C–protein kinase C (PLC–PKC) cellular pathway. Nerve activity of single unit cardiac sympathetic afferents was recorded from the left sympathetic chain or rami communicantes (T2–T5) in anaesthetized cats. Single fields of 39 afferents (conduction velocity = 0.27–3.65 m s−1) were identified in the left or right ventricle initially with mechanical stimulation and confirmed with a stimulating electrode. Five minutes of myocardial ischaemia stimulated all 39 cardiac afferents (8 Aδ-, 31 C-fibres) and the responses of these 39 afferents to chemical stimuli were further studied in the following four protocols. In the first protocol, 2.5, 5 and 10 μg of the TxA2 mimetic, U46619, injected into the left atrium (LA), stimulated seven ischaemically sensitive cardiac afferents in a dose-dependent manner. Second, BM13,177, a selective TxA2 receptor antagonist, abolished the responses of six afferents to 5 μg of U46619 injected into the left atrium and attenuated the ischaemia-related increase in activity of seven other afferents by 44%. In contrast, cardiac afferents, in the absence of TP receptor blockade responded consistently to repeated administration of U46619 (n = 6) and to recurrent myocardial ischaemia (n = 7). In the fourth protocol, administration of PKC-(19–36), a selective PKC inhibitor, attenuated the responses of six other cardiac afferents to U46619 by 38%. Finally, using an immunohistochemical staining approach, we observed that TP receptors were expressed in cardiac sensory neurons in thoracic dorsal root ganglia. Taken together, these data indicate that endogenous TxA2 contributes to the activation of cardiac afferents during myocardial ischaemia through direct stimulation of TP receptors probably located in the cardiac sensory nervous system and that the stimulating effect of TxA2 on cardiac afferents is dependent, at least in part, upon the PLC–PKC cellular pathway. PMID:18483073

Cardinal features of involuntary force variability can arise from the closed-loop control of viscoelastic afferented muscles

PubMed Central

Laine, Christopher M.; Valero-Cuevas, Francisco J.

2018-01-01

Involuntary force variability below 15 Hz arises from, and is influenced by, many factors including descending neural drive, proprioceptive feedback, and mechanical properties of muscles and tendons. However, their potential interactions that give rise to the well-structured spectrum of involuntary force variability are not well understood due to a lack of experimental techniques. Here, we investigated the generation, modulation, and interactions among different sources of force variability using a physiologically-grounded closed-loop simulation of an afferented muscle model. The closed-loop simulation included a musculotendon model, muscle spindle, Golgi tendon organ (GTO), and a tracking controller which enabled target-guided force tracking. We demonstrate that closed-loop control of an afferented musculotendon suffices to replicate and explain surprisingly many cardinal features of involuntary force variability. Specifically, we present 1) a potential origin of low-frequency force variability associated with co-modulation of motor unit firing rates (i.e.,‘common drive’), 2) an in-depth characterization of how proprioceptive feedback pathways suffice to generate 5-12 Hz physiological tremor, and 3) evidence that modulation of those feedback pathways (i.e., presynaptic inhibition of Ia and Ib afferents, and spindle sensitivity via fusimotor drive) influence the full spectrum of force variability. These results highlight the previously underestimated importance of closed-loop neuromechanical interactions in explaining involuntary force variability during voluntary ‘isometric’ force control. Furthermore, these results provide the basis for a unifying theory that relates spinal circuitry to various manifestations of altered involuntary force variability in fatigue, aging and neurological disease. PMID:29309405

Cardinal features of involuntary force variability can arise from the closed-loop control of viscoelastic afferented muscles.

PubMed

Nagamori, Akira; Laine, Christopher M; Valero-Cuevas, Francisco J

2018-01-01

Involuntary force variability below 15 Hz arises from, and is influenced by, many factors including descending neural drive, proprioceptive feedback, and mechanical properties of muscles and tendons. However, their potential interactions that give rise to the well-structured spectrum of involuntary force variability are not well understood due to a lack of experimental techniques. Here, we investigated the generation, modulation, and interactions among different sources of force variability using a physiologically-grounded closed-loop simulation of an afferented muscle model. The closed-loop simulation included a musculotendon model, muscle spindle, Golgi tendon organ (GTO), and a tracking controller which enabled target-guided force tracking. We demonstrate that closed-loop control of an afferented musculotendon suffices to replicate and explain surprisingly many cardinal features of involuntary force variability. Specifically, we present 1) a potential origin of low-frequency force variability associated with co-modulation of motor unit firing rates (i.e.,'common drive'), 2) an in-depth characterization of how proprioceptive feedback pathways suffice to generate 5-12 Hz physiological tremor, and 3) evidence that modulation of those feedback pathways (i.e., presynaptic inhibition of Ia and Ib afferents, and spindle sensitivity via fusimotor drive) influence the full spectrum of force variability. These results highlight the previously underestimated importance of closed-loop neuromechanical interactions in explaining involuntary force variability during voluntary 'isometric' force control. Furthermore, these results provide the basis for a unifying theory that relates spinal circuitry to various manifestations of altered involuntary force variability in fatigue, aging and neurological disease.

Validation and characterization of a novel method for selective vagal deafferentation of the gut.

PubMed

Diepenbroek, Charlene; Quinn, Danielle; Stephens, Ricky; Zollinger, Benjamin; Anderson, Seth; Pan, Annabelle; de Lartigue, Guillaume

2017-10-01

There is a lack of tools that selectively target vagal afferent neurons (VAN) innervating the gut. We use saporin (SAP), a potent neurotoxin, conjugated to the gastronintestinal (GI) hormone cholecystokinin (CCK-SAP) injected into the nodose ganglia (NG) of male Wistar rats to specifically ablate GI-VAN. We report that CCK-SAP ablates a subpopulation of VAN in culture. In vivo, CCK-SAP injection into the NG reduces VAN innervating the mucosal and muscular layers of the stomach and small intestine but not the colon, while leaving vagal efferent neurons intact. CCK-SAP abolishes feeding-induced c-Fos in the NTS, as well as satiation by CCK or glucagon like peptide-1 (GLP-1). CCK-SAP in the NG of mice also abolishes CCK-induced satiation. Therefore, we provide multiple lines of evidence that injection of CCK-SAP in NG is a novel selective vagal deafferentation technique of the upper GI tract that works in multiple vertebrate models. This method provides improved tissue specificity and superior separation of afferent and efferent signaling compared with vagotomy, capsaicin, and subdiaphragmatic deafferentation. NEW & NOTEWORTHY We develop a new method that allows targeted lesioning of vagal afferent neurons that innervate the upper GI tract while sparing vagal efferent neurons. This reliable approach provides superior tissue specificity and selectivity for vagal afferent over efferent targeting than traditional approaches. It can be used to address questions about the role of gut to brain signaling in physiological and pathophysiological conditions. Copyright © 2017 the American Physiological Society.

The sensory innervation of the calvarial periosteum is nociceptive and contributes to headache-like behavior

PubMed Central

Zhao, Jun; Levy, Dan

2014-01-01

Headaches are thought to result from the activation and sensitization of nociceptors that innervate deep cephalic tissues. A large body of evidence supports the view that some types of headaches originate intracranially, from activation of sensory neurons that innervate the cranial meninges. However the notion of an extracranial origin of headaches continues to be entertained, although the identity of deep extracranial cephalic tissues which might contribute to headaches remains elusive. Here we employed anatomical, electrophysiological, and behavioral approaches in rats to test the hypothesis that the sensory innervation of the calvarial periosteum is nociceptive. Neural tracing indicated that the calvarial periosteum overlying the frontal and parietal bones is innervated primarily by small and medium-sized neurons in the trigeminal ganglion’s ophthalmic division. In vivo single unit recording in the trigeminal ganglion revealed that calvarial periosteal afferents have slowly conducting axons, are mechanosensitive and respond to inflammatory mediators, consistent with a nociceptive function. Two distinct neuronal populations were distinguished based on their peripheral axonal trajectory: one that reached the periosteum through extracranial branches of the trigeminal nerve, and another that took an intracranial trajectory, innervating the cranial dura and apparently reaching the periosteum via the calvarial sutures. In behavioral studies, inflammatory stimulation of these afferents promoted periorbital tactile hypersensitivity, a sensory change linked to primary headaches. Activation and sensitization of calvarial periosteal afferents could play a role in mediating primary headaches of extracranial and perhaps also intracranial origin, as well as secondary headaches such as post-craniotomy and post-traumatic headaches. Targeting calvarial periosteal afferents may be effective in ameliorating these headaches. PMID:24769138

A role for the melanocortin 4 receptor in sexual function.

PubMed

Van der Ploeg, Lex H T; Martin, William J; Howard, Andrew D; Nargund, Ravi P; Austin, Christopher P; Guan, Xiaoming; Drisko, Jennifer; Cashen, Doreen; Sebhat, Iyassu; Patchett, Arthur A; Figueroa, David J; DiLella, Anthony G; Connolly, Brett M; Weinberg, David H; Tan, Carina P; Palyha, Oksana C; Pong, Sheng-Shung; MacNeil, Tanya; Rosenblum, Charles; Vongs, Aurawan; Tang, Rui; Yu, Hong; Sailer, Andreas W; Fong, Tung Ming; Huang, Cathy; Tota, Michael R; Chang, Ray S; Stearns, Ralph; Tamvakopoulos, Constantin; Christ, George; Drazen, Deborah L; Spar, Brian D; Nelson, Randy J; MacIntyre, D Euan

2002-08-20

By using a combination of genetic, pharmacological, and anatomical approaches, we show that the melanocortin 4 receptor (MC4R), implicated in the control of food intake and energy expenditure, also modulates erectile function and sexual behavior. Evidence supporting this notion is based on several findings: (i) a highly selective non-peptide MC4R agonist augments erectile activity initiated by electrical stimulation of the cavernous nerve in wild-type but not Mc4r-null mice; (ii) copulatory behavior is enhanced by administration of a selective MC4R agonist and is diminished in mice lacking Mc4r; (iii) reverse transcription (RT)-PCR and non-PCR based methods demonstrate MC4R expression in rat and human penis, and rat spinal cord, hypothalamus, brainstem, pelvic ganglion (major autonomic relay center to the penis), but not in rat primary corpus smooth muscle cavernosum cells; and (iv) in situ hybridization of glans tissue from the human and rat penis reveal MC4R expression in nerve fibers and mechanoreceptors in the glans of the penis. Collectively, these data implicate the MC4R in the modulation of penile erectile function and provide evidence that MC4R-mediated proerectile responses may be activated through neuronal circuitry in spinal cord erectile centers and somatosensory afferent nerve terminals of the penis. Our results provide a basis for the existence of MC4R-controlled neuronal pathways that control sexual function.

Convergence of excitatory and inhibitory hair cell transmitters shapes vestibular afferent responses.

PubMed

Holstein, Gay R; Rabbitt, Richard D; Martinelli, Giorgio P; Friedrich, Victor L; Boyle, Richard D; Highstein, Stephen M

2004-11-02

The vestibular semicircular canals respond to angular acceleration that is integrated to angular velocity by the biofluid mechanics of the canals and is the primary origin of afferent responses encoding velocity. Surprisingly, some afferents actually report angular acceleration. Our data indicate that hair-cell/afferent synapses introduce a mathematical derivative in these afferents that partially cancels the biomechanical integration and results in discharge rates encoding angular acceleration. We examined the role of convergent synaptic inputs from hair cells to this mathematical differentiation. A significant reduction in the order of the differentiation was observed for low-frequency stimuli after gamma-aminobutyric acid type B receptor antagonist administration. Results demonstrate that gamma-aminobutyric acid participates in shaping the temporal dynamics of afferent responses.

Muscle Spindle Traffic in Functionally Unstable Ankles During Ligamentous Stress

PubMed Central

Needle, Alan R.; Charles B. (Buz), Swanik; Farquhar, William B.; Thomas, Stephen J.; Rose, William C.; Kaminski, Thomas W.

2013-01-01

Context: Ankle sprains are common in athletes, with functional ankle instability (FAI) developing in approximately half of cases. The relationship between laxity and FAI has been inconclusive, suggesting that instability may be caused by insufficient sensorimotor function and dynamic restraint. Research has suggested that deafferentation of peripheral mechanoreceptors potentially causes FAI; however, direct evidence confirming peripheral sensory deficits has been elusive because previous investigators relied upon subjective proprioceptive tests. Objective: To develop a method for simultaneously recording peripheral sensory traffic, joint forces, and laxity and to quantify differences between healthy ankles and those with reported instability. Design: Case-control study. Setting: University laboratory. Patients or Other Participants: A total of 29 participants (age = 20.9 ± 2.2 years, height = 173.1 ± 8.9 cm, mass = 74.5 ± 12.7 kg) stratified as having healthy (HA, n = 19) or unstable ankles (UA, n = 10). Intervention(s): Sensory traffic from muscle spindle afferents in the peroneal nerve was recorded with microneurography while anterior (AP) and inversion (IE) stress was applied to ligamentous structures using an ankle arthrometer under test and sham conditions. Main Outcome Measure(s): Laxity (millimeters or degrees) and amplitude of sensory traffic (percentage) were determined at 0, 30, 60, 90, and 125 N of AP force and at 0, 1, 2, 3, and 4 Nm of IE torque. Two-factor repeated-measures analyses of variance were used to determine differences between groups and conditions. Results: No differences in laxity were observed between groups (P > .05). Afferent traffic increased with increased force and torque in test trials (P < .001). The UA group displayed decreased afferent activity at 30 N of AP force compared with the HA group (HA: 30.2% ± 9.9%, UA: 17.1% ± 16.1%, P < .05). Conclusions: The amplitude of sensory traffic increased simultaneously with greater ankle motion and loading, providing evidence of the integrated role of capsuloligamentous and musculotendinous mechanoreceptors in maintaining joint sensation. Unstable ankles demonstrated diminished afferent traffic at low levels of force, suggesting the early detection of joint loading may be compromised. PMID:23672383

Hair cell tufts and afferent innervation of the bullfrog crista ampullaris

NASA Technical Reports Server (NTRS)

Myers, Steven F.; Lewis, Edwin R.

1990-01-01

Within the bullfrog semicircular canal crista, hair cell tuft types were defined and mapped with the aid of scanning electron microscopy. Dye-filled planar afferent axons had mean distal axonal diameters of 1.6-4.9 microns, highly branched arbors, and contacted 11-24 hair cells. Dye-filled isthmus afferent axons had mean distal axonal diameters of 1.8-7.9 microns, with either small or large field arbors contacting 4-9 or 25-31 hair cells. The estimated mean number of contacts per innervated hair cell was 2.2 for planar and 1.3 for isthmus afferent neurons. Data on evoked afferent responses were available only for isthmus units that were observed to respond to our microrotational stimuli. Of 21 such afferent neurons, eight were successfully dye-filled. Within this sample, high-gain units had large field arbors and lower-gain units had small field arbors. The sensitivity of each afferent neuron was analyzed in terms of noise equivalent input (NEI), the stimulus amplitude for which the afferent response amplitude is just equivalent to the rms deviation of the instantaneous spike rate. NEI for isthmus units varied from 0.63 to 8.2 deg/s; the mean was 3.2 deg/s.

Primary afferent neurons express functional delta opioid receptors in inflamed skin.

PubMed

Brederson, Jill-Desiree; Honda, Christopher N

2015-07-21

Peripherally-restricted opiate compounds attenuate hyperalgesia in experimental models of inflammatory pain, but have little discernable effect on nociceptive behavior in normal animals. This suggests that activation of opioid receptors on peripheral sensory axons contributes to decreased afferent activity after injury. Previously, we reported that direct application of morphine to cutaneous receptive fields decreased mechanical and heat-evoked responses in a population of C-fiber nociceptors in inflamed skin. Consistent with reported behavioral studies, direct application of morphine had no effect on fiber activity in control skin. The aim of the present study was to determine whether mechanical responsiveness of nociceptors innervating inflamed skin was attenuated by direct activation of delta opioid receptors (DORs) on peripheral terminals. An ex vivo preparation of rat plantar skin and tibial nerve was used to examine effects of a selective DOR agonist, deltorphin II, on responsiveness of single fibers innervating inflamed skin. Electrical recordings were made eighteen hours after injection of complete Freund's adjuvant into the hindpaw. Deltorphin II produced an inhibition of the mechanical responsiveness of single fibers innervating inflamed skin; an effect blocked by the DOR-selective antagonist, naltrindole. The population of units responsive to deltorphin II was identified as consisting of C fiber mechanical nociceptors. Copyright © 2015 Elsevier B.V. All rights reserved.

[Acute pancreatitis and afferent loop syndrome. Case report].

PubMed

Barajas-Fregoso, Elpidio Manuel; Romero-Hernández, Teodoro; Macías-Amezcua, Michel Dassaejv

2013-01-01

The afferent syndrome loop is a mechanic obstruction of the afferent limb before a Billroth II or Roux-Y reconstruction, secondary in most of case to distal or subtotal gastrectomy. Clinical case: Male 76 years old, with antecedent of cholecystectomy, gastric adenocarcinoma six years ago, with subtotal gastrectomy and Roux-Y reconstruction. Beginning a several abdominal pain, nausea and vomiting, abdominal distension, without peritoneal irritation sings. Amylase 1246 U/L, lipase 3381 U/L. Computed Tomography with thickness wall and dilatation of afferent loop, pancreas with diffuse enlargement diagnostic of acute pancreatitis secondary an afferent loop syndrome. The afferent loop syndrome is presented in 0.3%-1% in all cases with Billroth II reconstruction, with a mortality of up to 57%, the obstruction lead accumulation of bile, pancreatic and intestinal secretions, increasing the pressure and resulting in afferent limb, bile conduct and Wirsung conduct dilatation, triggering an inflammatory response that culminates in pancreatic inflammation. The severity of the presentation is related to the degree and duration of the blockage.

Role of corticostriatal and nigrostriatal inputs in malonate-induced striatal toxicity.

PubMed

Meldrum, A; Dunnett, S B; Everitt, B J

2001-01-22

The striatal neuronal loss evident following cellular metabolic compromise may be dependent upon the presence of glutamate and dopamine within the striatum. In order to investigate the relative roles of corticostriatal and nigrostriatal projections in malonate-induced neuronal loss, the extent of toxicity was quantified in animals with cortical lesions to deplete the striatum of glutamate, nigrostriatal lesions to deplete the striatum of dopamine, or both. We found that malonate-induced striatal toxicity was significantly reduced following lesions of either the glutamatergic or dopaminergic afferents to the striatum. The extent of attenuation following the loss of both inputs within the same animal was similar to that seen following lesions of either alone. These data suggest that malonate-induced toxicity in the striatum depends upon the integrity of interactive influences from both glutamatergic and dopaminergic afferents.

Substance P presynaptically depresses the transmission of sensory input to bronchopulmonary neurons in the guinea pig nucleus tractus solitarii

PubMed Central

Sekizawa, Shin-ichi; Joad, Jesse P; Bonham, Ann C

2003-01-01

Substance P modulates the reflex regulation of respiratory function by its actions both peripherally and in the CNS, particularly in the nucleus tractus solitarii (NTS), the first central site for synaptic contact of the lung and airway afferent fibres. There is considerable evidence that the actions of substance P in the NTS augment respiratory reflex output, but the precise effects on synaptic transmission have not yet been determined. Therefore, we determined the effects of substance P on synaptic transmission at the first central synapses by using whole-cell voltage clamping in an NTS slice preparation. Studies were performed on second-order neurons in the slice anatomically identified as receiving monosynaptic input from sensory nerves in the lungs and airways. This was done by the fluorescent labelling of terminal boutons after 1,1′-dioctadecyl-3,3,3′,3′-tetra-methylindocarbo-cyanine perchlorate (DiI) was applied via tracheal instillation. Substance P (1.0, 0.3 and 0.1 μM) significantly decreased the amplitude of excitatory postsynaptic currents (eEPSCs) evoked by stimulation of the tractus solitarius, in a concentration-dependent manner. The decrease was accompanied by an increase in the paired-pulse ratio of two consecutive eEPSCs, and a decrease in the frequency, but not the amplitude, of spontaneous EPSCs and miniature EPSCs, findings consistent with a presynaptic site of action. The effects were consistently and significantly attenuated by a neurokinin-1 (NK1) receptor antagonist (SR140333, 3 μM). The data suggest a new site of action for substance P in the NTS (NK1 receptors on the central terminals of sensory fibres) and a new mechanism (depression of synaptic transmission) for regulating respiratory reflex function. PMID:14561836

Afferent control of central pattern generators: experimental analysis of scratching in the decerebrate cat.

PubMed

Baev, K V; Esipenko, V B; Shimansky, Y P

1991-01-01

Systematic quantitative analysis of changes in the spinal scratching generator motor activity evoked by tonic and phasic peripheral afferent signals during "fictitious" scratching was carried out in the cat. Correlations between the kinematics of hindlimb scratching movement, sensory inflow, and primary afferent depolarization were investigated. Reliable correlations between the parameters of generator motor activity during fictitious scratching were revealed: they depended on tonic peripheral afferent inflow. The functional role of these dependencies consists of providing stability for aiming the hindlimb to the itch site. It was shown that scratching generator reaction to a phasic sensory signal depended significantly on afferent input, signal intensity, and its arrival phase in the cycle of motor activity. Phase correction of "scratching" rhythm was performed by inhibition of the current stage of "scratching" cycle, the inhibition magnitude depending on the intensity of a sensory signal run along high threshold afferent fibers. The moments in the scratching cycle, in which the afferent signal caused no rearrangement in scratching generator activity, were discovered for all investigated afferent inputs. These moments corresponded to the transitions from one scratching cycle phase to another. Integral afferent activity was distributed unevenly in the cycle during real scratching. The main part of it was observed just in that scratching cycle part which included the above mentioned no rearrangement phase points. The data obtained allowed us to conclude that the scratching generator should be considered as a working program for the motor optimal control system containing the intrinsic model of the controlled object dynamics (e.g. hindlimb scratching movement dynamics), which produces an inner analog of peripheral flow. This inner flow interacts with peripheral afferent inflow just as one of the latter components. Centrally originated modulation of primary afferent depolarization is a result of affecting the depolarization generating system by this inner "sensory" activity. It is the model, with the aid of which the generator can work after deafferentation. The functional organization of a central pattern generator is considered.

Profiling of G protein-coupled receptors in vagal afferents reveals novel gut-to-brain sensing mechanisms.

PubMed

Egerod, Kristoffer L; Petersen, Natalia; Timshel, Pascal N; Rekling, Jens C; Wang, Yibing; Liu, Qinghua; Schwartz, Thue W; Gautron, Laurent

2018-06-01

G protein-coupled receptors (GPCRs) act as transmembrane molecular sensors of neurotransmitters, hormones, nutrients, and metabolites. Because unmyelinated vagal afferents richly innervate the gastrointestinal mucosa, gut-derived molecules may directly modulate the activity of vagal afferents through GPCRs. However, the types of GPCRs expressed in vagal afferents are largely unknown. Here, we determined the expression profile of all GPCRs expressed in vagal afferents of the mouse, with a special emphasis on those innervating the gastrointestinal tract. Using a combination of high-throughput quantitative PCR, RNA sequencing, and in situ hybridization, we systematically quantified GPCRs expressed in vagal unmyelinated Na v 1.8-expressing afferents. GPCRs for gut hormones that were the most enriched in Na v 1.8-expressing vagal unmyelinated afferents included NTSR1, NPY2R, CCK1R, and to a lesser extent, GLP1R, but not GHSR and GIPR. Interestingly, both GLP1R and NPY2R were coexpressed with CCK1R. In contrast, NTSR1 was coexpressed with GPR65, a marker preferentially enriched in intestinal mucosal afferents. Only few microbiome-derived metabolite sensors such as GPR35 and, to a lesser extent, GPR119 and CaSR were identified in the Na v 1.8-expressing vagal afferents. GPCRs involved in lipid sensing and inflammation (e.g. CB1R, CYSLTR2, PTGER4), and neurotransmitters signaling (CHRM4, DRD2, CRHR2) were also highly enriched in Na v 1.8-expressing neurons. Finally, we identified 21 orphan GPCRs with unknown functions in vagal afferents. Overall, this study provides a comprehensive description of GPCR-dependent sensing mechanisms in vagal afferents, including novel coexpression patterns, and conceivably coaction of key receptors for gut-derived molecules involved in gut-brain communication. Copyright © 2018 The Authors. Published by Elsevier GmbH.. All rights reserved.

Different types of spinal afferent nerve endings in stomach and esophagus identified by anterograde tracing from dorsal root ganglia.

PubMed

Spencer, Nick J; Kyloh, Melinda; Beckett, Elizabeth A; Brookes, Simon; Hibberd, Tim

2016-10-15

In visceral organs of mammals, most noxious (painful) stimuli as well as innocuous stimuli are detected by spinal afferent neurons, whose cell bodies lie in dorsal root ganglia (DRGs). One of the major unresolved questions is the location, morphology, and neurochemistry of the nerve endings of spinal afferents that actually detect these stimuli in the viscera. In the upper gastrointestinal (GI) tract, there have been many anterograde tracing studies of vagal afferent endings, but none on spinal afferent endings. Recently, we developed a technique that now provides selective labeling of only spinal afferents. We used this approach to identify spinal afferent nerve endings in the upper GI tract of mice. Animals were anesthetized, and injections of dextran-amine were made into thoracic DRGs (T8-T12). Seven days post surgery, mice were euthanized, and the stomach and esophagus were removed, fixed, and stained for calcitonin gene-related peptide (CGRP). Spinal afferent axons were identified that ramified extensively through many rows of myenteric ganglia and formed nerve endings in discrete anatomical layers. Most commonly, intraganglionic varicose endings (IGVEs) were identified in myenteric ganglia of the stomach and varicose simple-type endings in the circular muscle and mucosa. Less commonly, nerve endings were identified in internodal strands, blood vessels, submucosal ganglia, and longitudinal muscle. In the esophagus, only IGVEs were identified in myenteric ganglia. No intraganglionic lamellar endings (IGLEs) were identified in the stomach or esophagus. We present the first identification of spinal afferent endings in the upper GI tract. Eight distinct types of spinal afferent endings were identified in the stomach, and most of them were CGRP immunoreactive. J. Comp. Neurol. 524:3064-3083, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

The final stage of cholinergic differentiation occurs below inner hair cells during development of the rodent cochlea.

PubMed

Bergeron, Adam L; Schrader, Angela; Yang, Dan; Osman, Abdullah A; Simmons, Dwayne D

2005-12-01

To gain further insights into the cholinergic differentiation of presynaptic efferent terminals in the inner ear, we investigated the expression of the high-affinity choline transporter (ChT1) in comparison to other presynaptic and cholinergic markers. In the adult mammalian cochlea, cholinergic axons from medial olivocochlear (OC) neurons form axosomatic synapses with outer hair cells (OHCs), whereas axons from lateral OC neurons form axodendritic synapses on afferent fibers below inner hair cells (IHCs). Mouse brain and cochlea homogenates reveal at least two ChT1 isoforms: a nonglycosylated approximately 73 kDa protein and a glycosylated approximately 45 kDa protein. In mouse brain, ChT1 is preferentially expressed by neurons in periolivary regions of the superior olive consistent with the location of medial OC neurons. In the adult mouse cochlea, ChT1-positive terminals are located almost exclusively below OHCs consistent with a medial OC innervation. Between postnatal day 2 (P2) and P4, ChT1-positive terminals are below IHCs and occur after the expression of growth-associated protein 43, synapsin, and the vesicular acetylcholine transporter. By P15, ChT1-positive terminals are mostly on OHCs. Accounting for differences in gestational age, the developmental expression of ChT1 in the rat cochlea is similar to the mouse. However, in older rats ChT1-positive terminals are below IHCs and OHCs. In both rat and mouse, our observations indicate that the onset of ChT1 expression occurs after efferent terminals are below IHCs and express other presynaptic and cholinergic markers. In the mouse, but not in the rat, ChT1 may preferentially identify medial OC neurons.

Experiment K-7-31: Studies of Vestibular Primary Afferents and Eye Movements in Normal, Hypergravity and Hypogravity - Axon Cosmos Flight 2044

NASA Technical Reports Server (NTRS)

Correia, M. J.; Perachio, A. A.; Dickman, J. D.; Kozlovskaya, I.; Sirota, M.; Yakushin, S.; Beloozerova, I. N.

1994-01-01

Fourteen days of active head movements in microgravity appear to modify the gain and neural adaptation properties of the horizontal semicircular canals in the rhesus monkey. This is the first demonstration of adaptive plasticity in the sensory receptor. Reversing prisms, for example, do not modify the gain of the primary afferent response. Pulse yaw rotation, sinusoidal rotation, and sum of sinusoidal rotation testing during the first day following recovery revealed that the gain of a sample of afferents was significantly greater than the gain derived from afferent responses obtained during pre-flight and control monkey testing. There was no strong evidence of tilt sensitivity in the sample of afferents that we tested either during the pre-flight or control tests or during the first day post-flight. Two irregular afferents tested on postflight day 2 showed changes with tilt but the responses were not systematic. The spontaneous discharge did not change following flight. Mean firing rate and coefficient of variation remained constant during the post flight tests and was near the value measured during pre flight tests. The change in gain of horizontal canal afferents might be adaptive. The animals were required to look at a target for food. This required active head and eye movements. Active head movements have been shown to be hypometric and eye movements have been shown to be hypermetric during the first few days of past Cosmos flights (see introduction). It might be that the increased gain in the horizontal semicircular canals permit accurate target acquisition during hypometric head movements by driving the eyes to greater angles for smaller angles of head movement. The mechanism by which the semicircular canals recalibrate (increase their gain) is unknown. The efferent vestibular system is a logical candidate. Horizontal nystagmus during rotation about an earth vertical axis with the horizontal semicircular canals in the plane of rotation produced the same response during postflight day 1 and post-flight day 9. But when the head was pitched down 45? the nystagmus slow phase velocity was greater and the duration was about twice during post-flight day 1. Apparently, this response involving the interaction of the horizontal and vertical semicircular canals and the otoliths did not recalibrate during post-flight day 1. The 'DC' bias of the slow phase velocity of the horizontal nystagmus during constant velocity horizontal axis rotation was roughly 4 times for one flight monkey and roughly 2 times for the other on post-flight day 1 compared to post-flight day 9. These results suggest that the otolith mediated response during constant velocity rotation also did not recalibrate on post-flight day 1.

Evidence against a hypothesis of vestibular efferent function

NASA Technical Reports Server (NTRS)

Cochran, S. L.

1994-01-01

Efferent stimulation and nicotinic agonists can either decrease or increase the frequency of occurrence of EPSPs recorded from VIIIth nerve afferents in the frog. It has been hypothesized that the distribution of hair cell resting membrane potentials overlaps the equilibrium potential dictated by the nicotinic-gated channels on the hair cells. Nicotinic mediated increases in EPSP frequency would then be due to depolarization of hair cells that were more hyperpolarized at rest, while decreases in EPSP frequency would be due to hyperpolarization of hair cells more depolarized at rest. In order to test this hypothesis, while recording from afferents which showed an increase in EPSP frequency due to bath application of the nicotinic agonist DMPP (1,1-dimethyl-4-phenylpiperizinium iodide), hair cells were depolarized with 10 mM K+ in the bath, and then the effects of DMPP on EPSP frequency were assessed. In this situation, DMPP still increased EPSP frequency, suggesting that the equilibrium potential for the nicotinic-gated channel was much more positive than the resting potentials of the hair cells. An alternative hypothesis then seems likely, that the nicotinic receptors on hair cells are able to activate different iontophores that result in either hair cell depolarization or hyperpolarization, dependent upon which iontophore predominates in the hair cells innervating a particular afferent.

Synaptic pathology in the cerebellar dentate nucleus in chronic multiple sclerosis.

PubMed

Albert, Monika; Barrantes-Freer, Alonso; Lohrberg, Melanie; Antel, Jack P; Prineas, John W; Palkovits, Miklós; Wolff, Joachim R; Brück, Wolfgang; Stadelmann, Christine

2017-11-01

In multiple sclerosis, cerebellar symptoms are associated with clinical impairment and an increased likelihood of progressive course. Cortical atrophy and synaptic dysfunction play a prominent role in cerebellar pathology and although the dentate nucleus is a predilection site for lesion development, structural synaptic changes in this region remain largely unexplored. Moreover, the mechanisms leading to synaptic dysfunction have not yet been investigated at an ultrastructural level in multiple sclerosis. Here, we report on synaptic changes of dentate nuclei in post-mortem cerebella of 16 multiple sclerosis patients and eight controls at the histological level as well as an electron microscopy evaluation of afferent synapses of the cerebellar dentate and pontine nuclei of one multiple sclerosis patient and one control. We found a significant reduction of afferent dentate synapses in multiple sclerosis, irrespective of the presence of demyelination, and a close relationship between glial processes and dentate synapses. Ultrastructurally, we show autophagosomes containing degradation products of synaptic vesicles within dendrites, residual bodies within intact-appearing axons and free postsynaptic densities opposed to astrocytic appendages. Our study demonstrates loss of dentate afferent synapses and provides, for the first time, ultrastructural evidence pointing towards neuron-autonomous and neuroglia-mediated mechanisms of synaptic degradation in chronic multiple sclerosis. © 2016 International Society of Neuropathology.

Food choice as a key management strategy for functional gastrointestinal symptoms.

PubMed

Gibson, Peter R; Shepherd, Susan J

2012-05-01

Recognition of food components that induce functional gut symptoms in patient's functional bowel disorders (FBD) has been challenging. Food directly or indirectly provides considerable afferent input into the enteric nervous system. There is an altered relationship between the afferent input and perception/efferent response in FBD. Defining the nature of food-related stimuli may provide a means of minimizing such an input and gut symptoms. Using this premise, reducing the intake of FODMAPs (fermentable oligo-, di-, and mono-saccharides and polyols)--poorly absorbed short-chain carbohydrates that, by virtue of their small molecular size and rapid fermentability, will distend the intestinal lumen with liquid and gas--improves symptoms in the majority of patients. Well-developed methodologies to deliver the diet via dietician-led education are available. Another abundant source of afferent input is natural and added food chemicals (such as salicylates, amines, and glutamates). Studies are needed to assess the efficacy of the low food chemical dietary approach. A recent placebo-controlled trial of FODMAP-poor gluten provided the first valid evidence that non-celiac gluten intolerance might actually exist, but its prevalence and underlying mechanisms require elucidation. Food choice via the low FODMAP and potentially other dietary strategies is now a realistic and efficacious therapeutic approach for functional gut symptoms.

Neuron-Glia Crosstalk and Neuropathic Pain: Involvement in the Modulation of Motor Activity in the Orofacial Region.

PubMed

Hossain, Mohammad Zakir; Unno, Shumpei; Ando, Hiroshi; Masuda, Yuji; Kitagawa, Junichi

2017-09-26

Neuropathic orofacial pain (NOP) is a debilitating condition. Although the pathophysiology remains unclear, accumulating evidence suggests the involvement of multiple mechanisms in the development of neuropathic pain. Recently, glial cells have been shown to play a key pathogenetic role. Nerve injury leads to an immune response near the site of injury. Satellite glial cells are activated in the peripheral ganglia. Various neural and immune mediators, released at the central terminals of primary afferents, lead to the sensitization of postsynaptic neurons and the activation of glia. The activated glia, in turn, release pro-inflammatory factors, further sensitizing the neurons, and resulting in central sensitization. Recently, we observed the involvement of glia in the alteration of orofacial motor activity in NOP. Microglia and astroglia were activated in the trigeminal sensory and motor nuclei, in parallel with altered motor functions and a decreased pain threshold. A microglial blocker attenuated the reduction in pain threshold, reduced the number of activated microglia, and restored motor activity. We also found an involvement of the astroglial glutamate-glutamine shuttle in the trigeminal motor nucleus in the alteration of the jaw reflex. Neuron-glia crosstalk thus plays an important role in the development of pain and altered motor activity in NOP.

Neuron–Glia Crosstalk and Neuropathic Pain: Involvement in the Modulation of Motor Activity in the Orofacial Region

PubMed Central

Unno, Shumpei; Ando, Hiroshi; Masuda, Yuji; Kitagawa, Junichi

2017-01-01

Neuropathic orofacial pain (NOP) is a debilitating condition. Although the pathophysiology remains unclear, accumulating evidence suggests the involvement of multiple mechanisms in the development of neuropathic pain. Recently, glial cells have been shown to play a key pathogenetic role. Nerve injury leads to an immune response near the site of injury. Satellite glial cells are activated in the peripheral ganglia. Various neural and immune mediators, released at the central terminals of primary afferents, lead to the sensitization of postsynaptic neurons and the activation of glia. The activated glia, in turn, release pro-inflammatory factors, further sensitizing the neurons, and resulting in central sensitization. Recently, we observed the involvement of glia in the alteration of orofacial motor activity in NOP. Microglia and astroglia were activated in the trigeminal sensory and motor nuclei, in parallel with altered motor functions and a decreased pain threshold. A microglial blocker attenuated the reduction in pain threshold, reduced the number of activated microglia, and restored motor activity. We also found an involvement of the astroglial glutamate–glutamine shuttle in the trigeminal motor nucleus in the alteration of the jaw reflex. Neuron–glia crosstalk thus plays an important role in the development of pain and altered motor activity in NOP. PMID:28954391

A Comparison of Different Slicing Planes in Preservation of Major Hippocampal Pathway Fibers in the Mouse

PubMed Central

Xiong, Guoxiang; Metheny, Hannah; Johnson, Brian N.; Cohen, Akiva S.

2017-01-01

The hippocampus plays a critical role in learning and memory and higher cognitive functions, and its dysfunction has been implicated in various neuropathological disorders. Electrophysiological recording undertaken in live brain slices is one of the most powerful tools for investigating hippocampal cellular and network activities. The plane for cutting the slices determines which afferent and/or efferent connections are best preserved, and there are three commonly used slices: hippocampal-entorhinal cortex (HEC), coronal and transverse. All three slices have been widely used for studying the major afferent hippocampal pathways including the perforant path (PP), the mossy fibers (MFs) and the Schaffer collaterals (SCs). Surprisingly, there has never been a systematic investigation of the anatomical and functional consequences of slicing at a particular angle. In the present study, we focused on how well fiber pathways are preserved from the entorhinal cortex (EC) to the hippocampus, and within the hippocampus, in slices generated by sectioning at different angles. The postmortem neural tract tracer 1,1′-dioctadecyl-3,3,3′3′-tetramethylindocarbocyanine perchlorate (DiI) was used to label afferent fibers to hippocampal principal neurons in fixed slices or whole brains. Laser scanning confocal microscopy was adopted for imaging DiI-labeled axons and terminals. We demonstrated that PP fibers were well preserved in HEC slices, MFs in both HEC and transverse slices and SCs in all three types of slices. Correspondingly, field excitatory postsynaptic potentials (fEPSPs) could be consistently evoked in HEC slices when stimulating PP fibers and recorded in stratum lacunosum-moleculare (sl-m) of area CA1, and when stimulating the dentate granule cell layer (gcl) and recording in stratum lucidum (sl) of area CA3. The MF evoked fEPSPs could not be recorded in CA3 from coronal slices. In contrast to our DiI-tracing data demonstrating severely truncated PP fibers in coronal slices, fEPSPs could still be recorded in CA1 sl-m in this plane, suggesting that an additional afferent fiber pathway other than PP might be involved. The present study increases our understanding of which hippocampal pathways are best preserved in the three most common brain slice preparations, and will help investigators determine the appropriate slices to use for physiological studies depending on the subregion of interest. PMID:29201002

Permanent reorganization of Ia afferent synapses on motoneurons after peripheral nerve injuries

PubMed Central

Alvarez, Francisco J.; Bullinger, Katie L.; Titus, Haley E.; Nardelli, Paul; Cope, Timothy C.

2010-01-01

After peripheral nerve injuries to a motor nerve the axons of motoneurons and proprioceptors are disconnected from the periphery and monosynaptic connections from group I afferents and motoneurons become diminished in the spinal cord. Following successful reinnervation in the periphery, motor strength, proprioceptive sensory encoding, and Ia afferent synaptic transmission on motoneurons partially recover. Muscle stretch reflexes, however, never recover and motor behaviors remain uncoordinated. In this review, we summarize recent findings that suggest that lingering motor dysfunction might be in part related to decreased connectivity of Ia afferents centrally. First, sensory afferent synapses retract from lamina IX causing a permanent relocation of the inputs to more distal locations and significant disconnection from motoneurons. Second, peripheral reconnection between proprioceptive afferents and muscle spindles is imperfect. As a result, a proportion of sensory afferents that retain central connections with motoneurons might not reconnect appropriately in the periphery. A hypothetical model is proposed in which the combined effect of peripheral and central reconnection deficits might explain the failure of muscle stretch to initiate or modulate firing of many homonymous motoneurons. PMID:20536938

Rat isolated phrenic nerve-diaphragm preparation for pharmacological study of muscle spindle afferent activity: effect of oxotremorine.

PubMed Central

Ganguly, D K; Nath, D N; Ross, H G; Vedasiromoni, J R

1978-01-01

1. Muscle spindle afferent discharges exhibiting an approximately linear length-frequency relation could be recorded from the phrenic nerve in the isolated phrenic nerve-diaphragm preparation of the rat. 2. Muscle spindle afferent discharges could be identified by their characteristic "spindle pause" during muscle contraction and by their response to succinylcholine. 3. Cholinergic influence on spontaneous and stretch-induced afferent discharges was indicated by the augmentation produced by physostigmine and acetylcholine. (+)-Tubocurarine, but not atropine, prevented this augmentation indicating the presence of curariform cholinoceptors in muscle spindles. 4. Acetylcholine did not appear to be involved in the genesis of spindle afferent discharges as incubation with hemicholinium-3 and (+)-tubocurarine failed to affect the rate of spontaneous and stretch-induced spindle discharges. 5. Oxotremorine markedly increased the rate of spontaneous and stretch-induced spindle afferent discharges and this effect was prevented in the presence of hemicholinium-3 and (+)-tubocurarine. 6. These results with oxotremorine are of interest in connection with the observation that muscle spindle afferents and hyperactive in Parkinsonian patients. PMID:151569

Potentiation of NMDA receptor-mediated transmission in striatal cholinergic interneurons

PubMed Central

Oswald, Manfred J.; Schulz, Jan M.; Kelsch, Wolfgang; Oorschot, Dorothy E.; Reynolds, John N. J.

2015-01-01

Pauses in the tonic firing of striatal cholinergic interneurons (CINs) emerge during reward-related learning in response to conditioning of a neutral cue. We have previously reported that augmenting the postsynaptic response to cortical afferents in CINs is coupled to the emergence of a cell-intrinsic afterhyperpolarization (AHP) underlying pauses in tonic activity. Here we investigated in a bihemispheric rat-brain slice preparation the mechanisms of synaptic plasticity of excitatory afferents to CINs and the association with changes in the AHP. We found that high frequency stimulation (HFS) of commissural corticostriatal afferents from the contralateral hemisphere induced a robust long-term depression (LTD) of postsynaptic potentials (PSP) in CINs. Depression of the PSP of smaller magnitude and duration was observed in response to HFS of the ipsilateral white matter or cerebral cortex. In Mg2+-free solution HFS induced NMDA receptor-dependent potentiation of the PSP, evident in both the maximal slope and amplitude of the PSP. The increase in maximal slope corroborates previous findings, and was blocked by antagonism of either D1-like dopamine receptors with SCH23390 or D2-like dopamine receptors with sulpiride during HFS in Mg2+-free solution. Potentiation of the slower PSP amplitude component was due to augmentation of the NMDA receptor-mediated potential as this was completely reversed on subsequent application of the NMDA receptor antagonist AP5. HFS similarly potentiated NMDA receptor currents isolated by blockade of AMPA/kainate receptors with CNQX. The plasticity-induced increase in the slow PSP component was directly associated with an increase in the subsequent AHP. Thus plasticity of cortical afferent synapses is ideally suited to influence the cue-induced firing dynamics of CINs, particularly through potentiation of NMDA receptor-mediated synaptic transmission. PMID:25914618

Potentiation of NMDA receptor-mediated transmission in striatal cholinergic interneurons.

PubMed

Oswald, Manfred J; Schulz, Jan M; Kelsch, Wolfgang; Oorschot, Dorothy E; Reynolds, John N J

2015-01-01

Pauses in the tonic firing of striatal cholinergic interneurons (CINs) emerge during reward-related learning in response to conditioning of a neutral cue. We have previously reported that augmenting the postsynaptic response to cortical afferents in CINs is coupled to the emergence of a cell-intrinsic afterhyperpolarization (AHP) underlying pauses in tonic activity. Here we investigated in a bihemispheric rat-brain slice preparation the mechanisms of synaptic plasticity of excitatory afferents to CINs and the association with changes in the AHP. We found that high frequency stimulation (HFS) of commissural corticostriatal afferents from the contralateral hemisphere induced a robust long-term depression (LTD) of postsynaptic potentials (PSP) in CINs. Depression of the PSP of smaller magnitude and duration was observed in response to HFS of the ipsilateral white matter or cerebral cortex. In Mg(2+)-free solution HFS induced NMDA receptor-dependent potentiation of the PSP, evident in both the maximal slope and amplitude of the PSP. The increase in maximal slope corroborates previous findings, and was blocked by antagonism of either D1-like dopamine receptors with SCH23390 or D2-like dopamine receptors with sulpiride during HFS in Mg(2+)-free solution. Potentiation of the slower PSP amplitude component was due to augmentation of the NMDA receptor-mediated potential as this was completely reversed on subsequent application of the NMDA receptor antagonist AP5. HFS similarly potentiated NMDA receptor currents isolated by blockade of AMPA/kainate receptors with CNQX. The plasticity-induced increase in the slow PSP component was directly associated with an increase in the subsequent AHP. Thus plasticity of cortical afferent synapses is ideally suited to influence the cue-induced firing dynamics of CINs, particularly through potentiation of NMDA receptor-mediated synaptic transmission.

Plasticity of gastro-intestinal vagal afferent endings.

PubMed

Kentish, Stephen J; Page, Amanda J

2014-09-01

Vagal afferents are a vital link between the peripheral tissue and central nervous system (CNS). There is an abundance of vagal afferents present within the proximal gastrointestinal tract which are responsible for monitoring and controlling gastrointestinal function. Whilst essential for maintaining homeostasis there is a vast amount of literature emerging which describes remarkable plasticity of vagal afferents in response to endogenous as well as exogenous stimuli. This plasticity for the most part is vital in maintaining healthy processes; however, there are increased reports of vagal plasticity being disrupted in pathological states, such as obesity. Many of the disruptions, observed in obesity, have the potential to reduce vagal afferent satiety signalling which could ultimately perpetuate the obese state. Understanding how plasticity occurs within vagal afferents will open a whole new understanding of gut function as well as identify new treatment options for obesity. Copyright © 2014 Elsevier Inc. All rights reserved.

Antidromic propagation of action potentials in branched axons: implications for the mechanisms of action of deep brain stimulation.

PubMed

Grill, Warren M; Cantrell, Meredith B; Robertson, Matthew S

2008-02-01

Electrical stimulation of the central nervous system creates both orthodromically propagating action potentials, by stimulation of local cells and passing axons, and antidromically propagating action potentials, by stimulation of presynaptic axons and terminals. Our aim was to understand how antidromic action potentials navigate through complex arborizations, such as those of thalamic and basal ganglia afferents-sites of electrical activation during deep brain stimulation. We developed computational models to study the propagation of antidromic action potentials past the bifurcation in branched axons. In both unmyelinated and myelinated branched axons, when the diameters of each axon branch remained under a specific threshold (set by the antidromic geometric ratio), antidromic propagation occurred robustly; action potentials traveled both antidromically into the primary segment as well as "re-orthodromically" into the terminal secondary segment. Propagation occurred across a broad range of stimulation frequencies, axon segment geometries, and concentrations of extracellular potassium, but was strongly dependent on the geometry of the node of Ranvier at the axonal bifurcation. Thus, antidromic activation of axon terminals can, through axon collaterals, lead to widespread activation or inhibition of targets remote from the site of stimulation. These effects should be included when interpreting the results of functional imaging or evoked potential studies on the mechanisms of action of DBS.

Failure to activate the in-hospital emergency team: causes and outcomes.

PubMed

Barbosa, Vera; Gomes, Ernestina; Vaz, Senio; Azevedo, Gustavo; Fernandes, Gonçalo; Ferreira, Amélia; Araujo, Rui

2016-01-01

To determine the incidence of afferent limb failure of the in-hospital Medical Emergency Team, characterizing it and comparing the mortality between the population experiencing afferent limb failure and the population not experiencing afferent limb failure. A total of 478 activations of the Medical Emergency Team of Hospital Pedro Hispano occurred from January 2013 to July 2015. A sample of 285 activations was obtained after excluding incomplete records and activations for patients with less than 6 hours of hospitalization. The sample was divided into two groups: the group experiencing afferent limb failure and the group not experiencing afferent limb failure of the Medical Emergency Team. Both populations were characterized and compared. Statistical significance was set at p ≤ 0.05. Afferent limb failure was observed in 22.1% of activations. The causal analysis revealed significant differences in Medical Emergency Team activation criteria (p = 0.003) in the group experiencing afferent limb failure, with higher rates of Medical Emergency Team activation for cardiac arrest and cardiovascular dysfunction. Regarding patient outcomes, the group experiencing afferent limb failure had higher immediate mortality rates and higher mortality rates at hospital discharge, with no significant differences. No significant differences were found for the other parameters. The incidence of cardiac arrest and the mortality rate were higher in patients experiencing failure of the afferent limb of the Medical Emergency Team. This study highlights the need for health units to invest in the training of all healthcare professionals regarding the Medical Emergency Team activation criteria and emergency medical response system operations.

The optimal neural strategy for a stable motor task requires a compromise between level of muscle cocontraction and synaptic gain of afferent feedback

PubMed Central

Dideriksen, Jakob L.; Negro, Francesco

2015-01-01

Increasing joint stiffness by cocontraction of antagonist muscles and compensatory reflexes are neural strategies to minimize the impact of unexpected perturbations on movement. Combining these strategies, however, may compromise steadiness, as elements of the afferent input to motor pools innervating antagonist muscles are inherently negatively correlated. Consequently, a high afferent gain and active contractions of both muscles may imply negatively correlated neural drives to the muscles and thus an unstable limb position. This hypothesis was systematically explored with a novel computational model of the peripheral nervous system and the mechanics of one limb. Two populations of motor neurons received synaptic input from descending drive, spinal interneurons, and afferent feedback. Muscle force, simulated based on motor unit activity, determined limb movement that gave rise to afferent feedback from muscle spindles and Golgi tendon organs. The results indicated that optimal steadiness was achieved with low synaptic gain of the afferent feedback. High afferent gains during cocontraction implied increased levels of common drive in the motor neuron outputs, which were negatively correlated across the two populations, constraining instability of the limb. Increasing the force acting on the joint and the afferent gain both effectively minimized the impact of an external perturbation, and suboptimal adjustment of the afferent gain could be compensated by muscle cocontraction. These observations show that selection of the strategy for a given contraction implies a compromise between steadiness and effectiveness of compensations to perturbations. This indicates that a task-dependent selection of neural strategy for steadiness is necessary when acting in different environments. PMID:26203102

Somatotopy in the Medullary Dorsal Horn As a Basis for Orofacial Reflex Behavior

PubMed Central

Panneton, W. Michael; Pan, BingBing; Gan, Qi

2017-01-01

The somatotopy of the trigeminocervical complex of the rat was defined as a basis for describing circuitry for reflex behaviors directed through the facial motor nucleus. Thus, transganglionic transport of horseradish peroxidase conjugates applied to individual nerves/peripheral receptive fields showed that nerves innervating oropharyngeal structures projected most rostrally, followed by nerves innervating snout, periocular, and then periauricular receptive fields most caudally. Nerves innervating mucosae or glabrous receptive fields terminated densely in laminae I, II, and V of the trigeminocervical complex, while those innervating hairy skin terminated in laminae I–V. Projections to lamina II exhibited the most focused somatotopy when individual cases were compared. Retrograde transport of FluoroGold (FG) deposited into the facial motor nucleus resulted in labeled neurons almost solely in lamina V of the trigeminocervical complex. The distribution of these labeled neurons paralleled the somatotopy of primary afferent fibers, e.g., those labeled after FG injections into a functional group of motoneurons innervating lip musculature were found most rostrally while those labeled after injections into motoneurons innervating snout, periocular and preauricular muscles, respectively, were found at progressively more caudal levels. Anterograde transport of injections of biotinylated dextran amine into lamina V at different rostrocaudal levels of the trigeminocervical complex confirmed the notion that the somatotopy of orofacial sensory fields parallels the musculotopy of facial motor neurons. These data suggest that neurons in lamina V are important interneurons in a simple orofacial reflex circuit consisting of a sensory neuron, interneuron and motor neuron. Moreover, the somatotopy of primary afferent fibers from the head and neck confirms the “onion skin hypothesis” and suggests rostral cervical dermatomes blend seamlessly with “cranial dermatomes.” The transition area between subnucleus interpolaris and subnucleus caudalis is addressed while the paratrigeminal nucleus is discussed as an interface between the somatic and visceral nervous systems. PMID:29066998

Reinnervation following catheter-based radio-frequency renal denervation.

PubMed

Booth, Lindsea C; Nishi, Erika E; Yao, Song T; Ramchandra, Rohit; Lambert, Gavin W; Schlaich, Markus P; May, Clive N

2015-04-20

What is the topic of this review? Does catheter-based renal denervation effectively denervate the afferent and efferent renal nerves and does reinnervation occur? What advances does it highlight? Following catheter-based renal denervation, the afferent and efferent responses to electrical stimulation were abolished, renal sympathetic nerve activity was absent, and levels of renal noradrenaline and immunohistochemistry for tyrosine hydroxylase and calcitonin gene-related peptide were significantly reduced. By 11 months after renal denervation, both the functional responses and anatomical markers of afferent and efferent renal nerves had returned to normal, indicating reinnervation. Renal denervation reduces blood pressure in animals with experimental hypertension and, recently, catheter-based renal denervation was shown to cause a prolonged decrease in blood pressure in patients with resistant hypertension. The randomized, sham-controlled Symplicity HTN-3 trial failed to meet its primary efficacy end-point, but there is evidence that renal denervation was incomplete in many patients. Currently, there is little information regarding the effectiveness of catheter-based renal denervation and the extent of reinnervation. We assessed the effectiveness of renal nerve denervation with the Symplicity Flex catheter and the functional and anatomical reinnervation at 5.5 and 11 months postdenervation. In anaesthetized, non-denervated sheep, there was a high level of renal sympathetic nerve activity, and electrical stimulation of the renal nerve increased blood pressure and reduced heart rate (afferent response) and caused renal vasoconstriction and reduced renal blood flow (efferent response). Immediately after renal denervation, renal sympathetic nerve activity and the responses to electrical stimulation were absent, indicating effective denervation. By 11 months after denervation, renal sympathetic nerve activity was present and the responses to electrical stimulation were normal, indicating reinnervation. Anatomical measures of renal innervation by sympathetic efferent nerves (tissue noradrenaline and tyrosine hydroxylase) and afferent sensory nerves (calcitonin gene-related peptide) demonstrated large decreases at 1 week postdenervation, but normal levels at 11 months postdenervation. In summary, catheter-based renal denervation is effective, but reinnervation occurs. Studies of central and renal changes postdenervation are required to understand the causes of the prolonged hypotensive response to catheter-based renal denervation in human hypertension. © 2015 The Authors. Experimental Physiology © 2015 The Physiological Society.

Phase correlated adequate afferent action potentials as a drive of human spinal oscillators.

PubMed

Schalow, G

1993-12-01

1. By recording, with 2 pairs of wire electrodes, single-fibre action potentials (APs) from lower sacral nerve roots of a brain-dead human and a patient with spinal cord lesion, impulse patterns of afferent APs and impulse trains of oscillatory firing motoneurons could be identified and correlated. 2. Two highly activated secondary muscle spindle afferents increased and decreased their activity at about 0.3 Hz. The duration of the doublet interspike interval of a secondary spindle afferent fibre showed no correlation to the oscillation period of the motoneuron. 3. A continuously oscillatory firing motoneuron innervating the external and sphincter showed more transient breaks with the reduction of the number of phase correlated APs from 2 spindle afferents, indicating a looser oscillation. A transient brake of a 157 msec period alpha 2-oscillation could be correlated to the shift of a interspike interval distribution peak from 150 to 180 msec of the adequate afferent input, which suggests a transient loss of the necessary phase relation. 4. Oscillatory firing alpha 2-motoneurons innervating the external bladder and anal sphincters fired independently according to their phase correlated APs from the urinary bladder stretch receptor and muscle spindle afferents respectively; the bladder motoneuron slightly inhibited the anal motoneuron. 5. Receptors of the afferents and innervation sites of oscillatory firing motoneurons could be located within the urinary tract and the anal canal.

Low excitatory innervation balances high intrinsic excitability of immature dentate neurons

PubMed Central

Dieni, Cristina V.; Panichi, Roberto; Aimone, James B.; Kuo, Chay T.; Wadiche, Jacques I.; Overstreet-Wadiche, Linda

2016-01-01

Persistent neurogenesis in the dentate gyrus produces immature neurons with high intrinsic excitability and low levels of inhibition that are predicted to be more broadly responsive to afferent activity than mature neurons. Mounting evidence suggests that these immature neurons are necessary for generating distinct neural representations of similar contexts, but it is unclear how broadly responsive neurons help distinguish between similar patterns of afferent activity. Here we show that stimulation of the entorhinal cortex in mouse brain slices paradoxically generates spiking of mature neurons in the absence of immature neuron spiking. Immature neurons with high intrinsic excitability fail to spike due to insufficient excitatory drive that results from low innervation rather than silent synapses or low release probability. Our results suggest that low synaptic connectivity prevents immature neurons from responding broadly to cortical activity, potentially enabling excitable immature neurons to contribute to sparse and orthogonal dentate representations. PMID:27095423

Low excitatory innervation balances high intrinsic excitability of immature dentate neurons

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dieni, Cristina V.; Panichi, Roberto; Aimone, James B.

Persistent neurogenesis in the dentate gyrus produces immature neurons with high intrinsic excitability and low levels of inhibition that are predicted to be more broadly responsive to afferent activity than mature neurons. Mounting evidence suggests that these immature neurons are necessary for generating distinct neural representations of similar contexts, but it is unclear how broadly responsive neurons help distinguish between similar patterns of afferent activity. Here we show that stimulation of the entorhinal cortex in mouse brain slices paradoxically generates spiking of mature neurons in the absence of immature neuron spiking. Immature neurons with high intrinsic excitability fail to spikemore » due to insufficient excitatory drive that results from low innervation rather than silent synapses or low release probability. Here, our results suggest that low synaptic connectivity prevents immature neurons from responding broadly to cortical activity, potentially enabling excitable immature neurons to contribute to sparse and orthogonal dentate representations.« less

Low excitatory innervation balances high intrinsic excitability of immature dentate neurons

DOE PAGES

Dieni, Cristina V.; Panichi, Roberto; Aimone, James B.; ...

2016-04-20

Persistent neurogenesis in the dentate gyrus produces immature neurons with high intrinsic excitability and low levels of inhibition that are predicted to be more broadly responsive to afferent activity than mature neurons. Mounting evidence suggests that these immature neurons are necessary for generating distinct neural representations of similar contexts, but it is unclear how broadly responsive neurons help distinguish between similar patterns of afferent activity. Here we show that stimulation of the entorhinal cortex in mouse brain slices paradoxically generates spiking of mature neurons in the absence of immature neuron spiking. Immature neurons with high intrinsic excitability fail to spikemore » due to insufficient excitatory drive that results from low innervation rather than silent synapses or low release probability. Here, our results suggest that low synaptic connectivity prevents immature neurons from responding broadly to cortical activity, potentially enabling excitable immature neurons to contribute to sparse and orthogonal dentate representations.« less

An Interoceptive Predictive Coding Model of Conscious Presence

PubMed Central

Seth, Anil K.; Suzuki, Keisuke; Critchley, Hugo D.

2011-01-01

We describe a theoretical model of the neurocognitive mechanisms underlying conscious presence and its disturbances. The model is based on interoceptive prediction error and is informed by predictive models of agency, general models of hierarchical predictive coding and dopaminergic signaling in cortex, the role of the anterior insular cortex (AIC) in interoception and emotion, and cognitive neuroscience evidence from studies of virtual reality and of psychiatric disorders of presence, specifically depersonalization/derealization disorder. The model associates presence with successful suppression by top-down predictions of informative interoceptive signals evoked by autonomic control signals and, indirectly, by visceral responses to afferent sensory signals. The model connects presence to agency by allowing that predicted interoceptive signals will depend on whether afferent sensory signals are determined, by a parallel predictive-coding mechanism, to be self-generated or externally caused. Anatomically, we identify the AIC as the likely locus of key neural comparator mechanisms. Our model integrates a broad range of previously disparate evidence, makes predictions for conjoint manipulations of agency and presence, offers a new view of emotion as interoceptive inference, and represents a step toward a mechanistic account of a fundamental phenomenological property of consciousness. PMID:22291673

Paired associative stimulation induces change in presynaptic inhibition of Ia terminals in wrist flexors in humans.

PubMed

Lamy, Jean-Charles; Russmann, Heike; Shamim, Ejaz A; Meunier, Sabine; Hallett, Mark

2010-08-01

Enhancements in the strength of corticospinal projections to muscles are induced in conscious humans by paired associative stimulation (PAS) to the motor cortex. Although most of the previous studies support the hypothesis that the increase of the amplitude of motor evoked potentials (MEPs) by PAS involves long-term potentiation (LTP)-like mechanism in cortical synapses, changes in spinal excitability after PAS have been reported, suggestive of parallel modifications in both cortical and spinal excitability. In a first series of experiments (experiment 1), we confirmed that both flexor carpi radialis (FCR) MEPs and FCR H reflex recruitment curves are enhanced by PAS. To elucidate the mechanism responsible for this change in the H reflex amplitude, we tested, using the same subjects, the hypothesis that enhanced H reflexes are caused by a down-regulation of the efficacy of mechanisms controlling Ia afferent discharge, including presynaptic Ia inhibition and postactivation depression. To address this question, amounts of both presynaptic Ia inhibition of FCR Ia terminals (D1 and D2 inhibitions methods; experiment 2) and postactivation depression (experiment 3) were determined before and after PAS. Results showed that PAS induces a significant decrease of presynaptic Ia inhibition of FCR terminals, which was concomitant with the facilitation of the H reflex. Postactivation depression was unaffected by PAS. It is argued that enhancement of segmental excitation by PAS relies on a selective effect of PAS on the interneurons controlling presynaptic inhibition of Ia terminals.

Transneuronal pathways to the vestibulocerebellum

NASA Technical Reports Server (NTRS)

Kaufman, G. D.; Mustari, M. J.; Miselis, R. R.; Perachio, A. A.

1996-01-01

The alpha-herpes virus (pseudorabies, PRV) was used to observe central nervous system (CNS) pathways associated with the vestibulocerebellar system. Retrograde transneuronal migration of alpha-herpes virions from specific lobules of the gerbil and rat vestibulo-cerebellar cortex was detected immunohistochemically. Using a time series analysis, progression of infection along polyneuronal cerebellar afferent pathways was examined. Pressure injections of > 20 nanoliters of a 10(8) plaque forming units (pfu) per ml solution of virus were sufficient to initiate an infectious locus which resulted in labeled neurons in the inferior olivary subnuclei, vestibular nuclei, and their afferent cell groups in a progressive temporal fashion and in growing complexity with increasing incubation time. We show that climbing fibers and some other cerebellar afferent fibers transported the virus retrogradely from the cerebellum within 24 hours. One to three days after cerebellar infection discrete cell groups were labeled and appropriate laterality within crossed projections was preserved. Subsequent nuclei labeled with PRV after infection of the flocculus/paraflocculus, or nodulus/uvula, included the following: vestibular (e.g., z) and inferior olivary nuclei (e.g., dorsal cap), accessory oculomotor (e.g., Darkschewitsch n.) and accessory optic related nuclei, (e.g., the nucleus of the optic tract, and the medial terminal nucleus); noradrenergic, raphe, and reticular cell groups (e.g., locus coeruleus, dorsal raphe, raphe pontis, and the lateral reticular tract); other vestibulocerebellum sites, the periaqueductal gray, substantia nigra, hippocampus, thalamus and hypothalamus, amygdala, septal nuclei, and the frontal, cingulate, entorhinal, perirhinal, and insular cortices. However, there were differences in the resulting labeling between infection in either region. Double-labeling experiments revealed that vestibular efferent neurons are located adjacent to, but are not included among, flocculus-projecting supragenual neurons. PRV transport from the vestibular labyrinth and cervical muscles also resulted in CNS infections. Virus propagation in situ provides specific connectivity information based on the functional transport across synapses. The findings support and extend anatomical data regarding vestibulo-olivo-cerebellar pathways.

Inhibition by spinal mu- and delta-opioid agonists of afferent-evoked substance P release.

PubMed

Kondo, Ichiro; Marvizon, Juan Carlos G; Song, Bingbing; Salgado, Frances; Codeluppi, Simone; Hua, Xiao-Ying; Yaksh, Tony L

2005-04-06

Opioid mu- and delta-receptors are present on the central terminals of primary afferents, where they are thought to inhibit neurotransmitter release. This mechanism may mediate analgesia produced by spinal opiates; however, when they used neurokinin 1 receptor (NK1R) internalization as an indicator of substance P release, Trafton et al. (1999) noted that this evoked internalization was altered only modestly by morphine delivered intrathecally at spinal cord segment S1-S2. We reexamined this issue by studying the effect of opiates on NK1R internalization in spinal cord slices and in vivo. In slices, NK1R internalization evoked by dorsal root stimulation at C-fiber intensity was abolished by the mu agonist [D-Ala2, N-Me-Phe4, Gly-ol5]-enkephalin (DAMGO) (1 microM) and decreased by the delta agonist [D-Phe2,5]-enkephalin (DPDPE) (1 microM). In vivo, hindpaw compression induced NK1R internalization in ipsilateral laminas I-II. This evoked internalization was significantly reduced by morphine (60 nmol), DAMGO (1 nmol), and DPDPE (100 nmol), but not by the kappa agonist trans-(1S,2S)-3,4-dichloro-N-mathyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-benzeneacetamide hydrochloride (200 nmol), delivered at spinal cord segment L2 using intrathecal catheters. These doses of the mu and delta agonists were equi-analgesic as measured by a thermal escape test. Lower doses neither produced analgesia nor inhibited NK1R internalization. In contrast, morphine delivered by percutaneous injections at S1-S2 had only a modest effect on thermal escape, even at higher doses. Morphine decreased NK1R internalization after systemic delivery, but at a dose greater than that necessary to produce equivalent analgesia. All effects were reversed by naloxone. These results indicate that lumbar opiates inhibit noxious stimuli-induced neurotransmitter release from primary afferents at doses that are confirmed behaviorally as analgesic.

Endogenous bradykinin activates ischaemically sensitive cardiac visceral afferents through kinin B2 receptors in cats

PubMed Central

Tjen-A-Looi, Stephanie C; Pan, Hui-Lin; Longhurst, John C

1998-01-01

Activity of ischaemically sensitive cardiac visceral afferents during myocardial ischaemia induces both angina and cardiovascular reflexes. Increased production of bradykinin (BK) and cyclo-oxygenase products (i.e. prostaglandins (PGs)) occurs during myocardial ischaemia. However, the role of these agents in activation of ischaemically sensitive cardiac afferents has not been established. The present study tested the hypothesis that BK produced during ischaemia activates cardiac afferents through kinin B2 receptors. Single-unit activity of cardiac afferents innervating the left ventricle was recorded from the left thoracic sympathetic chain (T1–T4) of anaesthetized cats. Ischaemically sensitive cardiac afferents were identified according to their response to 5 min of myocardial ischaemia. The mechanism of BK in activation of ischaemically sensitive cardiac afferents was determined by injection of BK (1 μg kg−1 i.a.), des-Arg9-BK (1 μg kg−1 i.a., a specific kinin B1 receptor agonist), kinin B2 receptor antagonists: HOE140 (30 μg kg−1 i.v.) and NPC-17731 (40 μg kg−1 i.v.), cyclo-oxygenase inhibition with indomethacin (5 mg kg−1 i.v.) and NPC-17731 (40 μg kg−1 i.v.) after pretreatment with indomethacin (5 mg kg−1 i.v.). We observed that BK increased the discharge rate of all eleven ischaemically sensitive cardiac afferents from 0.39 ± 0.12 to 1.47 ± 0.37 impulses s−1 (P < 0.05). Conversely, des-Arg9-BK did not significantly increase the activity of eleven ischaemically sensitive fibres (0.58 ± 0.02 vs. 0.50 ± 0.18 impulses s−1). HOE140 significantly attenuated the response of twelve afferents to ischaemia (0.61 ± 0.22 to 1.85 ± 0.5 vs. 0.53 ± 0.16 to 1.09 ± 0.4 impulses s−1). NPC-17731, another kinin B2 receptor antagonist, had similar inhibitory effects on six other ischaemically sensitive cardiac afferents (0.35 ± 0.14 to 1.19 ± 0.29 vs. 0.22 ± 0.08 to 0.23 ± 0.07 impulses s−1). Indomethacin significantly reduced the responses of seven afferents to ischaemia (0.35 ± 0.13 to 1.89 ± 0.48 vs. 0.40 ± 0.10 to 0.76 ± 0.24 impulses s−1). Indomethacin also significantly reduced the responses of six ischaemically sensitive cardiac afferents to BK (2.65 ± 1.23 to 1.2 ± 0.51 impulses s−1). In six cats pretreated with indomethacin, NPC-17731 attenuated the impulse activity of six ischaemically sensitive cardiac afferents (0.39 ± 0.12 to 1.0 ± 0.3 vs. 0.26 ± 0.14 to 0.48 ± 0.20 impulses s−1). This study demonstrates that BK produced during ischaemia contributes to stimulation of ischaemically sensitive cardiac visceral afferents through activation of kinin B2 receptors. Furthermore, BK stimulates ischaemically sensitive cardiac visceral afferents through a mechanism that is, at least in part, independent of cyclo-oxygenase activation. PMID:9706010

Fatigue-induced changes in group IV muscle afferent activity: differences between high- and low-frequency electrically induced fatigues.

PubMed

Darques, J L; Jammes, Y

1997-03-07

Recordings of group IV afferent activity of tibialis anterior muscle were performed in paralysed rabbits during runs of electrically induced fatigue produced by direct muscle stimulation at a high (100 Hz, high-frequency fatigue HFF) or a low rate (10 Hz, low-frequency fatigue LFF). In addition to analysis of afferent nerve action potentials, muscle force and compound muscle action potentials (M waves) elicited by direct muscle stimulation with single shocks were recorded. Changes in M wave configuration were used as an index of the altered propagation of membrane potentials and the associated efflux of potassium from muscle fibers. The data show that increased group IV afferent activity occurred during LFF as well as HFF trials and developed parallel with force failure. Enhanced afferent activity was significantly higher during LFF (maximal delta f(impulses) = 249 +/- 35%) than HFF (147 +/- 45%). No correlation was obtained between the responses of group IV afferents to LFF or to pressure exerted on tibialis anterior muscle. On the other hand, decreased M wave amplitude was minimal with LFF while it was pronounced with HFF. Close correlations were found between fatigue-induced activation of group IV afferents and decreases in force or M wave amplitude, but their strength was significantly higher with LFF compared to HFF. Thus, electrically induced fatigue activates group IV muscle afferents with a prominent effect of low-frequency stimulation. The mechanism of muscle afferent stimulation does not seem to be due to the sole increase in extracellular potassium concentration, but also by the efflux of muscle metabolites, present during fatiguing contractions at low rate of stimulation.

Combined genetic and pharmacological inhibition of TRPV1 and P2X3 attenuates colorectal hypersensitivity and afferent sensitization

PubMed Central

Kiyatkin, Michael E.; Feng, Bin; Schwartz, Erica S.

2013-01-01

The ligand-gated channels transient receptor potential vanilloid 1 (TRPV1) and P2X3 have been reported to facilitate colorectal afferent neuron sensitization, thus contributing to organ hypersensitivity and pain. In the present study, we hypothesized that TRPV1 and P2X3 cooperate to modulate colorectal nociception and afferent sensitivity. To test this hypothesis, we employed TRPV1-P2X3 double knockout (TPDKO) mice and channel-selective pharmacological antagonists and evaluated combined channel contributions to behavioral responses to colorectal distension (CRD) and afferent fiber responses to colorectal stretch. Baseline responses to CRD were unexpectedly greater in TPDKO compared with control mice, but zymosan-produced CRD hypersensitivity was absent in TPDKO mice. Relative to control mice, proportions of mechanosensitive and -insensitive pelvic nerve afferent classes were not different in TPDKO mice. Responses of mucosal and serosal class afferents to mechanical probing were unaffected, whereas responses of muscular (but not muscular/mucosal) afferents to stretch were significantly attenuated in TPDKO mice; sensitization of both muscular and muscular/mucosal afferents by inflammatory soup was also significantly attenuated. In pharmacological studies, the TRPV1 antagonist A889425 and P2X3 antagonist TNP-ATP, alone and in combination, applied onto stretch-sensitive afferent endings attenuated responses to stretch; combined antagonism produced greater attenuation. In the aggregate, these observations suggest that 1) genetic manipulation of TRPV1 and P2X3 leads to reduction in colorectal mechanosensation peripherally and compensatory changes and/or disinhibition of other channels centrally, 2) combined pharmacological antagonism produces more robust attenuation of mechanosensation peripherally than does antagonism of either channel alone, and 3) the relative importance of these channels appears to be enhanced in colorectal hypersensitivity. PMID:23989007

Cellular projections from sensory hair cells form polarity-specific scaffolds during synaptogenesis

PubMed Central

Dow, Eliot; Siletti, Kimberly

2015-01-01

The assembly of a nervous system requires the extension of axons and dendrites to specific regions where they are matched with appropriate synaptic targets. Although the cues that guide long-range outgrowth have been characterized extensively, additional mechanisms are required to explain short-range guidance in neural development. Using a complementary combination of time-lapse imaging by fluorescence confocal microscopy and serial block-face electron microscopy, we identified a novel type of presynaptic projection that participates in the assembly of the vertebrate nervous system. Synapse formation by each hair cell of the zebrafish's lateral line occurs during a particular interval after the cell's birth. During the same period, projections emerge from the cellular soma, extending toward a specific subpopulation of mature hair cells and interacting with polarity-specific afferent nerve terminals. The terminals then extend along the projections to reach appropriately matched presynaptic sites, after which the projections recede. Our results suggest that presynaptic projections act as transient scaffolds for short-range partner matching, a mechanism that may occur elsewhere in the nervous system. PMID:25995190

Glutamatergic Receptor Activation in the Commisural Nucleus Tractus Solitarii (cNTS) Mediates Brain Glucose Retention (BGR) Response to Anoxic Carotid Chemoreceptor (CChr) Stimulation in Rats.

PubMed

Cuéllar, R; Montero, S; Luquín, S; García-Estrada, J; Dobrovinskaya, O; Melnikov, V; Lemus, M; de Álvarez-Buylla, E Roces

2015-01-01

Glutamate, released from central terminals of glossopharyngeal nerve, is a major excitatory neurotransmitter of commissural nucleus tractus solitarii (cNTS) afferent terminals, and brain derived neurotrophic factor (BDNF) has been shown to attenuate glutamatergic AMPA currents in NTS neurons. To test the hypothesis that AMPA contributes to glucose regulation in vivo modulating the hyperglycemic reflex with brain glucose retention (BGR), we microinjected AMPA and NBQX (AMPA antagonist) into the cNTS before carotid chemoreceptor stimulation in anesthetized normal Wistar rats, while hyperglycemic reflex an brain glucose retention (BGR) were analyzed. To investigate the underlying mechanisms, GluR2/3 receptor and c-Fos protein expressions in cNTS neurons were determined. We showed that AMPA in the cNTS before CChr stimulation inhibited BGR observed in aCSF group. In contrast, NBQX in similar conditions, did not modify the effects on glucose variables observed in aCSF control group. These experiments suggest that glutamatergic pathways, via AMPA receptors, in the cNTS may play a role in glucose homeostasis.

Physiological pathways regulating the activity of magnocellular neurosecretory cells.

PubMed

Leng, G; Brown, C H; Russell, J A

1999-04-01

Magnocellular oxytocin and vasopressin cells are among the most extensively studied neurons in the brain; their large size and high synthetic capacity, their discrete, homogeneous distribution and the anatomical separation of their terminals from their cell bodies, and the ability to determine their neuronal output readily by measurements of hormone concentration in the plasma, combine to make these systems amenable to a wide range of fundamental investigations. While vasopressin cells have intrinsic burst-generating properties, oxytocin cells are organized within local pattern-generating networks. In this review we consider the rôle played by particular afferent pathways in the regulation of the activity of oxytocin and vasopressin cells. For both cell types, the effects of changes in the activity of synaptic input can be complex.

Changes in Afferent Activity After Spinal Cord Injury

PubMed Central

de Groat, William C.; Yoshimura, Naoki

2010-01-01

Aims To summarize the changes that occur in the properties of bladder afferent neurons following spinal cord injury. Methods Literature review of anatomical, immunohistochemical, and pharmacologic studies of normal and dysfunctional bladder afferent pathways. Results Studies in animals indicate that the micturition reflex is mediated by a spinobulbospinal pathway passing through coordination centers (periaqueductal gray and pontine micturition center) located in the rostral brain stem. This reflex pathway, which is activated by small myelinated (Aδ) bladder afferent nerves, is in turn modulated by higher centers in the cerebral cortex involved in the voluntary control of micturition. Spinal cord injury at cervical or thoracic levels disrupts voluntary voiding, as well as the normal reflex pathways that coordinate bladder and sphincter function. Following spinal cord injury, the bladder is initially areflexic but then becomes hyperreflexic due to the emergence of a spinal micturition reflex pathway. The recovery of bladder function after spinal cord injury is dependent in part on the plasticity of bladder afferent pathways and the unmasking of reflexes triggered by unmyelinated, capsaicin-sensitive, C-fiber bladder afferent neurons. Plasticity is associated with morphologic, chemical, and electrical changes in bladder afferent neurons and appears to be mediated in part by neurotrophic factors released in the spinal cord and the peripheral target organs. Conclusions Spinal cord injury at sites remote from the lumbosacral spinal cord can indirectly influence properties of bladder afferent neurons by altering the function and chemical environment in the bladder or the spinal cord. PMID:20025033

PLCγ-activated signalling is essential for TrkB mediated sensory neuron structural plasticity

PubMed Central

2010-01-01

Background The vestibular system provides the primary input of our sense of balance and spatial orientation. Dysfunction of the vestibular system can severely affect a person's quality of life. Therefore, understanding the molecular basis of vestibular neuron survival, maintenance, and innervation of the target sensory epithelia is fundamental. Results Here we report that a point mutation at the phospholipase Cγ (PLCγ) docking site in the mouse neurotrophin tyrosine kinase receptor TrkB (Ntrk2) specifically impairs fiber guidance inside the vestibular sensory epithelia, but has limited effects on the survival of vestibular sensory neurons and growth of afferent processes toward the sensory epithelia. We also show that expression of the TRPC3 cation calcium channel, whose activity is known to be required for nerve-growth cone guidance induced by brain-derived neurotrophic factor (BDNF), is altered in these animals. In addition, we find that absence of the PLCγ mediated TrkB signalling interferes with the transformation of bouton type afferent terminals of vestibular dendrites into calyces (the largest synaptic contact of dendrites known in the mammalian nervous system) on type I vestibular hair cells; the latter are normally distributed in these mutants as revealed by an unaltered expression pattern of the potassium channel KCNQ4 in these cells. Conclusions These results demonstrate a crucial involvement of the TrkB/PLCγ-mediated intracellular signalling in structural aspects of sensory neuron plasticity. PMID:20932311

Classification of longissimus lumborum muscle spindle afferents in the anaesthetized cat

PubMed Central

Durbaba, R; Taylor, A; Ellaway, P H; Rawlinson, S

2006-01-01

Recordings have been made from 127 single muscle spindle afferents from the longissimus lumborum muscles of anaesthetized cats. They have been characterized by their responses to passive muscle stretch and the effects of succinylcholine (SCh) and by their sensitivity to vibration. The use of SCh permitted the assessment for each afferent of the influence of bag1 (b1) and bag2 (b2) intrafusal muscle fibres. From this, on the assumption that all afferents were affected by chain (c) fibres, they were classified in four groups: b1b2c (41.9%), b2c (51.4%), b1c (1.3%) and c (5.4%). All the afferents with b1 influence were able to respond one to one to vibration at frequencies above 100 Hz and were considered to belong to primary endings. On the basis of the vibration test, 64% of the b2c type afferents appeared to be primaries and 36% secondaries. Of the units classified as primaries, 41% were designated as b2c and would not therefore be able to respond to dynamic fusimotor activity. The significance of this relatively high proportion of b2c-type spindle primary afferents is discussed in relation to the specialized postural function of the back muscles. PMID:16410280

Morphology of the Vestibular Utricule in Toadfish, Opsanus Tau

NASA Technical Reports Server (NTRS)

Bass, L.; Smith, J.; Twombly, A.; Boyle, Richard; Varelas, Ehsanian J.; Johanson, C.

2003-01-01

The uticle is an otolith organ in the vertebrate inner ear that provides gravitoinertial acceleration information into the vestibular reflex pathways. The aim of the present study was to provide an anatomical description of this structure in the adult oyster toadfish, and establish a morphological basis for interpretation of subsequent functional studies. Light, scanning electron and transmission electron microscopy were applied to visualize the sensory epithelium and its neural innervation. Electrophysiological techniques were used to identify utricular afferents by their response to translation stimuli. Similar to nerve afferents supplying the semicircular canals and lagena, utricular afferents commonly exhibit a short-latency increase of firing rate in response to electrical activation of the central efferent pathway. Afferents were labeled with biocytin either intraaxonally or with extracellular bulk deposits. Light microscope images of serial thick sections were used to make three-dimensional reconstructions of individual labeled afferents to identify the dendritic morphology with respect to epithelial location. Scanning electron microscopy was used to visualize the surface of the otolith mass facing the otolith membrane, and the hair cell polarization patterns of strioler and extrastriolar regions. Transmission electron micrographs of serial thin sections were compiled to create a three-dimensional reconstruction of the labeled afferent over a segment of its dendritic field and to examine the hair cell-afferent synaptic contacts.

Baroreflex dysfunction induced by microgravity: potential relevance to postflight orthostatic intolerance

NASA Technical Reports Server (NTRS)

Ertl, A. C.; Diedrich, A.; Biaggioni, I.; Robertson, D. (Principal Investigator)

2000-01-01

Microgravity imposes adaptive changes in the human body. This review focuses on the changes in baroreflex function produced by actual spaceflight, or by experimental models that simulate microgravity, e.g., bed rest. We will analyze separately studies involving baroreflexes arising from carotid sinus and aortic arch afferents ("high-pressure baroreceptors"), and cardiopulmonary afferents ("low-pressure receptors"). Studies from unrelated laboratories using different techniques have concluded that actual or simulated exposure to microgravity reduces baroreflex function arising from carotid sinus afferents ("carotic-cardiac baroreflex"). The techniques used to study the carotid-cardiac baroreflex, using neck suction and compression to simulate changes in blood pressure, have been extensively validated. In contrast, it is more difficult to selectively study aortic arch or cardiopulmonary baroreceptors. Nonetheless, studies that have examined these baroreceptors suggest that microgravity produces the opposite effect, ie, an increase in the gain of aortic arch and cardiopulmonary baroreflexes. Furthermore, most studies have focus on instantaneous changes in heart rate, which almost exclusively examines the vagal limb of the baroreflex. In comparison, there is limited information about the effect of microgravity on sympathetic function. A substantial proportion of subjects exposed to microgravity develop transient orthostatic intolerance. It has been proposed that alterations in baroreflex function play a role in the orthostatic intolerance induced by microgravity. The evidence in favor and against this hypothesis is reviewed.

Interaction between vestibulosympathetic and skeletal muscle reflexes on sympathetic activity in humans

NASA Technical Reports Server (NTRS)

Ray, C. A.

2001-01-01

Evidence from animals indicates that skeletal muscle afferents activate the vestibular nuclei and that both vestibular and skeletal muscle afferents have inputs to the ventrolateral medulla. The purpose of the present study was to investigate the interaction between the vestibulosympathetic and skeletal muscle reflexes on muscle sympathetic nerve activity (MSNA) and arterial pressure in humans. MSNA, arterial pressure, and heart rate were measured in 17 healthy subjects in the prone position during three experimental trials. The three trials were 2 min of 1) head-down rotation (HDR) to engage the vestibulosympathetic reflex, 2) isometric handgrip (IHG) at 30% maximal voluntary contraction to activate skeletal muscle afferents, and 3) HDR and IHG performed simultaneously. The order of the three trials was randomized. HDR and IHG performed alone increased total MSNA by 46 +/- 16 and 77 +/- 24 units, respectively (P < 0.01). During the HDR plus IHG trial, MSNA increased 142 +/- 38 units (P < 0.01). This increase was not significantly different from the sum of the individual trials (130 +/- 41 units). This finding was also observed with mean arterial pressure (sum = 21 +/- 2 mmHg and HDR + IHG = 22 +/- 2 mmHg). These findings suggest that there is an additive interaction for MSNA and arterial pressure when the vestibulosympathetic and skeletal muscle reflexes are engaged simultaneously in humans. Therefore, no central modulation exists between these two reflexes with regard to MSNA output in humans.

Male hamster copulatory responses to a high molecular weight fraction of vaginal discharge: effects of vomeronasal organ removal.

PubMed

Clancy, A N; Macrides, F; Singer, A G; Agosta, W C

1984-10-01

The importance of the vomeronasal (accessory olfactory) system for the copulatory responses of male hamsters to a high molecular weight fraction (HMF) of vaginal discharge was assessed in animals that had their vomeronasal organs (VNO) removed. These organs were extirpated bilaterally using an oral approach through the palate so as to eliminate the peripheral afferents to the accessory olfactory bulb (AOB) with minimal or no damage to the main olfactory system. The selective peripheral deafferentation procedure was verified by applying horseradish peroxidase intranasally following intraperitoneal injections of epinephrine to facilitate the vomeronasal pumping mechanism that draws fluids into the VNO. Heavy, bilateral anterograde labeling was evident in the olfactory nerve afferents within the main olfactory bulb of males that had their VNO removed and of animals that received sham surgery. Sham-operated males also had heavy, bilateral labeling in the vomeronasal nerve afferents within the AOB, whereas no such labeling occurred among animals with bilateral removal of the VNO. In sham-operated animals, both the HMF and the unfractionated discharge significantly increased the incidence of intromission attempts toward anesthetized males (surrogate females) whose hindquarters were scented with these stimuli. The unfractionated discharge also produced a significant elevation of overt copulatory behavior in males with selective peripheral deafferentation of the vomeronasal system, whereas the HMF did not facilitate copulatory behavior in these animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Axon terminals expressing vesicular glutamate transporter VGLUT1 or VGLUT2 within the trigeminal motor nucleus of the rat: origins and distribution patterns.

PubMed

Pang, You-Wang; Ge, Shun-Nan; Nakamura, Kouichi C; Li, Jin-Lian; Xiong, Kang-Hui; Kaneko, Takeshi; Mizuno, Noboru

2009-02-10

Little is known about the significance of the two types of glutamatergic neurons (those expressing vesicular glutamate transporter VGLUT1 or VGLUT2) in the control of jaw movements. We thus examined the origin and distribution of axon terminals with VGLUT1 or VGLUT2 immunoreactivity within the trigeminal motor nucleus (Vm) in the rat. The Vm was divided into the dorsolateral division (Vm.dl; jaw-closing motoneuron pool) and the ventromedial division (Vm.vm; jaw-opening motoneuron pool). VGLUT1-immunopositive terminals were seen within the Vm.dl only, whereas VGLUT2-immunopositive ones were distributed to both the Vm.dl and the Vm.vm. Transection of the motor root eliminated almost all VGLUT1-immunopositive axons in the Vm.dl, with no changes of VGLUT2 immunoreactivity in the two divisions, indicating that the VGLUT1- and VGLUT2-immunopositive axons came from primary afferents in the mesencephalic trigeminal nucleus and premotor neurons for the Vm, respectively. In situ hybridization histochemistry revealed that VGLUT2 neurons were much more numerous than VGLUT1 neurons in the regions corresponding to the reported premotoneuron pool for the Vm. The results of immunofluorescence labeling combined with anterograde tract tracing further indicated that premotor neurons with VGLUT2 in the trigeminal sensory nuclei, the supratrigeminal region, and the reticular region ventral to the Vm sent axon terminals contacting trigeminal motoneurons and that some of the VGLUT1-expressing premotor neurons in the reticular region ventral to the Vm sent axon terminals to jaw-closing motoneurons. The present results suggested that the roles played by glutamatergic neurons in controlling jaw movements might be different between VGLUT1- and VGLUT2-expressing neurons.

Co-localization of corticotropin-releasing factor and vesicular glutamate transporters within axon terminals of the rat dorsal raphe nucleus.

PubMed

Waselus, Maria; Van Bockstaele, Elisabeth J

2007-10-12

Electrophysiological, microdialysis and behavioral studies support a modulatory role for corticotropin-releasing factor (CRF) in regulating the dorsal raphe nucleus (DRN)-serotonin (5-HT) system. CRF and 5-HT are implicated in the pathophysiology of depression, thus neuroanatomical substrates of CRF-DRN-5-HT interactions are of interest. Identification of co-transmitters within DRN CRF axon terminals is important for elucidating the complex effects underlying CRF afferent regulation of DRN neurons. This study investigated whether CRF-labeled axon terminals within the DRN contain immunoreactivity for vesicular glutamate transporters (isoforms vGlut1 and vGlut2) indicative of the excitatory neurotransmitter glutamate. Dual immunohistochemistry for CRF and either vGlut1 or vGlut2 was conducted within the same tissue section and immunofluorescence results indicated patterns of immunoreactivity consistent with previous reports. Abundant vGlut1- and vGlut2-immunoreactivity was found in puncta exhibiting a largely uniform distribution, whereas CRF-immunoreactivity was localized to topographically distributed varicose processes within the DRN. Profiles containing both CRF- and either vGlut1- or vGlut2-immunoreactivity were apparent in the DRN. Electron microscopy confirmed that immunoreactivity for CRF and vGlut1 was localized primarily to separate axon terminals in the DRN, with a subset co-localizing CRF and vGlut1. Examination of CRF and vGlut2 immunoreactivities in the DRN indicated that CRF and vGlut2 were found within the same axon terminal more frequently than CRF and vGlut1. Overall, these anatomical findings suggest that CRF may function, in part, with the excitatory neurotransmitter glutamate in the modulation of neuronal activity in the DRN.

Hair-cell counts and afferent innervation patterns in the cristae ampullares of the squirrel monkey with a comparison to the chinchilla

NASA Technical Reports Server (NTRS)

Fernandez, C.; Lysakowski, A.; Goldberg, J. M.

1995-01-01

1. The numbers of type I and type II hair cells were estimated by dissector techniques applied to semithin, stained sections of the horizontal, superior, and posterior cristae in the squirrel monkey and the chinchilla. 2. The crista in each species was divided into concentrically arranged central, intermediate, and peripheral zones of equal areas. The three zones can be distinguished by the sizes of individual hair cells and calyx endings, by the density of hair cells, and by the relative frequency of calyx endings innervating single or multiple type I hair cells. 3. In the monkey crista, type I hair cells outnumber type II hair cells by a ratio of almost 3:1. The ratio decreases from 4-5:1 in the central and intermediate zones to under 2:1 in the peripheral zone. For the chinchilla, the ratio is near 1:1 for the entire crista and decreases only slightly between the central and peripheral zones. 4. Nerve fibers supplying the cristae in the squirrel monkey were labeled by extracellular injections of horseradish peroxidase (HRP) into the vestibular nerve. Peripheral terminations of individual fibers were reconstructed and related to the zones of the cristae they innervated and to the sizes of their parent axons. Results were similar for the horizontal, superior, and posterior cristae. 5. Axons seldom bifurcate below the neuroepithelium. Most fibers begin branching shortly after crossing the basement membrane. Their terminal arbors are compact, usually extending no more than 50-100 microns from the parent exon. A small number of long intraepithelial fibers enter the intermediate and peripheral zones of the cristae near its base, then run unbranched for long distances through the neuroepithelium to reach the central zone. 6. There are three classes of afferent fibers innervating the monkey crista. Calyx fibers terminate exclusively on type I hair cells, and bouton fibers end only on type II hair cells. Dimorphic fibers provide a mixed innervation, including calyx endings to type I hair cells and bouton endings to type II hair cells. Long intraepithelial fibers are calyx and dimorphic units, whose terminal fields are similar to those of other fibers. The central zone is innervated by calyx and dimorphic fibers; the peripheral zone, by bouton and dimorphic fibers; and the intermediate zone, by all three kinds of fibers. Internal (axon) diameters are largest for calyx fibers and smallest for bouton fibers. Of the entire sample of 286 labeled fibers, 52% were dimorphic units, 40% were calyx units, and 8% were bouton units.(ABSTRACT TRUNCATED AT 400 WORDS).

Potentiation of mouse vagal afferent mechanosensitivity by ionotropic and metabotropic glutamate receptors

PubMed Central

Slattery, James A; Page, Amanda J; Dorian, Camilla L; Brierley, Stuart M; Blackshaw, L Ashley

2006-01-01

Glutamate acts at central synapses via ionotropic (iGluR – NMDA, AMPA and kainate) and metabotropic glutamate receptors (mGluRs). Group I mGluRs are excitatory whilst group II and III are inhibitory. Inhibitory mGluRs also modulate peripherally the mechanosensitivity of gastro-oesophageal vagal afferents. Here we determined the potential of excitatory GluRs to play an opposing role in modulating vagal afferent mechanosensitivity, and investigated expression of receptor subunit mRNA within the nodose ganglion. The responses of mouse gastro-oesophageal vagal afferents to graded mechanical stimuli were investigated before and during application of selective GluR ligands to their peripheral endings. Two types of vagal afferents were tested: tension receptors, which respond to circumferential tension, and mucosal receptors, which respond only to mucosal stroking. The selective iGluR agonists NMDA and AMPA concentration-dependently potentiated afferent responses. Their corresponding antagonists AP-5 and NBQX alone attenuated mechanosensory responses as did the non-selective antagonist kynurenate. The kainate selective agonist SYM-2081 had minor effects on mechanosensitivity, and the antagonist UBP 302 was ineffective. The mGluR5 antagonist MTEP concentration-dependently inhibited mechanosensitivity. Efficacy of agonists and antagonists differed on mucosal and tension receptors. We conclude that excitatory modulation of afferent mechanosensitivity occurs mainly via NMDA, AMPA and mGlu5 receptors, and the role of each differs according to afferent subtypes. PCR data indicated that all NMDA, kainate and AMPA receptor subunits plus mGluR5 are expressed, and are therefore candidates for the neuromodulation we observed. PMID:16945965

Potentiation of mouse vagal afferent mechanosensitivity by ionotropic and metabotropic glutamate receptors.

PubMed

Slattery, James A; Page, Amanda J; Dorian, Camilla L; Brierley, Stuart M; Blackshaw, L Ashley

2006-11-15

Glutamate acts at central synapses via ionotropic (iGluR--NMDA, AMPA and kainate) and metabotropic glutamate receptors (mGluRs). Group I mGluRs are excitatory whilst group II and III are inhibitory. Inhibitory mGluRs also modulate peripherally the mechanosensitivity of gastro-oesophageal vagal afferents. Here we determined the potential of excitatory GluRs to play an opposing role in modulating vagal afferent mechanosensitivity, and investigated expression of receptor subunit mRNA within the nodose ganglion. The responses of mouse gastro-oesophageal vagal afferents to graded mechanical stimuli were investigated before and during application of selective GluR ligands to their peripheral endings. Two types of vagal afferents were tested: tension receptors, which respond to circumferential tension, and mucosal receptors, which respond only to mucosal stroking. The selective iGluR agonists NMDA and AMPA concentration-dependently potentiated afferent responses. Their corresponding antagonists AP-5 and NBQX alone attenuated mechanosensory responses as did the non-selective antagonist kynurenate. The kainate selective agonist SYM-2081 had minor effects on mechanosensitivity, and the antagonist UBP 302 was ineffective. The mGluR5 antagonist MTEP concentration-dependently inhibited mechanosensitivity. Efficacy of agonists and antagonists differed on mucosal and tension receptors. We conclude that excitatory modulation of afferent mechanosensitivity occurs mainly via NMDA, AMPA and mGlu5 receptors, and the role of each differs according to afferent subtypes. PCR data indicated that all NMDA, kainate and AMPA receptor subunits plus mGluR5 are expressed, and are therefore candidates for the neuromodulation we observed.

Morphology of the utricular otolith organ in the toadfish, Opsanus tau.

PubMed

Boyle, Richard; Ehsanian, Reza; Mofrad, Alireza; Popova, Yekaterina; Varelas, Joseph

2018-06-15

The utricle provides the vestibular reflex pathways with the sensory codes of inertial acceleration of self-motion and head orientation with respect to gravity to control balance and equilibrium. Here we present an anatomical description of this structure in the adult oyster toadfish and establish a morphological basis for interpretation of subsequent functional studies. Light, scanning, and transmission electron microscopy techniques were applied to visualize the sensory epithelium at varying levels of detail, its neural innervation and its synaptic organization. Scanning electron microscopy was used to visualize otolith mass and morphological polarization patterns of hair cells. Afferent nerve fibers were visualized following labeling with biocytin, and light microscope images were used to make three-dimensional (3-D) reconstructions of individual labeled afferents to identify dendritic morphology with respect to epithelial location. Transmission electron micrographs were compiled to create a serial 3-D reconstruction of a labeled afferent over a segment of its dendritic field and to examine the cell-afferent synaptic contacts. Major observations are: a well-defined striola, medial and lateral extra-striolar regions with a zonal organization of hair bundles; prominent lacinia projecting laterally; dependence of hair cell density on macular location; narrow afferent dendritic fields that follow the hair bundle polarization; synaptic specializations issued by afferents are typically directed towards a limited number of 7-13 hair cells, but larger dendritic fields in the medial extra-striola can be associated with > 20 hair cells also; and hair cell synaptic bodies can be confined to only an individual afferent or can synapse upon several afferents. © 2018 Wiley Periodicals, Inc.

Acute cholangitis due to afferent loop syndrome after a Whipple procedure: a case report.

PubMed

Spiliotis, John; Karnabatidis, Demetrios; Vaxevanidou, Archodoula; Datsis, Anastasios C; Rogdakis, Athanasios; Zacharis, Georgios; Siamblis, Demetrios

2009-08-25

Patients with resection of stomach and especially with Billroth II reconstruction (gastro jejunal anastomosis), are more likely to develop afferent loop syndrome which is a rare complication. When the afferent part is obstructed, biliary and pancreatic secretions accumulate and cause the distention of this part. In the case of a complete obstruction (rare), there is a high risk developing necrosis and perforation. This complication has been reported once in the literature. A 54-year-old Greek male had undergone a pancreato-duodenectomy (Whipple procedure) one year earlier due to a pancreatic adenocarcinoma. Approximately 10 months after the initial operation, the patient started having episodes of cholangitis (fever, jaundice) and abdominal pain. This condition progressively worsened and the suspicion of local recurrence or stenosis of the biliary-jejunal anastomosis was discussed. A few days before his admission the patient developed signs of septic cholangitis. Our case demonstrates a rare complication with serious clinical manifestation of the afferent loop syndrome. This advanced form of afferent loop syndrome led to the development of huge enterobiliary reflux, which had a serious clinical manifestation as cholangitis and systemic sepsis, due to bacterial overgrowth, which usually present in the afferent loop. The diagnosis is difficult and the interventional radiology gives all the details to support the therapeutic decision making. A variety of factors can contribute to its development including adhesions, kinking and angulation of the loop, stenosis of gastro-jejunal anastomosis and internal herniation. In order to decompress the afferent loop dilatation due to adhesions, a lateral-lateral jejunal anastomosis was performed between the afferent loop and a small bowel loop.

Identification of the tracheal and laryngeal afferent neurones mediating cough in anaesthetized guinea-pigs

PubMed Central

Canning, Brendan J; Mazzone, Stuart B; Meeker, Sonya N; Mori, Nanako; Reynolds, Sandra M; Undem, Bradley J

2004-01-01

We have identified the tracheal and laryngeal afferent nerves regulating cough in anaesthetized guinea-pigs. Cough was evoked by electrical or mechanical stimulation of the tracheal or laryngeal mucosa, or by citric acid applied topically to the trachea or larynx. By contrast, neither capsaicin nor bradykinin challenges to the trachea or larynx evoked cough. Bradykinin and histamine administered intravenously also failed to evoke cough. Electrophysiological studies revealed that the majority of capsaicin-sensitive afferent neurones (both Aδ- and C-fibres) innervating the rostral trachea and larynx have their cell bodies in the jugular ganglia and project to the airways via the superior laryngeal nerves. Capsaicin-insensitive afferent neurones with cell bodies in the nodose ganglia projected to the rostral trachea and larynx via the recurrent laryngeal nerves. Severing the recurrent nerves abolished coughing evoked from the trachea and larynx whereas severing the superior laryngeal nerves was without effect on coughing. The data indicate that the tracheal and laryngeal afferent neurones regulating cough are polymodal Aδ-fibres that arise from the nodose ganglia. These afferent neurones are activated by punctate mechanical stimulation and acid but are unresponsive to capsaicin, bradykinin, smooth muscle contraction, longitudinal or transverse stretching of the airways, or distension. Comparing these physiological properties with those of intrapulmonary mechanoreceptors indicates that the afferent neurones mediating cough are quite distinct from the well-defined rapidly and slowly adapting stretch receptors innervating the airways and lungs. We propose that these airway afferent neurones represent a distinct subtype and that their primary function is regulation of the cough reflex. PMID:15004208

Peripheral oxytocin activates vagal afferent neurons to suppress feeding in normal and leptin-resistant mice: a route for ameliorating hyperphagia and obesity.

PubMed

Iwasaki, Yusaku; Maejima, Yuko; Suyama, Shigetomo; Yoshida, Masashi; Arai, Takeshi; Katsurada, Kenichi; Kumari, Parmila; Nakabayashi, Hajime; Kakei, Masafumi; Yada, Toshihiko

2015-03-01

Oxytocin (Oxt), a neuropeptide produced in the hypothalamus, is implicated in regulation of feeding. Recent studies have shown that peripheral administration of Oxt suppresses feeding and, when infused subchronically, ameliorates hyperphagic obesity. However, the route through which peripheral Oxt informs the brain is obscure. This study aimed to explore whether vagal afferents mediate the sensing and anorexigenic effect of peripherally injected Oxt in mice. Intraperitoneal Oxt injection suppressed food intake and increased c-Fos expression in nucleus tractus solitarius to which vagal afferents project. The Oxt-induced feeding suppression and c-Fos expression in nucleus tractus solitarius were blunted in mice whose vagal afferent nerves were blocked by subdiaphragmatic vagotomy or capsaicin treatment. Oxt induced membrane depolarization and increases in cytosolic Ca(2+) concentration ([Ca(2+)]i) in single vagal afferent neurons. The Oxt-induced [Ca(2+)]i increases were markedly suppressed by Oxt receptor antagonist. These Oxt-responsive neurons also responded to cholecystokinin-8 and contained cocaine- and amphetamine-regulated transcript. In obese diabetic db/db mice, leptin failed to increase, but Oxt increased [Ca(2+)]i in vagal afferent neurons, and single or subchronic infusion of Oxt decreased food intake and body weight gain. These results demonstrate that peripheral Oxt injection suppresses food intake by activating vagal afferent neurons and thereby ameliorates obesity in leptin-resistant db/db mice. The peripheral Oxt-regulated vagal afferent neuron provides a novel target for treating hyperphagia and obesity. Copyright © 2015 the American Physiological Society.

Does metabosensitive afferent fibers activity differ from slow- and fast-twitch muscles?

PubMed

Caron, Guillaume; Decherchi, Patrick; Marqueste, Tanguy

2015-09-01

This study was designed to investigate the metabosensitive afferent response evoked by electrically induced fatigue (EIF), lactic acid (LA) and potassium chloride (KCl) in three muscle types. We recorded the activity of groups III-IV afferents originating from soleus, gastrocnemius and tibialis anterior muscles. Our data showed a same pattern of response in the three muscles after chemical injections, i.e., a bell curve with maximal discharge rate at 1 mM for LA injections and a linear relationship between KCl concentrations and the afferent discharge rate. Furthermore, a stronger response was recorded after EIF in the gastrocnemius muscle compared to the two other muscles. The change in afferent discharge after 1 mM LA injection was higher for the gastrocnemius muscle compared to the response obtained with the corresponding concentration applied in the two other muscles, whereas changes to KCl injections did not dramatically differ between the three muscles. We conclude that anatomical (mass, phenotype, vascularization, receptor and afferent density…) and functional (flexor vs. extensor) differences between muscles could explain the amplitude of these responses.

Spatial orientation of semicircular canals and afferent sensitivity vectors in pigeons

NASA Technical Reports Server (NTRS)

Dickman, J. D.

1996-01-01

Rotational head motion in vertebrates is detected by the semicircular canal system, whose innervating primary afferent fibers carry information about movement in specific head planes. The semicircular canals have been qualitatively examined over a number of years, and the canal planes have been quantitatively characterized in several animal species. The present study first determined the geometric relationship between individual semicircular canals and between the canals and the stereotactic head planes in pigeons. Stereotactic measurements of multiple points along the circumference of the bony canals were taken, and the measured points fitted with a three-dimensional planar surface. Direction normals to the plane's surface were calculated and used to define angles between semicircular canal pairs. Because of the unusual shape of the anterior semicircular canals in pigeons, two planes, a major and a minor, were fitted to the canal's course. Calculated angle values for all canals indicated that the horizontal and posterior semicircular canals are nearly orthogonal, but the anterior canals have substantial deviations from orthogonality with other canal planes. Next, the responses of the afferent fibers that innervate each of the semicircular canals to 0.5 Hz sinusoidal rotation about an earth-vertical axis were obtained. The head orientation relative to the rotation axis was systematically varied so that directions of maximum sensitivity for each canal afferent could be determined. These sensitivity vectors were then compared with the canal plane direction normals. The afferents that innervated specific semicircular canals formed homogeneous clusters of sensitivity vectors in different head planes. The horizontal and posterior afferents had average sensitivity vectors that were largely co-incident with the innervated canal plane direction normals. Anterior canal afferents, however, appeared to synthesize contributions from the major and minor plane components of the bony canal structure to produce a resultant sensitivity vector that was positioned between the canal planes. Calculated angles between the average canal afferent sensitivity vectors revealed that direction orthogonality is preserved at the afferent signal level, even though deviations from canal plane orthogonality exist.

Activation of colo-rectal high-threshold afferent nerves by Interleukin-2 is tetrodotoxin-sensitive and upregulated in a mouse model of chronic visceral hypersensitivity.

PubMed

Campaniello, M A; Harrington, A M; Martin, C M; Ashley Blackshaw, L; Brierley, S M; Hughes, P A

2016-01-01

Chronic visceral pain is a defining feature of irritable bowel syndrome (IBS). IBS patients often show alterations in innate and adaptive immune function which may contribute to symptoms. Immune mediators are known to modulate the activity of viscero-sensory afferent nerves, but the focus has been on the innate immune system. Interleukin-2 (IL-2) is primarily associated with adaptive immune responses but its effects on colo-rectal afferent function in health or disease are unknown. Myeloperoxidase (MPO) activity determined the extent of inflammation in health, acute trinitrobenzene-sulfonic acid (TNBS) colitis, and in our post-TNBS colitis model of chronic visceral hypersensitivity (CVH). The functional effects of IL-2 on high-threshold colo-rectal afferents and the expression of IL-2R and NaV 1.7 mRNA in colo-rectal dorsal root ganglia (DRG) neurons were compared between healthy and CVH mice. MPO activity was increased during acute colitis, but subsided to levels comparable to health in CVH mice. IL-2 caused direct excitation of colo-rectal afferents that was blocked by tetrodotoxin. IL-2 did not affect afferent mechanosensitivity in health or CVH. However, an increased proportion of afferents responded directly to IL-2 in CVH mice compared with controls (73% vs 33%; p < 0.05), and the abundance of IL-2R and NaV 1.7 mRNA was increased 3.5- and 2-fold (p < 0.001 for both) in colo-rectal DRG neurons. IL-2, an immune mediator from the adaptive arm of the immune response, affects colo-rectal afferent function, indicating these effects are not restricted to innate immune mediators. Colo-rectal afferent sensitivity to IL-2 is increased long after healing from inflammation. © 2015 John Wiley & Sons Ltd.

Afferent control of central pattern generators: experimental analysis of locomotion in the decerebrate cat.

PubMed

Baev, K V; Esipenko, V B; Shimansky YuP

1991-01-01

Changes in the motor activity of the spinal locomotor generator evoked by tonic and phasic peripheral afferent signals during fictitious locomotion of both slow and fast rhythms were analysed in the cat. The tonic afferent inflow was conditioned by the position of the hindlimb. The phasic afferent signals were imitated by electrical stimulation of hindlimb nerves. The correlation between the kinematics of hindlimb locomotor movement and sensory inflow was investigated during actual locomotion. Reliable correlations between motor activity parameters during fictitious locomotion were revealed in cases of both slow and fast "locomotor" rhythms. The main difference between these cases was that correlations "duration-intensity" were positive in the first and negative in the second case. The functional role of "locomotor" pattern dependence on tonic sensory inflow consisted of providing stability for planting the hindlimb on the ground. For any investigated afferent input the phase moments in the "locomotor" cycle were found, in which an afferent signal caused no rearrangement in locomotor generator activity. These moments corresponded to the transitions between "flexion" and "extension" phases and to the bursts of integral afferent activity observed during real locomotion. The data obtained are compared with the results previously described for the scratching generator. The character of changes in "locomotor" activity in response to tonic and phasic sensory signals was similar to that of such changes in "scratching" rhythm in the case of fast "locomotion". Intensification of the "flexion" phase caused by phasic high-intensity stimulation of cutaneous afferents during low "locomotor" rhythm was changed to inhibition (such as observed during "scratching") when this rhythm was fast. It is concluded that the main regularities of peripheral afferent control for both the locomotor and scratching generators are the same. Moreover, these central pattern generators are just working regimes of a general spinal motor optimal control system containing the intrinsic model of limb movement dynamics. The consequences of this concept and ways of further research are discussed.

Lectin Ulex europaeus agglutinin I specifically labels a subset of primary afferent fibers which project selectively to the superficial dorsal horn of the spinal cord.

PubMed

Mori, K

1986-02-19

To examine differential carbohydrate expression among different subsets of primary afferent fibers, several fluorescein-isothiocyanate conjugated lectins were used in a histochemical study of the dorsal root ganglion (DRG) and spinal cord of the rabbit. The lectin Ulex europaeus agglutinin I specifically labeled a subset of DRG cells and primary afferent fibers which projected to the superficial laminae of the dorsal horn. These results suggest that specific carbohydrates containing L-fucosyl residue is expressed selectively in small diameter primary afferent fibers which subserve nociception or thermoception.

Connections from the rat dorsal column nuclei (DCN) to the periaqueductal gray matter (PAG).

PubMed

Barbaresi, Paolo; Mensà, Emanuela

2016-08-01

Electrical stimulation of the dorsal columns (DCs; spinal cord stimulation; SCS) has been proposed to treat chronic neuropathic pain. SCS may activate a dual mechanism that would affect both the spinal cord and supraspinal levels. Stimulation of DCs or DC nuclei (DCN) in animals where neuropathic pain has been induced causes activation of brainstem centers including the periaqueductal gray (PAG), which is involved in the endogenous pain suppression system. Biotinylated dextran-amine (BDA) was iontophoretically injected into the DCN to analyze the ascending projection directed to the PAG. Separate injections into the gracile nucleus (GrN) and the cuneate nucleus (CunN) showed BDA-positive fibers terminating in different regions of the contralateral PAG. GrN-PAG afferents terminated in the caudal and middle portions of PAG-l, whereas CunN-PAG fibers terminated in the middle and rostral portions of PAG-l. Based on the DCN somatotopic map, the GrN sends information to the PAG from the contralateral hindlimb and the tail and the CunN from the contralateral forelimb, shoulder, neck and ear. This somatotopic organization is consistent with earlier electrophysiological and PAG stimulation studies. These fibers could form part of the DCs-brainstem-spinal cord loop, which may be involved in the inhibitory effects of SCS on neuropathic pain. Copyright © 2016. Published by Elsevier Ireland Ltd.

Inputs from regularly and irregularly discharging vestibular nerve afferents to secondary neurons in squirrel monkey vestibular nuclei. III. Correlation with vestibulospinal and vestibuloocular output pathways

NASA Technical Reports Server (NTRS)

Boyle, R.; Goldberg, J. M.; Highstein, S. M.

1992-01-01

1. A previous study measured the relative contributions made by regularly and irregularly discharging afferents to the monosynaptic vestibular nerve (Vi) input of individual secondary neurons located in and around the superior vestibular nucleus of barbiturate-anesthetized squirrel monkeys. Here, the analysis is extended to more caudal regions of the vestibular nuclei, which are a major source of both vestibuloocular and vestibulospinal pathways. As in the previous study, antidromic stimulation techniques are used to classify secondary neurons as oculomotor or spinal projecting. In addition, spinal-projecting neurons are distinguished by their descending pathways, their termination levels in the spinal cord, and their collateral projections to the IIIrd nucleus. 2. Monosynaptic excitatory postsynaptic potentials (EPSPs) were recorded intracellularly from secondary neurons as shocks of increasing strength were applied to Vi. Shocks were normalized in terms of the threshold (T) required to evoke field potentials in the vestibular nuclei. As shown previously, the relative contribution of irregular afferents to the total monosynaptic Vi input of each secondary neuron can be expressed as a %I index, the ratio (x100) of the relative sizes of the EPSPs evoked by shocks of 4 x T and 16 x T. 3. Antidromic stimulation was used to type secondary neurons as 1) medial vestibulospinal tract (MVST) cells projecting to spinal segments C1 or C6; 2) lateral vestibulospinal tract (LVST) cells projecting to C1, C6; or L1; 3) vestibulooculo-collic (VOC) cells projecting both to the IIIrd nucleus and by way of the MVST to C1 or C6; and 4) vestibuloocular (VOR) neurons projecting to the IIIrd nucleus but not to the spinal cord. Most of the neurons were located in the lateral vestibular nucleus (LV), including its dorsal (dLV) and ventral (vLV) divisions, and adjacent parts of the medial (MV) and descending nuclei (DV). Cells receiving quite different proportions of their direct inputs from regular and irregular afferents were intermingled in all regions explored. 4. LVST neurons are restricted to LV and DV and show a somatotopic organization. Those destined for the cervical and thoracic cord come from vLV, from a transition zone between vLV and DV, and to a lesser extent from dLV. Lumbar-projecting neurons are located more dorsally in dLV and more caudally in DV. MVST neurons reside in MV and in the vLV-DV transition zone.(ABSTRACT TRUNCATED AT 400 WORDS).

Zincergic innervation from the anterior olfactory nucleus to the olfactory bulb displays plastic responses after mitral cell loss.

PubMed

Airado, Carmen; Gómez, Carmela; Recio, Javier S; Baltanás, Fernando C; Weruaga, Eduardo; Alonso, José R

2008-12-01

Zinc ions are selectively accumulated in certain neurons (zinc-enriched neurons). The mouse olfactory bulb is richly innervated by zinc-enriched terminals. Here, the plasticity of the zincergic system was studied in the olfactory bulb of the Purkinje Cell Degeneration mutant mouse, an animal with specific postnatal neurodegeneration of the main projection neurons of the olfactory bulb. The analysis focused particularly on the anterior olfactory nucleus since most centrifugal afferents coming to the olfactory bulb arise from this structure. Zinc-enriched terminals in the olfactory bulb and zinc-enriched somata in the anterior olfactory nucleus were visualized after selenite injections. Immunohistochemistry against the vesicular zinc transporter was also carried out to confirm the distribution pattern of zinc-enriched terminals in the olfactory bulb. The mutant mice showed a clear reorganization of zincergic centrifugal projections from the anterior olfactory nucleus to the olfactory bulb. First, all zincergic contralateral neurons projecting to the olfactory bulb were absent in the mutant mice. Second, a significant increase in the number of stained somata was detected in the ipsilateral anterior olfactory nucleus. Since no noticeable changes were observed in the zinc-enriched terminals in the olfactory bulb, it is conceivable that mitral cell loss could induce a reorganization of zinc-enriched projections coming from the anterior olfactory nucleus, probably directed at balancing the global zincergic centrifugal modulation. These results show that zincergic anterior olfactory nucleus cells projecting to the olfactory bulb undergo plastic changes to adapt to the loss of mitral cells in the olfactory bulb of Purkinje Cell Degeneration mutant mice.

Ultrastructural study of the GABAergic and cerebellar input to the nucleus reticularis tegmenti pontis.

PubMed

Verveer, C; Hawkins, R K; Ruigrok, T J; De Zeeuw, C I

1997-08-22

The nucleus reticularis tegmenti pontis is an intermediate of the cerebrocerebellar pathway and serves as a relay centre for sensorimotor and visual information. The central nuclei of the cerebellum provide a dense projection to the nucleus reticularis tegmenti pontis, but it is not known to what extent this projection is excitatory or inhibitory, and whether the terminals of this projection contact the neurons in the nucleus reticularis tegmenti pontis that give rise to the mossy fibre collaterals innervating the cerebellar nuclei. In the present study the nucleus reticularis tegmenti pontis of the cat was investigated at the ultrastructural level following anterograde and retrograde transport of wheat germ agglutinin coupled to horseradish peroxidase (WGA-HRP) from the cerebellar nuclei combined with postembedding GABA immunocytochemistry. The neuropil of this nucleus was found to contain many WGA-HRP labeled terminals, cell bodies and dendrites, but none of these pre- or postsynaptic structures was double labeled with GABA. The vast majority of the WGA-HRP labeled terminals contained clear spherical vesicles, showed asymmetric synapses, and contacted intermediate or distal dendrites. Many of the postsynaptic elements of the cerebellar afferents in the nucleus reticularis tegmenti pontis were retrogradely labeled with WGA-HRP, while relatively few were GABAergic. We conclude that all cerebellar terminals in the nucleus reticularis tegmenti pontis of the cat are nonGABAergic and excitatory, and that they contact predominantly neurons that project back to the cerebellum. Thus, the reciprocal circuit between the cerebellar nuclei and the nucleus reticularis tegmenti pontis appears to be well designed to function as an excitatory reverberating loop.

Information transmission and detection thresholds in the vestibular nuclei: single neurons vs. population encoding

PubMed Central

Massot, Corentin; Chacron, Maurice J.

2011-01-01

Understanding how sensory neurons transmit information about relevant stimuli remains a major goal in neuroscience. Of particular relevance are the roles of neural variability and spike timing in neural coding. Peripheral vestibular afferents display differential variability that is correlated with the importance of spike timing; regular afferents display little variability and use a timing code to transmit information about sensory input. Irregular afferents, conversely, display greater variability and instead use a rate code. We studied how central neurons within the vestibular nuclei integrate information from both afferent classes by recording from a group of neurons termed vestibular only (VO) that are known to make contributions to vestibulospinal reflexes and project to higher-order centers. We found that, although individual central neurons had sensitivities that were greater than or equal to those of individual afferents, they transmitted less information. In addition, their velocity detection thresholds were significantly greater than those of individual afferents. This is because VO neurons display greater variability, which is detrimental to information transmission and signal detection. Combining activities from multiple VO neurons increased information transmission. However, the information rates were still much lower than those of equivalent afferent populations. Furthermore, combining responses from multiple VO neurons led to lower velocity detection threshold values approaching those measured from behavior (∼2.5 vs. 0.5–1°/s). Our results suggest that the detailed time course of vestibular stimuli encoded by afferents is not transmitted by VO neurons. Instead, they suggest that higher vestibular pathways must integrate information from central vestibular neuron populations to give rise to behaviorally observed detection thresholds. PMID:21307329

Functional analysis of ultra high information rates conveyed by rat vibrissal primary afferents

PubMed Central

Chagas, André M.; Theis, Lucas; Sengupta, Biswa; Stüttgen, Maik C.; Bethge, Matthias; Schwarz, Cornelius

2013-01-01

Sensory receptors determine the type and the quantity of information available for perception. Here, we quantified and characterized the information transferred by primary afferents in the rat whisker system using neural system identification. Quantification of “how much” information is conveyed by primary afferents, using the direct method (DM), a classical information theoretic tool, revealed that primary afferents transfer huge amounts of information (up to 529 bits/s). Information theoretic analysis of instantaneous spike-triggered kinematic stimulus features was used to gain functional insight on “what” is coded by primary afferents. Amongst the kinematic variables tested—position, velocity, and acceleration—primary afferent spikes encoded velocity best. The other two variables contributed to information transfer, but only if combined with velocity. We further revealed three additional characteristics that play a role in information transfer by primary afferents. Firstly, primary afferent spikes show preference for well separated multiple stimuli (i.e., well separated sets of combinations of the three instantaneous kinematic variables). Secondly, neurons are sensitive to short strips of the stimulus trajectory (up to 10 ms pre-spike time), and thirdly, they show spike patterns (precise doublet and triplet spiking). In order to deal with these complexities, we used a flexible probabilistic neuron model fitting mixtures of Gaussians to the spike triggered stimulus distributions, which quantitatively captured the contribution of the mentioned features and allowed us to achieve a full functional analysis of the total information rate indicated by the DM. We found that instantaneous position, velocity, and acceleration explained about 50% of the total information rate. Adding a 10 ms pre-spike interval of stimulus trajectory achieved 80–90%. The final 10–20% were found to be due to non-linear coding by spike bursts. PMID:24367295

Reduced Short- and Long-Latency Afferent Inhibition Following Acute Muscle Pain: A Potential Role in the Recovery of Motor Output.

PubMed

Burns, Emma; Chipchase, Lucinda Sian; Schabrun, Siobhan May

2016-02-13

. Corticomotor output is reduced in response to acute muscle pain, yet the mechanisms that underpin this effect remain unclear. Here the authors investigate the effect of acute muscle pain on short-latency afferent inhibition, long-latency afferent inhibition, and long-interval intra-cortical inhibition to determine whether these mechanisms could plausibly contribute to reduced motor output in pain. . Observational same subject pre-post test design. . Neurophysiology research laboratory. . Healthy, right-handed human volunteers (n = 22, 9 male; mean age ± standard deviation, 22.6 ± 7.8 years). . Transcranial magnetic stimulation was used to assess corticomotor output, short-latency afferent inhibition, long-latency afferent inhibition, and long-interval intra-cortical inhibition before, during, immediately after, and 15 minutes after hypertonic saline infusion into right first dorsal interosseous muscle. Pain intensity and quality were recorded using an 11-point numerical rating scale and the McGill Pain Questionnaire. . Compared with baseline, corticomotor output was reduced at all time points (p = 0.001). Short-latency afferent inhibition was reduced immediately after (p = 0.039), and long-latency afferent inhibition 15 minutes after (p = 0.035), the resolution of pain. Long-interval intra-cortical inhibition was unchanged at any time point (p = 0.36). . These findings suggest short- and long-latency afferent inhibition, mechanisms thought to reflect the integration of sensory information with motor output at the cortex, are reduced following acute muscle pain. Although the functional relevance is unclear, the authors hypothesize a reduction in these mechanisms may contribute to the restoration of normal motor output after an episode of acute muscle pain. © 2016 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Modulation of jaw muscle spindle afferent activity following intramuscular injections with hypertonic saline.

PubMed

Ro, J Y; Capra, N F

2001-05-01

Transient noxious chemical stimulation of small diameter muscle afferents modulates jaw movement-related responses of caudal brainstem neurons. While it is likely that the effect is mediated from the spindle afferents in the mesencephalic nucleus (Vmes) via the caudally projecting Probst's tract, the mechanisms of pain induced modulations of jaw muscle spindle afferents is not known. In the present study, we tested the hypothesis that jaw muscle nociceptors gain access to muscle spindle afferents in the same muscle via central mechanisms and alter their sensitivity. Thirty-five neurons recorded from the Vmes were characterized as muscle spindle afferents based on their responses to passive jaw movements, muscle palpation, and electrical stimulation of the masseter nerve. Each cell was tested by injecting a small volume (250 microl) of either 5% hypertonic and/or isotonic saline into the receptor-bearing muscle. Twenty-nine units were tested with 5% hypertonic saline, of which 79% (23/29) showed significant modulation of mean firing rates (MFRs) during one or more phases of ramp-and-hold movements. Among the muscle spindle primary-like units (n = 12), MFRs of 4 units were facilitated, five reduced, two showed mixed responses and one unchanged. In secondary-like units (n = 17), MFRs of 9 were facilitated, three reduced and five unchanged. Thirteen units were tested with isotonic saline, of which 77% showed no significant changes of MFRs. Further analysis revealed that the hypertonic saline not only affected the overall output of muscle spindle afferents, but also increased the variability of firing and altered the relationship between afferent signal and muscle length. These results demonstrated that activation of muscle nociceptors significantly affects proprioceptive properties of jaw muscle spindles via central neural mechanisms. The changes can have deleterious effects on oral motor function as well as kinesthetic sensibility.

Hyperexcitability of bladder afferent neurons associated with reduction of Kv1.4 α-subunit in rats with spinal cord injury.

PubMed

Takahashi, Ryosuke; Yoshizawa, Tsuyoshi; Yunoki, Takakazu; Tyagi, Pradeep; Naito, Seiji; de Groat, William C; Yoshimura, Naoki

2013-12-01

To clarify the functional and molecular mechanisms inducing hyperexcitability of C-fiber bladder afferent pathways after spinal cord injury we examined changes in the electrophysiological properties of bladder afferent neurons, focusing especially on voltage-gated K channels. Freshly dissociated L6-S1 dorsal root ganglion neurons were prepared from female spinal intact and spinal transected (T9-T10 transection) Sprague Dawley® rats. Whole cell patch clamp recordings were performed on individual bladder afferent neurons. Kv1.2 and Kv1.4 α-subunit expression levels were also evaluated by immunohistochemical and real-time polymerase chain reaction methods. Capsaicin sensitive bladder afferent neurons from spinal transected rats showed increased cell excitability, as evidenced by lower spike activation thresholds and a tonic firing pattern. The peak density of transient A-type K+ currents in capsaicin sensitive bladder afferent neurons from spinal transected rats was significantly less than that from spinal intact rats. Also, the KA current inactivation curve was displaced to more hyperpolarized levels after spinal transection. The protein and mRNA expression of Kv1.4 α-subunits, which can form transient A-type K+ channels, was decreased in bladder afferent neurons after spinal transection. Results indicate that the excitability of capsaicin sensitive C-fiber bladder afferent neurons is increased in association with reductions in transient A-type K+ current density and Kv1.4 α-subunit expression in injured rats. Thus, the Kv1.4 α-subunit could be a molecular target for treating overactive bladder due to neurogenic detrusor overactivity. Copyright © 2013 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Vagal Afferent Innervation of the Airways in Health and Disease

PubMed Central

Mazzone, Stuart B.

2016-01-01

Vagal sensory neurons constitute the major afferent supply to the airways and lungs. Subsets of afferents are defined by their embryological origin, molecular profile, neurochemistry, functionality, and anatomical organization, and collectively these nerves are essential for the regulation of respiratory physiology and pulmonary defense through local responses and centrally mediated neural pathways. Mechanical and chemical activation of airway afferents depends on a myriad of ionic and receptor-mediated signaling, much of which has yet to be fully explored. Alterations in the sensitivity and neurochemical phenotype of vagal afferent nerves and/or the neural pathways that they innervate occur in a wide variety of pulmonary diseases, and as such, understanding the mechanisms of vagal sensory function and dysfunction may reveal novel therapeutic targets. In this comprehensive review we discuss historical and state-of-the-art concepts in airway sensory neurobiology and explore mechanisms underlying how vagal sensory pathways become dysfunctional in pathological conditions. PMID:27279650

Active touch and self-motion encoding by Merkel cell-associated afferents

PubMed Central

Severson, Kyle S.; Xu, Duo; Van de Loo, Margaret; Bai, Ling; Ginty, David D.; O’Connor, Daniel H.

2017-01-01

Summary Touch perception depends on integrating signals from multiple types of peripheral mechanoreceptors. Merkel-cell associated afferents are thought to play a major role in form perception by encoding surface features of touched objects. However, activity of Merkel afferents during active touch has not been directly measured. Here, we show that Merkel and unidentified slowly adapting afferents in the whisker system of behaving mice respond to both self-motion and active touch. Touch responses were dominated by sensitivity to bending moment (torque) at the base of the whisker and its rate of change, and largely explained by a simple mechanical model. Self-motion responses encoded whisker position within a whisk cycle (phase), not absolute whisker angle, and arose from stresses reflecting whisker inertia and activity of specific muscles. Thus, Merkel afferents send to the brain multiplexed information about whisker position and surface features, suggesting that proprioception and touch converge at the earliest neural level. PMID:28434802

Effective connectivity during processing of facial affect: evidence for multiple parallel pathways.

PubMed

Dima, Danai; Stephan, Klaas E; Roiser, Jonathan P; Friston, Karl J; Frangou, Sophia

2011-10-05

The perception of facial affect engages a distributed cortical network. We used functional magnetic resonance imaging and dynamic causal modeling to characterize effective connectivity during explicit (conscious) categorization of affective stimuli in the human brain. Specifically, we examined the modulation of connectivity from posterior regions of the face-processing network to the lateral ventral prefrontal cortex (VPFC) during affective categorization and we tested for a potential role of the amygdala (AMG) in mediating this modulation. We found that explicit processing of facial affect led to prominent modulation (increase) in the effective connectivity from the inferior occipital gyrus (IOG) to the VPFC, while there was less evidence for modulation of the afferent connections from fusiform gyrus and AMG to VPFC. More specifically, the forward connection from IOG to the VPFC exhibited a selective increase under anger (as opposed to fear or sadness). Furthermore, Bayesian model comparison suggested that the modulation of afferent connections to the VPFC was mediated directly by facial affect, as opposed to an indirect modulation mediated by the AMG. Our results thus suggest that affective information is conveyed to the VPFC along multiple parallel pathways and that AMG activity is not sufficient to account for the gating of information transfer to the VPFC during explicit emotional processing.

Site of anticonvulsant action on sodium channels: autoradiographic and electrophysiological studies in rat brain

DOE Office of Scientific and Technical Information (OSTI.GOV)

Worley, P.F.; Baraban, J.M.

1987-05-01

The anticonvulsants phenytoin and carbamazepine interact allosterically with the batrachotoxin binding site of sodium channels. In the present study, we demonstrate an autoradiographic technique to localize the batrachotoxin binding site on sodium channels in rat brain using (/sup 3/H)batrachotoxinin-A 20-alpha-benzoate (BTX-B). Binding of (/sup 3/H)BTX-B to brain sections is dependent on potentiating allosteric interactions with scorpion venom and is displaced by BTX-B (Kd approximately 200 nM), aconitine, veratridine, and phenytoin with the same rank order of potencies as described in brain synaptosomes. The maximum number of (/sup 3/H)BTX-B binding sites in forebrain sections also agrees with biochemical determinations. Autoradiographic localizationsmore » indicate that (/sup 3/H)BTX-B binding sites are not restricted to cell bodies and axons but are present in synaptic zones throughout the brain. For example, a particularly dense concentration of these sites in the substantia nigra is associated with afferent terminals of the striatonigral projection. By contrast, myelinated structures possess much lower densities of binding sites. In addition, we present electrophysiological evidence that synaptic transmission, as opposed to axonal conduction, is preferentially sensitive to the action of aconitine and veratridine. Finally, the synaptic block produced by these sodium channel activators is inhibited by phenytoin and carbamazepine at therapeutic anticonvulsant concentrations.« less

Laminar- and Target-Specific Amygdalar Inputs in Rat Primary Gustatory Cortex.

PubMed

Haley, Melissa S; Fontanini, Alfredo; Maffei, Arianna

2016-03-02

The primary gustatory cortex (GC) receives projections from the basolateral nucleus of the amygdala (BLA). Behavioral and electrophysiological studies demonstrated that this projection is involved in encoding the hedonic value of taste and is a source of anticipatory activity in GC. Anatomically, this projection is largest in the agranular portion of GC; however, its synaptic targets and synaptic properties are currently unknown. In vivo electrophysiological recordings report conflicting evidence about BLA afferents either selectively activating excitatory neurons or driving a compound response consistent with the activation of inhibitory circuits. Here we demonstrate that BLA afferents directly activate excitatory neurons and two distinct populations of inhibitory neurons in both superficial and deep layers of rat GC. BLA afferents recruit different proportions of excitatory and inhibitory neurons and show distinct patterns of circuit activation in the superficial and deep layers of GC. These results provide the first circuit-level analysis of BLA inputs to a sensory area. Laminar- and target-specific differences of BLA inputs likely explain the complexity of amygdalocortical interactions during sensory processing. Projections from the basolateral nucleus of the amygdala (BLA) to the cortex convey information about the emotional value and the expectation of a sensory stimulus. Although much work has been done to establish the behavioral role of BLA inputs to sensory cortices, very little is known about the circuit organization of BLA projections. Here we provide the first in-depth analysis of connectivity and synaptic properties of the BLA input to the gustatory cortex. We show that BLA afferents activate excitatory and inhibitory circuits in a layer-specific and pattern-specific manner. Our results provide important new information about how neural circuits establishing the hedonic value of sensory stimuli and driving anticipatory behaviors are organized at the synaptic level. Copyright © 2016 the authors 0270-6474/16/362623-15$15.00/0.

C-tactile afferent stimulating touch carries a positive affective value.

PubMed

Pawling, Ralph; Cannon, Peter R; McGlone, Francis P; Walker, Susannah C

2017-01-01

The rewarding sensation of touch in affiliative interactions is hypothesized to be underpinned by a specialized system of nerve fibers called C-Tactile afferents (CTs), which respond optimally to slowly moving, gentle touch, typical of a caress. However, empirical evidence to support the theory that CTs encode socially relevant, rewarding tactile information in humans is currently limited. While in healthy participants, touch applied at CT optimal velocities (1-10cm/sec) is reliably rated as subjectively pleasant, neuronopathy patients lacking large myelinated afferents, but with intact C-fibres, report that the conscious sensation elicited by stimulation of CTs is rather vague. Given this weak perceptual impact the value of self-report measures for assessing the specific affective value of CT activating touch appears limited. Therefore, we combined subjective ratings of touch pleasantness with implicit measures of affective state (facial electromyography) and autonomic arousal (heart rate) to determine whether CT activation carries a positive affective value. We recorded the activity of two key emotion-relevant facial muscle sites (zygomaticus major-smile muscle, positive affect & corrugator supercilii-frown muscle, negative affect) while participants evaluated the pleasantness of experimenter administered stroking touch, delivered using a soft brush, at two velocities (CT optimal 3cm/sec & CT non-optimal 30cm/sec), on two skin sites (CT innervated forearm & non-CT innervated palm). On both sites, 3cm/sec stroking touch was rated as more pleasant and produced greater heart rate deceleration than 30cm/sec stimulation. However, neither self-report ratings nor heart rate responses discriminated stimulation on the CT innervated arm from stroking of the non-CT innervated palm. In contrast, significantly greater activation of the zygomaticus major (smiling muscle) was seen specifically to CT optimal, 3cm/sec, stroking on the forearm in comparison to all other stimuli. These results offer the first empirical evidence in humans that tactile stimulation that optimally activates CTs carries a positive affective valence that can be measured implicitly.

Enzymatic inactivation of tachykinin neurotransmitters in the isolated spinal cord of the newborn rat.

PubMed

Yanagisawa, M; Yoshioka, K; Kurihara, T; Saito, K; Seno, N; Suzuki, H; Hosoki, R; Otsuka, M

1992-12-01

A mixture of peptidase inhibitors increased the magnitude of the saphenous nerve-evoked slow depolarization of a lumbar ventral root and prolonged the similarly evoked inhibition of monosynaptic reflex (MSR) in the isolated spinal cord of the newborn rat in the presence of naloxone. The saphenous nerve-evoked MSR inhibition was curtailed by a tachykinin antagonist, GR71251, and after the treatment with GR71251, the peptidase inhibitor mixture no more prolonged the MSR inhibition. The present results suggest that enzymatic degradation plays a role in the termination of action of tachykinins released from primary afferents in the newborn rat spinal cord. The results provide a further support for the notion that tachykinins serve as neurotransmitters in the spinal cord of the newborn rat.

Breadth of tuning in taste afferent neurons varies with stimulus strength

PubMed Central

Wu, An; Dvoryanchikov, Gennady; Pereira, Elizabeth; Chaudhari, Nirupa; Roper, Stephen D.

2015-01-01

Gustatory stimuli are detected by taste buds and transmitted to the hindbrain via sensory afferent neurons. Whether each taste quality (sweet, bitter and so on) is encoded by separate neurons (‘labelled lines') remains controversial. We used mice expressing GCaMP3 in geniculate ganglion sensory neurons to investigate taste-evoked activity. Using confocal calcium imaging, we recorded responses to oral stimulation with prototypic taste stimuli. Up to 69% of neurons respond to multiple tastants. Moreover, neurons tuned to a single taste quality at low concentration become more broadly tuned when stimuli are presented at higher concentration. Responses to sucrose and monosodium glutamate are most related. Although mice prefer dilute NaCl solutions and avoid concentrated NaCl, we found no evidence for two separate populations of sensory neurons that encode this distinction. Altogether, our data suggest that taste is encoded by activity in patterns of peripheral sensory neurons and challenge the notion of strict labelled line coding. PMID:26373451

Stimulus background influences phase invariant coding by correlated neural activity

PubMed Central

Metzen, Michael G; Chacron, Maurice J

2017-01-01

Previously we reported that correlations between the activities of peripheral afferents mediate a phase invariant representation of natural communication stimuli that is refined across successive processing stages thereby leading to perception and behavior in the weakly electric fish Apteronotus leptorhynchus (Metzen et al., 2016). Here, we explore how phase invariant coding and perception of natural communication stimuli are affected by changes in the sinusoidal background over which they occur. We found that increasing background frequency led to phase locking, which decreased both detectability and phase invariant coding. Correlated afferent activity was a much better predictor of behavior as assessed from both invariance and detectability than single neuron activity. Thus, our results provide not only further evidence that correlated activity likely determines perception of natural communication signals, but also a novel explanation as to why these preferentially occur on top of low frequency as well as low-intensity sinusoidal backgrounds. DOI: http://dx.doi.org/10.7554/eLife.24482.001 PMID:28315519

Role of TRPV1 in high-threshold rat colonic splanchnic afferents is revealed by inflammation.

PubMed

Phillis, Benjamin D; Martin, Chris M; Kang, Daiwu; Larsson, Håkan; Lindström, Erik A; Martinez, Vicente; Blackshaw, L Ashley

2009-08-07

The vanilloid-1 receptor TRPV1 is known to play a role in extrinsic gastrointestinal afferent function. We investigated the role of TRPV1 in mechanosensitivity in afferents from normal and inflamed tissue. Colonic mechanosensitivity was determined in an in vitro rat colon preparation by recording from attached splanchnic nerves. Recordings were made from serosal/mesenteric afferents responding only at high thresholds to graded mechanical stimulation with von Frey probes. Colonic inflammation was induced by adding 5% dextran sulphate sodium (DSS) to the drinking water for 5 days, and was confirmed by histopathology. The selective TRPV1 antagonist, SB-750364 (10(-8) to 10(-6)M), was tested on mechanosensory stimulus response functions of afferents from normal and inflamed preparations (N=7 each). Mechanosensory responses had thresholds of 1-2g, and maximal responses were observed at 12 g. The stimulus response function was not affected by DSS-induced colitis. SB-750364 had no effect on stimulus response functions in normal preparations, but reduced (up to 60%) in a concentration-dependent manner those in inflammation (2-way ANOVA, p<0.05). Moreover, in inflamed tissue, spontaneous afferent activity showed a dose-dependent trend toward reduction with SB-750364. We conclude that mechanosensitivity of high-threshold serosal colonic splanchnic afferents to graded stimuli is unaffected during DSS colitis. However, there is a positive influence of TRPV1 in mechanosensitivity in inflammation, suggesting up-regulation of excitatory TRPV1-mediated mechanisms.

Information analysis of posterior canal afferents in the turtle, Trachemys scripta elegans.

PubMed

Rowe, Michael H; Neiman, Alexander B

2012-01-24

We have used sinusoidal and band-limited Gaussian noise stimuli along with information measures to characterize the linear and non-linear responses of morpho-physiologically identified posterior canal (PC) afferents and to examine the relationship between mutual information rate and other physiological parameters. Our major findings are: 1) spike generation in most PC afferents is effectively a stochastic renewal process, and spontaneous discharges are fully characterized by their first order statistics; 2) a regular discharge, as measured by normalized coefficient of variation (cv*), reduces intrinsic noise in afferent discharges at frequencies below the mean firing rate; 3) coherence and mutual information rates, calculated from responses to band-limited Gaussian noise, are jointly determined by gain and intrinsic noise (discharge regularity), the two major determinants of signal to noise ratio in the afferent response; 4) measures of optimal non-linear encoding were only moderately greater than optimal linear encoding, indicating that linear stimulus encoding is limited primarily by internal noise rather than by non-linearities; and 5) a leaky integrate and fire model reproduces these results and supports the suggestion that the combination of high discharge regularity and high discharge rates serves to extend the linear encoding range of afferents to higher frequencies. These results provide a framework for future assessments of afferent encoding of signals generated during natural head movements and for comparison with coding strategies used by other sensory systems. This article is part of a Special Issue entitled: Neural Coding. Copyright © 2011 Elsevier B.V. All rights reserved.

Interdependency between mechanical parameters and afferent nerve discharge in remodeled diabetic Goto-Kakizaki rat intestine.

PubMed

Zhao, Jingbo; Yang, Jian; Liao, Donghua; Gregersen, Hans

2017-01-01

Gastrointestinal disorders are very common in diabetic patients, but the pathogenesis is still not well understood. Peripheral afferent nerves may be involved due to the complex regulation of gastrointestinal function by the enteric nervous system. We aimed to characterize the stimulus-response function of afferent fibers innervating the jejunum in the Goto-Kakizaki (GK) type 2 diabetic rat model. A key question is whether changes in afferent firing arise from remodeled tissue or from adaptive afferent processes. Seven 32-week-old male GK rats and seven age-matched normal Wistar rats were studied. Firing from mesenteric afferent nerves was recorded in excised jejunal segments of seven GK rats and seven normal Wistar rats during ramp test, stress relaxation test, and creep test. The circumferential stress-strain, spike rate increase ratio (SRIR), and single unit firing rates were calculated for evaluation of interdependency of the mechanical stimulations and the afferent nerve discharge. Elevated sensitivity to mechanical stimuli was found for diabetic nerve bundles and single unit activity ( P <0.05). The stress relaxed less in the diabetic intestinal segment ( P <0.05). Linear association between SRIR and the thickness of circumferential muscle layer was found at high stress levels as well as for SRIR and the glucose level. Altered viscoelastic properties and elevated mechanosensitivity were found in the GK rat intestine. The altered nerve signaling is related to muscle layer remodeling and glucose levels and may contribute to gastrointestinal symptoms experienced by diabetic patients.

Efferent-Mediated Responses in Vestibular Nerve Afferents of the Alert Macaque

PubMed Central

Sadeghi, Soroush G.; Goldberg, Jay M.; Minor, Lloyd B.; Cullen, Kathleen E.

2009-01-01

The peripheral vestibular organs have long been known to receive a bilateral efferent innervation from the brain stem. However, the functional role of the efferent vestibular system has remained elusive. In this study, we investigated efferent-mediated responses in vestibular afferents of alert behaving primates (macaque monkey). We found that efferent-mediated rotational responses could be obtained from vestibular nerve fibers innervating the semicircular canals after conventional afferent responses were nulled by placing the corresponding canal plane orthogonal to the plane of motion. Responses were type III, i.e., excitatory for rotational velocity trapezoids (peak velocity, 320°/s) in both directions of rotation, consistent with those previously reported in the decerebrate chinchilla. Responses consisted of both fast and slow components and were larger in irregular (∼10 spikes/s) than in regular afferents (∼2 spikes/s). Following unilateral labyrinthectomy (UL) on the side opposite the recording site, similar responses were obtained. To confirm the vestibular source of the efferent-mediated responses, the ipsilateral horizontal and posterior canals were plugged following the UL. Responses to high-velocity rotations were drastically reduced when the superior canal (SC), the only intact canal, was in its null position, compared with when the SC was pitched 50° upward from the null position. Our findings show that vestibular afferents in alert primates show efferent-mediated responses that are related to the discharge regularity of the afferent, are of vestibular origin, and can be the result of both afferent excitation and inhibition. PMID:19091917

Efferent-mediated responses in vestibular nerve afferents of the alert macaque.

PubMed

Sadeghi, Soroush G; Goldberg, Jay M; Minor, Lloyd B; Cullen, Kathleen E

2009-02-01

The peripheral vestibular organs have long been known to receive a bilateral efferent innervation from the brain stem. However, the functional role of the efferent vestibular system has remained elusive. In this study, we investigated efferent-mediated responses in vestibular afferents of alert behaving primates (macaque monkey). We found that efferent-mediated rotational responses could be obtained from vestibular nerve fibers innervating the semicircular canals after conventional afferent responses were nulled by placing the corresponding canal plane orthogonal to the plane of motion. Responses were type III, i.e., excitatory for rotational velocity trapezoids (peak velocity, 320 degrees/s) in both directions of rotation, consistent with those previously reported in the decerebrate chinchilla. Responses consisted of both fast and slow components and were larger in irregular (approximately 10 spikes/s) than in regular afferents (approximately 2 spikes/s). Following unilateral labyrinthectomy (UL) on the side opposite the recording site, similar responses were obtained. To confirm the vestibular source of the efferent-mediated responses, the ipsilateral horizontal and posterior canals were plugged following the UL. Responses to high-velocity rotations were drastically reduced when the superior canal (SC), the only intact canal, was in its null position, compared with when the SC was pitched 50 degrees upward from the null position. Our findings show that vestibular afferents in alert primates show efferent-mediated responses that are related to the discharge regularity of the afferent, are of vestibular origin, and can be the result of both afferent excitation and inhibition.

Edge orientation signals in tactile afferents of macaques

PubMed Central

Suresh, Aneesha K.

2016-01-01

The orientation of edges indented into the skin has been shown to be encoded in the responses of neurons in primary somatosensory cortex in a manner that draws remarkable analogies to their counterparts in primary visual cortex. According to the classical view, orientation tuning arises from the integration of untuned input from thalamic neurons with aligned but spatially displaced receptive fields (RFs). In a recent microneurography study with human subjects, the precise temporal structure of the responses of individual mechanoreceptive afferents to scanned edges was found to carry information about their orientation. This putative mechanism could in principle contribute to or complement the classical rate-based code for orientation. In the present study, we further examine orientation information carried by mechanoreceptive afferents of Rhesus monkeys. To this end, we record the activity evoked in cutaneous mechanoreceptive afferents when edges are indented into or scanned across the skin. First, we confirm that information about the edge orientation can be extracted from the temporal patterning in afferent responses of monkeys, as is the case in humans. Second, we find that while the coarse temporal profile of the response can be predicted linearly from the layout of the RF, the fine temporal profile cannot. Finally, we show that orientation signals in tactile afferents are often highly dependent on stimulus features other than orientation, which complicates putative decoding strategies. We discuss the challenges associated with establishing a neural code at the somatosensory periphery, where afferents are exquisitely sensitive and nearly deterministic. PMID:27655968

Acute effects of Dry Immersion on kinematic characteristics of postural corrective responses

NASA Astrophysics Data System (ADS)

Sayenko, D. G.; Miller, T. F.; Melnik, K. A.; Netreba, A. I.; Khusnutdinova, D. R.; Kitov, V. V.; Tomilovskaya, E. S.; Reschke, M. F.; Gerasimenko, Y. P.; Kozlovskaya, I. B.

2016-04-01

Impairments in balance control are inevitable following exposure to microgravity. However, the role of particular sensory system in postural disorders at different stages of the exposure to microgravity still remains unknown. We used a method called Dry Immersion (DI), as a ground-based model of microgravity, to elucidate the effects of 6-h of load-related afferent inputs on kinematic characteristics of postural corrective responses evoked by pushes to the chest of different intensities during upright standing. The structure of postural corrective responses was altered following exposure to DI, which was manifested by: (1) an increase of the ankle and knee flexion during perturbations of medium intensity, (2) the lack of the compensatory hip extension, as well as diminished knee and ankle flexion with a further increase of the perturbation intensity to submaximal level. We suggest that the lack of weight-bearing increases the reactivity of the balance control system, whereas the ability to scale the responses proportionally to the perturbation intensity decreases. Disrupted neuromuscular coordination of postural corrective responses following DI can be attributed to adaptive neural modifications on the spinal and cortical levels. The present study provides evidence that even a short-term lack of load-related afferent inputs alters kinematic patterns of postural corrective responses, and can result in decreased balance control. Because vestibular input is not primarily affected during the DI exposure, our results indicate that activity and the state of the load-related afferents play critical roles in balance control following real or simulated microgravity.

Effects from fine muscle and cutaneous afferents on spinal locomotion in cats

PubMed Central

Kniffki, K.-D.; Schomburg, E. D.; Steffens, H.

1981-01-01

1. The effects of chemically activated fine muscle afferents (groups III and IV) and electrically activated cutaneous afferents on motoneuronal discharges were studied before and during fictive locomotion induced pharmacologically by i.v. administration of nialamide and l-DOPA in high spinal cats. Efferent activity was recorded simultaneously from nerve filaments to ipsi- and contralateral extensor and flexor muscles. In addition, intracellular recordings were made from lumbar α-motoneurones. 2. After nialamide but before treatment with l-DOPA, in some cases, transient locomotor-like discharges were induced by an increased activity in fine muscle afferents. The response pattern in nerves to both hind limbs could be different showing e.g. only transient alternating activity between knee flexor and extensor of one limb but not of the other one. 3. Treatment with l-DOPA did not always cause fictive locomotion. Often not all motoneurone pools showed rhythmic activity. In these cases stimulation of group III and IV muscle afferents usually caused transient periodic activity. In cases with apparent rhythmic activity, algesic stimulation of the gastrocnemius—soleus muscle caused an accentuation of the rhythm by a more abrupt transition from the active phase to the non-active interval. Again, the response patterns on both sides were not uniform in all cases. 4. A second type of response to activation of fine muscle afferents had a quite different character: the rhythmic activity was more or less completely overridden by a strong transient tonic hyperactivity or the rhythm was transiently blocked. These phenomena did not occur in the same way in all nerves. 5. Electrical stimulation of cutaneous nerves of the hind limb generally induced the same response pattern as chemical stimulation of the group III and IV muscle afferents. The effects varied depending on the stimulus strength and the nerve. 6. The results revealed that cutaneous and fine muscle afferents not only have similar functions in the reflex control of a limb but also in evocation and modulation of locomotion. Therefore, it is assumed that both types of afferents may serve together as a peripheral feed-back to the spinal locomotor centre. PMID:7320927

Allodynia mediated by C-tactile afferents in human hairy skin.

PubMed

Nagi, Saad S; Rubin, Troy K; Chelvanayagam, David K; Macefield, Vaughan G; Mahns, David A

2011-08-15

We recently showed a contribution of low-threshold cutaneous mechanoreceptors to vibration-evoked changes in the perception of muscle pain. Neutral-touch stimulation (vibration) of the hairy skin during underlying muscle pain evoked an overall increase in pain intensity, i.e. allodynia. This effect appeared to be dependent upon cutaneous afferents, as allodynia was abolished by intradermal anaesthesia. However, it remains unclear whether allodynia results from activation of a single class of cutaneous afferents or the convergence of inputs from multiple classes. Intriguingly, no existing human study has examined the contribution of C-tactile (CT) afferents to allodynia. Detailed psychophysical observations were made in 29 healthy subjects (18 males and 11 females). Sustained muscle pain was induced by infusing hypertonic saline (HS: 5%) into tibialis anterior muscle (TA). Sinusoidal vibration (200 Hz–200 μm) was applied to the hairy skin overlying TA. Pain ratings were recorded using a visual analogue scale (VAS). In order to evaluate the role of myelinated and unmyelinated cutaneous afferents in the expression of vibration-evoked allodynia, compression block of the sciatic nerve, and low-dose intradermal anaesthesia (Xylocaine 0.25%) were used, respectively. In addition, the modulation of muscle pain by gentle brushing (1.0 and 3.0 cm s(−1))--known to excite CT fibres--was examined. Brushing stimuli were applied to the hairy skin with all fibres intact and following the blockade of myelinated afferents. During tonic muscle pain (VAS 4–6), vibration evoked a significant and reproducible increase in muscle pain (allodynia) that persisted following compression of myelinated afferents. During compression block, the sense of vibration was abolished, but the vibration-evoked allodynia persisted. In contrast, selective anaesthesia of unmyelinated cutaneous afferents abolished the allodynia, whereas the percept of vibration remained unaffected. Furthermore, allodynia was preserved in the adjacent non-anaesthetized skin. Conformingly, gentle brushing produced allodynia (at both brushing speeds) that persisted during the blockade of myelinated afferents. Prior to the induction and following cessation of muscle pain, all subjects reported vibration and brushing as non-painful (VAS = 0). These results demonstrate that CT fibres in hairy skin mediate allodynia, and that CT-mediated inputs have a pluripotent central effect.

The effect of vagal afferent on total vascular compliance in rats.

PubMed

Kinoshita, T

1993-04-01

This study was designed to investigate the effect of vagal afferent stimulation on total vascular compliance (TVC). Rats were anesthetized with sodium pentobarbital and artificially ventilated, TVC was determined together with stressed and unstressed blood volumes by measuring mean circulatory filling pressure (Pmcf) at three different levels of circulating blood volume. Measurements was repeated with the intact vagus, after vagotomy and during stimulation of vagal afferents. Vagotomy caused no change in TVC, Pmcf, and stressed and unstressed blood volumes. On the other hand, electrical stimulation of the vagal afferents for 30 sec increased TVC from 3.03 +/- 0.51 to 3.39 +/- 0.44 ml.mmHg(-1).kg(-1) (P < 0.05) and decreased Pmcf from 7.83 +/- 1.40 to 7.22 +/- 1.21 mmHg (P < 0.05). Neither stressed nor unstressed blood volume was changed by vagal stimulation. These results indicate that excitation of vagal afferent causes venodilation and increases TVC without changing stressed and unstressed blood volumes.

Directional selectivity of afferent neurons in zebrafish neuromasts is regulated by Emx2 in presynaptic hair cells

PubMed Central

Ji, Young Rae; Warrier, Sunita; Jiang, Tao

2018-01-01

The orientation of hair bundles on top of sensory hair cells (HCs) in neuromasts of the lateral line system allows fish to detect direction of water flow. Each neuromast shows hair bundles arranged in two opposing directions and each afferent neuron innervates only HCs of the same orientation. Previously, we showed that this opposition is established by expression of Emx2 in half of the HCs, where it mediates hair bundle reversal (Jiang et al., 2017). Here, we show that Emx2 also regulates neuronal selection: afferent neurons innervate either Emx2-positive or negative HCs. In emx2 knockout and gain-of-function neuromasts, all HCs are unidirectional and the innervation patterns and physiological responses of the afferent neurons are dependent on the presence or absence of Emx2. Our results indicate that Emx2 mediates the directional selectivity of neuromasts by two distinct processes: regulating hair bundle orientation in HCs and selecting afferent neuronal targets. PMID:29671737

Structure and Function of the Hair Cell Ribbon Synapse

PubMed Central

Nouvian, R.; Beutner, D.; Parsons, T.D.

2006-01-01

Faithful information transfer at the hair cell afferent synapse requires synaptic transmission to be both reliable and temporally precise. The release of neurotransmitter must exhibit both rapid on and off kinetics to accurately follow acoustic stimuli with a periodicity of 1 ms or less. To ensure such remarkable temporal fidelity, the cochlear hair cell afferent synapse undoubtedly relies on unique cellular and molecular specializations. While the electron microscopy hallmark of the hair cell afferent synapse — the electron-dense synaptic ribbon or synaptic body — has been recognized for decades, dissection of the synapse’s molecular make-up has only just begun. Recent cell physiology studies have added important insights into the synaptic mechanisms underlying fidelity and reliability of sound coding. The presence of the synaptic ribbon links afferent synapses of cochlear and vestibular hair cells to photoreceptors and bipolar neurons of the retina. This review focuses on major advances in understanding the hair cell afferent synapse molecular anatomy and function that have been achieved during the past years. PMID:16773499

The afferent pathways of discogenic low-back pain. Evaluation of L2 spinal nerve infiltration.

PubMed

Nakamura, S I; Takahashi, K; Takahashi, Y; Yamagata, M; Moriya, H

1996-07-01

The afferent pathways of discogenic low-back pain have not been fully investigated. We hypothesised that this pain was transmitted mainly by sympathetic afferent fibres in the L2 nerve root, and in 33 patients we used selective local anaesthesia of this nerve. Low-back pain disappeared or significantly decreased in all patients after the injection. Needle insertion provoked pain which radiated to the low back in 23 patients and the area of skin hypoalgesia produced included the area of pre-existing pain in all but one. None of the nine patients with related sciatica had relief of that component of their symptoms. Our findings show that the main afferent pathways of pain from the lower intervertebral discs are through the L2 spinal nerve root, presumably via sympathetic afferents from the sinuvertebral nerves. Discogenic low-back pain should be regarded as a visceral pain in respect of its neural pathways. Infiltration of the L2 nerve is a useful diagnostic test and also has some therapeutic value.

Afferent Connectivity of the Zebrafish Habenulae

PubMed Central

Turner, Katherine J.; Hawkins, Thomas A.; Yáñez, Julián; Anadón, Ramón; Wilson, Stephen W.; Folgueira, Mónica

2016-01-01

The habenulae are bilateral nuclei located in the dorsal diencephalon that are conserved across vertebrates. Here we describe the main afferents to the habenulae in larval and adult zebrafish. We observe afferents from the subpallium, nucleus rostrolateralis, posterior tuberculum, posterior hypothalamic lobe, median raphe; we also see asymmetric afferents from olfactory bulb to the right habenula, and from the parapineal to the left habenula. In addition, we find afferents from a ventrolateral telencephalic nucleus that neurochemical and hodological data identify as the ventral entopeduncular nucleus (vENT), confirming and extending observations of Amo et al. (2014). Fate map and marker studies suggest that vENT originates from the diencephalic prethalamic eminence and extends into the lateral telencephalon from 48 to 120 hour post-fertilization (hpf). No afferents to the habenula were observed from the dorsal entopeduncular nucleus (dENT). Consequently, we confirm that the vENT (and not the dENT) should be considered as the entopeduncular nucleus “proper” in zebrafish. Furthermore, comparison with data in other vertebrates suggests that the vENT is a conserved basal ganglia nucleus, being homologous to the entopeduncular nucleus of mammals (internal segment of the globus pallidus of primates) by both embryonic origin and projections, as previously suggested by Amo et al. (2014). PMID:27199671

Inhibition of Repulsive Guidance Molecule, RGMa, Increases Afferent Synapse Formation with Auditory Hair Cells

PubMed Central

Brugeaud, Aurore; Tong, Mingjie; Luo, Li; Edge, Albert S.B.

2017-01-01

The peripheral fibers that extend from auditory neurons to hair cells are sensitive to damage, and replacement of the fibers and their afferent synapse with hair cells would be of therapeutic interest. Here, we show that RGMa, a repulsive guidance molecule previously shown to play a role in the development of the chick visual system, is expressed in the developing, newborn, and mature mouse inner ear. The effect of RGMa on synaptogenesis between afferent neurons and hair cells, from which afferent connections had been removed, was assessed. Contact of neural processes with hair cells and elaboration of postsynaptic densities at sites of the ribbon synapse were increased by treatment with a blocking antibody to RGMa, and pruning of auditory fibers to achieve the mature branching pattern of afferent neurons was accelerated. Inhibition by RGMa could thus explain why auditory neurons have a low capacity to regenerate peripheral processes: postnatal spiral ganglion neurons retain the capacity to send out processes that respond to signals for synapse formation, but expression of RGMa postnatally appears to be detrimental to regeneration of afferent hair cell innervation and antagonizes synaptogenesis. Increased synaptogenesis after inhibition of RGMa suggests that manipulation of guidance or inhibitory factors may provide a route to increase formation of new synapses at deafferented hair cells. PMID:24123853

Maintenance of Mouse Gustatory Terminal Field Organization Is Disrupted following Selective Removal of Peripheral Sodium Salt Taste Activity at Adulthood

PubMed Central

Sun, Chengsan

2017-01-01

Neural activity plays a critical role in the development of central circuits in sensory systems. However, the maintenance of these circuits at adulthood is usually not dependent on sensory-elicited neural activity. Recent work in the mouse gustatory system showed that selectively deleting the primary transduction channel for sodium taste, the epithelial sodium channel (ENaC), throughout development dramatically impacted the organization of the central terminal fields of three nerves that carry taste information to the nucleus of the solitary tract. More specifically, deleting ENaCs during development prevented the normal maturation of the fields. The present study was designed to extend these findings by testing the hypothesis that the loss of sodium taste activity impacts the maintenance of the normal adult terminal field organization in male and female mice. To do this, we used an inducible Cre-dependent genetic recombination strategy to delete ENaC function after terminal field maturation occurred. We found that removal of sodium taste neural activity at adulthood resulted in significant reorganization of mature gustatory afferent terminal fields in the nucleus of the solitary tract. Specifically, the chorda tympani and greater superficial petrosal nerve terminal fields were 1.4× and 1.6× larger than age-matched controls, respectively. By contrast, the glossopharyngeal nerve, which is not highly sensitive to sodium taste stimulation, did not undergo terminal field reorganization. These surprising results suggest that gustatory nerve terminal fields remain plastic well into adulthood, which likely impacts central coding of taste information and taste-related behaviors with altered taste experience. SIGNIFICANCE STATEMENT Neural activity plays a major role in the development of sensory circuits in the mammalian brain. However, the importance of sensory-driven activity in maintaining these circuits at adulthood, especially in subcortical structures, appears to be much less. Here, we tested whether the loss of sodium taste activity in adult mice impacts the maintenance of how taste nerves project to the first central relay. We found that specific loss of sodium-elicited taste activity at adulthood produced dramatic and selective reorganization of terminal fields in the brainstem. This demonstrates, for the first time, that taste-elicited activity is necessary for the normal maintenance of central gustatory circuits at adulthood and highlights a level of plasticity not seen in other sensory system subcortical circuits. PMID:28676575

Modulated discharge of Purkinje and stellate cells persists after unilateral loss of vestibular primary afferent mossy fibers in mice

PubMed Central

Yakhnitsa, V.

2013-01-01

Cerebellar Purkinje cells are excited by two afferent pathways: climbing and mossy fibers. Climbing fibers evoke large “complex spikes” (CSs) that discharge at low frequencies. Mossy fibers synapse on granule cells whose parallel fibers excite Purkinje cells and may contribute to the genesis of “simple spikes” (SSs). Both afferent systems convey vestibular information to folia 9c–10. After making a unilateral labyrinthectomy (UL) in mice, we tested how the discharge of CSs and SSs was changed by the loss of primary vestibular afferent mossy fibers during sinusoidal roll tilt. We recorded from cells identified by juxtacellular neurobiotin labeling. The UL preferentially reduced vestibular modulation of CSs and SSs in folia 8–10 contralateral to the UL. The effects of a UL on Purkinje cell discharge were similar in folia 9c–10, to which vestibular primary afferents project, and in folia 8–9a, to which they do not project, suggesting that vestibular primary afferent mossy fibers were not responsible for the UL-induced alteration of SS discharge. UL also induced reduced vestibular modulation of stellate cell discharge contralateral to the UL. We attribute the decreased modulation to reduced vestibular modulation of climbing fibers. In summary, climbing fibers modulate CSs directly and SSs indirectly through activation of stellate cells. Whereas vestibular primary afferent mossy fibers cannot account for the modulated discharge of SSs or stellate cells, the nonspecific excitation of Purkinje cells by parallel fibers may set an operating point about which the discharges of SSs are sculpted by climbing fibers. PMID:23966673

Low- and high-threshold primary afferent inputs to spinal lamina III antenna-type neurons.

PubMed

Fernandes, Elisabete C; Santos, Ines C; Kokai, Eva; Luz, Liliana L; Szucs, Peter; Safronov, Boris V

2018-06-21

and non-nociceptive sensory information. Antenna-type neurons with cell bodies located in lamina III and large dendritic trees extending from the superficial lamina I to deep lamina IV are best shaped for the integration of a wide variety of inputs arising from primary afferent fibers and intrinsic spinal circuitries. While the somatodendritic morphology, the hallmark of antenna neurons, has been well studied, little is still known about the axon structure and basic physiological properties of these cells. Here we did whole-cell recordings in a rat (P9-P12) spinal cord preparation with attached dorsal roots to examine the axon course, intrinsic firing properties and primary afferent inputs of antenna cells. Nine antenna cells were identified from a large sample of biocytin-filled lamina III neurons (n = 46). Axon of antenna cells showed intensive branching in laminae III-IV and, in half of the cases, issued dorsally directed collaterals reaching lamina I. Antenna cells exhibited tonic and rhythmic firing patterns; single spikes were followed by hyper- or depolarization. The neurons received monosynaptic inputs from the low-threshold Aβ afferents, Aδ afferents as well as from the high-threshold Aδ and C afferents. When selectively activated, C-fiber-driven mono- and polysynaptic EPSPs were sufficiently strong to evoke firing in the neurons. Thus, lamina III antenna neurons integrate low-threshold and nociceptive high-threshold primary afferent inputs, and can function as wide-dynamic-range neurons able to directly connect deep dorsal horn with the major nociceptive projection area lamina I.

Interdependency between mechanical parameters and afferent nerve discharge in remodeled diabetic Goto-Kakizaki rat intestine

PubMed Central

Zhao, Jingbo; Yang, Jian; Liao, Donghua; Gregersen, Hans

2017-01-01

Background Gastrointestinal disorders are very common in diabetic patients, but the pathogenesis is still not well understood. Peripheral afferent nerves may be involved due to the complex regulation of gastrointestinal function by the enteric nervous system. Objective We aimed to characterize the stimulus–response function of afferent fibers innervating the jejunum in the Goto-Kakizaki (GK) type 2 diabetic rat model. A key question is whether changes in afferent firing arise from remodeled tissue or from adaptive afferent processes. Design Seven 32-week-old male GK rats and seven age-matched normal Wistar rats were studied. Firing from mesenteric afferent nerves was recorded in excised jejunal segments of seven GK rats and seven normal Wistar rats during ramp test, stress relaxation test, and creep test. The circumferential stress–strain, spike rate increase ratio (SRIR), and single unit firing rates were calculated for evaluation of interdependency of the mechanical stimulations and the afferent nerve discharge. Results Elevated sensitivity to mechanical stimuli was found for diabetic nerve bundles and single unit activity (P<0.05). The stress relaxed less in the diabetic intestinal segment (P<0.05). Linear association between SRIR and the thickness of circumferential muscle layer was found at high stress levels as well as for SRIR and the glucose level. Conclusion Altered viscoelastic properties and elevated mechanosensitivity were found in the GK rat intestine. The altered nerve signaling is related to muscle layer remodeling and glucose levels and may contribute to gastrointestinal symptoms experienced by diabetic patients. PMID:29238211

Effects of gastric distension and infusion of umami and bitter taste stimuli on vagal afferent activity.

PubMed

Horn, Charles C; Murat, Chloé; Rosazza, Matthew; Still, Liz

2011-10-24

Until recently, sensory nerve pathways from the stomach to the brain were thought to detect distension and play little role in nutritional signaling. Newer data have challenged this view, including reports on the presence of taste receptors in the gastrointestinal lumen and the stimulation of multi-unit vagal afferent activity by glutamate infusions into the stomach. However, assessing these chemosensory effects is difficult because gastric infusions typically evoke a distension-related vagal afferent response. In the current study, we recorded gastric vagal afferent activity in the rat to investigate the possibility that umami (glutamate, 150 mM) and bitter (denatonium, 10 mM) responses could be dissociated from distension responses by adjusting the infusion rate and opening or closing the drainage port in the stomach. Slow infusions of saline (5 ml over 2 min, open port) produced no significant effects on vagal activity. Using the same infusion rate, glutamate or denatonium solutions produced little or no effects on vagal afferent activity. In an attempt to reproduce a prior report that showed distention and glutamate responses, we produced a distension response by closing the exit port. Under this condition, response to the infusion of glutamate or denatonium was similar to saline. In summary, we found little or no effect of gastric infusion of glutamate or denatonium on gastric vagal afferent activity that could be distinguished from distension responses. The current results suggest that sensitivity to umami or bitter stimuli is not a common property of gastric vagal afferent fibers. Copyright © 2011 Elsevier B.V. All rights reserved.

Directional tuning of human forearm muscle afferents during voluntary wrist movements

PubMed Central

Jones, Kelvin E; Wessberg, Johan; Vallbo, Åke B

2001-01-01

Single unit activity was recorded with the microneurography technique from sixteen spindle afferents and one Golgi tendon organ afferent originating from the forearm extensor muscles. Impulse rates were studied while subjects performed unobstructed aiming movements at the wrist in eight different directions 45 deg apart. In addition, similar imposed movements were performed while the subject was instructed to remain relaxed. Movement amplitudes were about 5 deg and the speed 10–30 deg s−1. Joint movements were translated to movements of a cursor on a monitor to provide visual feedback. Individual spindle afferents modulated their activity over a number of targets, i.e. were broadly tuned, during these aiming movements. The preferred direction for a spindle afferent was the same during both passive and active movements, indicating that the fusimotor effects associated with active contractions had little or no effect on the direction of tuning. The direction of tuning of individual spindle afferents could be predicted from the biomechanically inferred length changes of the parent muscle. Thus spindle afferents responded as stretch receptors, i.e. impulse rates increased with lengthening and decreased with shortening, in active as well as passive movements. Spindles from muscles, which continuously counteracted gravity exhibited a stretch response and directional tuning during the phase of movement alone whereas their position sensitivity was poor. In contrast, spindle afferents from the muscles that had no or minimal antigravity role were directionally tuned during both the dynamic and the static phase of the aiming task and their position sensitivity was substantially higher. In spite of the limited data base from three extensor muscles it could be demonstrated that wrist joint position was remarkably well encoded in the ensemble muscle spindle data. In some cases the ensemble muscle spindle data encoded the instantaneous trajectory of movement as well. PMID:11600696

Mechanisms of reflex bladder activation by pudendal afferents

PubMed Central

Woock, John P.; Yoo, Paul B.

2011-01-01

Activation of pudendal afferents can evoke bladder contraction or relaxation dependent on the frequency of stimulation, but the mechanisms of reflex bladder excitation evoked by pudendal afferent stimulation are unknown. The objective of this study was to determine the contributions of sympathetic and parasympathetic mechanisms to bladder contractions evoked by stimulation of the dorsal nerve of the penis (DNP) in α-chloralose anesthetized adult male cats. Bladder contractions were evoked by DNP stimulation only above a bladder volume threshold equal to 73 ± 12% of the distension-evoked reflex contraction volume threshold. Bilateral hypogastric nerve transection (to eliminate sympathetic innervation of the bladder) or administration of propranolol (a β-adrenergic antagonist) decreased the stimulation-evoked and distension-evoked volume thresholds by −25% to −39%. Neither hypogastric nerve transection nor propranolol affected contraction magnitude, and robust bladder contractions were still evoked by stimulation at volume thresholds below the distension-evoked volume threshold. As well, inhibition of distention-evoked reflex bladder contractions by 10 Hz stimulation of the DNP was preserved following bilateral hypogastric nerve transection. Administration of phentolamine (an α-adrenergic antagonist) increased stimulation-evoked and distension-evoked volume thresholds by 18%, but again, robust contractions were still evoked by stimulation at volumes below the distension-evoked threshold. These results indicate that sympathetic mechanisms contribute to establishing the volume dependence of reflex contractions but are not critical to the excitatory pudendal to bladder reflex. A strong correlation between the magnitude of stimulation-evoked bladder contractions and bladder volume supports that convergence of pelvic afferents and pudendal afferents is responsible for bladder excitation evoked by pudendal afferents. Further, abolition of stimulation-evoked bladder contractions following administration of hexamethonium bromide confirmed that contractions were generated by pelvic efferent activation via the pelvic ganglion. These findings indicate that pudendal afferent stimulation evokes bladder contractions through convergence with pelvic afferents to increase pelvic efferent activity. PMID:21068196

Sodium Channel Nav1.8 Underlies TTX-Resistant Axonal Action Potential Conduction in Somatosensory C-Fibers of Distal Cutaneous Nerves.

PubMed

Klein, Amanda H; Vyshnevska, Alina; Hartke, Timothy V; De Col, Roberto; Mankowski, Joseph L; Turnquist, Brian; Bosmans, Frank; Reeh, Peter W; Schmelz, Martin; Carr, Richard W; Ringkamp, Matthias

2017-05-17

Voltage-gated sodium (Na V ) channels are responsible for the initiation and conduction of action potentials within primary afferents. The nine Na V channel isoforms recognized in mammals are often functionally divided into tetrodotoxin (TTX)-sensitive (TTX-s) channels (Na V 1.1-Na V 1.4, Na V 1.6-Na V 1.7) that are blocked by nanomolar concentrations and TTX-resistant (TTX-r) channels (Na V 1.8 and Na V 1.9) inhibited by millimolar concentrations, with Na V 1.5 having an intermediate toxin sensitivity. For small-diameter primary afferent neurons, it is unclear to what extent different Na V channel isoforms are distributed along the peripheral and central branches of their bifurcated axons. To determine the relative contribution of TTX-s and TTX-r channels to action potential conduction in different axonal compartments, we investigated the effects of TTX on C-fiber-mediated compound action potentials (C-CAPs) of proximal and distal peripheral nerve segments and dorsal roots from mice and pigtail monkeys ( Macaca nemestrina ). In the dorsal roots and proximal peripheral nerves of mice and nonhuman primates, TTX reduced the C-CAP amplitude to 16% of the baseline. In contrast, >30% of the C-CAP was resistant to TTX in distal peripheral branches of monkeys and WT and Na V 1.9 -/- mice. In nerves from Na V 1.8 -/- mice, TTX-r C-CAPs could not be detected. These data indicate that Na V 1.8 is the primary isoform underlying TTX-r conduction in distal axons of somatosensory C-fibers. Furthermore, there is a differential spatial distribution of Na V 1.8 within C-fiber axons, being functionally more prominent in the most distal axons and terminal regions. The enrichment of Na V 1.8 in distal axons may provide a useful target in the treatment of pain of peripheral origin. SIGNIFICANCE STATEMENT It is unclear whether individual sodium channel isoforms exert differential roles in action potential conduction along the axonal membrane of nociceptive, unmyelinated peripheral nerve fibers, but clarifying the role of sodium channel subtypes in different axonal segments may be useful for the development of novel analgesic strategies. Here, we provide evidence from mice and nonhuman primates that a substantial portion of the C-fiber compound action potential in distal peripheral nerves, but not proximal nerves or dorsal roots, is resistant to tetrodotoxin and that, in mice, this effect is mediated solely by voltage-gated sodium channel 1.8 (Na V 1.8). The functional prominence of Na V 1.8 within the axonal compartment immediately proximal to its termination may affect strategies targeting pain of peripheral origin. Copyright © 2017 the authors 0270-6474/17/375205-11$15.00/0.

Accumulation of K+ in the synaptic cleft modulates activity by influencing both vestibular hair cell and calyx afferent in the turtle

PubMed Central

Contini, Donatella; Price, Steven D.

2016-01-01

Key points In the synaptic cleft between type I hair cells and calyceal afferents, K+ ions accumulate as a function of activity, dynamically altering the driving force and permeation through ion channels facing the synaptic cleft.High‐fidelity synaptic transmission is possible due to large conductances that minimize hair cell and afferent time constants in the presence of significant membrane capacitance.Elevated potassium maintains hair cells near a potential where transduction currents are sufficient to depolarize them to voltages necessary for calcium influx and synaptic vesicle fusion.Elevated potassium depolarizes the postsynaptic afferent by altering ion permeation through hyperpolarization‐activated cyclic nucleotide‐gated (HCN) channels, and contributes to depolarizing the afferent to potentials where a single EPSP (quantum) can generate an action potential.With increased stimulation, hair cell depolarization increases the frequency of quanta released, elevates [K+]cleft and depolarizes the afferent to potentials at which smaller and smaller EPSPs would be sufficient to trigger APs. Abstract Fast neurotransmitters act in conjunction with slower modulatory effectors that accumulate in restricted synaptic spaces found at giant synapses such as the calyceal endings in the auditory and vestibular systems. Here, we used dual patch‐clamp recordings from turtle vestibular hair cells and their afferent neurons to show that potassium ions accumulating in the synaptic cleft modulated membrane potentials and extended the range of information transfer. High‐fidelity synaptic transmission was possible due to large conductances that minimized hair cell and afferent time constants in the presence of significant membrane capacitance. Increased potassium concentration in the cleft maintained the hair cell near potentials that promoted the influx of calcium necessary for synaptic vesicle fusion. The elevated potassium concentration also depolarized the postsynaptic neuron by altering ion permeation through hyperpolarization‐activated cyclic nucleotide‐gated (HCN) channels. This depolarization enabled the afferent to reliably generate action potentials evoked by single AMPA‐dependent EPSPs. Depolarization of the postsynaptic afferent could also elevate potassium in the synaptic cleft, and would depolarize other hair cells enveloped by the same neuritic process increasing the fidelity of neurotransmission at those synapses as well. Collectively, these data demonstrate that neuronal activity gives rise to potassium accumulation, and suggest that potassium ion action on HCN channels can modulate neurotransmission, preserving the fidelity of high‐speed synaptic transmission by dynamically shifting the resting potentials of both presynaptic and postsynaptic cells. PMID:27633787

Climbing fibers mediate vestibular modulation of both "complex" and "simple spikes" in Purkinje cells.

PubMed

Barmack, N H; Yakhnitsa, V

2015-10-01

Climbing and mossy fibers comprise two distinct afferent paths to the cerebellum. Climbing fibers directly evoke a large multispiked action potential in Purkinje cells termed a "complex spike" (CS). By logical exclusion, the other class of Purkinje cell action potential, termed "simple spike" (SS), has often been attributed to activity conveyed by mossy fibers and relayed to Purkinje cells through granule cells. Here, we investigate the relative importance of climbing and mossy fiber pathways in modulating neuronal activity by recording extracellularly from Purkinje cells, as well as from mossy fiber terminals and interneurons in folia 8-10. Sinusoidal roll-tilt vestibular stimulation vigorously modulates the discharge of climbing and mossy fiber afferents, Purkinje cells, and interneurons in folia 9-10 in anesthetized mice. Roll-tilt onto the side ipsilateral to the recording site increases the discharge of both climbing fibers (CSs) and mossy fibers. However, the discharges of SSs decrease during ipsilateral roll-tilt. Unilateral microlesions of the beta nucleus (β-nucleus) of the inferior olive blocks vestibular modulation of both CSs and SSs in contralateral Purkinje cells. The blockage of SSs occurs even though primary and secondary vestibular mossy fibers remain intact. When mossy fiber afferents are damaged by a unilateral labyrinthectomy (UL), vestibular modulation of SSs in Purkinje cells ipsilateral to the UL remains intact. Two inhibitory interneurons, Golgi and stellate cells, could potentially contribute to climbing fiber-induced modulation of SSs. However, during sinusoidal roll-tilt, only stellate cells discharge appropriately out of phase with the discharge of SSs. Golgi cells discharge in phase with SSs. When the vestibularly modulated discharge is blocked by a microlesion of the inferior olive, the modulated discharge of CSs and SSs is also blocked. When the vestibular mossy fiber pathway is destroyed, vestibular modulation of ipsilateral CSs and SSs persists. We conclude that climbing fibers are primarily responsible for the vestibularly modulated discharge of both CSs and SSs. Modulation of the discharge of SSs is likely caused by climbing fiber-evoked stellate cell inhibition.

Inertial vestibular coding of motion: concepts and evidence

NASA Technical Reports Server (NTRS)

Hess, B. J.; Angelaki, D. E.

1997-01-01

Central processing of inertial sensory information about head attitude and motion in space is crucial for motor control. Vestibular signals are coded relative to a non-inertial system, the head, that is virtually continuously in motion. Evidence for transformation of vestibular signals from head-fixed sensory coordinates to gravity-centered coordinates have been provided by studies of the vestibulo-ocular reflex. The underlying central processing depends on otolith afferent information that needs to be resolved in terms of head translation related inertial forces and head attitude dependent pull of gravity. Theoretical solutions have been suggested, but experimental evidence is still scarce. It appears, along these lines, that gaze control systems are intimately linked to motor control of head attitude and posture.

Neurophysiology of the esophagus.

PubMed

Brock, Christina; Brokjaer, Anne; Drewes, Asbjørn Mohr; Farmer, Adam D; Frøkjaer, Jens Brøndum; Gregersen, Hans; Lottrup, Christian

2014-09-01

The following, from the 12th OESO World Conference: Cancers of the Esophagus, includes commentaries on the methods and characteristics of esophageal afferents in humans; the pitfalls in characterization of mechanosensitive afferents; the sensitization of esophageal afferents in human studies; the brain source modeling in the understanding of the esophagus-brain axis; the use of evoked brain potentials in the esophagus; and measuring descending inhibition in animal and human studies. © 2014 New York Academy of Sciences.

The dimensions and characteristics of the subepidermal nerve plexus in human skin--terminal Schwann cells constitute a substantial cell population within the superficial dermis.

PubMed

Reinisch, Christina M; Tschachler, Erwin

2012-03-01

The skin constitutes the largest sensorial organ. Its nervous system consists of different types of afferent nerve fibers which spread out immediately beneath the skin surface to sense temperature, touch and pain. Our aim was to investigate the dimension and topographic relationship of the different nerve fibers of the subepidermal nerve plexus in human hairy skin and to analyze numbers and marker expression of terminal Schwann cells. Nerve fibers and Schwann cells were investigated on dermal sheet preparations and thick sections of skin from various body regions of 10 individuals. The dimension of subepidermal nerve fibers varied between different body sites with highest values in chest skin (100 ± 18 mm/mm(2)) and lowest in posterior forearm skin (53 ± 10 mm/mm(2)). The majority of fibers (85.79%) were unmyelinated, thus representing C-fibers, of which 7.84% were peptidergic. Neurofilament-positive fibers (A-fibers) accounted for 14.21% and fibers positive for both neurofilament and myelin (Aβ-fibers) for only 0.18%. The number of Schwann cells varied in accordance with nerve fiber length from 453 ± 108 on chest skin to 184 ± 58/mm(2) in skin of the posterior forearm. Terminal Schwann cells showed a marker profile comparable to Schwann cells in peripheral nerves with the notable exception of expression of NGFr, NCAM, L1CAM and CD146 on myelinating Schwann cells in the dermis but not in peripheral nerves. Our data show that terminal Schwann cells constitute a substantial cell population within the papillary dermis and that both nerve fiber length and Schwann cell numbers vary considerably between different body sites. Copyright © 2011 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.

Role of the NH2-terminus of substance P in the inhibition by capsaicin of behavioral sensitization to kainic acid-induced activity in the adult mouse.

PubMed

Larson, A A; Sun, X

1994-01-01

Activation of primary afferent C-fibers by repeated intrathecal injection of kainic acid (KA) in mice is inhibited after pretreatment with capsaicin. The increased behavioral response to multiple injections of KA is thought to be brought about by an action of the NH2-terminus of substance P (SP). In light of our recent observation that the antinociceptive effect of capsaicin may also involve an action of the NH2-terminus of SP, we tested the hypothesis that capsaicin inhibits behavioral sensitization to KA by a desensitization to the action of the NH2-terminus of SP. Using adult mice, pretreatment (24 hr) with either capsaicin (0.8 micrograms) or SP(1-7) (1 and 10 nmol) attenuated sensitization of the behavioral response to four injections of 25 pmol of KA at 2-min intervals. Pretreatment with 10 nmol of the COOH-terminal SP fragment, SP(5-11), had no effect. [D-Pro2,D-Phe7]-SP(1-7), a SP NH2-terminal antagonist, injected 5 min before capsaicin or SP(1-7), inhibited the effects of both capsaicin and SP(1-7) on KA sensitization whereas the COOH-terminal neurokinin antagonist, [D-Pro2,D-Trp7,9]-SP, did not. The similarities in behavioral responses after treatment with SP(1-7) or capsaicin, together with the sensitivity of these effects to D-SP(1-7), suggest that SP released in response to capsaicin may inhibit subsequent KA-induced activity 24 hr later. This action of SP appears to be brought about by its NH2-terminus and/or an accumulation of its NH2-terminal metabolites after capsaicin treatment.

Serotonergic innervation of mesencephalic trigeminal nucleus neurons: a light and electron microscopic study in the rat.

PubMed

Li, J; Xiong, K H; Li, Y Q; Kaneko, T; Mizuno, N

2000-06-01

Neurons of the mesencephalic trigeminal nucleus (MTN) are considered to be homologous to mechanosensitive neurons in the sensory ganglia. The sites of origin of serotonin (5HT)-immunoreactive axons on neuronal cell bodies in the MTN were studied in the rat by combining immunofluorescence histochemical techniques with retrograde tracing of Fluoro-Gold (FG) and anterograde tracing of biotin-conjugated dextran amine (BDA). The tracing studies, which were combined with multiple-labeling immunohistochemistry and confocal microscopy, indicated that 5HT-immunoreactive axon terminals on the cell bodies of MTN neurons originated from the medullary raphe nuclei, such as the nucleus raphes magmus (RMg), alpha part of the nucleus reticularis gigantocellularis (GiA) and nucleus raphes obscurus (ROb), as well as from the mesopontine raphe nuclei, such as the nucleus raphes dorsalis (DR), nucleus raphes pontis (PnR) and nucleus raphes medianus (MnR); mainly from the RMg, GiA and DR, and additionally from the ROb, PnR and MnR. The cell bodies in close apposition to 5HT-immunoreactive axon terminals were found through the whole rostrocaudal extent of the MTN. Electron microscopically a number of axon terminals that were labeled with BDA injected into the raphe nuclei were confirmed to be in asymmetric synaptic contact with the cell bodies of MTN neurons. It was also indicated that substance P existed in some of the 5HT-containing axosomatic terminals arising from the ROb, RMg and GiA. The present results indicated that proprioceptive sensory signals from the muscle spindles or periodontal ligament might be modulated at the level of the primary afferent cell bodies in the MTN by 5HT-containing axons from the mesopontine and medullary raphe nuclei including the GiA.

Laminar development of receptive fields, maps and columns in visual cortex: the coordinating role of the subplate.

PubMed

Grossberg, Stephen; Seitz, Aaron

2003-08-01

How is development of cortical maps in V1 coordinated across cortical layers to form cortical columns? Previous neural models propose how maps of orientation (OR), ocular dominance (OD), and related properties develop in V1. These models show how spontaneous activity, before eye opening, combined with correlation learning and competition, can generate maps similar to those found in vivo. These models have not discussed laminar architecture or how cells develop and coordinate their connections across cortical layers. This is an important problem since anatomical evidence shows that clusters of horizontal connections form, between iso-oriented regions, in layer 2/3 before being innervated by layer 4 afferents. How are orientations in different layers aligned before these connections form? Anatomical evidence demonstrates that thalamic afferents wait in the subplate for weeks before innervating layer 4. Other evidence shows that ablation of the cortical subplate interferes with the development of OR and OD columns. The model proposes how the subplate develops OR and OD maps, which then entrain and coordinate the development of maps in other lamina. The model demonstrates how these maps may develop in layer 4 by using a known transient subplate-to-layer 4 circuit as a teacher. The model subplate also guides the early clustering of horizontal connections in layer 2/3, and the formation of the interlaminar circuitry that forms cortical columns. It is shown how layer 6 develops and helps to stabilize the network when the subplate atrophies. Finally the model clarifies how brain-derived neurotrophic factor (BDNF) manipulations may influence cortical development.

Effect of fusimotor stimulation on Ia discharge during shortening of cat soleus muscle at different speeds

PubMed Central

Appenteng, K.; Prochazka, A.; Proske, U.; Wand, P.

1982-01-01

1. In barbiturate-anaesthetized cats, the L7 and S1 dorsal and ventral roots were dissected to isolate functionally single afferents identified as primary endings of soleus muscle spindles, and motor filaments which exerted a fusimotor action on the afferents with limited action on extrafusal muscle. Up to seven filaments, with an action on a given primary ending, could be isolated and each was classified as exerting either a predominantly dynamic or static action. 2. Combined stimulation of these filaments, at rates up to 200 impulses/s could maintain afferent firing during muscle shortenings at speeds up to 200 mm/s. 3. Fusimotor stimulation could also maintain afferent firing at a target frequency of 100 impulses/s during muscle shortenings up to 200 mm/s. The timing, in relation to the onset of shortening, and the rates of fusimotor stimulation were found to be critical in achieving the target frequency. 4. Sinusoidal modulation of the frequency of fusimotor stimulation was used to study the conditions required to achieve constant afferent firing in the face of imposed sinusoidal length changes. 5. For given depths of modulation, the phase advance of fusimotor stimulation needed to produce minimum modulation of afferent firing (best compensation) increased with increasing frequency of the sinusoids. The compensation deteriorated with an increase in the frequency of the sinusoids and a change in the mean muscle lengths, although in some cases it could be restored by adjustments to the depth of modulation of fusimotor rate. This suggests that for movements of varying speeds and amplitudes, settings which are appropriate for shortening at a given velocity and mean muscle length, do not apply if either of these two variables are altered. 6. These findings demonstrate that the fusimotor system is potentially capable of eliciting constant afferent firing as envisaged in the `servo-assistance' hypothesis (Matthews, 1964, 1972; Stein, 1974). This, and the fact that constant afferent firing is not seen during normal unobstructed shortenings at velocities greater than 0·2 resting length/s (Prochazka, 1981), are used to argue that it is by choice rather than necessity that `servo-assistance' (as defined above) is not employed during normal movements. However, servo-assistance of a different form (involving modulated spindle afferent feed-back from both agonists and antagonists) remains a viable alternative. PMID:6216336

[Adrenergic innervation of the kidneys in man and various laboratory animals].

PubMed

Shvalev, V N; Chzhao, L Kh

1988-07-01

By means of the neurohistochemical method for slice incubation in 2% solution of glyoxylic acid, innervation of the kidneys of a 57-year-old man after a sudden cardiac death has been investigated, as well as innervation of the kidneys in white rat, rabbit, guinea pig and cat. A rich adrenergic innervation in the organ's blood vessels has been revealed. In particular, adrenergic nervous fibers have been found along the course of afferent glomerular arterioles. Together with innervation of the proximal and distal convoluted tubules, a high density of the terminal adrenergic nervous plexus is revealed along the course of the nephron loops. Adrenergic nervous plexuses of high density are found in the area of the initial part of the urinary excretory pathways and their connection with nervous plexuses of the kidney itself.

Somatic influences on subjective well-being and affective disorders: the convergence of thermosensory and central serotonergic systems

PubMed Central

Raison, Charles L.; Hale, Matthew W.; Williams, Lawrence E.; Wager, Tor D.; Lowry, Christopher A.

2015-01-01

Current theories suggest that the brain is the sole source of mental illness. However, affective disorders, and major depressive disorder (MDD) in particular, may be better conceptualized as brain-body disorders that involve peripheral systems as well. This perspective emphasizes the embodied, multifaceted physiology of well-being, and suggests that afferent signals from the body may contribute to cognitive and emotional states. In this review, we focus on evidence from preclinical and clinical studies suggesting that afferent thermosensory signals contribute to well-being and depression. Although thermoregulatory systems have traditionally been conceptualized as serving primarily homeostatic functions, increasing evidence suggests neural pathways responsible for regulating body temperature may be linked more closely with emotional states than previously recognized, an affective warmth hypothesis. Human studies indicate that increasing physical warmth activates brain circuits associated with cognitive and affective functions, promotes interpersonal warmth and prosocial behavior, and has antidepressant effects. Consistent with these effects, preclinical studies in rodents demonstrate that physical warmth activates brain serotonergic neurons implicated in antidepressant-like effects. Together, these studies suggest that (1) thermosensory pathways interact with brain systems that control affective function, (2) these pathways are dysregulated in affective disorders, and (3) activating warm thermosensory pathways promotes a sense of well-being and has therapeutic potential in the treatment of affective disorders. PMID:25628593

Vagus Nerve as Modulator of the Brain–Gut Axis in Psychiatric and Inflammatory Disorders

PubMed Central

Breit, Sigrid; Kupferberg, Aleksandra; Rogler, Gerhard; Hasler, Gregor

2018-01-01

The vagus nerve represents the main component of the parasympathetic nervous system, which oversees a vast array of crucial bodily functions, including control of mood, immune response, digestion, and heart rate. It establishes one of the connections between the brain and the gastrointestinal tract and sends information about the state of the inner organs to the brain via afferent fibers. In this review article, we discuss various functions of the vagus nerve which make it an attractive target in treating psychiatric and gastrointestinal disorders. There is preliminary evidence that vagus nerve stimulation is a promising add-on treatment for treatment-refractory depression, posttraumatic stress disorder, and inflammatory bowel disease. Treatments that target the vagus nerve increase the vagal tone and inhibit cytokine production. Both are important mechanism of resiliency. The stimulation of vagal afferent fibers in the gut influences monoaminergic brain systems in the brain stem that play crucial roles in major psychiatric conditions, such as mood and anxiety disorders. In line, there is preliminary evidence for gut bacteria to have beneficial effect on mood and anxiety, partly by affecting the activity of the vagus nerve. Since, the vagal tone is correlated with capacity to regulate stress responses and can be influenced by breathing, its increase through meditation and yoga likely contribute to resilience and the mitigation of mood and anxiety symptoms. PMID:29593576

The role of capsaicin-sensitive C-fiber afferent pathways in the control of micturition in spinal-intact and spinal cord-injured mice.

PubMed

Kadekawa, Katsumi; Majima, Tsuyoshi; Shimizu, Takahiro; Wada, Naoki; de Groat, William C; Kanai, Anthony J; Goto, Momokazu; Yoshiyama, Mitsuharu; Sugaya, Kimio; Yoshimura, Naoki

2017-09-01

We examined bladder and urethral sphincter activity in mice with or without spinal cord injury (SCI) after C-fiber afferent desensitization induced by capsaicin pretreatment and changes in electrophysiological properties of mouse bladder afferent neurons 4 wk after SCI. Female C57BL/6N mice were divided into four groups: 1 ) spinal intact (SI)-control, 2 ) SI-capsaicin pretreatment (Cap), 3 ) SCI-control, and 4 ) SCI-Cap groups. Continuous cystometry and external urethral sphincter (EUS)-electromyogram (EMG) were conducted under an awake condition. In the Cap groups, capsaicin (25, 50, or 100 mg/kg) was injected subcutaneously 4 days before the experiments. In the SI-Cap group, 100 mg/kg capsaicin pretreatment significantly increased bladder capacity and decreased the silent period duration of EUS/EMG compared with the SI-control group. In the SCI-Cap group, 50 and 100 mg/kg capsaicin pretreatment decreased the number of nonvoiding contractions (NVCs) and the duration of reduced EUS activity during voiding, respectively, compared with the SCI-control group. In SCI mice, hexamethonium, a ganglionic blocker, almost completely blocked NVCs, suggesting that they are of neurogenic origin. Patch-clamp recordings in capsaicin-sensitive bladder afferent neurons from SCI mice showed hyperexcitability, which was evidenced by decreased spike thresholds and increased firing rate compared with SI mice. These results indicate that capsaicin-sensitive C-fiber afferent pathways, which become hyperexcitable after SCI, can modulate bladder and urethral sphincter activity in awake SI and SCI mice. Detrusor overactivity as shown by NVCs in SCI mice is significantly but partially dependent on capsaicin-sensitive C-fiber afferents, whereas the EUS relaxation during voiding is enhanced by capsaicin-sensitive C-fiber bladder afferents in SI and SCI mice. Copyright © 2017 the American Physiological Society.

TRPV1 receptors on unmyelinated C-fibres mediate colitis-induced sensitization of pelvic afferent nerve fibres in rats

PubMed Central

De Schepper, H U; De Winter, B Y; Van Nassauw, L; Timmermans, J-P; Herman, A G; Pelckmans, P A; De Man, J G

2008-01-01

Patients with inflammatory bowel disease often suffer from gastrointestinal motility and sensitivity disorders. The aim of the current study was to investigate the role of transient receptor potential of the vanilloid type 1 (TRPV1) receptors in the pathophysiology of colitis-induced pelvic afferent nerve sensitization. Trinitrobenzene sulphate (TNBS) colitis (7.5 mg, 30% ethanol) was induced in Wistar rats 72 h prior to the experiment. Single-fibre recordings were made from pelvic nerve afferents in the decentralized S1 dorsal root. Fibres responding to colorectal distension (CRD) were identified in controls and rats with TNBS colitis. The effect of the TRPV1 antagonist N-(4-tertiarybutylphenyl)-4-(3-chlorophyridin-2-yl)tetrahydropyrazine-1(2H)carboxamide (BCTC; 0.25–5 mg kg−1) or its vehicle (hydroxypropyl-β-cyclodextrin) was tested on the afferent response to repetitive distensions (60 mmHg). Immunocytochemical staining of TRPV1 and NF200, a marker for A-fibre neurons, was performed in the dorsal root ganglia L6–S1. TNBS colitis significantly increased the response to colorectal distension of pelvic afferent C-fibres. BCTC did not significantly affect the C-fibre response in controls, but normalized the sensitized response in rats with colitis. TNBS colitis increased the spontaneous activity of C-fibres, an effect which was insensitive to administration of BCTC. TNBS colitis had no effect on Aδ-fibres, nor was their activity modulated by BCTC. TNBS colitis caused an immunocytochemical up-regulation of TRPV1 receptors in the cell bodies of pelvic afferent NF200 negative neurons. TRPV1 signalling mediates the colitis-induced sensitization of pelvic afferent C-fibres to CRD, while Aδ-fibres are neither sensitized by colitis nor affected by TRPV1 inhibition. PMID:18755744

Electrophysiological characterization of human rectal afferents

PubMed Central

Ng, Kheng-Seong; Brookes, Simon J.; Montes-Adrian, Noemi A.; Mahns, David A.

2016-01-01

It is presumed that extrinsic afferent nerves link the rectum to the central nervous system. However, the anatomical/functional existence of such nerves has never previously been demonstrated in humans. Therefore, we aimed to identify and make electrophysiological recordings in vitro from extrinsic afferents, comparing human rectum to colon. Sections of normal rectum and colon were procured from anterior resection and right hemicolectomy specimens, respectively. Sections were pinned and extrinsic nerves dissected. Extracellular visceral afferent nerve activity was recorded. Neuronal responses to chemical [capsaicin and “inflammatory soup” (IS)] and mechanical (Von Frey probing) stimuli were recorded and quantified as peak firing rate (range) in 1-s intervals. Twenty-eight separate nerve trunks from eight rectums were studied. Of these, spontaneous multiunit afferent activity was recorded in 24 nerves. Peak firing rates increased significantly following capsaicin [median 6 (range 3–25) spikes/s vs. 2 (1–4), P < 0.001] and IS [median 5 (range 2–18) spikes/s vs. 2 (1–4), P < 0.001]. Mechanosensitive “hot spots” were identified in 16 nerves [median threshold 2.0 g (range 1.4–6.0 g)]. In eight of these, the threshold decreased after IS [1.0 g (0.4–1.4 g)]. By comparison, spontaneous activity was recorded in only 3/30 nerves studied from 10 colons, and only one hot spot (threshold 60 g) was identified. This study confirms the anatomical/functional existence of extrinsic rectal afferent nerves and characterizes their chemo- and mechanosensitivity for the first time in humans. They have different electrophysiological properties to colonic afferents and warrant further investigation in disease states. PMID:27789454

Response of vestibular-nerve afferents to active and passive rotations under normal conditions and after unilateral labyrinthectomy.

PubMed

Sadeghi, Soroush G; Minor, Lloyd B; Cullen, Kathleen E

2007-02-01

We investigated the possible contribution of signals carried by vestibular-nerve afferents to long-term processes of vestibular compensation after unilateral labyrinthectomy. Semicircular canal afferents were recorded from the contralesional nerve in three macaque monkeys before [horizontal (HC) = 67, anterior (AC) = 66, posterior (PC) = 50] and 1-12 mo after (HC = 192, AC = 86, PC = 57) lesion. Vestibular responses were evaluated using passive sinusoidal rotations with frequencies of 0.5-15 Hz (20-80 degrees /s) and fast whole-body rotations reaching velocities of 500 degrees /s. Sensitivities to nonvestibular inputs were tested by: 1) comparing responses during active and passive head movements, 2) rotating the body with the head held stationary to activate neck proprioceptors, and 3) encouraging head-restrained animals to attempt to make head movements that resulted in the production of neck torques of < or =2 Nm. Mean resting discharge rate before and after the lesion did not differ for the regular, D (dimorphic)-irregular, or C (calyx)-irregular afferents. In response to passive rotations, afferents showed no change in sensitivity and phase, inhibitory cutoff, and excitatory saturation after unilateral labyrinthectomy. Moreover, head sensitivities were similar during voluntary and passive head rotations and responses were not altered by neck proprioceptive or efference copy signals before or after the lesion. The only significant change was an increase in the proportion of C-irregular units postlesion, accompanied by a decrease in the proportion of regular afferents. Taken together, our findings show that changes in response properties of the vestibular afferent population are not likely to play a major role in the long-term changes associated with compensation after unilateral labyrinthectomy.

Excitatory and inhibitory synaptic mechanisms at the first stage of integration in the electroreception system of the shark

PubMed Central

Rotem, Naama; Sestieri, Emanuel; Hounsgaard, Jorn; Yarom, Yosef

2014-01-01

High impulse rate in afferent nerves is a common feature in many sensory systems that serve to accommodate a wide dynamic range. However, the first stage of integration should be endowed with specific properties that enable efficient handling of the incoming information. In elasmobranches, the afferent nerve originating from the ampullae of Lorenzini targets specific neurons located at the Dorsal Octavolateral Nucleus (DON), the first stage of integration in the electroreception system. Using intracellular recordings in an isolated brainstem preparation from the shark we analyze the properties of this afferent pathway. We found that stimulating the afferent nerve activates a mixture of excitatory and inhibitory synapses mediated by AMPA-like and GABAA receptors, respectively. The excitatory synapses that are extremely efficient in activating the postsynaptic neurons display unusual voltage dependence, enabling them to operate as a current source. The inhibitory input is powerful enough to completely eliminate the excitatory action of the afferent nerve but is ineffective regarding other excitatory inputs. These observations can be explained by the location and efficiency of the synapses. We conclude that the afferent nerve provides powerful and reliable excitatory input as well as a feed-forward inhibitory input, which is partially presynaptic in origin. These results question the cellular location within the DON where cancelation of expected incoming signals occurs. PMID:24639631

Laryngeal and tracheal afferent nerve stimulation evokes swallowing in anaesthetized guinea pigs

PubMed Central

Tsujimura, Takanori; Udemgba, Chioma; Inoue, Makoto; Canning, Brendan J

2013-01-01

We describe swallowing reflexes evoked by laryngeal and tracheal vagal afferent nerve stimulation in anaesthetized guinea pigs. The swallowing reflexes evoked by laryngeal citric acid challenges were abolished by recurrent laryngeal nerve (RLN) transection and mimicked by electrical stimulation of the central cut ends of an RLN. By contrast, the number of swallows evoked by upper airway/pharyngeal distensions was not significantly reduced by RLN transection but they were virtually abolished by superior laryngeal nerve transection. Laryngeal citric acid-evoked swallowing was mimicked by laryngeal capsaicin challenges, implicating transient receptor potential vanilloid 1 (TRPV1)-expressing laryngeal afferent nerves arising from the jugular ganglia. The swallowing evoked by citric acid and capsaicin and evoked by electrical stimulation of either the tracheal or the laryngeal mucosa occurred at stimulation intensities that were typically subthreshold for evoking cough in these animals. Swallowing evoked by airway afferent nerve stimulation also desensitized at a much slower rate than cough. We speculate that swallowing is an essential component of airway protection from aspiration associated with laryngeal and tracheal afferent nerve activation. PMID:23858010

The organization of the lateral geniculate nucleus and of the geniculocortical pathway that develops without retinal afferents.

PubMed

Guillery, R W; Ombrellaro, M; LaMantia, A L

1985-06-01

The fine structure and cortical connections of the dorsal lateral geniculate nucleus have been studied in postnatal (3.5-14-month-old) ferrets in which all retinal afferents had been removed prenatally at the time these fibers are first starting to invade the nucleus. The synaptic profiles in the mature nucleus show the cytological characteristics and arrangements that would remain if the retinal afferents were removed, with no significant compensatory ingrowth of foreign specific afferents. The nucleus is reduced in overall volume, but the geniculocortical and corticogeniculate interconnections show an essentially normal topography. Although in these experiments the geniculocortical projections can establish a normal topographic pattern in the absence of retinal afferents an accompanying paper shows that this topographic pattern can also be modified in the presence of abnormal retinogeniculate inputs. We conclude that two separate mechanisms contribute to the formation of retinal maps within the geniculocortical pathways and that different interactions between these two mechanisms produce the different patterns of abnormal geniculocortical pathways that have been described in pigment-deficient cats, mink and ferrets.

Hyperpolarization-activated current (I(h)) in vestibular calyx terminals: characterization and role in shaping postsynaptic events.

PubMed

Meredith, Frances L; Benke, Tim A; Rennie, Katherine J

2012-12-01

Calyx afferent terminals engulf the basolateral region of type I vestibular hair cells, and synaptic transmission across the vestibular type I hair cell/calyx is not well understood. Calyces express several ionic conductances, which may shape postsynaptic potentials. These include previously described tetrodotoxin-sensitive inward Na(+) currents, voltage-dependent outward K(+) currents and a K(Ca) current. Here, we characterize an inwardly rectifying conductance in gerbil semicircular canal calyx terminals (postnatal days 3-45), sensitive to voltage and to cyclic nucleotides. Using whole-cell patch clamp, we recorded from isolated calyx terminals still attached to their type I hair cells. A slowly activating, noninactivating current (I(h)) was seen with hyperpolarizing voltage steps negative to the resting potential. External Cs(+) (1-5 mM) and ZD7288 (100 μM) blocked the inward current by 97 and 83 %, respectively, confirming that I(h) was carried by hyperpolarization-activated, cyclic nucleotide gated channels. Mean half-activation voltage of I(h) was -123 mV, which shifted to -114 mV in the presence of cAMP. Activation of I(h) was well described with a third order exponential fit to the current (mean time constant of activation, τ, was 190 ms at -139 mV). Activation speeded up significantly (τ=136 and 127 ms, respectively) when intracellular cAMP and cGMP were present, suggesting that in vivo I(h) could be subject to efferent modulation via cyclic nucleotide-dependent mechanisms. In current clamp, hyperpolarizing current steps produced a time-dependent depolarizing sag followed by either a rebound afterdepolarization or an action potential. Spontaneous excitatory postsynaptic potentials (EPSPs) became larger and wider when I(h) was blocked with ZD7288. In a three-dimensional mathematical model of the calyx terminal based on Hodgkin-Huxley type ionic conductances, removal of I(h) similarly increased the EPSP, whereas cAMP slightly decreased simulated EPSP size and width.

Evidence that antidromically stimulated vagal afferents activate inhibitory neurones innervating guinea-pig trachealis.

PubMed Central

Canning, B J; Undem, B J

1994-01-01

1. We recently described a capsaicin-sensitive vagal pathway mediating non-adrenergic, non-cholinergic (NANC) relaxations of an isolated, innervated rostral guinea-pig tracheal preparation. These afferent fibres are carried by the superior laryngeal nerves and relaxations elicited by their activation are insensitive to autonomic ganglion blockers such as hexamethonium. In the present study this vagal relaxant pathway was further characterized. 2. Relaxations of the trachealis elicited by electrical stimulation of capsaicin-sensitive vagal afferents were mimicked by bath application of capsaicin. Relaxations elicited by both methods were abolished when the tissue between the trachea and the adjacent oesophagus was disrupted. Indeed, separating the trachea from the oesophagus uncovered a contractile effect of capsaicin administration on the trachealis. 3. Capsaicin-induced, oesophagus-dependent relaxations of the trachealis were blocked by pretreatment with the fast sodium channel blocker tetrodotoxin (TTX). By contrast, capsaicin-induced contractions of the trachealis (obtained in the absence of the oesophagus) were unaffected by tetrodotoxin. 4. Substance P, neurokinin A (NKA) and neurokinin B (NKB) also elicited NANC relaxations of precontracted trachealis that were abolished by separating the trachea from the oesophagus or by TTX pretreatment. Like capsaicin, the tachykinins elicited only contractions of the trachealis following TTX pretreatment or separation of the trachea from the adjacent oesophagus. 5. Relaxations elicited by stimulation of the capsaicin-sensitive nerves were unaffected by a concentration of the tachykinin NK2 receptor-selective antagonist, SR 48968, that is selective for NK2 receptor blockade and were not mimicked by the NK2 receptor-selective agonist [beta-Ala8]-NKA(4-10). This suggests that NK2 receptors are not responsible for these relaxations. By contrast, the NK3 receptor-selective agonist, senktide analogue, and the NK1 receptor-selective agonist, acetyl-[Arg6, Sar9, Met (O2)11]-SP(6-11), elicited oesophagus-dependent relaxations of the trachealis that were abolished by oesophagus removal. Furthermore, pretreatment with the NK1-selective antagonists, CP 96345 and CP 99994, or pretreatment with a concentration of SR 48968 that also blocks NK3 receptors, markedly attenuated relaxations elicited by stimulation of the capsaicin-sensitive vagal pathways. 6. The data are consistent with the hypothesis that relaxations elicited by stimulation of capsaicin-sensitive vagal afferents involve tachykinin-mediated activation of peripheral NANC inhibitory neurones that are in some way associated with the oesophagus. The data also indicate that airway smooth muscle tone might be regulated by peripheral reflexes initiated by activation of capsaicin-sensitive afferent fibres. PMID:7869272

Physiological identification of morphologically distinct afferent classes innervating the cristae ampullares of the squirrel monkey

NASA Technical Reports Server (NTRS)

Lysakowski, A.; Minor, L. B.; Fernandez, C.; Goldberg, J. M.

1995-01-01

1. Semicircular-canal afferents in the squirrel monkey were characterized by their resting discharge, discharge regularity, sensitivity to galvanic currents delivered to the ear (beta *), the gain (g2Hz), and phase lead (phi 2Hz) of their response to 2-Hz sinusoidal head rotations, and their antidromic conduction velocity. Discharge regularity was measured by a normalized coefficient of variation (CV*); the higher the CV*, the more irregular the discharge. g2Hz and phi 2Hz were expressed relative to angular head velocity. 2. These physiological measures were used in an attempt to discern the discharge properties of the three morphological classes of afferents innervating the crista. Presumed bouton (B) fibers were identified as slowly conducting afferents. Presumed calyx (C) fibers were recognized by their irregular discharge and low rotational gains. The remaining fibers were considered to be dimorphic (D) units. Single letters (B, C, and D) are used to emphasize that the classification is based on circumstantial evidence and may be wrong for individual fibers. Of the 125 identified fibers, 13 (10%) were B units, 36 (29%) were C units, and 76 (61%) were D units. 3. B units were regularly discharging D units ranged from regularly to irregularly discharging. C units were the most irregularly discharging afferents encountered. The mean resting discharge for the entire sample was 74 spikes/s. Resting rates were similar for regularly discharging B and D units and higher than those for irregularly discharging C and D units. 4. Except for their lower conduction velocities, the discharge properties of B units are indistinguishable from those of regularly discharging D units. Many of the discharge properties of B and D units vary with discharge regularity. There is a strong, positive relation when beta *, g2Hz, or phi 2Hz is plotted against CV*. For beta * or phi 2Hz, C units conform to the relation for B and D units. In contrast, values of g2Hz for C units are three to four times lower than predicted from the relation for the other two classes. 5. Internal (axon) diameters (dp) of peripheral vestibular-nerve fibers were estimated from central antidromic conduction velocities. Thick fibers (dp > or = 49 microns) were irregularly discharging, mostly C units. Medium-sized fibers (dp = 1.5-4 microns) included regular, intermediate, and irregular D units, as well as C units. Thin fibers (dp < or = 1.5 microns) were defined as B units.(ABSTRACT TRUNCATED AT 400 WORDS).

Entorhinal Denervation Induces Homeostatic Synaptic Scaling of Excitatory Postsynapses of Dentate Granule Cells in Mouse Organotypic Slice Cultures

PubMed Central

Vlachos, Andreas; Becker, Denise; Jedlicka, Peter; Winkels, Raphael; Roeper, Jochen; Deller, Thomas

2012-01-01

Denervation-induced changes in excitatory synaptic strength were studied following entorhinal deafferentation of hippocampal granule cells in mature (≥3 weeks old) mouse organotypic entorhino-hippocampal slice cultures. Whole-cell patch-clamp recordings revealed an increase in excitatory synaptic strength in response to denervation during the first week after denervation. By the end of the second week synaptic strength had returned to baseline. Because these adaptations occurred in response to the loss of excitatory afferents, they appeared to be in line with a homeostatic adjustment of excitatory synaptic strength. To test whether denervation-induced changes in synaptic strength exploit similar mechanisms as homeostatic synaptic scaling following pharmacological activity blockade, we treated denervated cultures at 2 days post lesion for 2 days with tetrodotoxin. In these cultures, the effects of denervation and activity blockade were not additive, suggesting that similar mechanisms are involved. Finally, we investigated whether entorhinal denervation, which removes afferents from the distal dendrites of granule cells while leaving the associational afferents to the proximal dendrites of granule cells intact, results in a global or a local up-scaling of granule cell synapses. By using computational modeling and local electrical stimulations in Strontium (Sr2+)-containing bath solution, we found evidence for a lamina-specific increase in excitatory synaptic strength in the denervated outer molecular layer at 3–4 days post lesion. Taken together, our data show that entorhinal denervation results in homeostatic functional changes of excitatory postsynapses of denervated dentate granule cells in vitro. PMID:22403720

Retraining the injured spinal cord

NASA Technical Reports Server (NTRS)

Edgerton, V. R.; Leon, R. D.; Harkema, S. J.; Hodgson, J. A.; London, N.; Reinkensmeyer, D. J.; Roy, R. R.; Talmadge, R. J.; Tillakaratne, N. J.; Timoszyk, W.;

Experimental studies of gastric dysfunction in motion sickness: The effect of gastric and vestibular stimulation on the vagal and splanchnic gastric efferents

NASA Technical Reports Server (NTRS)

Niijima, A.; Jiang, Z. Y.; Daunton, Nancy G.; Fox, Robert A.

1991-01-01

The experiments were conducted in anaesthetized rats. In the first part of the experiments, the effect of CuSO4 on the afferent activity in the gastric branch of the vagus nerve was investigated. Gastric perfusion of CuSO4 solution (0.04 percent and 0.08 percent) provoked an increase in afferent activity. In the second part of the experiments, the reflex effects of gastric perfusion of CuSO4 solution, repetitive stimulation of the gastric vagus nerve, and caloric stimulation of the right vestibular apparatus (5-18 C water) on gastric autonomic outflow were investigated. The results of these experiments showed that these three different types of stimulation caused an inhibition in efferent activity of the gastric vagus nerve and a slight activation of the splanchnic gastric efferents. The summation of the effect of each stimulation was also observed. These results, therefore, provide evidence for a possible integrative inhibitory function of the vagal gastric center as well as an excitatory function of gastric sympathetic motoneurons in relation to motion sickness.

In Vivo Recording of Neural and Behavioral Correlates of Anesthesia Induction, Reversal, and Euthanasia in Cephalopod Molluscs.

PubMed

Butler-Struben, Hanna M; Brophy, Samantha M; Johnson, Nasira A; Crook, Robyn J

2018-01-01

Cephalopod molluscs are among the most behaviorally and neurologically complex invertebrates. As they are now included in research animal welfare regulations in many countries, humane and effective anesthesia is required during invasive procedures. However, currently there is no evidence that agents believed to act as anesthetics produce effects beyond immobility. In this study we demonstrate, for the first time, that two of the most commonly used agents in cephalopod general anesthesia, magnesium chloride and ethanol, are capable of producing strong and reversible blockade of afferent and efferent neural signal; thus they are genuine anesthetics, rather than simply sedating agents that render animals immobile but not insensible. Additionally, we demonstrate that injected magnesium chloride and lidocaine are effective local anesthetic agents. This represents a considerable advance for cephalopod welfare. Using a reversible, minimally invasive recording procedure, we measured activity in the pallial nerve of cuttlefish ( Sepia bandensis ) and octopus ( Abdopus aculeatus, Octopus bocki ), during induction and reversal for five putative general anesthetic and two local anesthetic agents. We describe the temporal relationship between loss of behavioral responses (immobility), loss of efferent neural signal (loss of "consciousness") and loss of afferent neural signal (anesthesia) for general anesthesia, and loss of afferent signal for local anesthesia. Both ethanol and magnesium chloride were effective as bath-applied general anesthetics, causing immobility, complete loss of behavioral responsiveness and complete loss of afferent and efferent neural signal. Cold seawater, diethyl ether, and MS-222 (tricaine) were ineffective. Subcutaneous injection of either lidocaine or magnesium chloride blocked behavioral and neural responses to pinch in the injected area, and we conclude that both are effective local anesthetic agents for cephalopods. Lastly, we demonstrate that a standard euthanasia protocol-immersion in isotonic magnesium chloride followed by surgical decerebration-produced no behavioral response and no neural activity during surgical euthanasia. Based on these data, we conclude that both magnesium chloride and ethanol can function as general anesthetic agents, and lidocaine and magnesium chloride can function as local anesthetic agents for cephalopod molluscs.

In Vivo Recording of Neural and Behavioral Correlates of Anesthesia Induction, Reversal, and Euthanasia in Cephalopod Molluscs

PubMed Central

Butler-Struben, Hanna M.; Brophy, Samantha M.; Johnson, Nasira A.; Crook, Robyn J.

2018-01-01

Cephalopod molluscs are among the most behaviorally and neurologically complex invertebrates. As they are now included in research animal welfare regulations in many countries, humane and effective anesthesia is required during invasive procedures. However, currently there is no evidence that agents believed to act as anesthetics produce effects beyond immobility. In this study we demonstrate, for the first time, that two of the most commonly used agents in cephalopod general anesthesia, magnesium chloride and ethanol, are capable of producing strong and reversible blockade of afferent and efferent neural signal; thus they are genuine anesthetics, rather than simply sedating agents that render animals immobile but not insensible. Additionally, we demonstrate that injected magnesium chloride and lidocaine are effective local anesthetic agents. This represents a considerable advance for cephalopod welfare. Using a reversible, minimally invasive recording procedure, we measured activity in the pallial nerve of cuttlefish (Sepia bandensis) and octopus (Abdopus aculeatus, Octopus bocki), during induction and reversal for five putative general anesthetic and two local anesthetic agents. We describe the temporal relationship between loss of behavioral responses (immobility), loss of efferent neural signal (loss of “consciousness”) and loss of afferent neural signal (anesthesia) for general anesthesia, and loss of afferent signal for local anesthesia. Both ethanol and magnesium chloride were effective as bath-applied general anesthetics, causing immobility, complete loss of behavioral responsiveness and complete loss of afferent and efferent neural signal. Cold seawater, diethyl ether, and MS-222 (tricaine) were ineffective. Subcutaneous injection of either lidocaine or magnesium chloride blocked behavioral and neural responses to pinch in the injected area, and we conclude that both are effective local anesthetic agents for cephalopods. Lastly, we demonstrate that a standard euthanasia protocol—immersion in isotonic magnesium chloride followed by surgical decerebration—produced no behavioral response and no neural activity during surgical euthanasia. Based on these data, we conclude that both magnesium chloride and ethanol can function as general anesthetic agents, and lidocaine and magnesium chloride can function as local anesthetic agents for cephalopod molluscs. PMID:29515454

CX3CL1-mediated macrophage activation contributed to paclitaxel-induced DRG neuronal apoptosis and painful peripheral neuropathy.

PubMed

Huang, Zhen-Zhen; Li, Dai; Liu, Cui-Cui; Cui, Yu; Zhu, He-Quan; Zhang, Wen-Wen; Li, Yong-Yong; Xin, Wen-Jun

2014-08-01

Painful peripheral neuropathy is a dose-limiting side effect of paclitaxel therapy, which hampers the optimal clinical management of chemotherapy in cancer patients. Currently the underlying mechanisms remain largely unknown. Here we showed that the clinically relevant dose of paclitaxel (3×8mg/kg, cumulative dose 24mg/kg) induced significant upregulation of the chemokine CX3CL1 in the A-fiber primary sensory neurons in vivo and in vitro and infiltration of macrophages into the dorsal root ganglion (DRG) in rats. Paclitaxel treatment also increased cleaved caspase-3 expression, induced the loss of primary afferent terminal fibers and decreased sciatic-evoked A-fiber responses in the spinal dorsal horn, indicating DRG neuronal apoptosis induced by paclitaxel. In addition, the paclitaxel-induced DRG neuronal apoptosis occurred exclusively in the presence of macrophage in vitro study. Intrathecal or systemic injection of CX3CL1 neutralizing antibody blocked paclitaxel-induced macrophage recruitment and neuronal apoptosis in the DRG, and also attenuated paclitaxel-induced allodynia. Furthermore, depletion of macrophage by systemic administration of clodronate inhibited paclitaxel-induced allodynia. Blocking CX3CL1 decreased activation of p38 MAPK in the macrophage, and inhibition of p38 MAPK activity blocked the neuronal apoptosis and development of mechanical allodynia induced by paclitaxel. These findings provide novel evidence that CX3CL1-recruited macrophage contributed to paclitaxel-induced DRG neuronal apoptosis and painful peripheral neuropathy. Copyright © 2014 Elsevier Inc. All rights reserved.

A transmission and scanning electron microscopic study of the saccule in five species of catfishes.

PubMed

Jenkins, D B

1979-01-01

The sacculi of five species of catfishes were studied by transmission and scanning electron microscopy. In four species, the sagitta exhibited a multifluted anterior part and a tapered posterior part; in Corydoras aeneus, however, the fluted part was absent, and a vertical component extended dorsally to terminate near the opening of the transverse canal. In all species, the otoliths had a laminar structure. An otolithic membrane was present, and hair cell bundles projected into cavities on the macular surface of the membrane. Attachments of the otolithic membrane to the neuroepithelium included short extensions of the membrane to the tallest components of the hair cell bundles of the peripheral cells and more delicate connections to the kinocilium and taller stereocilia of central cells; in addition, attachments to the microvilli of supporting cells were present. In both hair cells and supporting cells single microtubules and bundles of microtubules were present; the bundles had an orderly arrangement and were associated with cytoplasmic densities surrounding the desmosomes. The hair cells were innervated by both afferent and efferent nerve endings. Studies of the polarization of the hair cells in all species (except C. aeneus) showed that there was a single longitudinal axis that divided dorsally polarized cells from those oriented ventrally. In Doras spinosissimus and Bunocephalus bicolor, an additional line of polarization was evident in a small area in the anterior part of the macula; therefore, in these forms there was a double bipolar orientation.

Expression of S100 beta in sensory and secretory cells of the vertebrate inner ear

NASA Technical Reports Server (NTRS)

Fermin, C. D.; Martin, D. S.

1995-01-01

We evaluated anti-S100 beta expression in the chick (Gallus domesticus) inner ear and determined that: 1) the monomer anti-S100 beta is expressed differentially in the vestibular and auditory perikarya; 2) expression of S100 beta in the afferent nerve terminals is time-related to synapse and myelin formation; 3) the expression of the dimer anti-S100 alpha alpha beta beta and monomer anti-S100 beta overlaps in most inner ear cell types. Most S100 alpha alpha beta beta positive cells express S100 beta, but S100 beta positive cells do not always express S100 alpha alpha beta beta. 4) the expression of S100 beta is diffused over the perikaryal cytoplasm and nuclei of the acoustic ganglia but is concentrated over the nuclei of the vestibular perikarya. 6) S100 beta is expressed in secretory cells, and it is co-localized with GABA in sensory cells. 7) Color thresholding objective quantitation indicates that the amount of S100 beta was higher (mean 22, SD +/- 4) at E19 than at E9 (mean 34, SD +/- 3) in afferent axons. 8) Moreover, S100 beta was unchanged between E11-E19 in the perikaryal cytoplasm, but did change over the nuclei. At E9, 74%, and at E21, 5% of vestibular perikarya were positive. The data suggest that S100 beta may be physically associated with neuronal and ionic controlling cells of the vertebrate inner ear, where it could provide a dual ionic and neurotrophic modulatory function.

Corollary discharge inhibition of wind-sensitive cercal giant interneurons in the singing field cricket

PubMed Central

Hedwig, Berthold

2014-01-01

Crickets carry wind-sensitive mechanoreceptors on their cerci, which, in response to the airflow produced by approaching predators, triggers escape reactions via ascending giant interneurons (GIs). Males also activate their cercal system by air currents generated due to the wing movements underlying sound production. Singing males still respond to external wind stimulation, but are not startled by the self-generated airflow. To investigate how the nervous system discriminates sensory responses to self-generated and external airflow, we intracellularly recorded wind-sensitive afferents and ventral GIs of the cercal escape pathway in fictively singing crickets, a situation lacking any self-stimulation. GI spiking was reduced whenever cercal wind stimulation coincided with singing motor activity. The axonal terminals of cercal afferents showed no indication of presynaptic inhibition during singing. In two ventral GIs, however, a corollary discharge inhibition occurred strictly in phase with the singing motor pattern. Paired intracellular recordings revealed that this inhibition was not mediated by the activity of the previously identified corollary discharge interneuron (CDI) that rhythmically inhibits the auditory pathway during singing. Cercal wind stimulation, however, reduced the spike activity of this CDI by postsynaptic inhibition. Our study reveals how precisely timed corollary discharge inhibition of ventral GIs can prevent self-generated airflow from triggering inadvertent escape responses in singing crickets. The results indicate that the responsiveness of the auditory and wind-sensitive pathway is modulated by distinct CDIs in singing crickets and that the corollary discharge inhibition in the auditory pathway can be attenuated by cercal wind stimulation. PMID:25318763

The effect of state anxiety on the online and offline control of fast target-directed movements.

PubMed

Lawrence, Gavin P; Khan, Michael A; Hardy, Lew

2013-07-01

In target-directed aiming, afferent information is used to adjust limb trajectories during movement execution (i.e. online) and to enhance the programming of subsequent trials (i.e. offline). The objective of the present study was to determine the influence of state anxiety on both online and offline afferent information processing for the first time. Participants practiced either a directional aiming task (Experiment 1) or an amplitude aiming task (Experiment 2) without anxiety before being transferred to a high anxiety condition. In both experiments, results revealed that anxiety resulted in a decrement in performance. Furthermore, use of afferent information to adjust movement trajectories online was disrupted when movements were performed with anxiety, whereas there were no differences in the offline processing of afferent information between the low anxiety and high anxiety conditions.

Cardiac effects of electrically induced intrathoracic autonomic reflexes.

PubMed

Armour, J A

1988-06-01

Electrical stimulation of the afferent components in one cardiopulmonary nerve (the left vagosympathetic complex at a level immediately caudal to the origin of the left recurrent laryngeal nerve) in acutely decentralized thoracic autonomic ganglionic preparations altered cardiac chronotropism and inotropism in 17 of 44 dogs. Since these neural preparations were acutely decentralized, the effects were mediated presumably via intrathoracic autonomic reflexes. The lack of consistency of these reflexly generated cardiac responses presumably were due in part to anatomical variation of afferent axons in the afferent nerve stimulated. As stimulation of the afferent components in the same neural structure caudal to the heart (where cardiopulmonary afferent axons are not present) failed to elicit cardiac responses in any dog, it is presumed that when cardiac responses were elicited by the more cranially located stimulations, these were due to activation of afferent axons arising from the heart and (or) lungs. When cardiac responses were elicited, intramyocardial pressures in the right ventricular conus as well as the ventral and lateral walls of the left ventricle were augmented. Either bradycardia or tachycardia was elicited. Following hexamethonium administration no responses were produced, demonstrating that nicotonic cholinergic synaptic mechanisms were involved in these intrathoracic cardiopulmonary-cardiac reflexes. In six of the animals, when atropine was administered before hexamethonium, reflexly generated responses were attenuated. The same thing occurred when morphine was administered in four animals. In contrast, in four animals following administration of phentolamine, the reflexly generated changes were enhanced.(ABSTRACT TRUNCATED AT 250 WORDS)

Group III/IV locomotor muscle afferents alter motor cortical and corticospinal excitability and promote central fatigue during cycling exercise

PubMed Central

Sidhu, Simranjit K.; Weavil, Joshua C.; Mangum, Tyler S.; Jessop, Jacob E.; Richardson, Russell S.; Morgan, David E.; Amann, Markus

2017-01-01

Objective To investigate the influence of group III/IV muscle afferents on the development of central fatigue and corticospinal excitability during exercise. Methods Fourteen males performed cycling-exercise both under control-conditions (CTRL) and with lumbar intrathecal fentanyl (FENT) impairing feedback from leg muscle afferents. Transcranial magnetic- and cervicomedullary stimulation was used to monitor cortical versus spinal excitability. Results While fentanyl-blockade during non-fatiguing cycling had no effect on motor-evoked potentials (MEPs), cervicomedullary-evoked motor potentials (CMEPs) were 13 ± 3% higher (P < 0.05), resulting in a decrease in MEP/CMEP (P < 0.05). Although the pre- to post-exercise reduction in resting twitch was greater in FENT vs. CTRL (−53 ± 3% vs. −39 ± 3%; P < 0.01), the reduction in voluntary muscle activation was smaller (−2 ± 2% vs. −10 ± 2%; P < 0.05). Compared to the start of fatiguing exercise, MEPs and CMEPs were unchanged at exhaustion in CTRL. In contrast, MEPs and MEP/CMEP increased 13 ± 3% and 25 ± 6% in FENT (P < 0.05). Conclusion During non-fatiguing exercise, group III/IV muscle afferents disfacilitate, or inhibit, spinal motoneurons and facilitate motor cortical cells. In contrast, during exhaustive exercise, group III/IV muscle afferents disfacilitate/inhibit the motor cortex and promote central fatigue. Significance Group III/IV muscle afferents influence corticospinal excitability and central fatigue during whole-body exercise in humans. PMID:27866119

Group III/IV locomotor muscle afferents alter motor cortical and corticospinal excitability and promote central fatigue during cycling exercise.

PubMed

Sidhu, Simranjit K; Weavil, Joshua C; Mangum, Tyler S; Jessop, Jacob E; Richardson, Russell S; Morgan, David E; Amann, Markus

2017-01-01

To investigate the influence of group III/IV muscle afferents on the development of central fatigue and corticospinal excitability during exercise. Fourteen males performed cycling-exercise both under control-conditions (CTRL) and with lumbar intrathecal fentanyl (FENT) impairing feedback from leg muscle afferents. Transcranial magnetic- and cervicomedullary stimulation was used to monitor cortical versus spinal excitability. While fentanyl-blockade during non-fatiguing cycling had no effect on motor-evoked potentials (MEPs), cervicomedullary-evoked motor potentials (CMEPs) were 13±3% higher (P<0.05), resulting in a decrease in MEP/CMEP (P<0.05). Although the pre- to post-exercise reduction in resting twitch was greater in FENT vs. CTRL (-53±3% vs. -39±3%; P<0.01), the reduction in voluntary muscle activation was smaller (-2±2% vs. -10±2%; P<0.05). Compared to the start of fatiguing exercise, MEPs and CMEPs were unchanged at exhaustion in CTRL. In contrast, MEPs and MEP/CMEP increased 13±3% and 25±6% in FENT (P<0.05). During non-fatiguing exercise, group III/IV muscle afferents disfacilitate, or inhibit, spinal motoneurons and facilitate motor cortical cells. In contrast, during exhaustive exercise, group III/IV muscle afferents disfacilitate/inhibit the motor cortex and promote central fatigue. Group III/IV muscle afferents influence corticospinal excitability and central fatigue during whole-body exercise in humans. Copyright © 2016 International Federation of Clinical Neurophysiology. All rights reserved.

Vesicular glutamate transporters VGLUT1 and VGLUT2 define two subsets of unipolar brush cells in organotypic cultures of mouse vestibulocerebellum.

PubMed

Nunzi, M G; Russo, M; Mugnaini, E

2003-01-01

Different isoforms of a vesicular glutamate transporter (VGLUT) mediate glutamate uptake into synaptic vesicles of excitatory neurons. There is agreement that the VGLUTs are differentially expressed in brain, and that two isoforms, VGLUT1 and VGLUT2, are localized to excitatory axon terminals in the cerebellar cortex. While granule cells express solely VGLUT1, there is no report about the VGLUT(s) of the unipolar brush cell (UBC), the second type of glutamatergic interneuron residing in the cerebellar granular layer. In the mouse, UBCs are particularly numerous in the uvula (lobule IX) and nodulus (lobule X). These folia contain two distinct subsets of UBCs: one kind expresses the calcium-binding protein calretinin (CR), and the other kind expresses the metabotropic glutamate receptor (mGluR) 1alpha. UBCs give rise to an extensive system of intrinsic mossy fibers (MF), whose terminals innervate granule cells and other UBCs, altogether similar to those formed by the extrinsic MFs. The presence of both extrinsic and intrinsic MFs in the vestibulocerebellum makes it difficult to determine which type of VGLUT is contained in MFs formed by the UBC axons. Hence, the nodulus was isolated from sagittal cerebellar slices from postnatal day 10 mice, and cultured for 15-20 days in vitro. Double immunofluorescence and confocal microscopy showed that mossy terminals of CR-positive (CR(+)) UBCs were immunoreactive for VGLUT1 and VGLUT2, while mossy terminals of mGluR1alpha-positive (mGluR1alpha(+)) UBCs were provided with VGLUT1 only. Moreover, CR(+) dendritic brushes were contacted by mossy terminals provided with both transporters, while mGluR1alpha(+) dendritic brushes were contacted by mossy terminals immunopositive for VGLUT1 and immunonegative for VGLUT2. These data indicate that the two UBC subsets use different modalities of vesicular glutamate storage and form separate networks. We consider it possible that expressions of CR with VGLUT1/VGLUT2 and mGluR1alpha(+) with VGLUT1 in the two subsets of vestibulocerebellar UBCs are determined by specific vestibular inputs, carried by groups of primary and/or secondary vestibular afferents.

Development and implementation of sepsis alert systems

PubMed Central

Harrison, Andrew M.; Gajic, Ognjen; Pickering, Brian W.; Herasevich, Vitaly

2016-01-01

Synopsis/Summary Development and implementation of sepsis alert systems is challenging, particularly outside the monitored intensive care unit (ICU) setting. Important barriers to wider use of sepsis alerts include evolving clinical definitions of sepsis, information overload & alert fatigue, due to suboptimal alert performance. Outside the ICU, additional barriers include differences in health care delivery models, charting behaviors, and availability of electronic data. Currently available evidence does not support routine use of sepsis alert systems in clinical practice. However, continuous improvement in both the afferent (data availability and accuracy of detection algorithms) and efferent (evidence-based decision support and smoother integration into clinical workflow) limbs of sepsis alert systems will help translate theoretical advantages into measurable patient benefit. PMID:27229639

Peptides and neurotransmitters that affect renin secretion

NASA Technical Reports Server (NTRS)

Ganong, W. F.; Porter, J. P.; Bahnson, T. D.; Said, S. I.

1984-01-01

Substance P inhibits renin secretion. This polypeptide is a transmitter in primary afferent neurons and is released from the peripheral as well as the central portions of these neurons. It is present in afferent nerves from the kidneys. Neuropeptide Y, which is a cotransmitter with norepinephrine and epinephrine, is found in sympathetic neurons that are closely associated with and presumably innervate the juxtagolmerular cells. Its effect on renin secretion is unknown, but it produces renal vasoconstriction and natriuresis. Vasoactive intestinal polypeptide (VIP) is a cotransmitter with acetylocholine in cholinergic neurons, and this polypeptide stimulates renin secretion. We cannot find any evidence for its occurence in neurons in the kidneys, but various stimuli increase plasma VIP to levels comparable to those produced by doses of exogenous VIP which stimulated renin secretion. Neostigmine increases plasma VIP and plasma renin activity, and the VIP appears to be responsible for the increase in renin secretion, since the increase is not blocked by renal denervation or propranolol. Stimulation of various areas in the brain produces sympathetically mediated increases in plasma renin activity associated with increases in blood pressure. However, there is pharmacological evidence that the renin response can be separated from the blood pressure response. In anaesthetized dogs, drugs that increase central serotonergic discharge increase renin secretion without increasing blood pressure. In rats, activation of sertonergic neurons in the dorsal raphe nucleus increases renin secretion by a pathway that projects from this nucleus to the ventral hypothalamus, and from there to the kidneys via the sympathetic nervous system. The serotonin releasing drug parachloramphetamine also increases plasma VIP, but VIP does not appear to be the primary mediator of the renin response. There is preliminary evidence that the serotonergic neurons in the dorsal raphe nucleus are part of the pathway by which psychosocial stimuli increase renin secretion.

Resting afferent renal nerve discharge and renal inflammation: Elucidating the role of afferent and efferent renal nerves in DOCA-salt hypertension

PubMed Central

Banek, Christopher T.; Knuepfer, Mark M.; Foss, Jason D.; Fiege, Jessica K.; Asirvatham-Jeyaraj, Ninitha; Van Helden, Dusty; Shimizu, Yoji; Osborn, John W.

2016-01-01

Renal sympathetic denervation (RDNx) has emerged as a novel therapy for hypertension; however, the therapeutic mechanisms remain unclear. Efferent renal sympathetic nerve activity (RSNA) has recently been implicated in trafficking renal inflammatory immune cells and inflammatory chemokine and cytokine release. Several of these inflammatory mediators are known to activate or sensitize afferent nerves. This study aimed to elucidate the roles of efferent and afferent renal nerves in renal inflammation and hypertension in the deoxycorticosterone acetate (DOCA)-salt rat model. Uninephrectomized male Sprague Dawley rats (275–300g) underwent selective afferent-selective RDNx (A-RDNx; n=10), total RDNx (T-RDNx; n=10), or Sham (n=10) and were instrumented for measurement of mean arterial pressure (MAP) and heart rate (HR) by radiotelemetry. Rats received 100mg DOCA (s.c.) and 0.9% saline for 21 days. Resting afferent renal nerve activity (ARNA) in DOCA and Vehicle animals was measured after the treatment protocol. Renal tissue inflammation was assessed by renal cytokine content and T-cell infiltration and activation. Resting ARNA, expressed as a percent of peak afferent nerve activity (%Amax), was substantially increased in DOCA vs. Vehicle (35.8±4.4 vs. 15.3±2.8%Amax). The DOCA-Sham hypertension (132±12 mmHg) was attenuated by ~50% in both T-RDNx (111±8) and A-RDNx (117±5mmHg) groups. Renal inflammation induced by DOCA-salt was attenuated by T-RDNx, and unaffected by A-RDNx. These data suggest ARNA may mediate the hypertensive response to DOCA-salt, but inflammation may be mediated primarily by efferent RSNA. Also, resting ARNA is elevated in DOCA-salt rats, which may highlight a crucial neural mechanism in the development and maintenance of hypertension. PMID:27698066

Presynaptic muscarinic control of glutamatergic synaptic transmission.

PubMed

Buño, W; Cabezas, C; Fernández de Sevilla, D

2006-01-01

The hippocampus receives cholinergic projections from the medial septal nucleus and Broca's diagonal band that terminate in the CA1, CA3, and dentate gyrus regions (Frotscher and Leranth, 1985). Glutamatergic synapses between CA3 and CA1 pyramidal neurons are presynaptically inhibited by acetylcholine (ACh), via activation of muscarinic ACh receptors (mAChRs) at the terminals of Schaffer collaterals (SCs) (Hounsgaard, 1978; Fernández de Sevilla et al., 2002, 2003). There are two types of SC-CA1 pyramidal neuron synapses. One type, called functional synapse, shows postsynaptic alpha- amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA)-receptor mediated currents at resting potential (Vm) and both AMPA and N-methyl-D-aspartate receptor (NMDAR)-mediated currents when depolarized. The other type, termed silent synapse, only displays postsynaptic NMDAR-mediated currents at depolarized Vms, but does not respond at the resting Vm (Isaac et al., 1995). Using hippocampal slices obtained from young Wistar rats, we examined the effects of activation of cholinergic afferents at the stratum oriens/alveus on excitatory postsynaptic currents (EPSCs) evoked in CA1 pyramidal neurons by stimulation of SCs. We also tested the action of the nonhydrolyzable cholinergic agonist carbamylcholine chloride (CCh) on EPSCs evoked by minimal stimulation of SCs (which activates a single or very few synapses) in functional and silent synapses.

Maintenance of Mouse Gustatory Terminal Field Organization Is Disrupted following Selective Removal of Peripheral Sodium Salt Taste Activity at Adulthood.

PubMed

Skyberg, Rolf; Sun, Chengsan; Hill, David L

2017-08-09

Neural activity plays a critical role in the development of central circuits in sensory systems. However, the maintenance of these circuits at adulthood is usually not dependent on sensory-elicited neural activity. Recent work in the mouse gustatory system showed that selectively deleting the primary transduction channel for sodium taste, the epithelial sodium channel (ENaC), throughout development dramatically impacted the organization of the central terminal fields of three nerves that carry taste information to the nucleus of the solitary tract. More specifically, deleting ENaCs during development prevented the normal maturation of the fields. The present study was designed to extend these findings by testing the hypothesis that the loss of sodium taste activity impacts the maintenance of the normal adult terminal field organization in male and female mice. To do this, we used an inducible Cre-dependent genetic recombination strategy to delete ENaC function after terminal field maturation occurred. We found that removal of sodium taste neural activity at adulthood resulted in significant reorganization of mature gustatory afferent terminal fields in the nucleus of the solitary tract. Specifically, the chorda tympani and greater superficial petrosal nerve terminal fields were 1.4× and 1.6× larger than age-matched controls, respectively. By contrast, the glossopharyngeal nerve, which is not highly sensitive to sodium taste stimulation, did not undergo terminal field reorganization. These surprising results suggest that gustatory nerve terminal fields remain plastic well into adulthood, which likely impacts central coding of taste information and taste-related behaviors with altered taste experience. SIGNIFICANCE STATEMENT Neural activity plays a major role in the development of sensory circuits in the mammalian brain. However, the importance of sensory-driven activity in maintaining these circuits at adulthood, especially in subcortical structures, appears to be much less. Here, we tested whether the loss of sodium taste activity in adult mice impacts the maintenance of how taste nerves project to the first central relay. We found that specific loss of sodium-elicited taste activity at adulthood produced dramatic and selective reorganization of terminal fields in the brainstem. This demonstrates, for the first time, that taste-elicited activity is necessary for the normal maintenance of central gustatory circuits at adulthood and highlights a level of plasticity not seen in other sensory system subcortical circuits. Copyright © 2017 the authors 0270-6474/17/377619-12$15.00/0.

A DISCRETE-EVENT SIMULATION APPROACH TO IDENTIFY RULES THAT GOVERN ARBOR REMODELING FOR BRANCHING CUTANEOUS AFFERENTS IN HAIRY SKIN.

PubMed

Kang, Hyojung; Orlowsky, Rachel L; Gerling, Gregory J

2017-12-01

In mammals, touch is encoded by sensory receptors embedded in the skin. For one class of receptors in the mouse, the architecture of its Merkel cells, unmyelinated neurites, and heminodes follow particular renewal and remodeling trends over hair cycle stages from ages 4 to 10 weeks. As it is currently impossible to observe such trends across a single animal's hair cycle, this work employs discrete event simulation to identify and evaluate policies of Merkel cell and heminode dynamics. Well matching the observed data, the results show that the baseline model replicates dynamic remodeling behaviors between stages of the hair cycle - based on particular addition and removal polices and estimated probabilities tied to constituent parts of Merkel cells, terminal branch neurites and heminodes. The analysis shows further that certain policies hold greater influence than others. This use of computation is a novel approach to understanding neuronal development.

A subcortical inhibitory signal for behavioral arrest in the thalamus

PubMed Central

Dugué, Guillaume P.; Bokor, Hajnalka; Rousseau, Charly V.; Maglóczky, Zsófia; Havas, László; Hangya, Balázs; Wildner, Hendrik; Zeilhofer, Hanns Ulrich; Dieudonné, Stéphane; Acsády, László

2016-01-01

Organization of behavior requires rapid coordination of brainstem and forebrain activity. The exact mechanisms of effective communication between these regions are presently unclear. The intralaminar thalamus (IL) probably serves as a central hub in this circuit by connecting the critical brainstem and forebrain areas. Here we found that GABAergic/glycinergic fibers ascending from the pontine reticular formation (PRF) of the brainstem evoke fast and reliable inhibition in the IL thalamus via large, multisynaptic terminals. This inhibition was fine-tuned through heterogeneous GABAergic/glycinergic receptor ratios expressed at individual synapses. Optogenetic activation of PRF axons in the IL of freely moving mice led to behavioral arrest and transient interruption of awake cortical activity. An afferent system with comparable morphological features was also found in the human IL. These data reveal an evolutionarily conserved ascending system which gates forebrain activity through fast and powerful synaptic inhibition of the IL thalamus. PMID:25706472

The nature of catecholamine-containing neurons in the enteric nervous system in relationship with organogenesis, normal human anatomy and neurodegeneration.

PubMed

Natale, G; Ryskalin, L; Busceti, C L; Biagioni, F; Fornai, F

2017-09-01

The gastrointestinal tract is provided with extrinsic and intrinsic innervation. The extrinsic innervation includes the classic vagal parasympathetic and sympathetic components, with afferent sensitive and efferent secretomotor fibers. The intrinsic innervations is represented by the enteric nervous system (ENS), which is recognized as a complex neural network controlling a variety of cell populations, including smooth muscle cells, mucosal secretory cells, endocrine cells, microvasculature, immune and inflammatory cells. This is finalized to regulate gastrointestinal secretion, absorption and motility. In particular, this network is organized in several plexuses each one providing quite autonomous control of gastrointestinal functions (hence the definition of "second brain"). The similarity between ENS and CNS is further substantiated by the presence of local sensitive pseudo- unipolar ganglionic neurons with both peripheral and central branching which terminate in the enteric wall. A large variety of neurons and neurotransmitters takes part in the ENS. However, the nature of these neurons and their role in the regulation of gastrointestinal functions is debatable. In particular, the available literature reporting the specific nature of catecholamine- containing neurons provides conflicting evidence. This is critical both for understanding the specific role of each catecholamine in the gut and, mostly, to characterize specifically the enteric neuropathology occurring in a variety of diseases. An emphasis is posed on neurodegenerative disorders, such as Parkinson's disease, which is associated with the loss of catecholamine neurons. In this respect, the recognition of the nature of such neurons within the ENS would contribute to elucidate the pathological mechanisms which produce both CNS and ENS degeneration and to achieve more effective therapeutic approaches. Despite a great emphasis is posed on the role of noradrenaline to regulate enteric activities only a few reports are available on the anatomy and physiology of enteric dopamine neurons. Remarkably, this review limits the presence of enteric noradrenaline (and adrenaline) only within extrinsic sympathetic nerve terminals. This is based on careful morphological studies showing that the only catecholamine-containing neurons within ENS would be dopaminergic. This means that enteric pathology of catecholamine neurons should be conceived as axon pathology for noradrenaline neurons and whole cell pathology for dopamine neurons which would be the sole catecholamine cell within intrinsic circuitries affecting gut motility and secretions.The gastrointestinal tract is provided with extrinsic and intrinsic innervation. The extrinsic innervation includes the classic vagal parasympathetic and sympathetic components, with afferent sensitive and efferent secretomotor fibers. The intrinsic innervations is represented by the enteric nervous system (ENS), which is recognized as a complex neural network  controlling a variety of cell populations, including smooth muscle cells, mucosal secretory cells, endocrine cells, microvasculature, immune and inflammatory cells. This is finalized to regulate gastrointestinal secretion, absorption and motility. In particular, this network is organized in several plexuses each one providing quite autonomous control of gastrointestinal functions (hence the definition of "second brain"). The similarity between ENS and CNS is further substantiated by the presence of local sensitive pseudounipolar ganglionic neurons with both peripheral and central branching which terminate in the enteric wall. A large variety of neurons and neurotransmitters takes part in the ENS. However, the nature of these neurons and their role in the regulation of gastrointestinal functions is debatable. In particular, the available literature reporting the specific nature of catecholamine-containing neurons provides conflicting evidence. This is critical both for understanding the specific role of each catecholamine in the gut and, mostly, to characterize specifically the enteric neuropathology occurring in a variety of diseases. An emphasis is posed on neurodegenerative disorders, such as including Parkinson's disease, which is associated with the loss of catecholamine neurons. In this respect, the recognition of the nature of such neurons within the ENS would contribute to elucidate the pathological mechanisms which produce both CNS and ENS degeneration and to achieve more effective therapeutic approaches. Despite a great emphasis is posed on the role of noradrenaline to regulate enteric activities only a few reports are available on the anatomy and physiology of enteric dopamine neurons. Remarkably, this review limits the presence of enteric noradrenaline (and adrenaline) only within extrinsic sympathetic nerve terminals. This is based on careful morphological studies showing that the only catecholamine-containing neurons within ENS would be dopaminergic. This means that enteric pathology of catecholamine neurons should be conceived as axon pathology for noradrenaline neurons and whole cell pathology for dopamine neurons which would be the sole catecholamine cell within intrinsic circuitries affecting gut motility and secretions.

Neurovestibular adaptation in the utricular otolith in fish to hypergravity exposure and re-adaptation to 1G

NASA Astrophysics Data System (ADS)

Boyle, R.; Popova, Ye.; Varelas, J.; Mofrad, A.

The inner ear utricular organ senses the sum of inertial force due to head translation and head tilt relative to the gravitational vertical. A change in gravitational force has a profound effect on how an organism maintains equilibrium, and the neural response might involve the peripheral otolith receptors, the brain or both. If the influence of G leads to adaptation and subsequent re-adaptation processes in otolith function upon return to 1G, then this raises fundamental questions: does the transfer from 1G to 3G impart the opposite effects on changes of synaptic structure and gravitational sensitivity seen following G exposure? Do the effects accompanying transfer from the 3G to the 1G conditions resemble in part (as an analog) the transfer from 1G to the G? The use of well-controlled hyper-G experiments allows us to address these questions. Adult fish were placed in groups and exposed to 3G for 1, 2, 3, 4, 5, 8, 16, 24, and 32 days. Re-adaptation to 1G was studied in 3G exposure (4-and 16-day) following 1-8 day of recovery. Typically ∼60 afferents are well characterized in each fish. Directional sensitivity of each afferent defined as the vector with the magnitude measured in unit gain (imp/s/g) is determined. It allows us to consider the diagram of directional sensitivity of the whole macula. For quantitative estimates of the change of afferent sensitivity in hyper-G experiments two functions have been introduced: probability function (maximum sensitivity of each afferent is plotted as a percentage of population sensitivity whose values is less than the individual sensitivity) and the frequency function (or probability density function-PDF) of the population of afferents on the gain. These functions enable us to extract additional information about the details of evolution of gain-afferent distribution. Results to date show a biphasic pattern in reaction to 3G exposures: an initial sensitivity up-regulation (3-and 4-day) followed by a significant decrease after 16-day exposure. Return to control values following 16-day exposure is on the order of 8 days. On-Center Controls (228/s rotation about Earth vertical) at 4-and 16-days do not show any difference compare to ground controls. Utricular sensitivity is strongly regulated by altered gravity exposure, and transition from hypergravity to normal gravity seem to resemble the transfer from 1G to microgravity, and might be used as a ground-based model to study the neural response to transitions in gravity. Preliminary analysis of the afferent distributions changes caused by adaptation to hyper-G and re-adaptation to 1G that uses PDF allows us to assume that hyper-G and G cause the redistribution of afferents with different gains: those with higher gains become more activated (sensitive) than those with lower gains. The case of down-regulation corresponds to decrease of the PDF dispersion. It should be noted that efferent vestibular actions are not uniform on hair cells and afferents, and it is proposed that the changes brought on in otolith afferents by the transitions from one gravity state to another will be most prevalent and coincident in afferents strongly affected by efferent activation. Support Contributed By: NASA 03-OBPR-04

Somatotopic organization of primary afferent perikarya of the guinea-pig extraocular muscles in the trigeminal ganglion: a post-mortem DiI-tracing study.

PubMed

Aigner, M; Robert Lukas, J; Denk, M; Ziya-Ghazvini, F; Kaider, A; Mayr, R

2000-04-01

Apart from the somatotopic organization of the trigeminal ganglion (TG) into the ophthalmic, maxillary and mandibular divisions along the mediolateral axis, there exist further somatotopic organizations within these three divisions. According to literature, the cell organization in the TG and the somatotopy in the brainstem develop together, formed by naturally occurring cell death in the TG. Thus, the somatotopy of the primary afferent trigeminal perikarya is of special interest. The aim of this study was to investigate the location of the primary afferent perikarya of the extraocular muscles (EOMs) in the TG of guinea-pig. The primary afferent perikarya were labeled by post-mortem application of the carbocyanine DiI on the oculomotor nerve branches near their entrance into the single EOMs. The DiI-positive perikarya were found musculo-somatically organized in the ipsilateral ophthalmic part of the TG at a wide range along the dorsoventral axis, expressing an overlap of the representation areas. The primary afferent perikarya of the superior rectus and the superior oblique muscles were mainly localized in the dorsal part of the ganglion while those of the inferior rectus and the inferior oblique muscle mainly in ventral part. The lateral and the medial rectus were predominantly represented in between. An organization along the mediolateral axis of the TG was not observed. Although guinea-pigs lack classical EOM proprioceptors, the somatotopic representation of the extraocular muscle primary afferent perikarya in the TG found in this study is in line with findings in species with well known encapsulated proprioceptors within the EOMs.

Ankle joint movements are encoded by both cutaneous and muscle afferents in humans.

PubMed

Aimonetti, Jean-Marc; Roll, Jean-Pierre; Hospod, Valérie; Ribot-Ciscar, Edith

2012-08-01

We analyzed the cutaneous encoding of two-dimensional movements by investigating the coding of movement velocity for differently oriented straight-line movements and the coding of complex trajectories describing cursive letters. The cutaneous feedback was then compared with that of the underlying muscle afferents previously recorded during the same "writing-like" movements. The unitary activity of 43 type II cutaneous afferents was recorded in the common peroneal nerve in healthy subjects during imposed ankle movements. These movements consisted first of ramp-and-hold movements imposed at two different and close velocities in seven directions and secondly of "writing-like" movements. In both cases, the responses were analyzed using the neuronal population vector model. The results show that movement velocity encoding depended on the direction of the ongoing movement. Discriminating between two velocities therefore involved processing the activity of afferent populations located in the various skin areas surrounding the moving joint, as shown by the statistically significant difference observed in the amplitude of the sum vectors. Secondly, "writing-like" movements induced cutaneous neuronal patterns of activity, which were reproducible and specific to each trajectory. Lastly, the "cutaneous neuronal trajectories," built by adding the sum vectors tip-to-tail, nearly matched both the movement trajectories and the "muscle neuronal trajectories," built from previously recorded muscle afferents. It was concluded that type II cutaneous and the underlying muscle afferents show similar encoding properties of two-dimensional movement parameters. This similarity is discussed in relation to a central gating process that would for instance increase the gain of cutaneous inputs when muscle information is altered by the fusimotor drive.

Bicuculline and strychnine suppress the mesencephalic locomotor region-induced inhibition of group III muscle afferent input to the dorsal horn.

PubMed

Degtyarenko, A M; Kaufman, M P

2003-01-01

We examined the effect of iontophoretic application of bicuculline methiodide and strychnine hydrochloride on the mesencephalic locomotor region (MLR)-induced inhibition of dorsal horn cells in paralyzed cats. The activity of 60 dorsal horn cells was recorded extracellularly in laminae I, II, V-VII of spinal segments L7-S1. Each of the cells was shown to receive group III muscle afferent input as demonstrated by their responses to electrical stimulation of the tibial nerve (mean latency and threshold of activation: 20.1+/-6.4 ms and 15.2+/-1.4 times motor threshold, respectively). Electrical stimulation of the MLR suppressed transmission in group III muscle afferent pathways to dorsal horn cells. Specifically the average number of impulses generated by the dorsal horn neurons in response to a single pulse applied to the tibial nerve was decreased by 78+/-2.8% (n=60) during the MLR stimulation. Iontophoretic application (10-50 nA) of bicuculline and strychnine (5-10 mM) suppressed the MLR-induced inhibition of transmission of group III afferent input to laminae I and II cells by 69+/-5% (n=10) and 29+/-7% (n=7), respectively. Likewise, bicuculline and strychnine suppressed the MLR-induced inhibition of transmission of group III afferent input to lamina V cells by 59+/-13% (n=14) and 39+/-11% (n=10), respectively. Our findings raise the possibility that GABA and glycine release onto dorsal horn neurons in the spinal cord may play an important role in the suppression by central motor command of thin fiber muscle afferent-reflex pathways.

Gut vagal afferents differentially modulate innate anxiety and learned fear.

PubMed

Klarer, Melanie; Arnold, Myrtha; Günther, Lydia; Winter, Christine; Langhans, Wolfgang; Meyer, Urs

2014-05-21

Vagal afferents are an important neuronal component of the gut-brain axis allowing bottom-up information flow from the viscera to the CNS. In addition to its role in ingestive behavior, vagal afferent signaling has been implicated modulating mood and affect, including distinct forms of anxiety and fear. Here, we used a rat model of subdiaphragmatic vagal deafferentation (SDA), the most complete and selective vagal deafferentation method existing to date, to study the consequences of complete disconnection of abdominal vagal afferents on innate anxiety, conditioned fear, and neurochemical parameters in the limbic system. We found that compared with Sham controls, SDA rats consistently displayed reduced innate anxiety-like behavior in three procedures commonly used in preclinical rodent models of anxiety, namely the elevated plus maze test, open field test, and food neophobia test. On the other hand, SDA rats exhibited increased expression of auditory-cued fear conditioning, which specifically emerged as attenuated extinction of conditioned fear during the tone re-exposure test. The behavioral manifestations in SDA rats were associated with region-dependent changes in noradrenaline and GABA levels in key areas of the limbic system, but not with functional alterations in the hypothalamus-pituitary-adrenal grand stress. Our study demonstrates that innate anxiety and learned fear are both subjected to visceral modulation through abdominal vagal afferents, possibly via changing limbic neurotransmitter systems. These data add further weight to theories emphasizing an important role of afferent visceral signals in the regulation of emotional behavior. Copyright © 2014 the authors 0270-6474/14/347067-10$15.00/0.

Activity-dependent sensitivity of proprioceptive sensory neurons in the stick insect femoral chordotonal organ.

PubMed

DiCaprio, Ralph A; Wolf, Harald; Büschges, Ansgar

2002-11-01

Mechanosensory neurons exhibit a wide range of dynamic changes in response, including rapid and slow adaptation. In addition to mechanical factors, electrical processes may also contribute to sensory adaptation. We have investigated adaptation of afferent neurons in the stick insect femoral chordotonal organ (fCO). The fCO contains sensory neurons that respond to position, velocity, and acceleration of the tibia. We describe the influence of random mechanical stimulation of the fCO on the response of fCO afferent neurons. The activity of individual sensory neurons was recorded intracellularly from their axons in the main leg nerve. Most fCO afferents (93%) exhibited a marked decrease in response to trapezoidal stimuli following sustained white noise stimulation (bandwidth = 60 Hz, amplitudes from +/-5 to +/-30 degrees ). Concurrent decreases in the synaptic drive to leg motoneurons and interneurons were also observed. Electrical stimulation of spike activity in individual fCO afferents in the absence of mechanical stimulation also led to a dramatic decrease in response in 15 of 19 afferents tested. This indicated that electrical processes are involved in the regulation of the generator potential or encoding of action potentials and partially responsible for the decreased response of the afferents. Replacing Ca(2+) with Ba(2+) in the saline surrounding the fCO greatly reduced or blocked the decrease in response elicited by electrically induced activity or mechanical stimulation when compared with control responses. Our results indicate that activity of fCO sensory neurons strongly affects their sensitivity, most likely via Ca(2+)-dependent processes.

The muscarinic inhibition of the potassium M-current modulates the action-potential discharge in the vestibular primary-afferent neurons of the rat.

PubMed

Pérez, C; Limón, A; Vega, R; Soto, E

2009-02-18

There is consensus that muscarinic and nicotinic receptors expressed in vestibular hair cells and afferent neurons are involved in the efferent modulation of the electrical activity of the afferent neurons. However the underlying mechanisms of postsynaptic control in neurons are not well understood. In our work we show that the activation of muscarinic receptors in the vestibular neurons modulates the potassium M-current modifying the activity of afferent neurons. Whole-cell patch-clamp recordings were made on vestibular-afferent neurons isolated from Wistar rats (postnatal days 7-10) and held in primary culture (18-24 h). The M-current was studied during its deactivation after depolarizing voltage-clamp pulses. In 68% of the cells studied, those of larger capacitance, the M-current antagonists linopirdine and XE-991 reduced the amplitude of the M-current by 54%+/-7% and 50%+/-3%. The muscarinic-receptor agonist oxotremorine-M also significantly reduced the M-current by 58%+/-12% in the cells. The action of oxotremorine-M was blocked by atropine, thus indicating its cholinergic nature. The erg-channel blocker E-4031 did not significantly modify the M-current amplitude. In current-clamp experiments, linopirdine, XE-991, and oxotremorine-M modified the discharge response to current pulses from single spike to multiple spiking, reducing the adaptation of the electrical discharge. Our results indicate that large soma-size cultured vestibular-afferent neurons (most probably calyx-bearing neurons) express the M-current and that the modulation of this current by activation of muscarinic-receptor reduces its spike-frequency adaptation.

Damage to cochlear efferents following AF64A intoxication.

PubMed

Smith, D W; Mount, R J

1993-07-01

Damage to cochlear efferents in chinchillas was assessed using transmission electron microscopy following unilateral treatment with the cholinotoxin ethylcholine mustard aziridinium ion (AF64A). AF64A was diluted in artificial perilymph to concentrations ranging from 0.5 to 100 microM. Survival times ranged from 1 to 12 weeks. At concentrations above 10 microM, widespread damage was noted to efferent fibers within the inner spiral bundle (ISB), tunnel spiral bundle (TSB), tunnel radial fibers (TRF) and efferent terminals at the base of OHCs. This damage included degeneration of fibers and terminals, delamination of mitochondria, vacuolization, and loss of cell membrane. However, at high concentrations, non-specific damage was also noted as thinnings or discontinuities of the membrane of OHCs and afferent fibers. At concentrations between 3 and 10 microM, selective damage was observed to efferent fibers within the ISB, TSB, TRF, and to terminals at the base of the OHCs, with all other structures appearing normal. At concentrations of 0.5 and 1 microM, damage was limited to efferent fibers within the TSB and ISB below the inner hair cells. In general, insult was greatest to middle- and basal-turn efferents, and longer survival times did not produce greater damage to, or loss of, efferents. These data suggest that at low concentrations, AF64A produces a partial yet selective degeneration of cochlear efferents within both the medial and lateral tracts, and that at the lowest concentrations used in these studies, AF64A produces a preferential insult on lateral olivocochlear efferents.

Early segregation of layered projections from the lateral superior olivary nucleusto the central nucleus of the inferior colliculus in the neonatal cat

PubMed Central

Gabriele, Mark L.; Shahmoradian, Sarah H.; French, Christopher C.; Henkel, Craig K.we; McHaffie, John G.

2007-01-01

The central nucleus of the inferior colliculus (IC) is a laminated structure that receives multiple converging afferent projections. These projections terminate in a layered arrangement and are aligned with dendritic arbors of the predominant disc-shaped neurons, forming fibrodendritic laminae. Within this structural framework, inputs terminate in a precise manner, establishing a mosaic of partially overlapping domains that likely define functional compartments. Although several of these patterned inputs have been described in the adult, relatively little is known about their organization prior to hearing onset. The present study used the lipophilic carbocyanine dyes DiI and DiD to examine the ipsilateral and contralateral projections from the lateral superior olivary (LSO) nucleus to the IC in a developmental series of paraformaldehyde-fixed kitten tissue. By birth, the crossed and uncrossed projections had reached the IC and were distributed across the frequency axis of the central nucleus. At this earliest postnatal stage, projections already exhibited a characteristic banded arrangement similar to that described in the adult. The heaviest terminal fields of the two inputs were always complementary in nature, with the ipsilateral input appearing slightly denser. This early arrangement of interdigitating ipsilateral and contralateral LSO axonal bands that occupy adjacent sublayers supports the idea that the initial establishment of this highly organized mosaic of inputs that defines distinct synaptic domains within the IC occurs largely in the absence of auditory experience. Potential developmental mechanisms that may shape these highly ordered inputs prior to hearing onset are discussed. PMID:17850770

Brain BLAQ: Post-hoc thick-section histochemistry for localizing optogenetic constructs in neurons and their distal terminals

PubMed Central

Kupferschmidt, David A.; Cody, Patrick A.; Lovinger, David M.; Davis, Margaret I.

2015-01-01

Optogenetic constructs have revolutionized modern neuroscience, but the ability to accurately and efficiently assess their expression in the brain and associate it with prior functional measures remains a challenge. High-resolution imaging of thick, fixed brain sections would make such post-hoc assessment and association possible; however, thick sections often display autofluorescence that limits their compatibility with fluorescence microscopy. We describe and evaluate a method we call “Brain BLAQ” (Block Lipids and Aldehyde Quench) to rapidly reduce autofluorescence in thick brain sections, enabling efficient axon-level imaging of neurons and their processes in conventional tissue preparations using standard epifluorescence microscopy. Following viral-mediated transduction of optogenetic constructs and fluorescent proteins in mouse cortical pyramidal and dopaminergic neurons, we used BLAQ to assess innervation patterns in the striatum, a region in which autofluorescence often obscures the imaging of fine neural processes. After BLAQ treatment of 250–350 μm-thick brain sections, axons and puncta of labeled afferents were visible throughout the striatum using a standard epifluorescence stereomicroscope. BLAQ histochemistry confirmed that motor cortex (M1) projections preferentially innervated the matrix component of lateral striatum, whereas medial prefrontal cortex projections terminated largely in dorsal striosomes and distinct nucleus accumbens subregions. Ventral tegmental area dopaminergic projections terminated in a similarly heterogeneous pattern within nucleus accumbens and ventral striatum. Using a minimal number of easily manipulated and visualized sections, and microscopes available in most neuroscience laboratories, BLAQ enables simple, high-resolution assessment of virally transduced optogenetic construct expression, and post-hoc association of this expression with molecular markers, physiology and behavior. PMID:25698938

Inhibitory Interneurons That Express GFP in the PrP-GFP Mouse Spinal Cord Are Morphologically Heterogeneous, Innervated by Several Classes of Primary Afferent and Include Lamina I Projection Neurons among Their Postsynaptic Targets

PubMed Central

Ganley, Robert P.; Iwagaki, Noboru; del Rio, Patricia; Baseer, Najma; Dickie, Allen C.; Boyle, Kieran A.; Polgár, Erika; Watanabe, Masahiko; Abraira, Victoria E; Zimmerman, Amanda

2015-01-01

The superficial dorsal horn of the spinal cord contains numerous inhibitory interneurons, which regulate the transmission of information perceived as touch, pain, or itch. Despite the importance of these cells, our understanding of their roles in the neuronal circuitry is limited by the difficulty in identifying functional populations. One group that has been identified and characterized consists of cells in the mouse that express green fluorescent protein (GFP) under control of the prion protein (PrP) promoter. Previous reports suggested that PrP-GFP cells belonged to a single morphological class (central cells), received inputs exclusively from unmyelinated primary afferents, and had axons that remained in lamina II. However, we recently reported that the PrP-GFP cells expressed neuronal nitric oxide synthase (nNOS) and/or galanin, and it has been shown that nNOS-expressing cells are more diverse in their morphology and synaptic connections. We therefore used a combined electrophysiological, pharmacological, and anatomical approach to reexamine the PrP-GFP cells. We provide evidence that they are morphologically diverse (corresponding to “unclassified” cells) and receive synaptic input from a variety of primary afferents, with convergence onto individual cells. We also show that their axons project into adjacent laminae and that they target putative projection neurons in lamina I. This indicates that the neuronal circuitry involving PrP-GFP cells is more complex than previously recognized, and suggests that they are likely to have several distinct roles in regulating the flow of somatosensory information through the dorsal horn. PMID:25972186

An inhibitory interaction of human cortical responses to stimuli preferentially exciting Aδ or C fibers

PubMed Central

Tran, Tuan D.; Matre, Dagfinn; Casey, Kenneth L.

2008-01-01

Finely myelinated (type Aδ) and unmyelinated (type C) fibers are the major afferent inputs to spinothalamic tract neurons mediating sensory and reflex responses to noxious and thermal stimuli. These two fiber types differ in their sensory and biophysical properties, raising questions about the interaction of their supraspinal responses. Therefore, we investigated the interaction of cortical responses to stimuli that preferentially excite these fibers in human subjects using evoked potential recordings in a paired conditioning stimulation (CS) and test stimulation (TS) paradigm. There were two experiments, one with Aδ as CS and C as TS (Aδ-C) and another with these stimuli reversed (C-Aδ). We used intra-epidermal electrical pulses applied to the dorsal left hand at 2 and 1 × pinprick threshold (pp) for the preferential stimulation of Aδ fibers and 37 – 50°C contact heat pulses applied to the left or right thenar and left hypothenar eminences for the preferential stimulation of C fibers. We found that the cortical response to preferential Aδ or C fiber stimulation was attenuated whenever either cortical response preceded the other. Standardized values of peak and integrated amplitudes were < 1 in all paring conditions and in all subjects in both experiments. The suppressive effect varied in magnitude with the intensity of the conditioning stimulus in both Aδ-C and C-Aδ experiments. Furthermore, intra-segmental interaction was differentially effective for Aδ conditioning, (peak amplitude, p < 0.008; ANOVA). Our experiments provide the first neurophysiological evidence for a somatotopically distributed, mutually suppressive interaction between cortical responses to preferentially activated Aδ and C afferents in humans. This suppressive interaction of cortical responses suggests contrasting and possibly mutually exclusive sensori-motor functions mediated through the Aδ and C fiber afferent channels. PMID:18308475

Influence of oculomotor nerve afferents on central endings of primary trigeminal fibers.

PubMed

Manni, E; Bortolami, R; Pettorossi, V E; Lucchi, M L; Callegari, E; Draicchio, F

1987-12-01

Painful fibers running in the third nerve and originating from the ophthalmic trigeminal area send their central projections at level of substantia gelatinosa of nucleus caudalis trigemini. The central endings of these fibers form axoaxonic synapses with trigeminal fibers entering the brain stem through the trigeminal root. The effect of electrical stimulation of the third nerve central stump on the central endings of trigeminal afferent fibers consists in an increased excitability, possibly resulting in a presynaptic inhibition. This inhibitory influence is due to both direct and indirect connections of the third nerve afferent fibers with the trigeminal ones.

[Two cases of afferent loop syndrome caused by obstruction at the jejuno-jejunostomy site in the Roux-en-Y loop that were successfully treated by endoscopic balloon dilatation].

PubMed

Yasuda, Atsushi; Imamoto, Haruhiko; Furukawa, Hiroshi; Imano, Motohiro; Yasuda, Takushi; Okuno, Kiyokata

2014-11-01

We report 2 rare cases of afferent loop syndrome caused by obstruction at the jejuno-jejunostomy site in the Roux-en-Y loop after total gastrectomy, which was successfully treated by endoscopic balloon dilatation of the anastomotic stenosis. Case 1: A 62-year-old woman presented with malaise and lower abdominal distension 6 months after laparoscopy-assisted total gastrectomy with Roux-en-Y reconstruction. She was diagnosed with afferent loop syndrome; CT imaging indicated marked dilatation of the afferent loop, with membranous obstruction at the jejuno-jejunostomy site in the Roux-en-Y loop. Although almost complete occlusion was noted at the jejuno-jejunostomy site, the obstruction was successfully relieved by endoscopic balloon dilation using TandemTM XL Triple Lumen ERCP Cannula (Boston Scientific)®. Case 2: A 70-year-old man presented with malaise and lower abdominal distension 3 years after laparoscopy-assisted total gastrectomy with Roux-en-Y reconstruction. He was diagnosed with afferent loop syndrome; CT imaging indicated complete obstruction at the jejuno-jejunostomy site in the Roux-en-Y loop. As in case 1, the obstruction was successfully treated by endoscopic balloon dilatation of the occluded anastomosis.

Glycinergic Input to the Mouse Basal Forebrain Cholinergic Neurons

PubMed Central

Bardóczi, Zsuzsanna; Pál, Balázs; Kőszeghy, Áron; Wilheim, Tamás; Záborszky, László; Liposits, Zsolt

2017-01-01

The basal forebrain (BF) receives afferents from brainstem ascending pathways, which has been implicated first by Moruzzi and Magoun (1949) to induce forebrain activation and cortical arousal/waking behavior; however, it is very little known about how brainstem inhibitory inputs affect cholinergic functions. In the current study, glycine, a major inhibitory neurotransmitter of brainstem neurons, and gliotransmitter of local glial cells, was tested for potential interaction with BF cholinergic (BFC) neurons in male mice. In the BF, glycine receptor α subunit-immunoreactive (IR) sites were localized in choline acetyltransferase (ChAT)-IR neurons. The effect of glycine on BFC neurons was demonstrated by bicuculline-resistant, strychnine-sensitive spontaneous IPSCs (sIPSCs; 0.81 ± 0.25 × 10−1 Hz) recorded in whole-cell conditions. Potential neuronal as well as glial sources of glycine were indicated in the extracellular space of cholinergic neurons by glycine transporter type 1 (GLYT1)- and GLYT2-IR processes found in apposition to ChAT-IR cells. Ultrastructural analyses identified synapses of GLYT2-positive axon terminals on ChAT-IR neurons, as well as GLYT1-positive astroglial processes, which were localized in the vicinity of synapses of ChAT-IR neurons. The brainstem raphe magnus was determined to be a major source of glycinergic axons traced retrogradely from the BF. Our results indicate a direct effect of glycine on BFC neurons. Furthermore, the presence of high levels of plasma membrane glycine transporters in the vicinity of cholinergic neurons suggests a tight control of extracellular glycine in the BF. SIGNIFICANCE STATEMENT Basal forebrain cholinergic (BFC) neurons receive various activating inputs from specific brainstem areas and channel this information to the cortex via multiple projections. So far, very little is known about inhibitory brainstem afferents to the BF. The current study established glycine as a major regulator of BFC neurons by (1) identifying glycinergic neurons in the brainstem projecting to the BF, (2) showing glycine receptor α subunit-immunoreactive (IR) sites in choline acetyltransferase (ChAT)-IR neurons, (3) demonstrating glycine transporter type 2 (GLYT2)-positive axon terminals synapsing on ChAT-IR neurons, and (4) localizing GLYT1-positive astroglial processes in the vicinity of synapses of ChAT-IR neurons. The effect of glycine on BFC neurons was demonstrated by bicuculline-resistant, strychnine-sensitive spontaneous IPSCs recorded in whole-cell conditions. PMID:28874448

Calcitonin Gene-Related Peptide Reduces Taste-Evoked ATP Secretion from Mouse Taste Buds.

PubMed

Huang, Anthony Y; Wu, Sandy Y

2015-09-16

Immunoelectron microscopy revealed that peripheral afferent nerve fibers innervating taste buds contain calcitonin gene-related peptide (CGRP), which may be as an efferent transmitter released from peripheral axon terminals. In this report, we determined the targets of CGRP within taste buds and studied what effect CGRP exerts on taste bud function. We isolated mouse taste buds and taste cells, conducted functional imaging using Fura-2, and used cellular biosensors to monitor taste-evoked transmitter release. The findings showed that a subset of Presynaptic (Type III) taste cells (53%) responded to 0.1 μm CGRP with an increase in intracellular Ca(2+). In contrast, Receptor (Type II) taste cells rarely (4%) responded to 0.1 μm CGRP. Using pharmacological tools, the actions of CGRP were probed and elucidated by the CGRP receptor antagonist CGRP(8-37). We demonstrated that this effect of CGRP was dependent on phospholipase C activation and was prevented by the inhibitor U73122. Moreover, applying CGRP caused taste buds to secrete serotonin (5-HT), a Presynaptic (Type III) cell transmitter, but not ATP, a Receptor (Type II) cell transmitter. Further, our previous studies showed that 5-HT released from Presynaptic (Type III) cells provides negative paracrine feedback onto Receptor (Type II) cells by activating 5-HT1A receptors, and reducing ATP secretion. Our data showed that CGRP-evoked 5-HT release reduced taste-evoked ATP secretion. The findings are consistent with a role for CGRP as an inhibitory transmitter that shapes peripheral taste signals via serotonergic signaling during processing gustatory information in taste buds. The taste sensation is initiated with a highly complex set of interactions between a variety of cells located within the taste buds before signal propagation to the brain. Afferent signals from the oral cavity are carried to the brain in chemosensory fibers that contribute to chemesthesis, the general chemical sensitivity of the mucus membranes in the oronasal cavities and being perceived as pungency, irritation, or heat. This is a study of a fundamental question in neurobiology: how are signals processed in sensory end organs, taste buds? More specifically, taste-modifying interactions, via transmitters, between gustatory and chemosensory afferents inside taste buds will help explain how a coherent output is formed before being transmitted to the brain. Copyright © 2015 the authors 0270-6474/15/3512714-11$15.00/0.

A-type potassium channels differentially tune afferent pathways from rat solitary tract nucleus to caudal ventrolateral medulla or paraventricular hypothalamus

PubMed Central

Bailey, T W; Hermes, S M; Whittier, K L; Aicher, S A; Andresen, M C

2007-01-01

The solitary tract nucleus (NTS) conveys visceral information to diverse central networks involved in homeostatic regulation. Although afferent information content arriving at various CNS sites varies substantially, little is known about the contribution of processing within the NTS to these differences. Using retrograde dyes to identify specific NTS projection neurons, we recently reported that solitary tract (ST) afferents directly contact NTS neurons projecting to caudal ventrolateral medulla (CVLM) but largely only indirectly contact neurons projecting to the hypothalamic paraventricular nucleus (PVN). Since intrinsic properties impact information transmission, here we evaluated potassium channel expression and somatodendritic morphology of projection neurons and their relation to afferent information output directed to PVN or CVLM pathways. In slices, tracer-identified projection neurons were classified as directly or indirectly (polysynaptically) coupled to ST afferents by EPSC latency characteristics (directly coupled, jitter < 200 μs). In each neuron, voltage-dependent potassium currents (IK) were evaluated and, in representative neurons, biocytin-filled structures were quantified. Both CVLM- and PVN-projecting neurons had similar, tetraethylammonium-sensitive IK. However, only PVN-projecting NTS neurons displayed large transient, 4aminopyridine-sensitive, A-type currents (IKA). PVN-projecting neurons had larger cell bodies with more elaborate dendritic morphology than CVLM-projecting neurons. ST shocks faithfully (> 75%) triggered action potentials in CVLM-projecting neurons but spike output was uniformly low (< 20%) in PVN-projecting neurons. Pre-conditioning hyperpolarization removed IKA inactivation and attenuated ST-evoked spike generation along PVN but not CVLM pathways. Thus, multiple differences in structure, organization, synaptic transmission and ion channel expression tune the overall fidelity of afferent signals that reach these destinations. PMID:17510187

Permanent central synaptic disconnection of proprioceptors after nerve injury and regeneration. I. Loss of VGLUT1/IA synapses on motoneurons

PubMed Central

Titus-Mitchell, Haley E.; Bullinger, Katie L.; Kraszpulski, Michal; Nardelli, Paul; Cope, Timothy C.

2011-01-01

Motor and sensory proprioceptive axons reinnervate muscles after peripheral nerve transections followed by microsurgical reattachment; nevertheless, motor coordination remains abnormal and stretch reflexes absent. We analyzed the possibility that permanent losses of central IA afferent synapses, as a consequence of peripheral nerve injury, are responsible for this deficit. VGLUT1 was used as a marker of proprioceptive synapses on rat motoneurons. After nerve injuries synapses are stripped from motoneurons, but while other excitatory and inhibitory inputs eventually recover, VGLUT1 synapses are permanently lost on the cell body (75–95% synaptic losses) and on the proximal 100 μm of dendrite (50% loss). Lost VGLUT1 synapses did not recover, even many months after muscle reinnervation. Interestingly, VGLUT1 density in more distal dendrites did not change. To investigate whether losses are due to VGLUT1 downregulation in injured IA afferents or to complete synaptic disassembly and regression of IA ventral projections, we studied the central trajectories and synaptic varicosities of axon collaterals from control and regenerated afferents with IA-like responses to stretch that were intracellularly filled with neurobiotin. VGLUT1 was present in all synaptic varicosities, identified with the synaptic marker SV2, of control and regenerated afferents. However, regenerated afferents lacked axon collaterals and synapses in lamina IX. In conjunction with the companion electrophysiological study [Bullinger KL, Nardelli P, Pinter MJ, Alvarez FJ, Cope TC. J Neurophysiol (August 10, 2011). doi:10.1152/jn.01097.2010], we conclude that peripheral nerve injuries cause a permanent retraction of IA afferent synaptic varicosities from lamina IX and disconnection with motoneurons that is not recovered after peripheral regeneration and reinnervation of muscle by sensory and motor axons. PMID:21832035

Fatigue-related firing of muscle nociceptors reduces voluntary activation of ipsilateral but not contralateral lower limb muscles.

PubMed

Kennedy, David S; Fitzpatrick, Siobhan C; Gandevia, Simon C; Taylor, Janet L

2015-02-15

During fatiguing upper limb exercise, maintained firing of group III/IV muscle afferents can limit voluntary drive to muscles within the same limb. It is not known if this effect occurs in the lower limb. We investigated the effects of group III/IV muscle afferent firing from fatigued ipsilateral and contralateral extensor muscles and ipsilateral flexor muscles of the knee on voluntary activation of the knee extensors. In three experiments, we examined voluntary activation of the knee extensors by measuring changes in superimposed twitches evoked by femoral nerve stimulation. Subjects attended on 2 days for each experiment. On one day a sphygmomanometer cuff occluded blood flow of the fatigued muscles to maintain firing of group III/IV muscle afferents. After a 2-min extensor contraction (experiment 1; n = 9), mean voluntary activation was lower with than without maintained ischemia (47 ± 19% vs. 87 ± 8%, respectively; P < 0.001). After a 2-min knee flexor maximal voluntary contraction (MVC) (experiment 2; n = 8), mean voluntary activation was also lower with than without ischemia (59 ± 21% vs. 79 ± 9%; P < 0.01). After the contralateral (left) MVC (experiment 3; n = 8), mean voluntary activation of the right leg was similar with or without ischemia (92 ± 6% vs. 93 ± 4%; P = 0.65). After fatiguing exercise, activity in group III/IV muscle afferents reduces voluntary activation of the fatigued muscle and nonfatigued antagonist muscles in the same leg. However, group III/IV muscle afferents from the fatigued left leg had no effect on the unfatigued right leg. This suggests that any "crossover" of central fatigue in the lower limbs is not mediated by group III/IV muscle afferents. Copyright © 2015 the American Physiological Society.

The role of capsaicin-sensitive muscle afferents in fatigue-induced modulation of the monosynaptic reflex in the rat.

PubMed

Pettorossi, V E; Della Torre, G; Bortolami, R; Brunetti, O

1999-03-01

1. The role of group III and IV afferent fibres of the lateral gastrocnemious muscle (LG) in modulating the homonymous monosynaptic reflex was investigated during muscle fatigue in spinalized rats. 2. Muscle fatigue was induced by a series of increasing tetanic electrical stimuli (85 Hz, 600 ms) delivered to the LG muscle nerve. Series consisted of increasing train numbers from 1 to 60. 3. Potentials from the spinal cord LG motor pool and from the ventral root were recorded in response to proprioceptive afferent stimulation and analysed before and during tetanic muscle activations. Both the pre- and postsynaptic waves showed an initial enhancement and, after a '12-train' series, an increasing inhibition. 4. The enhancement of the responses to muscle fatiguing stimulation disappeared after L3-L6 dorsal root section, while a partial reflex inhibition was still present. Conversely, after section of the corresponding ventral root, there was only a reduction in the inhibitory effect. 5. The monosynaptic reflex was also studied in animals in which a large number of group III and IV muscle afferents were eliminated by injecting capsaicin (10 mM) into the LG muscle. As a result of capsaicin treatment, the fatigue-induced inhibition of the pre- and postsynaptic waves disappeared, while the response enhancement remained. 6. We concluded that the monosynaptic reflex inhibition, but not the enhancement, was mediated by those group III and IV muscle afferents that are sensitive to the toxic action of capsaicin. The afferents that are responsible for the response enhancement enter the spinal cord through the dorsal root, while those responsible for the inhibition enter the spinal cord through both the ventral and dorsal roots.

The role of capsaicin-sensitive muscle afferents in fatigue-induced modulation of the monosynaptic reflex in the rat

PubMed Central

Pettorossi, V E; Torre, G Della; Bortolami, R; Brunetti, O

1999-01-01

The role of group III and IV afferent fibres of the lateral gastrocnemious muscle (LG) in modulating the homonymous monosynaptic reflex was investigated during muscle fatigue in spinalized rats. Muscle fatigue was induced by a series of increasing tetanic electrical stimuli (85 Hz, 600 ms) delivered to the LG muscle nerve. Series consisted of increasing train numbers from 1 to 60. Potentials from the spinal cord LG motor pool and from the ventral root were recorded in response to proprioceptive afferent stimulation and analysed before and during tetanic muscle activations. Both the pre- and postsynaptic waves showed an initial enhancement and, after a ‘12-train’ series, an increasing inhibition. The enhancement of the responses to muscle fatiguing stimulation disappeared after L3-L6 dorsal root section, while a partial reflex inhibition was still present. Conversely, after section of the corresponding ventral root, there was only a reduction in the inhibitory effect. The monosynaptic reflex was also studied in animals in which a large number of group III and IV muscle afferents were eliminated by injecting capsaicin (10 mM) into the LG muscle. As a result of capsaicin treatment, the fatigue-induced inhibition of the pre- and postsynaptic waves disappeared, while the response enhancement remained. We concluded that the monosynaptic reflex inhibition, but not the enhancement, was mediated by those group III and IV muscle afferents that are sensitive to the toxic action of capsaicin. The afferents that are responsible for the response enhancement enter the spinal cord through the dorsal root, while those responsible for the inhibition enter the spinal cord through both the ventral and dorsal roots. PMID:10050025

Spinal afferent neurons projecting to the rat lung and pleura express acid sensitive channels

PubMed Central

Groth, Michael; Helbig, Tanja; Grau, Veronika; Kummer, Wolfgang; Haberberger, Rainer V

2006-01-01

Background The acid sensitive ion channels TRPV1 (transient receptor potential vanilloid receptor-1) and ASIC3 (acid sensing ion channel-3) respond to tissue acidification in the range that occurs during painful conditions such as inflammation and ischemia. Here, we investigated to which extent they are expressed by rat dorsal root ganglion neurons projecting to lung and pleura, respectively. Methods The tracer DiI was either injected into the left lung or applied to the costal pleura. Retrogradely labelled dorsal root ganglion neurons were subjected to triple-labelling immunohistochemistry using antisera against TRPV1, ASIC3 and neurofilament 68 (marker for myelinated neurons), and their soma diameter was measured. Results Whereas 22% of pulmonary spinal afferents contained neither channel-immunoreactivity, at least one is expressed by 97% of pleural afferents. TRPV1+/ASIC3- neurons with probably slow conduction velocity (small soma, neurofilament 68-negative) were significantly more frequent among pleural (35%) than pulmonary afferents (20%). TRPV1+/ASIC3+ neurons amounted to 14 and 10% respectively. TRPV1-/ASIC3+ neurons made up between 44% (lung) and 48% (pleura) of neurons, and half of them presumably conducted in the A-fibre range (larger soma, neurofilament 68-positive). Conclusion Rat pleural and pulmonary spinal afferents express at least two different acid-sensitive channels that make them suitable to monitor tissue acidification. Patterns of co-expression and structural markers define neuronal subgroups that can be inferred to subserve different functions and may initiate specific reflex responses. The higher prevalence of TRPV1+/ASIC3- neurons among pleural afferents probably reflects the high sensitivity of the parietal pleura to painful stimuli. PMID:16813657

Decoding tactile afferent activity to obtain an estimate of instantaneous force and torque applied to the fingerpad

PubMed Central

Birznieks, Ingvars; Redmond, Stephen J.

2015-01-01

Dexterous manipulation is not possible without sensory information about object properties and manipulative forces. Fundamental neuroscience has been unable to demonstrate how information about multiple stimulus parameters may be continuously extracted, concurrently, from a population of tactile afferents. This is the first study to demonstrate this, using spike trains recorded from tactile afferents innervating the monkey fingerpad. A multiple-regression model, requiring no a priori knowledge of stimulus-onset times or stimulus combination, was developed to obtain continuous estimates of instantaneous force and torque. The stimuli consisted of a normal-force ramp (to a plateau of 1.8, 2.2, or 2.5 N), on top of which −3.5, −2.0, 0, +2.0, or +3.5 mNm torque was applied about the normal to the skin surface. The model inputs were sliding windows of binned spike counts recorded from each afferent. Models were trained and tested by 15-fold cross-validation to estimate instantaneous normal force and torque over the entire stimulation period. With the use of the spike trains from 58 slow-adapting type I and 25 fast-adapting type I afferents, the instantaneous normal force and torque could be estimated with small error. This study demonstrated that instantaneous force and torque parameters could be reliably extracted from a small number of tactile afferent responses in a real-time fashion with stimulus combinations that the model had not been exposed to during training. Analysis of the model weights may reveal how interactions between stimulus parameters could be disentangled for complex population responses and could be used to test neurophysiologically relevant hypotheses about encoding mechanisms. PMID:25948866

Neuromuscular deficits after peripheral joint injury: a neurophysiological hypothesis.

PubMed

Ward, Sarah; Pearce, Alan J; Pietrosimone, Brian; Bennell, Kim; Clark, Ross; Bryant, Adam L

2015-03-01

In addition to biomechanical disturbances, peripheral joint injuries (PJIs) can also result in chronic neuromuscular alterations due in part to loss of mechanoreceptor-mediated afferent feedback. An emerging perspective is that PJI should be viewed as a neurophysiological dysfunction, not simply a local injury. Neurophysiological and neuroimaging studies have provided some evidence for central nervous system (CNS) reorganization at both the cortical and spinal levels after PJI. The novel hypothesis proposed is that CNS reorganization is the underlying mechanism for persisting neuromuscular deficits after injury, particularly muscle weakness. There is a lack of direct evidence to support this hypothesis, but future studies utilizing force-matching tasks with superimposed transcranial magnetic stimulation may be help clarify this notion. © 2014 Wiley Periodicals, Inc.

Measurement of the relative afferent pupillary defect in retinal detachment.

PubMed

Bovino, J A; Burton, T C

1980-07-01

A swinging flashlight test and calibrated neutral density filters were used to quantitate the depth of relative afferent pupillary defects in ten patients with retinal detachment. Postoperatively, the pupillary responses returned to normal in seven of nine patients with anatomically successful surgery.

Spatial Object Recognition Enables Endogenous LTD that Curtails LTP in the Mouse Hippocampus

PubMed Central

Goh, Jinzhong Jeremy

2013-01-01

Although synaptic plasticity is believed to comprise the cellular substrate for learning and memory, limited direct evidence exists that hippocampus-dependent learning actually triggers synaptic plasticity. It is likely, however, that long-term potentiation (LTP) works in concert with its counterpart, long-term depression (LTD) in the creation of spatial memory. It has been reported in rats that weak synaptic plasticity is facilitated into persistent plasticity if afferent stimulation is coupled with a novel spatial learning event. It is not known if this phenomenon also occurs in other species. We recorded from the hippocampal CA1 of freely behaving mice and observed that novel spatial learning triggers endogenous LTD. Specifically, we observed that LTD is enabled when test-pulse afferent stimulation is given during the learning of object constellations or during a spatial object recognition task. Intriguingly, LTP is significantly impaired by the same tasks, suggesting that LTD is the main cellular substrate for this type of learning. These data indicate that learning-facilitated plasticity is not exclusive to rats and that spatial learning leads to endogenous LTD in the hippocampus, suggesting an important role for this type of synaptic plasticity in the creation of hippocampus-dependent memory. PMID:22510536

Trying to Move Your Unseen Static Arm Modulates Visually-Evoked Kinesthetic Illusion

PubMed Central

Metral, Morgane; Blettery, Baptiste; Bresciani, Jean-Pierre; Luyat, Marion; Guerraz, Michel

2013-01-01

Although kinesthesia is known to largely depend on afferent inflow, recent data suggest that central signals originating from volitional control (efferent outflow) could also be involved and interact with the former to build up a coherent percept. Evidence derives from both clinical and experimental observations where vision, which is of primary importance in kinesthesia, was systematically precluded. The purpose of the present experiment was to assess the role of volitional effort in kinesthesia when visual information is available. Participants (n=20) produced isometric contraction (10-20% of maximal voluntary force) of their right arm while their left arm, which image was reflected in a mirror, either was passively moved into flexion/extension by a motorized manipulandum, or remained static. The contraction of the right arm was either congruent with or opposite to the passive displacements of the left arm. Results revealed that in most trials, kinesthetic illusions were visually driven, and their occurrence and intensity were modulated by whether volitional effort was congruent or not with visual signals. These results confirm the impact of volitional effort in kinesthesia and demonstrate for the first time that these signals interact with visual afferents to offer a coherent and unified percept. PMID:24348909

Serotonin modulates substance P-induced plasma extravasation and vasodilatation in rat skin by an action through capsaicin-sensitive primary afferent nerves.

PubMed

Khalil, Z; Helme, R D

1990-09-17

Using a blister model of inflammation in the rat hind footpad, the present study was undertaken to examine the ability of serotonin (5-HT) to modulate an inflammatory reaction manifested as plasma extravasation and vasodilatation induced by the neuropeptide substance P (SP). In addition, the role of primary afferent sensory nerve fibres in these modulatory effects was studied in capsaicin pretreated rats. Using a protocol of simultaneous perfusion of amine and peptide over the blister base, no major modulatory effect was observed. On the other hand, using a protocol of sequential perfusion, 5-HT was found to extend the plasma extravasation and vasodilatation responses to SP. 5-HT maintained the plasma extravasation response to SP after cessation of stimulation (during the post-stimulation period). On the other hand, it extended the vasodilatation response to SP during the actual stimulation period by preventing the occurrence of tachyphylaxis. These modulatory effects were absent in capsacin-pretreated rats. The present study provides evidence for the first time in vivo to suggest that serotonin can modulate an inflammatory response to SP via a mechanism that involves capsaicin-sensitive sensory fibres.

Long-term potentiation in the rat medial vestibular nuclei depends on locally synthesized 17beta-estradiol.

PubMed

Grassi, Silvarosa; Frondaroli, Adele; Dieni, Cristina; Scarduzio, Mariangela; Pettorossi, Vito E

2009-08-26

In male rat brainstem slices, we investigated the involvement of locally synthesized 17beta-estradiol (E(2)) in the induction in the medial vestibular nucleus (MVN) of long-term potentiation (LTP) by high-frequency stimulation (HFS) of the primary vestibular afferents. We demonstrated that the blockade of aromatase by letrozole or of E(2) receptors (ERalpha and ERbeta) by ICI 182,780 prevented the HFS-induced LTP of the N1 wave of the evoked field potential (FP) without affecting baseline responses. Only prolonged afferent activation could induce low LTP. In contrast, HFS applied under a combined blockade of GABA(A) receptors and aromatase or ERs was still able to induce LTP, but it was significantly lower and slower. These findings demonstrate that E(2) does not have a tonic influence on the activity of the MVN neurons and provide the first evidence of the crucial role played by local synthesis of E(2) in inducing LTP. We suggest that the synthesis of E(2) occurs after aromatase activation during HFS and facilitates the development of vestibular synaptic plasticity by influencing glutamate and GABA transmission.

Somatosensory pleasure circuit: from skin to brain and back.

PubMed

Lloyd, Donna M; McGlone, Francis P; Yosipovitch, Gil

2015-05-01

The skin senses serve a discriminative function, allowing us to manipulate objects and detect touch and temperature, and an affective/emotional function, manifested as itch or pain when the skin is damaged. Two different classes of nerve fibre mediate these dissociable aspects of cutaneous somatosensation: (i) myelinated A-beta and A-delta afferents that provide rapid information about the location and physical characteristics of skin contact; and (ii) unmyelinated, slow-conducting C-fibre afferents that are typically associated with coding the emotional properties of pain and itch. However, recent research has identified a third class of C-fibre afferents that code for the pleasurable properties of touch - c-tactile afferents or CTs. Clinical application of treatments that target pleasant, CT-mediated touch (such as massage therapy) could, in the future, provide a complementary, non-pharmacological means of treating both the physical and psychological aspects of chronic skin conditions such as itch and eczema. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Merkel cells transduce and encode tactile stimuli to drive Aβ-afferent impulses

PubMed Central

Ikeda, Ryo; Cha, Myeounghoon; Ling, Jennifer; Jia, Zhanfeng; Coyle, Dennis; Gu, Jianguo G.

2014-01-01

SUMMARY Sensory systems for detecting tactile stimuli have evolved from touch-sensing nerves in invertebrates to complicated tactile end-organs in mammals. Merkel discs are tactile end-organs consisting of Merkel cells and Aβ-afferent nerve endings, and are localized in fingertips, whisker hair follicles and other touch-sensitive spots. Merkel discs transduce touch into slowly adapting impulses to enable tactile discrimination, but their transduction and encoding mechanisms remain unknown. Using rat whisker hair follicles, we show that Merkel cells rather than Aβ-afferent nerve endings are primary sites of tactile transduction, and identify the Piezo2 ion channel as the Merkel cell mechanical transducer. Piezo2 transduces tactile stimuli into Ca2+-action potentials in Merkel cells, which drive Aβ-afferent nerve endings to fire slowly adapting impulses. We further demonstrate that Piezo2 and Ca2+-action potentials in Merkel cells are required for behavioral tactile responses. Our findings provide insights into how tactile end-organs function and have clinical implications for tactile dysfunctions. PMID:24746027

pH modulation of glial glutamate transporters regulates synaptic transmission in the nucleus of the solitary tract

PubMed Central

McCrimmon, Donald R.; Martina, Marco

2013-01-01

The nucleus of the solitary tract (NTS) is the major site for termination of visceral sensory afferents contributing to homeostatic regulation of, for example, arterial pressure, gastric motility, and breathing. Whereas much is known about how different neuronal populations influence these functions, information about the role of glia remains scant. In this article, we propose that glia may contribute to NTS functions by modulating excitatory neurotransmission. We found that acidification (pH 7.0) depolarizes NTS glia by inhibiting K+-selective membrane currents. NTS glia also showed functional expression of voltage-sensitive glutamate transporters, suggesting that extracellular acidification regulates synaptic transmission by compromising glial glutamate uptake. To test this hypothesis, we evoked glutamatergic slow excitatory potentials (SEPs) in NTS neurons with repetitive stimulation (20 pulses at 10 Hz) of the solitary tract. This SEP depends on accumulation of glutamate following repetitive stimulation, since it was potentiated by blocking glutamate uptake with dl-threo-β-benzyloxyaspartic acid (TBOA) or a glia-specific glutamate transport blocker, dihydrokainate (DHK). Importantly, extracellular acidification (pH 7.0) also potentiated the SEP. This effect appeared to be mediated through a depolarization-induced inhibition of glial transporter activity, because it was occluded by TBOA and DHK. In agreement, pH 7.0 did not directly alter d-aspartate-induced responses in NTS glia or properties of presynaptic glutamate release. Thus acidification-dependent regulation of glial function affects synaptic transmission within the NTS. These results suggest that glia play a modulatory role in the NTS by integrating local tissue signals (such as pH) with synaptic inputs from peripheral afferents. PMID:23615553

More a finger than a nose: the trigeminal motor and sensory innervation of the Schnauzenorgan in the elephant-nose fish Gnathonemus petersii.

PubMed

Amey-Özel, Monique; von der Emde, Gerhard; Engelmann, Jacob; Grant, Kirsty

2015-04-01

The weakly electric fish Gnathonemus petersii uses its electric sense to actively probe the environment. Its highly mobile chin appendage, the Schnauzenorgan, is rich in electroreceptors. Physical measurements have demonstrated the importance of the position of the Schnauzenorgan in funneling the fish's self-generated electric field. The present study focuses on the trigeminal motor pathway that controls Schnauzenorgan movement and on its trigeminal sensory innervation and central representation. The nerves entering the Schnauzenorgan are very large and contain both motor and sensory trigeminal components as well as an electrosensory pathway. With the use of neurotracer techniques, labeled Schnauzenorgan motoneurons were found throughout the ventral main body of the trigeminal motor nucleus but not among the population of larger motoneurons in its rostrodorsal region. The Schnauzenorgan receives no motor or sensory innervation from the facial nerve. There are many anastomoses between the peripheral electrosensory and trigeminal nerves, but these senses remain separate in the sensory ganglia and in their first central relays. Schnauzenorgan trigeminal primary afferent projections extend throughout the descending trigeminal sensory nuclei, and a few fibers enter the facial lobe. Although no labeled neurons could be identified in the brain as the trigeminal mesencephalic root, some Schnauzenorgan trigeminal afferents terminated in the trigeminal motor nucleus, suggesting a monosynaptic, possibly proprioceptive, pathway. In this first step toward understanding multimodal central representation of the Schnauzenorgan, no direct interconnections were found between the trigeminal sensory and electromotor command system, or the electrosensory and trigeminal motor command. The pathways linking perception to action remain to be studied. © 2014 Wiley Periodicals, Inc.

Synaptic Regulator α-Synuclein in Dopaminergic Fibers Is Essentially Required for the Maintenance of Subependymal Neural Stem Cells.

PubMed

Perez-Villalba, Ana; Sirerol-Piquer, M Salomé; Belenguer, Germán; Soriano-Cantón, Raúl; Muñoz-Manchado, Ana Belén; Villadiego, Javier; Alarcón-Arís, Diana; Soria, Federico N; Dehay, Benjamin; Bezard, Erwan; Vila, Miquel; Bortolozzi, Analía; Toledo-Aral, Juan José; Pérez-Sánchez, Francisco; Fariñas, Isabel

2018-01-24

Synaptic protein α-synuclein (α-SYN) modulates neurotransmission in a complex and poorly understood manner and aggregates in the cytoplasm of degenerating neurons in Parkinson's disease. Here, we report that α-SYN present in dopaminergic nigral afferents is essential for the normal cycling and maintenance of neural stem cells (NSCs) in the brain subependymal zone of adult male and female mice. We also show that premature senescence of adult NSCs into non-neurogenic astrocytes in mice lacking α-SYN resembles the effects of dopaminergic fiber degeneration resulting from chronic exposure to 1-methyl-4-phenyl-1,2,3,6-tetra-hydropyridine or intranigral inoculation of aggregated toxic α-SYN. Interestingly, NSC loss in α-SYN-deficient mice can be prevented by viral delivery of human α-SYN into their sustantia nigra or by treatment with l-DOPA, suggesting that α-SYN regulates dopamine availability to NSCs. Our data indicate that α-SYN, present in dopaminergic nerve terminals supplying the subependymal zone, acts as a niche component to sustain the neurogenic potential of adult NSCs and identify α-SYN and DA as potential targets to ameliorate neurogenic defects in the aging and diseased brain. SIGNIFICANCE STATEMENT We report an essential role for the protein α-synuclein present in dopaminergic nigral afferents in the regulation of adult neural stem cell maintenance, identifying the first synaptic regulator with an implication in stem cell niche biology. Although the exact role of α-synuclein in neural transmission is not completely clear, our results indicate that it is required for stemness and the preservation of neurogenic potential in concert with dopamine. Copyright © 2018 the authors 0270-6474/18/380815-12$15.00/0.

The role of active muscle mass in determining the magnitude of peripheral fatigue during dynamic exercise.

PubMed

Rossman, Matthew J; Garten, Ryan S; Venturelli, Massimo; Amann, Markus; Richardson, Russell S

2014-06-15

Greater peripheral quadriceps fatigue at the voluntary termination of single-leg knee-extensor exercise (KE), compared with whole-body cycling, has been attributed to confining group III and IV skeletal muscle afferent feedback to a small muscle mass, enabling the central nervous system (CNS) to tolerate greater peripheral fatigue. However, as task specificity and vastly differing systemic challenges may have complicated this interpretation, eight males were studied during constant workload trials to exhaustion at 85% of peak workload during single-leg and double-leg KE. It was hypothesized that because of the smaller muscle mass engaged during single-leg KE, a greater magnitude of peripheral quadriceps fatigue would be present at exhaustion. Vastus lateralis integrated electromyogram (iEMG) signal relative to the first minute of exercise, preexercise to postexercise maximal voluntary contractions (MVCs) of the quadriceps, and twitch-force evoked by supramaximal magnetic femoral nerve stimulation (Qtw,pot) quantified peripheral quadriceps fatigue. Trials performed with single-leg KE (8.1 ± 1.2 min; 45 ± 4 W) resulted in significantly greater peripheral quadriceps fatigue than double-leg KE (10 ± 1.3 min; 83 ± 7 W), as documented by changes in the iEMG signal (147 ± 24 vs. 85 ± 13%), MVC (-25 ± 3 vs. -12 ± 3%), and Qtw,pot (-44 ± 6 vs. -33 ± 7%), for single-leg and double-leg KE, respectively. Therefore, avoiding concerns over task specificity and cardiorespiratory limitations, this study reveals that a reduction in muscle mass permits the development of greater peripheral muscle fatigue and supports the concept that the CNS tolerates a greater magnitude of peripheral fatigue when the source of group III/IV afferent feedback is limited to a small muscle mass.

Viscerosensory input drives angiotensin II type 1A receptor-expressing neurons in the solitary tract nucleus.

PubMed

Carter, D A; Guo, H; Connelly, A A; Bassi, J K; Fong, A Y; Allen, A M; McDougall, S J

2018-02-01

Homeostatic regulation of visceral organ function requires integrated processing of neural and neurohormonal sensory signals. The nucleus of the solitary tract (NTS) is the primary sensory nucleus for cranial visceral sensory afferents. Angiotensin II (ANG II) is known to modulate peripheral visceral reflexes, in part, by activating ANG II type 1A receptors (AT 1A R) in the NTS. AT 1A R-expressing NTS neurons occur throughout the NTS with a defined subnuclear distribution, and most of these neurons are depolarized by ANG II. In this study we determined whether AT 1A R-expressing NTS neurons receive direct visceral sensory input, and whether this input is modulated by ANG II. Using AT 1A R-GFP mice to make targeted whole cell recordings from AT 1A R-expressing NTS neurons, we demonstrate that two-thirds (37 of 56) of AT 1A R-expressing neurons receive direct excitatory, visceral sensory input. In half of the neurons tested (4 of 8) the excitatory visceral sensory input was significantly reduced by application of the transient receptor potential vallinoid type 1 receptor agonist, capsaicin, indicating AT 1A R-expressing neurons can receive either C- or A-fiber-mediated input. Application of ANG II to a subset of second-order AT 1A R-expressing neurons did not affect spontaneous, evoked, or asynchronous glutamate release from visceral sensory afferents. Thus it is unlikely that AT 1A R-expressing viscerosensory neurons terminate on AT 1A R-expressing NTS neurons. Our data suggest that ANG II is likely to modulate multiple visceral sensory modalities by altering the excitability of second-order AT 1A R-expressing NTS neurons.

Src family kinases mediate the inhibition of substance P release in the rat spinal cord by μ-opioid receptors and GABAB receptors, but not α2 adrenergic receptors

PubMed Central

Zhang, Guohua; Chen, Wenling; Marvizón, Juan Carlos G.

2010-01-01

GABAB, μ-opioid, and adrenergic α2 receptors inhibit substance P release from primary afferent terminals in the dorsal horn. Studies in cell expression systems suggest that μ-opioid and GABAB receptors inhibit transmitter release from primary afferents by activating Src family kinases (SFKs), which then phosphorylate and inhibit voltage-gated calcium channels. This study investigated whether SFKs mediate the inhibition of substance P release by these three receptors. Substance P release was measured as neurokinin 1 receptor (NK1R) internalization in spinal cord slices and in vivo. In slices, NK1R internalization induced by high frequency dorsal root stimulation was inhibited by the μ-opioid agonist DAMGO and the GABAB agonist baclofen. This inhibition was reversed by the SFK inhibitor PP1. NK1R internalization induced by low frequency stimulation was also inhibited by DAMGO, but PP1 did not reverse this effect. In vivo, NK1R internalization induced by noxious mechanical stimulation of the hind paw was inhibited by intrathecal DAMGO and baclofen. This inhibition was reversed by intrathecal PP1, but not by the inactive PP1 analog PP3. PP1 produced no effect by itself. The α2 adrenergic agonists medetomidine and guanfacine produced a small but statistically significant inhibition of NK1R internalization induced by low frequency dorsal root stimulation. PP1 did not reverse the inhibition by guanfacine. These results show that SFKs mediate the inhibition of substance P release by μ-opioid and GABAB receptors, but not by α2 receptors, which is probably mediated by the binding of G protein βγ subunits to calcium channels. PMID:20726886

Synaptic calcium regulation in hair cells of the chicken basilar papilla.

PubMed

Im, Gi Jung; Moskowitz, Howard S; Lehar, Mohammed; Hiel, Hakim; Fuchs, Paul Albert

2014-12-10

Cholinergic inhibition of hair cells occurs by activation of calcium-dependent potassium channels. A near-membrane postsynaptic cistern has been proposed to serve as a store from which calcium is released to supplement influx through the ionotropic ACh receptor. However, the time and voltage dependence of acetylcholine (ACh)-evoked potassium currents reveal a more complex relationship between calcium entry and release from stores. The present work uses voltage steps to regulate calcium influx during the application of ACh to hair cells in the chicken basilar papilla. When calcium influx was terminated at positive membrane potential, the ACh-evoked potassium current decayed exponentially over ∼100 ms. However, at negative membrane potentials, this current exhibited a secondary rise in amplitude that could be eliminated by dihydropyridine block of the voltage-gated calcium channels of the hair cell. Calcium entering through voltage-gated channels may transit through the postsynaptic cistern, since ryanodine and sarcoendoplasmic reticulum calcium-ATPase blockers altered the time course and magnitude of this secondary, voltage-dependent contribution to ACh-evoked potassium current. Serial section electron microscopy showed that efferent and afferent synaptic structures are juxtaposed, supporting the possibility that voltage-gated influx at afferent ribbon synapses influences calcium homeostasis during long-lasting cholinergic inhibition. In contrast, spontaneous postsynaptic currents ("minis") resulting from stochastic efferent release of ACh were made briefer by ryanodine, supporting the hypothesis that the synaptic cistern serves primarily as a calcium barrier and sink during low-level synaptic activity. Hypolemmal cisterns such as that at the efferent synapse of the hair cell can play a dynamic role in segregating near-membrane calcium for short-term and long-term signaling. Copyright © 2014 the authors 0270-6474/14/3416688-10$15.00/0.

Synaptic Calcium Regulation in Hair Cells of the Chicken Basilar Papilla

PubMed Central

Im, Gi Jung; Moskowitz, Howard S.; Lehar, Mohammed; Hiel, Hakim

2014-01-01

Cholinergic inhibition of hair cells occurs by activation of calcium-dependent potassium channels. A near-membrane postsynaptic cistern has been proposed to serve as a store from which calcium is released to supplement influx through the ionotropic ACh receptor. However, the time and voltage dependence of acetylcholine (ACh)-evoked potassium currents reveal a more complex relationship between calcium entry and release from stores. The present work uses voltage steps to regulate calcium influx during the application of ACh to hair cells in the chicken basilar papilla. When calcium influx was terminated at positive membrane potential, the ACh-evoked potassium current decayed exponentially over ∼100 ms. However, at negative membrane potentials, this current exhibited a secondary rise in amplitude that could be eliminated by dihydropyridine block of the voltage-gated calcium channels of the hair cell. Calcium entering through voltage-gated channels may transit through the postsynaptic cistern, since ryanodine and sarcoendoplasmic reticulum calcium-ATPase blockers altered the time course and magnitude of this secondary, voltage-dependent contribution to ACh-evoked potassium current. Serial section electron microscopy showed that efferent and afferent synaptic structures are juxtaposed, supporting the possibility that voltage-gated influx at afferent ribbon synapses influences calcium homeostasis during long-lasting cholinergic inhibition. In contrast, spontaneous postsynaptic currents (“minis”) resulting from stochastic efferent release of ACh were made briefer by ryanodine, supporting the hypothesis that the synaptic cistern serves primarily as a calcium barrier and sink during low-level synaptic activity. Hypolemmal cisterns such as that at the efferent synapse of the hair cell can play a dynamic role in segregating near-membrane calcium for short-term and long-term signaling. PMID:25505321

Developmental Programming: Reproductive Endocrinopathies in the Adult Female Sheep After Prenatal Testosterone Treatment Are Reflected in Altered Ontogeny of GnRH Afferents

PubMed Central

Hershey, John; Mytinger, Andrea; Foster, Douglas L.; Padmanabhan, Vasantha

2011-01-01

The GnRH system represents a useful model of long-term neural plasticity. An unexplored facet of this plasticity relates to the ontogeny of GnRH neural afferents during critical periods when the hypothalamic-pituitary-gonadal axis is highly susceptible to perturbation by sex steroids. Sheep treated with testosterone (T) in utero exhibit profound reproductive neuroendocrine dysfunctions during their lifespan. The current study tested the hypothesis that these changes are associated with alterations in the normal ontogeny of GnRH afferents and glial associations. Adult pregnant sheep (n = 50) were treated with vehicle [control (CONT)] or T daily from gestational day (GD)30 to GD90. CONT and T fetuses (n = 4–6/treatment per age group) were removed by cesarean section on GD90 and GD140 and the brains frozen at −80°C. Brains were also collected from CONT and T females at 20–23 wk (prepubertal), 10 months (normal onset of puberty and oligo-anovulation), and 21 months (oligo-anovulation in T females). Tissue was analyzed for GnRH immunoreactivity (ir), total GnRH afferents (Synapsin-I ir), glutamate [vesicular glutamate transporter-2 (VGLUT2)-ir], and γ-aminobutyric acid [GABA, vesicular GABA transporter (VGAT)-ir] afferents and glial associations (glial fibrillary acidic protein-ir) with GnRH neurons using optical sectioning techniques. The results revealed that: 1) GnRH soma size was slightly reduced by T, 2) the total (Synapsin-I) GnRH afferents onto both somas and dendrites increased significantly with age and was reduced by T, 3) numbers of both VGAT and VGLUT inputs increased significantly with age and were also reduced by T, and 4) glial associations with GnRH neurons were reduced (<10%) by T. Together, these findings reveal a previously unknown developmental plasticity in the GnRH system of the sheep. The altered developmental trajectory of GnRH afferents after T reinforces the notion that prenatal programming plays an important role in the normal development of the reproductive neuroendocrine axis. PMID:21933866

Optimal delineation of single C-tactile and C-nociceptive afferents in humans by latency slowing.

PubMed

Watkins, Roger H; Wessberg, Johan; Backlund Wasling, Helena; Dunham, James P; Olausson, Håkan; Johnson, Richard D; Ackerley, Rochelle

2017-04-01

C-mechanoreceptors in humans comprise a population of unmyelinated afferents exhibiting a wide range of mechanical sensitivities. C-mechanoreceptors are putatively divided into those signaling gentle touch (C-tactile afferents, CTs) and nociception (C-mechanosensitive nociceptors, CMs), giving rise to positive and negative affect, respectively. We sought to distinguish, compare, and contrast the properties of a population of human C-mechanoreceptors to see how fundamental the divisions between these putative subpopulations are. We used microneurography to record from individual afferents in humans and applied electrical and mechanical stimulation to their receptive fields. We show that C-mechanoreceptors can be distinguished unequivocally into two putative populations, comprising CTs and CMs, by electrically evoked spike latency changes (slowing). After both natural mechanical stimulation and repetitive electrical stimulation there was markedly less latency slowing in CTs compared with CMs. Electrical receptive field stimulation, which bypasses the receptor end organ, was most effective in classifying C-mechanoreceptors, as responses to mechanical receptive field stimulation overlapped somewhat, which may lead to misclassification. Furthermore, we report a subclass of low-threshold CM responding to gentle mechanical stimulation and a potential subclass of CT afferent displaying burst firing. We show that substantial differences exist in the mechanisms governing axonal conduction between CTs and CMs. We provide clear electrophysiological "signatures" (extent of latency slowing) that can be used in unequivocally identifying populations of C-mechanoreceptors in single-unit and multiunit microneurography studies and in translational animal research into affective touch. Additionally, these differential mechanisms may be pharmacologically targetable for separate modulation of positive and negative affective touch information. NEW & NOTEWORTHY Human skin encodes a plethora of touch interactions, and affective tactile information is primarily signaled by slowly conducting C-mechanoreceptive afferents. We show that electrical stimulation of low-threshold C-tactile afferents produces markedly different patterns of activity compared with high-threshold C-mechanoreceptive nociceptors, although the populations overlap in their responses to mechanical stimulation. This fundamental distinction demonstrates a divergence in affective touch signaling from the first stage of sensory processing, having implications for the processing of interpersonal touch. Copyright © 2017 the American Physiological Society.

Effect of copper sulphate on the rate of afferent discharge in the gastric branch of the vagus nerve in the rat

NASA Technical Reports Server (NTRS)

Niijima, Akira; Jiang, Zheng-Yao; Daunton, Nancy G.; Fox, Robert A.

1991-01-01

The afferent nerve activity was recorded from a nerve filament isolated from the peripheral cut end of the gastric branch of the vagus nerve. The gastric perfusion of 4 ml of two different concentrations (0.04 percent and 0.08 percent) of CuSO4 solution provoked an increase in afferent activity. The stimulating effect of the 0.08 percent solution was stronger than that of the 0.04 percent solution, and lasted for a longer period of time. The observations suggest a possible mechanism by which CuSO4 elicits emesis.

Chewing-induced hypertension in afferent baroreflex failure: a sympathetic response?

PubMed

Fuente Mora, Cristina; Norcliffe-Kaufmann, Lucy; Palma, Jose-Alberto; Kaufmann, Horacio

2015-11-01

What is the central question of this study? Our goal was to understand the autonomic responses to eating in patients with congenital afferent baroreflex failure, by documenting changes in blood pressure and heart rate with chewing, swallowing and stomach distension. What is the main finding and its importance? Patients born with lesions in the afferent baroreceptor pathways have an exaggerated pressor response to food intake. This appears to be a sympathetically mediated response, triggered by chewing, that occurs independently of swallowing or distension of the stomach. The chewing-induced pressor response may be useful as a counter-manoeuvre to prevent orthostatic hypotension in these patients. Familial dysautonomia (FD) is a rare genetic disease with extremely labile blood pressure resulting from baroreflex deafferentation. Patients have marked surges in sympathetic activity, frequently surrounding meals. We conducted an observational study to document the autonomic responses to eating in patients with FD and to determine whether sympathetic activation was caused by chewing, swallowing or stomach distension. Blood pressure and R-R intervals were measured continuously while chewing gum (n = 15), eating (n = 20) and distending the stomach by percutaneous endoscopic gastrostomy tube feeding (n = 9). Responses were compared with those of normal control subjects (n = 10) and of patients with efferent autonomic failure (n = 10) who have chronically impaired sympathetic outflow. In patients with FD, eating was associated with a marked but transient pressor response (P < 0.0001) and additional signs of sympathetic activation, including tachycardia, diaphoresis and flushing of the skin. Chewing gum evoked a similar increase in blood pressure that was higher in patients with FD than in control subjects (P = 0.0001), but was absent in patients with autonomic failure. In patients with FD, distending the stomach by percutaneous endoscopic gastrostomy tube feeding failed to elicit a pressor response. The results provide indirect evidence that chewing triggers sympathetic activation. The increase in blood pressure is exaggerated in patients with FD as a result of blunted afferent baroreceptor signalling. The chewing pressor response may be useful as a counter-manoeuvre to raise blood pressure and prevent symptomatic orthostatic hypotension in patients with FD. © 2015 The Authors. Experimental Physiology © 2015 The Physiological Society.

Presynaptic gain control by endogenous cotransmission of dopamine and GABA in the olfactory bulb.

PubMed

Vaaga, Christopher E; Yorgason, Jordan T; Williams, John T; Westbrook, Gary L

2017-03-01

In the olfactory bulb, lateral inhibition mediated by local juxtaglomerular interneurons has been proposed as a gain control mechanism, important for decorrelating odorant responses. Among juxtaglomerular interneurons, short axon cells are unique as dual-transmitter neurons that release dopamine and GABA. To examine their intraglomerular function, we expressed channelrhodopsin under control of the DAT-cre promoter and activated olfactory afferents within individual glomeruli. Optical stimulation of labeled cells triggered endogenous dopamine release as measured by cyclic voltammetry and GABA release as measured by whole cell GABA A receptor currents. Activation of short axon cells reduced the afferent presynaptic release probability via D 2 and GABA B receptor activation, resulting in reduced spiking in both mitral and external tufted cells. Our results suggest that short axon cells influence glomerular activity not only by direct inhibition of external tufted cells but also by inhibition of afferent inputs to external tufted and mitral cells. NEW & NOTEWORTHY Sensory systems, including the olfactory system, encode information across a large dynamic range, making synaptic mechanisms of gain control critical to proper function. Here we demonstrate that a dual-transmitter interneuron in the olfactory bulb controls the gain of intraglomerular afferent input via two distinct mechanisms, presynaptic inhibition as well as inhibition of a principal neuron subtype, and thereby potently controls the synaptic gain of afferent inputs. Copyright © 2017 the American Physiological Society.

Differential role of afferent and efferent renal nerves in the maintenance of early- and late-phase Dahl S hypertension

PubMed Central

Foss, Jason D.; Fink, Gregory D.

2015-01-01

Clinical data suggest that renal denervation (RDNX) may be an effective treatment for human hypertension; however, it is unclear whether this therapeutic effect is due to ablation of afferent or efferent renal nerves. We have previously shown that RDNX lowers arterial pressure in hypertensive Dahl salt-sensitive (S) rats to a similar degree observed in clinical trials. In addition, we have recently developed a method for selective ablation of afferent renal nerves (renal-CAP). In the present study, we tested the hypothesis that the antihypertensive effect of RDNX in the Dahl S rat is due to ablation of afferent renal nerves by comparing the effect of complete RDNX to renal-CAP during two phases of hypertension in the Dahl S rat. In the early phase, rats underwent treatment after 3 wk of high-NaCl feeding when mean arterial pressure (MAP) was ∼140 mmHg. In the late phase, rats underwent treatment after 9 wk of high NaCl feeding, when MAP was ∼170 mmHg. RDNX reduced MAP ∼10 mmHg compared with sham surgery in both the early and late phase, whereas renal-CAP had no antihypertensive effect. These results suggest that, in the Dahl S rat, the antihypertensive effect of RDNX is not dependent on pretreatment arterial pressure, nor is it due to ablation of afferent renal nerves. PMID:26661098

The gut-brain axis rewired: adding a functional vagal nicotinic "sensory synapse".

PubMed

Perez-Burgos, Azucena; Mao, Yu-Kang; Bienenstock, John; Kunze, Wolfgang A

2014-07-01

It is generally accepted that intestinal sensory vagal fibers are primary afferent, responding nonsynaptically to luminal stimuli. The gut also contains intrinsic primary afferent neurons (IPANs) that respond to luminal stimuli. A psychoactive Lactobacillus rhamnosus (JB-1) that affects brain function excites both vagal fibers and IPANs. We wondered whether, contrary to its primary afferent designation, the sensory vagus response to JB-1 might depend on IPAN to vagal fiber synaptic transmission. We recorded ex vivo single- and multiunit afferent action potentials from mesenteric nerves supplying mouse jejunal segments. Intramural synaptic blockade with Ca(2+) channel blockers reduced constitutive or JB-1-evoked vagal sensory discharge. Firing of 60% of spontaneously active units was reduced by synaptic blockade. Synaptic or nicotinic receptor blockade reduced firing in 60% of vagal sensory units that were stimulated by luminal JB-1. In control experiments, increasing or decreasing IPAN excitability, respectively increased or decreased nerve firing that was abolished by synaptic blockade or vagotomy. We conclude that >50% of vagal afferents function as interneurons for stimulation by JB-1, receiving input from an intramural functional "sensory synapse." This was supported by myenteric plexus nicotinic receptor immunohistochemistry. These data offer a novel therapeutic target to modify pathological gut-brain axis activity.-Perez-Burgos, A., Mao, Y.-K., Bienenstock, J., Kunze, W. A. The gut-brain axis rewired: adding a functional vagal nicotinic "sensory synapse." © FASEB.

Mechanoreceptor afferent activity compared with receptor field dimensions and pressure changes in feline urinary bladder.

PubMed

Downie, J W; Armour, J A

1992-11-01

The relationship between vesical mechanoreceptor field dimensions and afferent nerve activity recorded in pelvic plexus nerve filaments was examined in chloralose-anesthetized cats. Orthogonal receptor field dimensions were monitored with piezoelectric ultrasonic crystals. Reflexly generated bladder contractile activity made measurements difficult, therefore data were collected from cats subjected to actual sacral rhizotomy. Afferent activity was episodic and was initiated at different pressure and receptor field dimension thresholds. Maximum afferent activity did not correlate with maximum volume or pressure. Furthermore, activity was not linearly related to intravesical pressure, receptor field dimensions, or calculated wall tension. Pressure-length hysteresis of the receptor fields occurred. The responses of identified afferent units and their associated receptor field dimensions to brief contractions elicited by the ganglion stimulant 1,1-dimethyl-4-phenylpiperazinium iodide (2.5-20 micrograms i.a.), studied under constant volume or constant pressure conditions, are compatible with bladder mechanoreceptors behaving as tension receptors. Because activity generated by bladder mechanoreceptors did not correlate in a simple fashion with intravesical pressure or receptor field dimensions, it is concluded that such receptors are influenced by the viscoelastic properties of the bladder wall. Furthermore, as a result of the heterogeneity of the bladder wall, receptor field tension appears to offer a more precise relationship with the activity of bladder wall mechanoreceptors than does intravesical pressure.

Role of irregular otolith afferents in the steady-state nystagmus during off-vertical axis rotation

NASA Technical Reports Server (NTRS)

Angelaki, D. E.; Perachio, A. A.; Mustari, M. J.; Strunk, C. L.

1992-01-01

1. During constant velocity off-vertical axis rotations (OVAR) in the dark a compensatory ocular nystagmus is present throughout rotation despite the lack of a maintained signal from the semicircular canals. Lesion experiments and canal plugging have attributed the steady-state ocular nystagmus during OVAR to inputs from the otolith organs and have demonstrated that it depends on an intact velocity storage mechanism. 2. To test whether irregularly discharging otolith afferents play a crucial role in the generation of the steady-state eye nystagmus during OVAR, we have used anodal (inhibitory) currents bilaterally to selectively and reversibly block irregular vestibular afferent discharge. During delivery of DC anodal currents (100 microA) bilaterally to both ears, the slow phase eye velocity of the steady-state nystagmus during OVAR was reduced or completely abolished. The disruption of the steady-state nystagmus was transient and lasted only during the period of galvanic stimulation. 3. To distinguish a possible effect of ablation of the background discharge rates of irregular vestibular afferents on the velocity storage mechanism from specific contributions of the dynamic responses from irregular otolith afferents to the circuit responsible for the generation of the steady-state nystagmus, bilateral DC anodal galvanic stimulation was applied during optokinetic nystagmus (OKN) and optokinetic afternystagmus (OKAN). No change in OKN and OKAN was observed.(ABSTRACT TRUNCATED AT 250 WORDS).

Emerging role of neurotensin in regulation of the cardiovascular system.

PubMed

Osadchii, Oleg E

2015-09-05

There is increasing evidence in support of an important role played by neurotensin (NT), a tridecapeptide originally found in bovine hypothalamus, in regulation of cardiovascular system. Elevated systemic levels of NT may contribute to pathogenesis of acute circulatory disoders, and predict the risk for cardiovascular morbidity and mortality in population-based studies. Within cardiovascular system, NT-containing neural fibers are found in close contact with atrial and ventricular cardiac myocytes, cardiac conduction system, intracardiac ganglia, as well as coronary vessels in humans and various animal species. The density of NT-immunoreactive innervation is reduced in cardiac disease. NT produces a variety of cardiovascular actions including effects on heart rate, myocardial contractility, systemic blood pressure, coronary vascular tone, venous smooth muscle tone, and regional blood flow in gastrointestinal tract, cutaneous and adipose tissue. NT could trigger cardiovascular reflexes by stimulating primary visceral afferents synaptically connected with preganglionic sympathetic neurons at the spinal cord. Structural determinants of biological activity of NT reside primarily in the C-terminal portion of its molecule which is responsible for receptor activation. NT effects are mediated via activation of NT receptors, or produced indirectly via stimulation of release of various endogenous neuromodulators/neurotransmitters such as histamine, catecholamines and prostaglandins. Three subtypes of NT receptor (NTS1, NTS2 and NTS3) have been shown to be expressed in the myocardium. NTS1, a high-affinity NT binding site coupled to phospholipase C-inositoltrisphosphate transduction pathway, is thought to mediate NT-induced cardiovascular responses. Copyright © 2015 Elsevier B.V. All rights reserved.

The anorexic agents, sibutramine and fenfluramine, depress GABAB-induced inhibitory postsynaptic potentials in rat mesencephalic dopaminergic cells

PubMed Central

Ledonne, Ada; Sebastianelli, Luca; Federici, Mauro; Bernardi, Giorgio; Mercuri, Nicola Biagio

2009-01-01

Background and purpose Nutrition is the result of a complex interaction among environmental, homeostatic and reward-related processes. Accumulating evidence supports key roles for the dopaminergic neurons of the ventral midbrain in regulating feeding behaviour. For this reason, in the present study, we have investigated the electrophysiological effects of two centrally acting anorexic agents, fenfluramine and sibutramine, on these cells. Experimental approach Rat midbrain slices were used to make intracellular recordings from dopaminergic neurons of the substantia nigra and the ventral tegmental area. Gamma-aminobutyric acid (GABA)-mediated synaptic transmission was assessed from the inhibitory postsynaptic potentials (IPSPs) mediated by GABAA and GABAB receptors. Key results Fenfluramine and sibutramine reduced, concentration-dependently, the GABAB IPSPs, without affecting the GABAA-mediated potentials. This effect is presynaptic, as postsynaptic membrane responses induced by application of a GABAB receptor agonist, baclofen, were not affected by the two drugs. Furthermore, the selective 5-hydroxytriptamine 1B (5-HT1B) receptor antagonist, SB216641, blocked the reduction of GABAB IPSPs caused by fenfluramine and sibutramine, indicating that the receptor mediating this effect is 5-HT1B. Conclusions and implications Two anorexic agents, fenfluramine and sibutramine, induced the activation of 5-HT1B receptors located on presynaptic GABAergic terminals, thus reducing the release of GABA. This action can alter the strength of synaptic afferents that modify the activity of dopaminergic neurons, inducing neuronal excitation. Our results reveal an additional mechanism of action for fenfluramine and sibutramine that might contribute to reducing food intake, by influencing the pleasurable and motor aspects of feeding behaviour. PMID:19298257

Descending projections of the hamster intergeniculate leaflet: relationship to the sleep/arousal and visuomotor systems

NASA Technical Reports Server (NTRS)

Morin, Lawrence P.; Blanchard, Jane H.

2005-01-01

The intergeniculate leaflet (IGL), homolog of the primate pregeniculate nucleus, modulates circadian rhythms. However, its extensive anatomical connections suggest that it may regulate other systems, particularly those for visuomotor function and sleep/arousal. Here, descending IGL-efferent pathways are identified with the anterograde tracer, Phaseolus vulgaris leucoagglutinin, with projections to over 50 brain stem nuclei. Projections of the ventral lateral geniculate are similar, but more limited. Many of the nuclei with IGL afferents contribute to circuitry governing visuomotor function. These include the oculomotor, trochlear, anterior pretectal, Edinger-Westphal, and the terminal nuclei; all layers of the superior colliculus, interstitial nucleus of the medial longitudinal fasciculus, supraoculomotor periaqueductal gray, nucleus of the optic tract, the inferior olive, and raphe interpositus. Other target nuclei are known to be involved in the regulation of sleep, including the lateral dorsal and pedunculopontine tegmentum. The dorsal raphe also receives projections from the IGL and may contribute to both sleep/arousal and visuomotor function. However, the locus coeruleus and medial vestibular nucleus, which contribute to sleep and eye movement regulation and which send projections to the IGL, do not receive reciprocal projections from it. The potential involvement of the IGL with the sleep/arousal system is further buttressed by existing evidence showing IGL-efferent projections to the ventrolateral preoptic area, dorsomedial, and medial tuberal hypothalamus. In addition, the great majority of all regions receiving IGL projections also receive input from the orexin/hypocretin system, suggesting that this system contributes not only to the regulation of sleep, but to eye movement control as well.

The role of excitatory amino acids and substance P in the mediation of the cough reflex within the nucleus tractus solitarii of the rabbit.

PubMed

Mutolo, Donatella; Bongianni, Fulvia; Fontana, Giovanni A; Pantaleo, Tito

2007-09-28

We hypothesized that cough evoked by mechanical stimulation of the tracheobronchial tree in the rabbit is primarily mediated by glutamatergic neurotransmission at the level of the caudal portions of the medial subnucleus of the nucleus tractus solitarii (NTS) and the lateral commissural NTS where cough-related afferents terminate, and that this reflex is potentiated by local release of substance P. To test our hypothesis, we performed bilateral microinjections (30-50 nl) of ionotropic glutamate receptor antagonists or substance P into these locations in pentobarbitone anaesthetized, spontaneously breathing rabbits. Blockade of NMDA and non-NMDA receptors by 50mM kynurenic acid abolished the cough reflex without affecting the Breuer-Hering inflation reflex or the pulmonary chemoreflex. Blockade of non-NMDA receptors using 10mM CNQX or 5mM NBQX caused identical effects. Blockade of NMDA receptors by 10mM D-AP5 strongly reduced, but did not abolish cough responses. Microinjections of 1mM substance P increased peak and rate of rise of abdominal muscle activity as well as cough number. These results are the first to provide evidence that ionotropic glutamate receptors, especially non-NMDA receptors, located within specific regions of NTS are primarily involved in the mediation of cough evoked by mechanical stimulation of the tracheobronchial tree in the rabbit. Present findings on substance P cough-enhancing effects extend previous observations and are relevant to the tachykinin-mediated central sensitization of the cough reflex. They also may provide hints for further studies on centrally acting antitussive drugs.

Nucleus of the solitary tract in the C57BL/6J mouse: Subnuclear parcellation, chorda tympani nerve projections, and brainstem connections.

PubMed

Ganchrow, Donald; Ganchrow, Judith R; Cicchini, Vanessa; Bartel, Dianna L; Kaufman, Daniel; Girard, David; Whitehead, Mark C

2014-05-01

The nucleus of the solitary tract (NST) processes gustatory and related somatosensory information rostrally and general viscerosensory information caudally. To compare its connections with those of other rodents, this study in the C57BL/6J mouse provides a subnuclear cytoarchitectonic parcellation (Nissl stain) of the NST into rostral, intermediate, and caudal divisions. Subnuclei are further characterized by NADPH staining and P2X2 immunoreactivity (IR). Cholera toxin subunit B (CTb) labeling revealed those NST subnuclei receiving chorda tympani nerve (CT) afferents, those connecting with the parabrachial nucleus (PBN) and reticular formation (RF), and those interconnecting NST subnuclei. CT terminals are densest in the rostral central (RC) and medial (M) subnuclei; less dense in the rostral lateral (RL) subnucleus; and sparse in the ventral (V), ventral lateral (VL), and central lateral (CL) subnuclei. CTb injection into the PBN retrogradely labels cells in the aforementioned subnuclei; RC and M providing the largest source of PBN projection neurons. Pontine efferent axons terminate mainly in V and rostral medial (RM) subnuclei. CTb injection into the medullary RF labels cells and axonal endings predominantly in V at rostral and intermediate NST levels. Small CTb injections within the NST label extensive projections from the rostral division to caudal subnuclei. Projections from the caudal division primarily interconnect subnuclei confined to the caudal division of the NST; they also connect with the area postrema. P2X2 -IR identifies probable vagal nerve terminals in the central (Ce) subnucleus in the intermediate/caudal NST. Ce also shows intense NADPH staining and does not project to the PBN. Copyright © 2013 Wiley Periodicals, Inc.

Nucleus of the solitary tract in the C57BL/6J mouse: Subnuclear parcellation, chorda tympani nerve projections, and brainstem connections

PubMed Central

Ganchrow, Donald; Ganchrow, Judith R; Cicchini, Vanessa; Bartel, Dianna L; Kaufman, Daniel; Girard, David; Whitehead, Mark C

2013-01-01

The nucleus of the solitary tract (NST) processes gustatory and related somatosensory information rostrally and general viscerosensory information caudally. To compare its connections with those of other rodents, this study in the C57BL/6J mouse provides a subnuclear cytoarchitectonic parcellation (Nissl stain) of the NST into rostral, intermediate, and caudal divisions. Subnuclei are further characterized by NADPH staining and P2X2 immunoreactivity (IR). Cholera toxin subunit B (CTb) labeling revealed those NST subnuclei receiving chorda tympani nerve (CT) afferents, those connecting with the parabrachial nucleus (PBN) and reticular formation (RF), and those interconnecting NST subnuclei. CT terminals are densest in the rostral central (RC) and medial (M) subnuclei; less dense in the rostral lateral (RL) subnucleus; and sparse in the ventral (V), ventral lateral (VL), and central lateral (CL) subnuclei. CTb injection into the PBN retrogradely labels cells in the aforementioned subnuclei; RC and M providing the largest source of PBN projection neurons. Pontine efferent axons terminate mainly in V and rostral medial (RM) subnuclei. CTb injection into the medullary RF labels cells and axonal endings predominantly in V at rostral and intermediate NST levels. Small CTb injections within the NST label extensive projections from the rostral division to caudal subnuclei. Projections from the caudal division primarily interconnect subnuclei confined to the caudal division of the NST; they also connect with the area postrema. P2X2-IR identifies probable vagal nerve terminals in the central (Ce) subnucleus in the intermediate/caudal NST. Ce also shows intense NADPH staining and does not project to the PBN. J. Comp. Neurol. 522:1565–1596, 2014. PMID:24151133

Single Body Parts are Processed by Individual Neurons in the Mouse Dorsolateral Striatum

PubMed Central

Coffey, Kevin R.; Nader, Miles; West, Mark O.

2016-01-01

Interest in the dorsolateral striatum (DLS) has generated numerous scientific studies of its neuropathologies, as well as its roles in normal sensorimotor integration and learning. Studies are informed by knowledge of DLS functional organization, the guiding principle being its somatotopic afferent projections from primary somatosensory (S1) and motor (M1) cortices. The potential to connect behaviorally relevant function to detailed structure is elevated by mouse models, which have access to extensive genetic neuroscience tool kits. Remaining to be demonstrated, however, is whether the correspondence between S1/M1 corticostriatal terminal distributions and the physiological properties of DLS neurons demonstrated in rats and non-human primates exists in mice. Given that the terminal distribution of S1/M1 projections to the DLS in mice is similar to that in rats, we studied whether firing rates (FRs) of DLS neurons in awake, behaving mice are related to activity of individual body parts. MSNs exhibited robust, selective increases in FR during movement or somatosensory stimulation of single body parts. Properties of MSNs, including baseline FRs, locations, responsiveness to stimulation, and proportions of responsive neurons were similar to properties observed in rats. Future studies can be informed by the present demonstration that the mouse lateral striatum functions as a somatic sensorimotor sector of the striatum and appears to be a homolog of the primate putamen, as demonstrated in rats (Carelli and West, 1991). PMID:26827625

Trigeminal Medullary Dorsal Horn Neurons Activated by Nasal Stimulation Coexpress AMPA, NMDA, and NK1 Receptors

PubMed Central

McCulloch, P. F.; DiNovo, K. M.; Westerhaus, D. J.; Vizinas, T. A.; Peevey, J. F.; Lach, M. A.; Czarnocki, P.

2013-01-01

Afferent information initiating the cardiorespiratory responses during nasal stimulation projects from the nasal passages to neurons within the trigeminal medullary dorsal horn (MDH) via the anterior ethmoidal nerve (AEN). Central AEN terminals are thought to release glutamate to activate the MDH neurons. This study was designed to determine which neurotransmitter receptors (AMPA, kainate, or NMDA glutamate receptor subtypes or the Substance P receptor NK1) are expressed by these activated MDH neurons. Fos was used as a neuronal marker of activated neurons, and immunohistochemistry combined with epifluorescent microscopy was used to determine which neurotransmitter receptor subunits were coexpressed by activated MDH neurons. Results indicate that, during nasal stimulation with ammonia vapors in urethane-anesthetized Sprague-Dawley rats, activated neurons within the superficial MDH coexpress the AMPA glutamate receptor subunits GluA1 (95.8%) and GluA2/3 (88.2%), the NMDA glutamate receptor subunits GluN1 (89.1%) and GluN2A (41.4%), and NK1 receptors (64.0%). It is therefore likely that during nasal stimulation the central terminals of the AEN release glutamate and substance P that then produces activation of these MDH neurons. The involvement of AMPA and NMDA receptors may mediate fast and slow neurotransmission, respectively, while NK1 receptor involvement may indicate activation of a nociceptive pathway. PMID:24967301

Expression of vesicular glutamate transporters in peripheral vestibular structures and vestibular nuclear complex of rat.

PubMed

Zhang, F X; Pang, Y W; Zhang, M M; Zhang, T; Dong, Y L; Lai, C H; Shum, D K Y; Chan, Y S; Li, J L; Li, Y Q

2011-01-26

Glutamate transmission from vestibular end organs to central vestibular nuclear complex (VNC) plays important role in transferring sensory information about head position and movements. Three isoforms of vesicular glutamate transporters (VGLUTs) have been considered so far the most specific markers for glutamatergic neurons/cells. In this study, VGLUT1 and VGLUT2 were immunohistochemically localized to axon terminals in VNC and somata of vestibular primary afferents in association with their central and peripheral axon endings, and VGLUT1 and VGLUT3 were co-localized to hair cells of otolith maculae and cristae ampullaris. VGLUT1 and VGLUT2 defined three subsets of Scarpa's neurons (vestibular ganglionic neurons): those co-expressing VGLUT1 and VGLUT2 or expressing only VGLUT2, and those expressing neither. In addition, many neurons located in all vestibular subnuclei were observed to contain hybridized signals for VGLUT2 mRNA and a few VNC neurons, mostly scattered in medial vestibular nucleus (MVe), displayed VGLUT1 mRNA labelling. Following unilateral ganglionectomy, asymmetries of VGLUT1-immunoreactivity (ir) and VGLUT2-ir occurred between two VNCs, indicating that the VNC terminals containing VGLUT1 and/or VGLUT2 are partly of peripheral origin. The present data indicate that the constituent cells/neurons along the vestibular pathway selectively apply VGLUT isoforms to transport glutamate into synaptic vesicles for glutamate transmission. © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.

A bioinspired flexible organic artificial afferent nerve

NASA Astrophysics Data System (ADS)

Kim, Yeongin; Chortos, Alex; Xu, Wentao; Liu, Yuxin; Oh, Jin Young; Son, Donghee; Kang, Jiheong; Foudeh, Amir M.; Zhu, Chenxin; Lee, Yeongjun; Niu, Simiao; Liu, Jia; Pfattner, Raphael; Bao, Zhenan; Lee, Tae-Woo

2018-06-01

The distributed network of receptors, neurons, and synapses in the somatosensory system efficiently processes complex tactile information. We used flexible organic electronics to mimic the functions of a sensory nerve. Our artificial afferent nerve collects pressure information (1 to 80 kilopascals) from clusters of pressure sensors, converts the pressure information into action potentials (0 to 100 hertz) by using ring oscillators, and integrates the action potentials from multiple ring oscillators with a synaptic transistor. Biomimetic hierarchical structures can detect movement of an object, combine simultaneous pressure inputs, and distinguish braille characters. Furthermore, we connected our artificial afferent nerve to motor nerves to construct a hybrid bioelectronic reflex arc to actuate muscles. Our system has potential applications in neurorobotics and neuroprosthetics.

Neural readaptation to Earth's gravity following return from space.

PubMed

Boyle, R; Mensinger, A F; Yoshida, K; Usui, S; Intravaia, A; Tricas, T; Highstein, S M

2001-10-01

The consequence of exposure to microgravity on the otolith organs was studied by recording the responses of vestibular nerve afferents supplying the utricular otolith organ to inertial accelerations in four toadfish, Opsanus tau, sequentially for 5 days following two National Aeronautics and Space Administration shuttle orbital flights. Within the first day postflight, the magnitude of response to an applied translation was on average three times greater than for controls. The reduced gravitational acceleration in orbit apparently resulted in an upregulation of the sensitivity of utricular afferents. By 30 h postflight, responses were statistically similar to control. The time course of return to normal afferent sensitivity parallels the reported decrease in vestibular disorientation in astronauts following return from space.

Neural readaptation to Earth's gravity following return from space

NASA Technical Reports Server (NTRS)

Boyle, R.; Mensinger, A. F.; Yoshida, K.; Usui, S.; Intravaia, A.; Tricas, T.; Highstein, S. M.

2001-01-01

The consequence of exposure to microgravity on the otolith organs was studied by recording the responses of vestibular nerve afferents supplying the utricular otolith organ to inertial accelerations in four toadfish, Opsanus tau, sequentially for 5 days following two National Aeronautics and Space Administration shuttle orbital flights. Within the first day postflight, the magnitude of response to an applied translation was on average three times greater than for controls. The reduced gravitational acceleration in orbit apparently resulted in an upregulation of the sensitivity of utricular afferents. By 30 h postflight, responses were statistically similar to control. The time course of return to normal afferent sensitivity parallels the reported decrease in vestibular disorientation in astronauts following return from space.

Urothelial effects of oral agents for overactive bladder.

PubMed

Andersson, Karl-Erik; Fullhase, Claudius; Soler, Roberto

2008-11-01

The cholinergic system of the bladder includes muscarinic receptors distributed to detrusor myocytes and structures within mucosa including bladder afferent (sensory) nerves. The receptors have been shown to be involved in afferent signaling from the bladder, but it has not been established to what extent effects on this mucosal signaling pathway contribute to the therapeutic efficacy of the clinically used antimuscarinics. Mucosa can be influenced by antimuscarinics via the bloodstream. However, some antimuscarinics and their active metabolites are excreted in urine in amounts that may affect the mucosal muscarinic receptors from the luminal side. This has not yet been demonstrated to imply superior clinical efficacy. Nevertheless, mucosal afferent signaling pathways are therapeutically interesting targets that should be further explored.

On the nature of the afferent fibers of oculomotor nerve.

PubMed

Manni, E; Draicchio, F; Pettorossi, V E; Carobi, C; Grassi, S; Bortolami, R; Lucchi, M L

1989-03-01

The oculogyric nerves contain afferent fibers originating from the ophthalmic territory, the somata of which are located in the ipsilateral semilunar ganglion. These primary sensory neurons project to the Subnucleus Gelatinosus of the Nucleus Caudalis Trigemini, where they make presynaptic contact with the central endings of the primary trigeminal afferents running in the fifth cranial nerve. After complete section of the trigeminal root, the antidromic volleys elicited in the trunk of the third cranial nerve by stimulating SG of NCT consisted of two waves belonging to the A delta and C groups. The area of both components of the antidromic volleys decreased both after bradykinin and hystamine injection into the corresponding cutaneous region and after thermic stimulation of the ipsilateral trigeminal ophthalmic territory. The reduction of such potentials can be explained in terms of collision between the antidromic volleys and those elicited orthodromically by chemical and thermic stimulation. Also, capsaicin applied on the nerve induced an immediate increase, followed by a long lasting decrease, of orthodromic evoked response area. These findings bring further support to the nociceptive nature of the afferent fibers running into the oculomotor nerve.

A simple model of mechanotransduction in primate glabrous skin

PubMed Central

Dong, Yi; Mihalas, Stefan; Kim, Sung Soo; Yoshioka, Takashi; Niebur, Ernst

2013-01-01

Tactile stimulation of the hand evokes highly precise and repeatable patterns of activity in mechanoreceptive afferents; the strength (i.e., firing rate) and timing of these responses have been shown to convey stimulus information. To achieve an understanding of the mechanisms underlying the representation of tactile stimuli in the nerve, we developed a two-stage computational model consisting of a nonlinear mechanical transduction stage followed by a generalized integrate-and-fire mechanism. The model improves upon a recently published counterpart in two important ways. First, complexity is dramatically reduced (at least one order of magnitude fewer parameters). Second, the model comprises a saturating nonlinearity and therefore can be applied to a much wider range of stimuli. We show that both the rate and timing of afferent responses are predicted with remarkable precision and that observed adaptation patterns and threshold behavior are well captured. We conclude that the responses of mechanoreceptive afferents can be understood using a very parsimonious mechanistic model, which can then be used to accurately simulate the responses of afferent populations. PMID:23236001

Role of primary afferents in the developmental regulation of motor axon synapse numbers on Renshaw cells

PubMed Central

Siembab, Valerie C.; Gomez-Perez, Laura; Rotterman, Travis M.; Shneider, Neil A.; Alvarez, Francisco J.

2015-01-01

Motor function in mammalian species depends on the maturation of spinal circuits formed by a large variety of interneurons that regulate motoneuron firing and motor output. Interneuron activity is in turn modulated by the organization of their synaptic inputs, but the principles governing the development of specific synaptic architectures unique to each premotor interneuron are unknown. For example, Renshaw cells receive, at least in the neonate, convergent inputs from sensory afferents (likely Ia) and motor axons raising the question of whether they interact during Renshaw cell development. In other well-studied neurons, like Purkinje cells, heterosynaptic competition between inputs from different sources shapes synaptic organization. To examine the possibility that sensory afferents modulate synaptic maturation on developing Renshaw cells, we used three animal models in which afferent inputs in the ventral horn are dramatically reduced (Er81(−/−) knockout), weakened (Egr3(−/−) knockout) or strengthened (mlcNT3(+/−) transgenic). We demonstrate that increasing the strength of sensory inputs on Renshaw cells prevents their de-selection and reduces motor axon synaptic density and, in contrast, absent or diminished sensory afferent inputs correlate with increased densities of motor axons synapses. No effects were observed on other glutamatergic inputs. We conclude that the early strength of Ia synapses influences their maintenance or weakening during later development and that heterosynaptic influences from sensory synapses during early development regulates the density and organization of motor inputs on mature Renshaw cells. PMID:26660356

Spatiotemporal definition of neurite outgrowth, refinement and retraction in the developing mouse cochlea.

PubMed

Huang, Lin-Chien; Thorne, Peter R; Housley, Gary D; Montgomery, Johanna M

2007-08-01

The adult mammalian cochlea receives dual afferent innervation: the inner sensory hair cells are innervated exclusively by type I spiral ganglion neurons (SGN), whereas the sensory outer hair cells are innervated by type II SGN. We have characterized the spatiotemporal reorganization of the dual afferent innervation pattern as it is established in the developing mouse cochlea. This reorganization occurs during the first postnatal week just before the onset of hearing. Our data reveal three distinct phases in the development of the afferent innervation of the organ of Corti: (1) neurite growth and extension of both classes of afferents to all hair cells (E18-P0); (2) neurite refinement, with formation of the outer spiral bundles innervating outer hair cells (P0-P3); (3) neurite retraction and synaptic pruning to eliminate type I SGN innervation of outer hair cells, while retaining their innervation of inner hair cells (P3-P6). The characterization of this developmental innervation pattern was made possible by the finding that tetramethylrhodamine-conjugated dextran (TMRD) specifically labeled type I SGN. Peripherin and choline-acetyltransferase immunofluorescence confirmed the type II and efferent innervation patterns, respectively, and verified the specificity of the type I SGN neurites labeled by TMRD. These findings define the precise spatiotemporal neurite reorganization of the two afferent nerve fiber populations in the cochlea, which is crucial for auditory neurotransmission. This reorganization also establishes the cochlea as a model system for studying CNS synapse development, plasticity and elimination.

Measuring flow velocity and flow direction by spatial and temporal analysis of flow fluctuations.

PubMed

Chagnaud, Boris P; Brücker, Christoph; Hofmann, Michael H; Bleckmann, Horst

2008-04-23

If exposed to bulk water flow, fish lateral line afferents respond only to flow fluctuations (AC) and not to the steady (DC) component of the flow. Consequently, a single lateral line afferent can encode neither bulk flow direction nor velocity. It is possible, however, for a fish to obtain bulk flow information using multiple afferents that respond only to flow fluctuations. We show by means of particle image velocimetry that, if a flow contains fluctuations, these fluctuations propagate with the flow. A cross-correlation of water motion measured at an upstream point with that at a downstream point can then provide information about flow velocity and flow direction. In this study, we recorded from pairs of primary lateral line afferents while a fish was exposed to either bulk water flow, or to the water motion caused by a moving object. We confirm that lateral line afferents responded to the flow fluctuations and not to the DC component of the flow, and that responses of many fiber pairs were highly correlated, if they were time-shifted to correct for gross flow velocity and gross flow direction. To prove that a cross-correlation mechanism can be used to retrieve the information about gross flow velocity and direction, we measured the flow-induced bending motions of two flexible micropillars separated in a downstream direction. A cross-correlation of the bending motions of these micropillars did indeed produce an accurate estimate of the velocity vector along the direction of the micropillars.

Attention modulates specific motor cortical circuits recruited by transcranial magnetic stimulation.

PubMed

Mirdamadi, J L; Suzuki, L Y; Meehan, S K

2017-09-17

Skilled performance and acquisition is dependent upon afferent input to motor cortex. The present study used short-latency afferent inhibition (SAI) to probe how manipulation of sensory afference by attention affects different circuits projecting to pyramidal tract neurons in motor cortex. SAI was assessed in the first dorsal interosseous muscle while participants performed a low or high attention-demanding visual detection task. SAI was evoked by preceding a suprathreshold transcranial magnetic stimulus with electrical stimulation of the median nerve at the wrist. To isolate different afferent intracortical circuits in motor cortex SAI was evoked using either posterior-anterior (PA) or anterior-posterior (PA) monophasic current. In an independent sample, somatosensory processing during the same attention-demanding visual detection tasks was assessed using somatosensory-evoked potentials (SEP) elicited by median nerve stimulation. SAI elicited by AP TMS was reduced under high compared to low visual attention demands. SAI elicited by PA TMS was not affected by visual attention demands. SEPs revealed that the high visual attention load reduced the fronto-central P20-N30 but not the contralateral parietal N20-P25 SEP component. P20-N30 reduction confirmed that the visual attention task altered sensory afference. The current results offer further support that PA and AP TMS recruit different neuronal circuits. AP circuits may be one substrate by which cognitive strategies shape sensorimotor processing during skilled movement by altering sensory processing in premotor areas. Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

Self-organizing neural network models for visual pattern recognition.

PubMed

Fukushima, K

1987-01-01

Two neural network models for visual pattern recognition are discussed. The first model, called a "neocognitron", is a hierarchical multilayered network which has only afferent synaptic connections. It can acquire the ability to recognize patterns by "learning-without-a-teacher": the repeated presentation of a set of training patterns is sufficient, and no information about the categories of the patterns is necessary. The cells of the highest stage eventually become "gnostic cells", whose response shows the final result of the pattern-recognition of the network. Pattern recognition is performed on the basis of similarity in shape between patterns, and is not affected by deformation, nor by changes in size, nor by shifts in the position of the stimulus pattern. The second model has not only afferent but also efferent synaptic connections, and is endowed with the function of selective attention. The afferent and the efferent signals interact with each other in the hierarchical network: the efferent signals, that is, the signals for selective attention, have a facilitating effect on the afferent signals, and at the same time, the afferent signals gate efferent signal flow. When a complex figure, consisting of two patterns or more, is presented to the model, it is segmented into individual patterns, and each pattern is recognized separately. Even if one of the patterns to which the models is paying selective attention is affected by noise or defects, the model can "recall" the complete pattern from which the noise has been eliminated and the defects corrected.

Physiology of primary saccular afferents of goldfish: implications for Mauthner cell response.

PubMed

Fay, R R

1995-01-01

Mauthner cells receive neurally coded information from the otolith organs in fishes, and it is most likely that initiation and directional characteristics of the C-start response depend on this input. In the goldfish, saccular afferents are sensitive to sound pressure (< -30 dB re: 1 dyne cm-2) in the most sensitive frequency range (200 to 800 Hz). This input arises from volume fluctuations of the swimbladder in response to the sound pressure waveform and is thus nondirectional. Primary afferents of the saccule, lagena, and utricle of the goldfish also respond with great sensitivity to acoustic particle motion (< 1 nanometer between 100 and 200 Hz). This input arises from the acceleration of the fish in a sound field and is inherently directional. Saccular afferents can be divided into two groups based on their tuning: one group is tuned at about 250 Hz, and the other tuned between 400 Hz and 1 kHz. All otolithic primary afferents phaselock to sinusoids throughout the frequency range of hearing (up to about 2 kHz). Based on physiological and behavioral studies on Mauthner cells, it appears that highly correlated binaural input to the M-cell, from the sacculi responding to sound pressure, may be required for a decision to respond but that the direction of the response is extracted from small deviations from a perfect interaural correlation arising from the directional response of otolith organs to acoustic particle motion.

Sensory Feedback in Interlimb Coordination: Contralateral Afferent Contribution to the Short-Latency Crossed Response during Human Walking.

PubMed

Gervasio, Sabata; Voigt, Michael; Kersting, Uwe G; Farina, Dario; Sinkjær, Thomas; Mrachacz-Kersting, Natalie

2017-01-01

A constant coordination between the left and right leg is required to maintain stability during human locomotion, especially in a variable environment. The neural mechanisms underlying this interlimb coordination are not yet known. In animals, interneurons located within the spinal cord allow direct communication between the two sides without the need for the involvement of higher centers. These may also exist in humans since sensory feedback elicited by tibial nerve stimulation on one side (ipsilateral) can affect the muscles activation in the opposite side (contralateral), provoking short-latency crossed responses (SLCRs). The current study investigated whether contralateral afferent feedback contributes to the mechanism controlling the SLCR in human gastrocnemius muscle. Surface electromyogram, kinematic and kinetic data were recorded from subjects during normal walking and hybrid walking (with the legs moving in opposite directions). An inverse dynamics model was applied to estimate the gastrocnemius muscle proprioceptors' firing rate. During normal walking, a significant correlation was observed between the magnitude of SLCRs and the estimated muscle spindle secondary afferent activity (P = 0.04). Moreover, estimated spindle secondary afferent and Golgi tendon organ activity were significantly different (P ≤ 0.01) when opposite responses have been observed, that is during normal (facilitation) and hybrid walking (inhibition) conditions. Contralateral sensory feedback, specifically spindle secondary afferents, likely plays a significant role in generating the SLCR. This observation has important implications for our understanding of what future research should be focusing on to optimize locomotor recovery in patient populations.

New perspectives concerning feedback influences on cardiorespiratory control during rhythmic exercise and on exercise performance.

PubMed

Dempsey, Jerome A

2012-09-01

The cardioaccelerator and ventilatory responses to rhythmic exercise in the human are commonly viewed as being mediated predominantly via feedforward 'central command' mechanisms, with contributions from locomotor muscle afferents to the sympathetically mediated pressor response. We have assessed the relative contributions of three types of feedback afferents on the cardiorespiratory response to voluntary, rhythmic exercise by inhibiting their normal 'tonic' activity in healthy animals and humans and in chronic heart failure. Transient inhibition of the carotid chemoreceptors during moderate intensity exercise reduced muscle sympathetic nerve activity (MSNA) and increased limb vascular conductance and blood flow; and reducing the normal level of respiratory muscle work during heavier intensity exercise increased limb vascular conductance and blood flow. These cardiorespiratory effects were prevented via ganglionic blockade and were enhanced in chronic heart failure and in hypoxia. Blockade of μ opioid sensitive locomotor muscle afferents, with preservation of central motor output via intrathecal fentanyl: (a) reduced the mean arterial blood pressure (MAP), heart rate and ventilatory responses to all steady state exercise intensities; and (b) during sustained high intensity exercise, reduced O(2) transport, increased central motor output and end-exercise muscle fatigue and reduced endurance performance. We propose that these three afferent reflexes - probably acting in concert with feedforward central command - contribute significantly to preserving O(2) transport to locomotor and to respiratory muscles during exercise. Locomotor muscle afferents also appear to provide feedback concerning the metabolic state of the muscle to influence central motor output, thereby limiting peripheral fatigue development.

Dural afferents express acid-sensing ion channels: a role for decreased meningeal pH in migraine headache.

PubMed

Yan, Jin; Edelmayer, Rebecca M; Wei, Xiaomei; De Felice, Milena; Porreca, Frank; Dussor, Gregory

2011-01-01

Migraine headache is one of the most common neurological disorders. The pathological conditions that directly initiate afferent pain signaling are poorly understood. In trigeminal neurons retrogradely labeled from the cranial meninges, we have recorded pH-evoked currents using whole-cell patch-clamp electrophysiology. Approximately 80% of dural-afferent neurons responded to a pH 6.0 application with a rapidly activating and rapidly desensitizing ASIC-like current that often exceeded 20nA in amplitude. Inward currents were observed in response to a wide range of pH values and 30% of the neurons exhibited inward currents at pH 7.1. These currents led to action potentials in 53%, 30% and 7% of the dural afferents at pH 6.8, 6.9 and 7.0, respectively. Small decreases in extracellular pH were also able to generate sustained window currents and sustained membrane depolarizations. Amiloride, a non-specific blocker of ASIC channels, inhibited the peak currents evoked upon application of decreased pH while no inhibition was observed upon application of TRPV1 antagonists. The desensitization time constant of pH 6.0-evoked currents in the majority of dural afferents was less than 500ms which is consistent with that reported for ASIC3 homomeric or heteromeric channels. Finally, application of pH 5.0 synthetic-interstitial fluid to the dura produced significant decreases in facial and hind-paw withdrawal threshold, an effect blocked by amiloride but not TRPV1 antagonists, suggesting that ASIC activation produces migraine-related behavior in vivo. These data provide a cellular mechanism by which decreased pH in the meninges following ischemic or inflammatory events directly excites afferent pain-sensing neurons potentially contributing to migraine headache. Copyright © 2010 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

A role for protein kinase intracellular messengers in substance P- and nociceptor afferent-mediated excitation and expression of the transcription factor Fos in rat dorsal horn neurons in vitro.

PubMed

Badie-Mahdavi, H; Worsley, M A; Ackley, M A; Asghar, A U; Slack, J R; King, A E

2001-08-01

Expression of the inducible transcription factor Fos in the spinal dorsal horn in vivo is associated with nociceptive afferent activation, but the underlying stimulation-transcription pathway is less clear. This in vitro spinal cord study concerns the role of protein kinase A and C second messengers in substance P receptor (NK1R)-mediated or nociceptive afferent-evoked neuronal excitation and Fos expression. Nociceptive afferent (dorsal root) stimulation of isolated spinal cords (10-14 day old rats) evoked a 'prolonged' excitatory polysynaptic potential (DR-EPSP) that was attenuated (P < 0.05) by: the protein kinase A inhibitor, Rp-cAMP; the protein kinase C inhibitor, bisindolymaleimide I; and the selective NK1R antagonist, GR82334. Neuronal excitations induced by the NK1R agonist [Sar9,Met(O2)11]-SP were attenuated by Rp-cAMP, bisindolymaleimide I and GR82334. Effects of the protein kinase A and C inhibitors on the DR-EPSP or the [Sar9,Met(O2)11]-SP-induced depolarization were nonadditive, suggesting convergence of these intracellular signalling pathways onto a common final target. Nociceptor afferent-induced Fos, detected by immunohistochemistry in superficial and deep dorsal horn laminae, was attenuated by Rp-cAMP, bisindolymaleimide I and GR82334. In spinal cords pretreated with TTX to eliminate indirect neuronal activation, [Sar9,Met(O2)11]-SP (1-20 microM) elicited a dose-related expression of Fos that was reduced by Rp-cAMP, bisindolymaleimide I and GR82334. The effects of these inhibitors were most pronounced in the deep laminae. These data support a causal relationship between protein kinase A- or C-dependent signal transduction, nociceptive afferent- or NK1R-induced neuronal excitation and Fos expression in dorsal horn. Implications for short- versus long-term modulation of nociceptive circuitry are discussed.

Activation of GLP-1 receptors on vascular smooth muscle cells reduces the autoregulatory response in afferent arterioles and increases renal blood flow.

PubMed

Jensen, Elisa P; Poulsen, Steen S; Kissow, Hannelouise; Holstein-Rathlou, Niels-Henrik; Deacon, Carolyn F; Jensen, Boye L; Holst, Jens J; Sorensen, Charlotte M

2015-04-15

Glucagon-like peptide (GLP)-1 has a range of extrapancreatic effects, including renal effects. The mechanisms are poorly understood, but GLP-1 receptors have been identified in the kidney. However, the exact cellular localization of the renal receptors is poorly described. The aim of the present study was to localize renal GLP-1 receptors and describe GLP-1-mediated effects on the renal vasculature. We hypothesized that renal GLP-1 receptors are located in the renal microcirculation and that activation of these affects renal autoregulation and increases renal blood flow. In vivo autoradiography using (125)I-labeled GLP-1, (125)I-labeled exendin-4 (GLP-1 analog), and (125)I-labeled exendin 9-39 (GLP-1 receptor antagonist) was performed in rodents to localize specific GLP-1 receptor binding. GLP-1-mediated effects on blood pressure, renal blood flow (RBF), heart rate, renin secretion, urinary flow rate, and Na(+) and K(+) excretion were investigated in anesthetized rats. Effects of GLP-1 on afferent arterioles were investigated in isolated mouse kidneys. Specific binding of (125)I-labeled GLP-1, (125)I-labeled exendin-4, and (125)I-labeled exendin 9-39 was observed in the renal vasculature, including afferent arterioles. Infusion of GLP-1 increased blood pressure, RBF, and urinary flow rate significantly in rats. Heart rate and plasma renin concentrations were unchanged. Exendin 9-39 inhibited the increase in RBF. In isolated murine kidneys, GLP-1 and exendin-4 significantly reduced the autoregulatory response of afferent arterioles in response to stepwise increases in pressure. We conclude that GLP-1 receptors are located in the renal vasculature, including afferent arterioles. Activation of these receptors reduces the autoregulatory response of afferent arterioles to acute pressure increases and increases RBF in normotensive rats. Copyright © 2015 the American Physiological Society.

Effects of stimulation of muscarinic receptors on bladder afferent nerves in the in vitro bladder-pelvic afferent nerve preparation of the rat.

PubMed

Yu, Yongbei; de Groat, William C

2010-11-18

Effects of a muscarinic receptor agonist oxotremorine-M (oxo-M) on bladder afferent nerve (BAN) activity were studied in an in vitro bladder-pelvic nerve preparation. Distension of the bladder induced rhythmic bladder contractions that were accompanied by multiunit afferent firing. Intravesical administration of 25 and 50 μM oxo-M significantly increased afferent firing from 41 ± 2 spikes/s to 51 ± 4 spikes/s and 60.5 ± 5 spikes/s, respectively, but did not change the maximum amplitude of spontaneous bladder contractions. The afferent nerve firing induced by isotonic distension of the bladder (10-40 cmH(2)O) was increased 22-100% by intravesical administration of 50 μM oxo-M. Electrical stimulation on the surface of the bladder elicited action potentials (AP) in BAN. Oxo-M significantly decreased the voltage threshold by 40% (p<0.05) and increased by 157% (p<0.05) the area of the AP evoked at a submaximal stimulus intensity. These effects were blocked by intravesical injection of 5 μM atropine methyl nitrate (AMN). Intravesical administration of 5 μM AMN alone did not alter BAN firing or the amplitude of bladder contractions. The facilitatory effects induced by oxo-M on BAN activity were also suppressed (p<0.05) by intravesical administration of 2',3'-0-trinitrophenyl-ATP (TNP-ATP) (30 μM). In preparations pretreated with capsaicin (125 mg/kg, s.c.) the facilitatory effects of 50 μM oxo-M on BAN activity were absent. These results suggest that activation of muscarinic receptors facilitates mechano-sensitive, capsaicin-sensitive BAN activity in part by mechanisms involving purinergic receptors located near the luminal surface of the bladder and ATP release which presumably occurs in the urothelium. Copyright © 2010 Elsevier B.V. All rights reserved.

Sympatho-excitatory response to pulmonary chemosensitive spinal afferent activation in anesthetized, vagotomized rats.

PubMed

Shanks, Julia; Xia, Zhiqiu; Lisco, Steven J; Rozanski, George J; Schultz, Harold D; Zucker, Irving H; Wang, Han-Jun

2018-06-01

The sensory innervation of the lung is well known to be innervated by nerve fibers of both vagal and sympathetic origin. Although the vagal afferent innervation of the lung has been well characterized, less is known about physiological effects mediated by spinal sympathetic afferent fibers. We hypothesized that activation of sympathetic spinal afferent nerve fibers of the lung would result in an excitatory pressor reflex, similar to that previously characterized in the heart. In this study, we evaluated changes in renal sympathetic nerve activity (RSNA) and hemodynamics in response to activation of TRPV1-sensitive pulmonary spinal sensory fibers by agonist application to the visceral pleura of the lung and by administration into the primary bronchus in anesthetized, bilaterally vagotomized, adult Sprague-Dawley rats. Application of bradykinin (BK) to the visceral pleura of the lung produced an increase in mean arterial pressure (MAP), heart rate (HR), and RSNA. This response was significantly greater when BK was applied to the ventral surface of the left lung compared to the dorsal surface. Conversely, topical application of capsaicin (Cap) onto the visceral pleura of the lung, produced a biphasic reflex change in MAP, coupled with increases in HR and RSNA which was very similar to the hemodynamic response to epicardial application of Cap. This reflex was also evoked in animals with intact pulmonary vagal innervation and when BK was applied to the distal airways of the lung via the left primary bronchus. In order to further confirm the origin of this reflex, epidural application of a selective afferent neurotoxin (resiniferatoxin, RTX) was used to chronically ablate thoracic TRPV1-expressing afferent soma at the level of T1-T4 dorsal root ganglia pleura. This treatment abolished all sympatho-excitatory responses to both cardiac and pulmonary application of BK and Cap in vagotomized rats 9-10 weeks post-RTX. These data suggest the presence of an excitatory pulmonary chemosensitive sympathetic afferent reflex. This finding may have important clinical implications in pulmonary conditions inducing sensory nerve activation such as pulmonary inflammation and inhalation of chemical stimuli. © 2018 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

Ageing and gastrointestinal sensory function: altered colonic mechanosensory and chemosensory function in the aged mouse

PubMed Central

Keating, Christopher; Nocchi, Linda; Yu, Yang; Donovan, Jemma; Grundy, David

2016-01-01

Key points Remarkably little is known about how age affects the sensory signalling pathways in the gastrointestinal tract despite age‐related gastrointestinal dysfunction being a prime cause of morbidity amongst the elderly populationHigh‐threshold gastrointestinal sensory nerves play a key role in signalling distressing information from the gut to the brain.We found that ageing is associated with attenuated high‐threshold afferent mechanosensitivity in the murine colon, and associated loss of TRPV1 channel function.These units have the capacity to sensitise in response to injurious events, and their loss in ageing may predispose the elderly to lower awareness of GI injury or disease. Abstract Ageing has a profound effect upon gastrointestinal function through mechanisms that are poorly understood. Here we investigated the effect of age upon gastrointestinal sensory signalling pathways in order to address the mechanisms underlying these changes. In vitro mouse colonic and jejunal preparations with attached splanchnic and mesenteric nerves were used to study mechanosensory and chemosensory afferent function in 3‐, 12‐ and 24‐month‐old C57BL/6 animals. Quantitative RT‐PCR was used to investigate mRNA expression in colonic tissue and dorsal root ganglion (DRG) cells isolated from 3‐ and 24‐month animals, and immunohistochemistry was used to quantify the number of 5‐HT‐expressing enterochromaffin (EC) cells. Colonic and jejunal afferent mechanosensory function was attenuated with age and these effects appeared earlier in the colon compared to the jejunum. Colonic age‐related loss of mechanosensory function was more pronounced in high‐threshold afferents compared to low‐threshold afferents. Chemosensory function was attenuated in the 24‐month colon, affecting TRPV1 and serotonergic signalling pathways. High‐threshold mechanosensory afferent fibres and small‐diameter DRG neurons possessed lower functional TRPV1 receptor responses, which occurred without a change in TRPV1 mRNA expression. Serotonergic signalling was attenuated at 24 months, but TPH1 and TPH2 mRNA expression was elevated in colonic tissue. In conclusion, we saw an age‐associated decrease in afferent mechanosensitivity in the mouse colon affecting HT units. These units have the capacity to sensitise in response to injurious events, and their loss in ageing may predispose the elderly to lower awareness of GI injury or disease. PMID:26592729

Capsaicin-sensitive intestinal mucosal afferent mechanism and body fat distribution.

PubMed

Leung, Felix W

2008-07-04

This report summarizes clinical and experimental data in support of the hypothesis that capsaicin-sensitive intestinal mucosal afferent mechanism plays a role in regulating body fat distribution. Epidemiological data have revealed that the consumption of foods containing capsaicin is associated with a lower prevalence of obesity. Rural Thai people consume diets containing 0.014% capsaicin. Rodents fed a diet containing 0.014% capsaicin showed no change in caloric intake but a significant 24% and 29% reduction in the visceral (peri-renal) fat weight. Increase in intestinal blood flow facilitates nutrient energy absorption and decrease in adipose tissue blood flow facilitates storage of nutrient energy in adipose tissue. Stimulation of intestinal mucosal afferent nerves increases intestinal blood flow, but decreases visceral (mesenteric) adipost tissue blood flow. In in vitro cell studies capsaicin has a direct effect on adipocytes. Intravenous capsaicin produces measurable plasma level and subcutaneous capsaicin retards accumulation of adipose tissue. The data on a direct effect of oral capsaicin on adipose tissue at remote sites, however, are conflicting. Capsaicin absorbed from the gut lumen is almost completely metabolized before reaching the general circulation. Oral capsaicin significantly increases transient receptor potential vanilloid type-1 (TRPV1) channel expression as well as TRPV1 messenger ribonucleic acid (mRNA) in visceral adipose tissue. In TRPV1 knockout mice on a high fat diet the body weight was not significantly different in the absence or presence of oral capsaicin. In rodent experiments, daily intragastric administration of capsaicin for two weeks led to defunctionalization of intestinal mucosal afferent nerves, manifested by loss of acute mucosal capsaicin-induced effects; but not the corneal afferent nerves, with preservation of the paw wiping reflex of the eye exposed briefly to dilute capsaicin. The latter indicated the absence of an oral capsaicin effect at one remote site. There was an accompanying decrease and an increase in the proportion of body fat in visceral and subcutaenous compartments, respectively. Taken together, if oral capsaicin could regulate adipose tissue distribution, the process might involve the effect of intestinal mucosal afferent nerves in modulating intestinal and visceral adipose tissue blood flow. The hypothesis that the intestinal mucosal afferent mechanism is a plausible therapeutic target for abating visceral obesity deserves to be further evaluated.

Effects and distribution of vagal capsaicin-sensitive substance P neurons with special reference to the trachea and lungs.

PubMed

Lundberg, J M; Brodin, E; Saria, A

1983-11-01

The origin of substance P (SP)-immunoreactive neurons in the lower respiratory tract, esophagus and heart of guinea-pigs was demonstrated by surgical denervation or capsaicin pretreatment with subsequent determination of the tissue levels of SP by radioimmunoassay. In other experiments the effect of vagal nerve stimulation on the SP levels in these tissues was studied. The effects of capsaicin-sensitive afferents in the respiratory tract mucosa and bronchial smooth muscle was also studied by analysis of vascular permeability to Evans blue and insufflation-pressure changes. Our present data indicate that all SP nerves in the trachea and lung are afferent and capsaicin-sensitive. The trachea and stem bronchi receive SP afferents mainly from the right vagus nerve with cell bodies located in both the nodose and jugular ganglia. The SP innervation of the lung seems to have a dual origin: 1. Afferents from both vagal nerves with a crossed type of innervation pattern. 2. A non-vagal source which consists of about 40% of the SP nerves in the lung. These nerves probably originate from thoracic spinal ganglia. The effects of ether and capsaicin on insufflation pressure and increase in vascular permeability were dependent on the integrity of capsaicin-sensitive afferents of both vagal and non-vagal origin. In the guinea pig, systemic capsaicin pretreatment to adult animals seemed to result in irreversible changes in the respiratory tract, while in the rat a successive recovery of the functional response of capsaicin-sensitive afferents occurred. Different regimes of systemic capsaicin pretreatment induced different effects on the cholinergic (atropine-sensitive) insufflation-pressure response. Capsaicin pretreatment, using multiple injections over two days, depressed the cholinergic insufflation-pressure increase, while the cholinergic vagal component was unaffected in animals which received a single dose of capsaicin or local pretreatment with capsaicin on the vagal nerves. The local treatment was more effective with regard to SP depletion in target areas when using alcohol as solvent than when capsaicin was dissolved in paraffin oil, while the functional deficits were similar. The SP nerves in the esophagus were mainly of vagal afferent origin, while the heart atrium seemed to have a dual innervation by both vagal and non-vagal SP nerves.

Selective Deletion of Sodium Salt Taste during Development Leads to Expanded Terminal Fields of Gustatory Nerves in the Adult Mouse Nucleus of the Solitary Tract.

PubMed

Sun, Chengsan; Hummler, Edith; Hill, David L

2017-01-18

Neuronal activity plays a key role in the development of sensory circuits in the mammalian brain. In the gustatory system, experimental manipulations now exist, through genetic manipulations of specific taste transduction processes, to examine how specific taste qualities (i.e., basic tastes) impact the functional and structural development of gustatory circuits. Here, we used a mouse knock-out model in which the transduction component used to discriminate sodium salts from other taste stimuli was deleted in taste bud cells throughout development. We used this model to test the hypothesis that the lack of activity elicited by sodium salt taste impacts the terminal field organization of nerves that carry taste information from taste buds to the nucleus of the solitary tract (NST) in the medulla. The glossopharyngeal, chorda tympani, and greater superficial petrosal nerves were labeled to examine their terminal fields in adult control mice and in adult mice in which the α-subunit of the epithelial sodium channel was conditionally deleted in taste buds (αENaC knockout). The terminal fields of all three nerves in the NST were up to 2.7 times greater in αENaC knock-out mice compared with the respective field volumes in control mice. The shapes of the fields were similar between the two groups; however, the density and spread of labels were greater in αENaC knock-out mice. Overall, our results show that disruption of the afferent taste signal to sodium salts disrupts the normal age-dependent "pruning" of all terminal fields, which could lead to alterations in sensory coding and taste-related behaviors. Neural activity plays a major role in the development of sensory circuits in the mammalian brain. To date, there has been no direct test of whether taste-elicited neural activity has a role in shaping central gustatory circuits. However, recently developed genetic tools now allow an assessment of how specific taste stimuli, in this case sodium salt taste, play a role in the maturation of the terminal fields in the mouse brainstem. We found that the specific deletion of sodium salt taste during development produced terminal fields in adults that were dramatically larger than in control mice, demonstrating for the first time that sodium salt taste-elicited activity is necessary for the normal maturation of gustatory inputs into the brain. Copyright © 2017 the authors 0270-6474/17/370660-13$15.00/0.

Selective Deletion of Sodium Salt Taste during Development Leads to Expanded Terminal Fields of Gustatory Nerves in the Adult Mouse Nucleus of the Solitary Tract

PubMed Central

Sun, Chengsan; Hummler, Edith

2017-01-01

Neuronal activity plays a key role in the development of sensory circuits in the mammalian brain. In the gustatory system, experimental manipulations now exist, through genetic manipulations of specific taste transduction processes, to examine how specific taste qualities (i.e., basic tastes) impact the functional and structural development of gustatory circuits. Here, we used a mouse knock-out model in which the transduction component used to discriminate sodium salts from other taste stimuli was deleted in taste bud cells throughout development. We used this model to test the hypothesis that the lack of activity elicited by sodium salt taste impacts the terminal field organization of nerves that carry taste information from taste buds to the nucleus of the solitary tract (NST) in the medulla. The glossopharyngeal, chorda tympani, and greater superficial petrosal nerves were labeled to examine their terminal fields in adult control mice and in adult mice in which the α-subunit of the epithelial sodium channel was conditionally deleted in taste buds (αENaC knockout). The terminal fields of all three nerves in the NST were up to 2.7 times greater in αENaC knock-out mice compared with the respective field volumes in control mice. The shapes of the fields were similar between the two groups; however, the density and spread of labels were greater in αENaC knock-out mice. Overall, our results show that disruption of the afferent taste signal to sodium salts disrupts the normal age-dependent “pruning” of all terminal fields, which could lead to alterations in sensory coding and taste-related behaviors. SIGNIFICANCE STATEMENT Neural activity plays a major role in the development of sensory circuits in the mammalian brain. To date, there has been no direct test of whether taste-elicited neural activity has a role in shaping central gustatory circuits. However, recently developed genetic tools now allow an assessment of how specific taste stimuli, in this case sodium salt taste, play a role in the maturation of the terminal fields in the mouse brainstem. We found that the specific deletion of sodium salt taste during development produced terminal fields in adults that were dramatically larger than in control mice, demonstrating for the first time that sodium salt taste-elicited activity is necessary for the normal maturation of gustatory inputs into the brain. PMID:28100747

Development and Implementation of Sepsis Alert Systems.

PubMed

Harrison, Andrew M; Gajic, Ognjen; Pickering, Brian W; Herasevich, Vitaly

2016-06-01

Development and implementation of sepsis alert systems is challenging, particularly outside the monitored intensive care unit (ICU) setting. Barriers to wider use of sepsis alerts include evolving clinical definitions of sepsis, information overload, and alert fatigue, due to suboptimal alert performance. Outside the ICU, barriers include differences in health care delivery models, charting behaviors, and availability of electronic data. Current evidence does not support routine use of sepsis alert systems in clinical practice. Continuous improvement in the afferent and efferent aspects will help translate theoretic advantages into measurable patient benefit. Copyright © 2016 Elsevier Inc. All rights reserved.

[Renal denervation as treatment option for hypertension].

PubMed

Blankestijn, P J; Bots, M L

2016-01-01

The rationale behind catheter-based renal denervation is that afferent and efferent renal nerves play a role in the pathogenesis and maintenance of high blood pressure, and that this can be prevented by blocking the function of the renal nerves. Since the introduction of catheter-based renal denervation, several observational and a small number of randomised controlled trials have been conducted. The available evidence does not allow for a definitive conclusion regarding its efficacy. There have been no serious side-effects reported. The development of this treatment concept has not been finalised; new trials have just commenced or will start in the near future.

Characterization of auditory synaptic inputs to gerbil perirhinal cortex

PubMed Central

Kotak, Vibhakar C.; Mowery, Todd M.; Sanes, Dan H.

2015-01-01

The representation of acoustic cues involves regions downstream from the auditory cortex (ACx). One such area, the perirhinal cortex (PRh), processes sensory signals containing mnemonic information. Therefore, our goal was to assess whether PRh receives auditory inputs from the auditory thalamus (MG) and ACx in an auditory thalamocortical brain slice preparation and characterize these afferent-driven synaptic properties. When the MG or ACx was electrically stimulated, synaptic responses were recorded from the PRh neurons. Blockade of type A gamma-aminobutyric acid (GABA-A) receptors dramatically increased the amplitude of evoked excitatory potentials. Stimulation of the MG or ACx also evoked calcium transients in most PRh neurons. Separately, when fluoro ruby was injected in ACx in vivo, anterogradely labeled axons and terminals were observed in the PRh. Collectively, these data show that the PRh integrates auditory information from the MG and ACx and that auditory driven inhibition dominates the postsynaptic responses in a non-sensory cortical region downstream from the ACx. PMID:26321918

A DISCRETE-EVENT SIMULATION APPROACH TO IDENTIFY RULES THAT GOVERN ARBOR REMODELING FOR BRANCHING CUTANEOUS AFFERENTS IN HAIRY SKIN

PubMed Central

Kang, Hyojung; Orlowsky, Rachel L.; Gerling, Gregory J.

2018-01-01

In mammals, touch is encoded by sensory receptors embedded in the skin. For one class of receptors in the mouse, the architecture of its Merkel cells, unmyelinated neurites, and heminodes follow particular renewal and remodeling trends over hair cycle stages from ages 4 to 10 weeks. As it is currently impossible to observe such trends across a single animal’s hair cycle, this work employs discrete event simulation to identify and evaluate policies of Merkel cell and heminode dynamics. Well matching the observed data, the results show that the baseline model replicates dynamic remodeling behaviors between stages of the hair cycle – based on particular addition and removal polices and estimated probabilities tied to constituent parts of Merkel cells, terminal branch neurites and heminodes. The analysis shows further that certain policies hold greater influence than others. This use of computation is a novel approach to understanding neuronal development. PMID:29527094

Two receptor tyrosine phosphatases dictate the depth of axonal stabilizing layer in the visual system

PubMed Central

Takechi, Hiroki; Kawamura, Hinata

2017-01-01

Formation of a functional neuronal network requires not only precise target recognition, but also stabilization of axonal contacts within their appropriate synaptic layers. Little is known about the molecular mechanisms underlying the stabilization of axonal connections after reaching their specifically targeted layers. Here, we show that two receptor protein tyrosine phosphatases (RPTPs), LAR and Ptp69D, act redundantly in photoreceptor afferents to stabilize axonal connections to the specific layers of the Drosophila visual system. Surprisingly, by combining loss-of-function and genetic rescue experiments, we found that the depth of the final layer of stable termination relied primarily on the cumulative amount of LAR and Ptp69D cytoplasmic activity, while specific features of their ectodomains contribute to the choice between two synaptic layers, M3 and M6, in the medulla. These data demonstrate how the combination of overlapping downstream but diversified upstream properties of two RPTPs can shape layer-specific wiring. PMID:29116043

Ziconotide for treatment of severe chronic pain.

PubMed

Schmidtko, Achim; Lötsch, Jörn; Freynhagen, Rainer; Geisslinger, Gerd

2010-05-01

Pharmacological management of severe chronic pain is difficult to achieve with currently available analgesic drugs, and remains a large unmet therapeutic need. The synthetic peptide ziconotide has been approved by the US Food and Drug Administration and the European Medicines Agency for intrathecal treatment of patients with severe chronic pain that is refractory to other treatment modalities. Ziconotide is the first member in the new drug class of selective N-type voltage-sensitive calcium-channel blockers. The ziconotide-induced blockade of N-type calcium channels in the spinal cord inhibits release of pain-relevant neurotransmitters from central terminals of primary afferent neurons. By this mechanism, ziconotide can effectively reduce pain. However, ziconotide has a narrow therapeutic window because of substantial CNS side-effects, and thus treatment with ziconotide is appropriate for only a small subset of patients with severe chronic pain. We provide an overview of the benefits and limitations of intrathecal ziconotide treatment and review potential future developments in this new drug class. Copyright 2010 Elsevier Ltd. All rights reserved.

Differential Role of Inhibition in Habituation of Two Independent Afferent Pathways to a Common Motor Output

ERIC Educational Resources Information Center

Bristol, Adam S.; Carew, Thomas J.

2005-01-01

Many studies of the neural mechanisms of learning have focused on habituation, a simple form of learning in which a response decrements with repeated stimulation. In the siphon-elicited siphon withdrawal reflex (S-SWR) of the marine mollusk "Aplysia," the prevailing view is that homosynaptic depression of primary sensory afferents underlies…

NEURAL NETWORK INTERACTIONS AND INGESTIVE BEHAVIOR CONTROL DURING ANOREXIA

PubMed Central

Watts, Alan G.; Salter, Dawna S.; Neuner, Christina M.

2007-01-01

Many models have been proposed over the years to explain how motivated feeding behavior is controlled. One of the most compelling is based on the original concepts of Eliot Stellar whereby sets of interosensory and exterosensory inputs converge on a hypothalamic control network that can either stimulate or inhibit feeding. These inputs arise from information originating in the blood, the viscera, and the telencephalon. In this manner the relative strengths of the hypothalamic stimulatory and inhibitory networks at a particular time dictates how an animal feeds. Anorexia occurs when the balance within the networks consistently favors the restraint of feeding. This article discusses experimental evidence supporting a model whereby the increases in plasma osmolality that result from drinking hypertonic saline activate pathways projecting to neurons in the paraventricular nucleus of the hypothalamus (PVH) and lateral hypothalamic area (LHA). These neurons constitute the hypothalamic controller for ingestive behavior, and receive a set of afferent inputs from regions of the brain that process sensory information that is critical for different aspects of feeding. Important sets of inputs arise in the arcuate nucleus, the hindbrain, and in the telencephalon. Anorexia is generated in dehydrated animals by way of osmosensitive projections to the behavior control neurons in the PVH and LHA, rather than by actions on their afferent inputs. PMID:17531275

Neurorehabilitation strategies for poststroke oropharyngeal dysphagia: from compensation to the recovery of swallowing function.

PubMed

Cabib, Christopher; Ortega, Omar; Kumru, Hatice; Palomeras, Ernest; Vilardell, Natalia; Alvarez-Berdugo, Daniel; Muriana, Desirée; Rofes, Laia; Terré, Rosa; Mearin, Fermín; Clavé, Pere

2016-09-01

Oropharyngeal dysphagia (OD) is very prevalent among poststroke patients, causing severe complications but lacking specific neurorehabilitation treatment. This review covers advances in the pathophysiology, diagnosis, and physiologically based neurorehabilitation strategies for poststroke OD. The pathophysiology of oropharyngeal biomechanics can be assessed by videofluoroscopy, as delayed laryngeal vestibule closure is closely associated with aspiration. Stroke may affect afferent or efferent neuronal circuits participating in deglutition. The integrity of oropharyngeal-cortical afferent pathways can be assessed by electroencephalography through sensory-evoked potentials by pharyngeal electrical stimulation, while corticopharyngeal efferent pathways can be characterized by electromyography through motor-evoked potentials by transcranial magnetic stimulation. Dysfunction in both cortico-mediated evoked responses is associated with delayed swallow response and aspiration. Studies have reported hemispherical asymmetry on motor control of swallowing and the relevance of impaired oropharyngeal sensitivity on aspiration. Advances in treatment include improvements in compensatory strategies but are mainly focused on (1) peripheral stimulation strategies and (2) central, noninvasive stimulation strategies with evidence of their clinical benefits. Characterization of poststroke OD is evolving from the assessment of impaired biomechanics to the sensorimotor integration processes involved in deglutition. Treatment is also changing from compensatory strategies to promoting brain plasticity, both to recover swallow function and to improve brain-related swallowing dysfunction. © 2016 New York Academy of Sciences.

Evolutionary origins of taste buds: phylogenetic analysis of purinergic neurotransmission in epithelial chemosensors

PubMed Central

Kirino, Masato; Parnes, Jason; Hansen, Anne; Kiyohara, Sadao; Finger, Thomas E.

2013-01-01

Taste buds are gustatory endorgans which use an uncommon purinergic signalling system to transmit information to afferent gustatory nerve fibres. In mammals, ATP is a crucial neurotransmitter released by the taste cells to activate the afferent nerve fibres. Taste buds in mammals display a characteristic, highly specific ecto-ATPase (NTPDase2) activity, suggesting a role in inactivation of the neurotransmitter. The purpose of this study was to test whether the presence of markers of purinergic signalling characterize taste buds in anamniote vertebrates and to test whether similar purinergic systems are employed by other exteroceptive chemosensory systems. The species examined include several teleosts, elasmobranchs, lampreys and hagfish, the last of which lacks vertebrate-type taste buds. For comparison, Schreiner organs of hagfish and solitary chemosensory cells (SCCs) of teleosts, both of which are epidermal chemosensory end organs, were also examined because they might be evolutionarily related to taste buds. Ecto-ATPase activity was evident in elongate cells in all fish taste buds, including teleosts, elasmobranchs and lampreys. Neither SCCs nor Schreiner organs show specific ecto-ATPase activity, suggesting that purinergic signalling is not crucial in those systems as it is for taste buds. These findings suggest that the taste system did not originate from SCCs but arose independently in early vertebrates. PMID:23466675

Evolutionary origins of taste buds: phylogenetic analysis of purinergic neurotransmission in epithelial chemosensors.

PubMed

Kirino, Masato; Parnes, Jason; Hansen, Anne; Kiyohara, Sadao; Finger, Thomas E

2013-03-06

Taste buds are gustatory endorgans which use an uncommon purinergic signalling system to transmit information to afferent gustatory nerve fibres. In mammals, ATP is a crucial neurotransmitter released by the taste cells to activate the afferent nerve fibres. Taste buds in mammals display a characteristic, highly specific ecto-ATPase (NTPDase2) activity, suggesting a role in inactivation of the neurotransmitter. The purpose of this study was to test whether the presence of markers of purinergic signalling characterize taste buds in anamniote vertebrates and to test whether similar purinergic systems are employed by other exteroceptive chemosensory systems. The species examined include several teleosts, elasmobranchs, lampreys and hagfish, the last of which lacks vertebrate-type taste buds. For comparison, Schreiner organs of hagfish and solitary chemosensory cells (SCCs) of teleosts, both of which are epidermal chemosensory end organs, were also examined because they might be evolutionarily related to taste buds. Ecto-ATPase activity was evident in elongate cells in all fish taste buds, including teleosts, elasmobranchs and lampreys. Neither SCCs nor Schreiner organs show specific ecto-ATPase activity, suggesting that purinergic signalling is not crucial in those systems as it is for taste buds. These findings suggest that the taste system did not originate from SCCs but arose independently in early vertebrates.

The effect of neck torsion on postural stability in subjects with persistent whiplash.

PubMed

Yu, Li-Ju; Stokell, Raina; Treleaven, Julia

2011-08-01

Dysfunction of cervical receptors in neck disorders has been shown to lead to disturbances in postural stability. The neck torsion manoeuvre used in the smooth pursuit neck torsion (SPNT) test is thought to be a specific measure of neck afferent dysfunction on eye movement in those with neck pain. This study aimed to determine whether neck torsion could change balance responses in those with persistent whiplash-associated disorders (WADs). Twenty subjects with persistent WAD and 20 healthy controls aged between 18 and 50 years stood on a computerised force plate with eyes closed in comfortable stance under 5 conditions: neutral head, head turned to left and right and neck torsion to left and right. Root mean square (rms) amplitude of sway was measured in the anterior-posterior (AP) and medial-lateral (ML) directions. The whiplash group had significantly greater rms amplitude in the AP direction following neck torsion compared to the control group (p < 0.03). The results show that the neck torsion manoeuvre may lead to greater postural deficits in individuals with persistent WAD and provides further evidence of neck torsion to identify abnormal cervical afferent input, as an underlying cause of balance disturbances in WAD. Further research is warranted. Crown Copyright © 2011. Published by Elsevier Ltd. All rights reserved.

Dizziness, Unsteadiness, Visual Disturbances, and Sensorimotor Control in Traumatic Neck Pain.

PubMed

Treleaven, Julia

2017-07-01

Synopsis There is considerable evidence to support the importance of cervical afferent dysfunction in the development of dizziness, unsteadiness, visual disturbances, altered balance, and altered eye and head movement control following neck trauma, especially in those with persistent symptoms. However, there are other possible causes for these symptoms, and secondary adaptive changes should also be considered in differential diagnosis. Understanding the nature of these symptoms and differential diagnosis of their potential origin is important for rehabilitation. In addition to symptoms, the evaluation of potential impairments (altered cervical joint position and movement sense, static and dynamic balance, and ocular mobility and coordination) should become an essential part of the routine assessment of those with traumatic neck pain, including those with concomitant injuries such as concussion and vestibular or visual pathology or deficits. Once adequately assessed, appropriate tailored management should be implemented. Research to further assist differential diagnosis and to understand the most important contributing factors associated with abnormal cervical afferent input and subsequent disturbances to the sensorimotor control system, as well as the most efficacious management of such symptoms and impairments, is important for the future. J Orthop Sports Phys Ther 2017;47(7):492-502. Epub 16 Jun 2017. doi:10.2519/jospt.2017.7052.

Motor Control of Human Spinal Cord Disconnected from the Brain and Under External Movement.

PubMed

Mayr, Winfried; Krenn, Matthias; Dimitrijevic, Milan R

2016-01-01

Motor control after spinal cord injury is strongly depending on residual ascending and descending pathways across the lesion. The individually altered neurophysiology is in general based on still intact sublesional control loops with afferent sensory inputs linked via interneuron networks to efferent motor outputs. Partial or total loss of translesional control inputs reduces and alters the ability to perform voluntary movements and results in motor incomplete (residual voluntary control of movement functions) or motor complete (no residual voluntary control) spinal cord injury classification. Of particular importance are intact functionally silent neural structures with residual brain influence but reduced state of excitability that inhibits execution of voluntary movements. The condition is described by the term discomplete spinal cord injury. There are strong evidences that artificial afferent input, e.g., by epidural or noninvasive electrical stimulation of the lumbar posterior roots, can elevate the state of excitability and thus re-enable or augment voluntary movement functions. This modality can serve as a powerful assessment technique for monitoring details of the residual function profile after spinal cord injury, as a therapeutic tool for support of restoration of movement programs and as a neuroprosthesis component augmenting and restoring movement functions, per se or in synergy with classical neuromuscular or muscular electrical stimulation.

Differential sympathetic neural control of oxygenation in resting and exercising human skeletal muscle.

PubMed Central

Hansen, J; Thomas, G D; Harris, S A; Parsons, W J; Victor, R G

1996-01-01

Metabolic products of skeletal muscle contraction activate metaboreceptor muscle afferents that reflexively increase sympathetic nerve activity (SNA) targeted to both resting and exercising skeletal muscle. To determine effects of the increased sympathetic vasoconstrictor drive on muscle oxygenation, we measured changes in tissue oxygen stores and mitochondrial cytochrome a,a3 redox state in rhythmically contracting human forearm muscles with near infrared spectroscopy while simultaneously measuring muscle SNA with microelectrodes. The major new finding is that the ability of reflex-sympathetic activation to decrease muscle oxygenation is abolished when the muscle is exercised at an intensity > 10% of maximal voluntary contraction (MVC). During high intensity handgrip, (45% MVC), contraction-induced decreases in muscle oxygenation remained stable despite progressive metaboreceptor-mediated reflex increases in SNA. During mild to moderate handgrips (20-33% MVC) that do not evoke reflex-sympathetic activation, experimentally induced increases in muscle SNA had no effect on oxygenation in exercising muscles but produced robust decreases in oxygenation in resting muscles. The latter decreases were evident even during maximal metabolic vasodilation accompanying reactive hyperemia. We conclude that in humans sympathetic neural control of skeletal muscle oxygenation is sensitive to modulation by metabolic events in the contracting muscles. These events are different from those involved in either metaboreceptor muscle afferent activation or reactive hyperemia. PMID:8755671

Role of tachykinins in bronchial hyper-responsiveness.

PubMed

Reynolds, P N; Holmes, M D; Scicchitano, R

1997-01-01

1. Sensory afferent fibres mediate important protective reflexes in the lung. Small, unmyelinated C-fibre nerves have both sensory afferent and effector functions. C-fibres contain a number of neuropeptides, including the tachykinins, which have pro-inflammatory effects in the airways. Following stimulation with capsaicin and other stimuli, neuropeptides are released from the nerve endings, either directly or by axonal reflexes. 2. Important tachykinin effects include smooth muscle contraction, vasodilatation and oedema, mucus secretion and inflammatory cell activation. There are also trophic effects, including proliferation of fibroblasts, smooth muscle and epithelial cells. 3. Tachykinins mediate their effects by binding to G-proteinlinked receptors. Receptor-specific agonists and antagonists are available, which have helped clarify the effects of tachykinins. These agents may have therapeutic potential. 4. Tachykinins are degraded by the enzyme neutral endo-peptidase. 5. Studies in humans in vivo show an increase in airways resistance following challenge with tachykinins. There is some evidence for an increase in tachykinins and their receptors in airway inflammation, but this has not been found in all studies. A reduction in neutral endopeptidase has been seen in some animal models of airway inflammation, but this has not been shown in human disease. 6. Trials of tachykinin receptor antagonists in human asthma have begun, but it is too early to say what their therapeutic impact will be.

Vibration-evoked reciprocal inhibition between human wrist muscles.

PubMed

Cody, F W; Plant, T

1989-01-01

Reciprocal inhibition of the voluntarily contracting wrist extensor (extensor carpi radialis, ECR) evoked by proprioceptive afferent input from the flexor (flexor carpi radialis, FCR), was studied in healthy human subjects. Vibration of the FCR tendon was used to elicit Ia-dominated afferent discharge whilst inhibition of ECR was assessed as the reduction in asynchronous, on-going EMG. A small early phase of inhibition (I1) was evident in 25% of trials. The latency (ca. 25 ms) of this component suggested that it was mediated by an Ia oligosynaptic. possibly 'classical' disynaptic, inhibitory pathway. A later and apparently separate phase of reduced activity (I2, ca. 40 ms) was, however, far more consistently observed (96% of trials) and of greater magnitude. The I2 component was usually followed, some 20 ms later, by a phase of elevated activity (E1, 72% trials). Reductions in simultaneously recorded net extensor torque commenced at about 60 ms following the onset of flexor tendon vibration, i.e. some 20 ms after the main I2 EMG component. These mechanical responses must have almost exclusively resulted from reciprocal inhibition of extensor EMG since vibration of the relaxed FCR evoked minimal excitatory flexor activity. The reflex pattern, in any individual subject, was relatively unaffected by altering the duration of the vibration train between one and nineteen cycles (125 Hz). This suggests that the entire response complex resulted largely from the initial afferent volley. The sizes of both the I1 and I2 reductions in ECR activity increased with increasing voluntary extensor contraction so that their depths remained constant proportions of background EMG. Very similar results were obtained when reciprocal inhibition of FCR was produced by vibration of the belly of ECR. Thus, reciprocal inhibition between wrist muscles is mainly expressed as a rather stereotyped, short duration reduction in EMG whose depth is determined by the pre-existing level of motor activity. Some functional implications of this form of reflex behaviour are discussed.

Concurrent gradients of ribbon volume and AMPA-receptor patch volume in cochlear afferent synapses on gerbil inner hair cells.

PubMed

Zhang, Lichun; Engler, Sina; Koepcke, Lena; Steenken, Friederike; Köppl, Christine

2018-07-01

The Mongolian gerbil is a classic animal model for age-related hearing loss. As a prerequisite for studying age-related changes, we characterized cochlear afferent synaptic morphology in young adult gerbils, using immunolabeling and quantitative analysis of confocal microscopic images. Cochlear wholemounts were triple-labeled with a hair-cell marker, a marker of presynaptic ribbons, and a marker of postsynaptic AMPA-type glutamate receptors. Seven cochlear positions covering an equivalent frequency range from 0.5 - 32 kHz were evaluated. The spatial positions of synapses were determined in a coordinate system with reference to their individual inner hair cell. Synapse numbers confirmed previous reports for gerbils (on average, 20-22 afferents per inner hair cell). The volumes of presynaptic ribbons and postsynaptic glutamate receptor patches were positively correlated: larger ribbons associated with larger receptor patches and smaller ribbons with smaller patches. Furthermore, the volumes of both presynaptic ribbons and postsynaptic receptor patches co-varied along the modiolar-pillar and the longitudinal axes of their hair cell. The gradients in ribbon volume are consistent with previous findings in cat, guinea pig, mouse and rat and further support a role in differentiating the physiological properties of type I afferents. However, the positive correlation between the volumes of pre- and postsynaptic elements in the gerbil is different to the opposing gradients found in the mouse, suggesting species-specific differences in the postsynaptic AMPA receptors that are unrelated to the fundamental classes of type I afferents. Copyright © 2018 Elsevier B.V. All rights reserved.

Growth hormone regulates the sensitization of developing peripheral nociceptors during cutaneous inflammation.

PubMed

Liu, Xiaohua; Green, Kathryn J; Ford, Zachary K; Queme, Luis F; Lu, Peilin; Ross, Jessica L; Lee, Frank B; Shank, Aaron T; Hudgins, Renita C; Jankowski, Michael P

2017-02-01

Cutaneous inflammation alters the function of primary afferents and gene expression in the affected dorsal root ganglia (DRG). However, specific mechanisms of injury-induced peripheral afferent sensitization and behavioral hypersensitivity during development are not fully understood. Recent studies in children suggest a potential role for growth hormone (GH) in pain modulation. Growth hormone modulates homeostasis and tissue repair after injury, but how GH affects nociception in neonates is not known. To determine whether GH played a role in modulating sensory neuron function and hyperresponsiveness during skin inflammation in young mice, we examined behavioral hypersensitivity and the response properties of cutaneous afferents using an ex vivo hairy skin-saphenous nerve-DRG-spinal cord preparation. Results show that inflammation of the hairy hind paw skin initiated at either postnatal day 7 (P7) or P14 reduced GH levels specifically in the affected skin. Furthermore, pretreatment of inflamed mice with exogenous GH reversed mechanical and thermal hypersensitivity in addition to altering nociceptor function. These effects may be mediated through an upregulation of insulin-like growth factor 1 receptor (IGFr1) as GH modulated the transcriptional output of IGFr1 in DRG neurons in vitro and in vivo. Afferent-selective knockdown of IGFr1 during inflammation also prevented the observed injury-induced alterations in cutaneous afferents and behavioral hypersensitivity similar to that after GH pretreatment. These results suggest that GH can block inflammation-induced nociceptor sensitization during postnatal development leading to reduced pain-like behaviors, possibly by suppressing the upregulation of IGFr1 within DRG.

Enhanced Muscle Afferent Signals during Motor Learning in Humans.

PubMed

Dimitriou, Michael

2016-04-25

Much has been revealed concerning human motor learning at the behavioral level [1, 2], but less is known about changes in the involved neural circuits and signals. By examining muscle spindle responses during a classic visuomotor adaptation task [3-6] performed by fully alert humans, I found substantial modulation of sensory afferent signals as a function of adaptation state. Specifically, spindle control was independent of concurrent muscle activity but was specific to movement direction (representing muscle lengthening versus shortening) and to different stages of learning. Increased spindle afferent responses to muscle stretch occurring early during learning reflected individual error size and were negatively related to subsequent antagonist activity (i.e., 60-80 ms thereafter). Relative increases in tonic afferent output early during learning were predictive of the subjects' adaptation rate. I also found that independent spindle control during sensory realignment (the "washout" stage) induced afferent signal "linearization" with respect to muscle length (i.e., signals were more tuned to hand position). The results demonstrate for the first time that motor learning also involves independent and state-related modulation of sensory mechanoreceptor signals. The current findings suggest that adaptive motor performance also relies on the independent control of sensors, not just of muscles. I propose that the "γ" motor system innervating spindles acts to facilitate the acquisition and extraction of task-relevant information at the early stages of sensorimotor adaptation. This designates a more active and targeted role for the human proprioceptive system during motor learning. Copyright © 2016 Elsevier Ltd. All rights reserved.

Population Coding of Forelimb Joint Kinematics by Peripheral Afferents in Monkeys

PubMed Central

Umeda, Tatsuya; Seki, Kazuhiko; Sato, Masa-aki; Nishimura, Yukio; Kawato, Mitsuo; Isa, Tadashi

2012-01-01

Various peripheral receptors provide information concerning position and movement to the central nervous system to achieve complex and dexterous movements of forelimbs in primates. The response properties of single afferent receptors to movements at a single joint have been examined in detail, but the population coding of peripheral afferents remains poorly defined. In this study, we obtained multichannel recordings from dorsal root ganglion (DRG) neurons in cervical segments of monkeys. We applied the sparse linear regression (SLiR) algorithm to the recordings, which selects useful input signals to reconstruct movement kinematics. Multichannel recordings of peripheral afferents were performed by inserting multi-electrode arrays into the DRGs of lower cervical segments in two anesthetized monkeys. A total of 112 and 92 units were responsive to the passive joint movements or the skin stimulation with a painting brush in Monkey 1 and Monkey 2, respectively. Using the SLiR algorithm, we reconstructed the temporal changes of joint angle, angular velocity, and acceleration at the elbow, wrist, and finger joints from temporal firing patterns of the DRG neurons. By automatically selecting a subset of recorded units, the SLiR achieved superior generalization performance compared with a regularized linear regression algorithm. The SLiR selected not only putative muscle units that were responsive to only the passive movements, but also a number of putative cutaneous units responsive to the skin stimulation. These results suggested that an ensemble of peripheral primary afferents that contains both putative muscle and cutaneous units encode forelimb joint kinematics of non-human primates. PMID:23112841

New perspectives concerning feedback influences on cardiorespiratory control during rhythmic exercise and on exercise performance

PubMed Central

Dempsey, Jerome A

2012-01-01

The cardioaccelerator and ventilatory responses to rhythmic exercise in the human are commonly viewed as being mediated predominantly via feedforward ‘central command’ mechanisms, with contributions from locomotor muscle afferents to the sympathetically mediated pressor response. We have assessed the relative contributions of three types of feedback afferents on the cardiorespiratory response to voluntary, rhythmic exercise by inhibiting their normal ‘tonic’ activity in healthy animals and humans and in chronic heart failure. Transient inhibition of the carotid chemoreceptors during moderate intensity exercise reduced muscle sympathetic nerve activity (MSNA) and increased limb vascular conductance and blood flow; and reducing the normal level of respiratory muscle work during heavier intensity exercise increased limb vascular conductance and blood flow. These cardiorespiratory effects were prevented via ganglionic blockade and were enhanced in chronic heart failure and in hypoxia. Blockade of μ opioid sensitive locomotor muscle afferents, with preservation of central motor output via intrathecal fentanyl: (a) reduced the mean arterial blood pressure (MAP), heart rate and ventilatory responses to all steady state exercise intensities; and (b) during sustained high intensity exercise, reduced O2 transport, increased central motor output and end-exercise muscle fatigue and reduced endurance performance. We propose that these three afferent reflexes – probably acting in concert with feedforward central command – contribute significantly to preserving O2 transport to locomotor and to respiratory muscles during exercise. Locomotor muscle afferents also appear to provide feedback concerning the metabolic state of the muscle to influence central motor output, thereby limiting peripheral fatigue development. PMID:22826128

Stochastic resonance in the synaptic transmission between hair cells and vestibular primary afferents in development.

PubMed

Flores, A; Manilla, S; Huidobro, N; De la Torre-Valdovinos, B; Kristeva, R; Mendez-Balbuena, I; Galindo, F; Treviño, M; Manjarrez, E

2016-05-13

The stochastic resonance (SR) is a phenomenon of nonlinear systems in which the addition of an intermediate level of noise improves the response of such system. Although SR has been studied in isolated hair cells and in the bullfrog sacculus, the occurrence of this phenomenon in the vestibular system in development is unknown. The purpose of the present study was to explore for the existence of SR via natural mechanical-stimulation in the hair cell-vestibular primary afferent transmission. In vitro experiments were performed on the posterior semicircular canal of the chicken inner ear during development. Our experiments showed that the signal-to-noise ratio of the afferent multiunit activity from E15 to P5 stages of development exhibited the SR phenomenon, which was characterized by an inverted U-like response as a function of the input noise level. The inverted U-like graphs of SR acquired their higher amplitude after the post-hatching stage of development. Blockage of the synaptic transmission with selective antagonists of the NMDA and AMPA/Kainate receptors abolished the SR of the afferent multiunit activity. Furthermore, computer simulations on a model of the hair cell - primary afferent synapse qualitatively reproduced this SR behavior and provided a possible explanation of how and where the SR could occur. These results demonstrate that a particular level of mechanical noise on the semicircular canals can improve the performance of the vestibular system in their peripheral sensory processing even during embryonic stages of development. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

The correlated blanching of synaptic bodies and reduction in afferent firing rates caused by transmitter-depleting agents in the frog semicircular canal

NASA Technical Reports Server (NTRS)

Guth, P.; Norris, C.; Fermin, C. D.; Pantoja, M.

1993-01-01

Synaptic bodies (SBs) associated with rings of synaptic vesicles and well-defined, pre- and post-synaptic membrane structures are indicators of maturity in most hair cell-afferent nerve junctions. The role of the SBs remains elusive despite several experiments showing that they may be involved in storage of neurotransmitter. Our results demonstrate that SBs of the adult posterior semicircular canal (SCC) cristae hair cells become less electron dense following incubation of the SCC with the transmitter-depleting drug tetrabenazine (TBZ). Objective quantification and comparison of the densities of the SBs in untreated and TBZ-treated frog SCC demonstrated that TBZ significantly decreased the electron density of SBs. This reduction in electron density was accompanied by a reduction in firing rates of afferent fibers innervating the posterior SCC. A second transmitter-depleting drug, guanethidine, previously shown to reduce the electron density of hair cell SBs, also reduced the firing rates of afferent fibers innervating the posterior SCC. In contrast, the electron density of dense granules (DG), similar in size and shape to synaptic bodies (SB) in hair cells, did not change after incubation in TBZ, thus indicating that granules and SBs are not similar in regard to their electron density. The role of SBs in synaptic transmission and the transmitter, if any, stored in the SBs remain unknown. Nonetheless, the association of the lessening of electron density with a reduction in afferent firing rate provides impetus for the further investigation of the SB's role in neurotransmission.

Growth hormone regulates the sensitization of developing peripheral nociceptors during cutaneous inflammation

PubMed Central

Liu, Xiaohua; Green, Kathryn J.; Ford, Zachary K.; Queme, Luis F.; Lu, Peilin; Ross, Jessica L.; Lee, Frank B.; Shank, Aaron T.; Hudgins, Renita C.; Jankowski, Michael P.

2016-01-01

Cutaneous inflammation alters the function of primary afferents and gene expression in the affected dorsal root ganglia (DRGs). However specific mechanisms of injury-induced peripheral afferent sensitization and behavioral hypersensitivity during development are not fully understood. Recent studies in children suggest a potential role for growth hormone (GH) in pain modulation. GH modulates homeostasis and tissue repair after injury, but how GH effects nociception in neonates is not known. To determine if GH played a role in modulating sensory neuron function and hyper-responsiveness during skin inflammation in young mice, we examined behavioral hypersensitivity and the response properties of cutaneous afferents using an ex vivo hairy skin-saphenous nerve-dorsal root ganglion (DRG)-spinal cord preparation. Results show that inflammation of the hairy hindpaw skin initiated at either postnatal day 7 (P7) or P14 reduced GH levels specifically in the affected skin. Furthermore, pretreatment of inflamed mice with exogenous GH reversed mechanical and thermal hypersensitivity in addition to altering nociceptor function. These effects may be mediated via an upregulation of insulin-like growth factor 1 receptor (IGFr1) as GH modulated the transcriptional output of IGFr1 in DRG neurons in vitro and in vivo. Afferent-selective knockdown of IGFr1 during inflammation also prevented the observed injury-induced alterations in cutaneous afferents and behavioral hypersensitivity similar to that following GH pretreatment. These results suggest that GH can block inflammation-induced nociceptor sensitization during postnatal development leading to reduced pain-like behaviors, possibly by suppressing the upregulation of IGFr1 within DRGs. PMID:27898492

Subcortical afferent connections of the amygdala in the monkey

NASA Technical Reports Server (NTRS)

Mehler, W. R.

1980-01-01

The cells of origin of the afferent connections of the amygdala in the rhesus and squirrel monkeys are determined according to the retrograde axonal transport of the enzyme horseradish peroxidase injected into various quadrants of the amygdala. Analysis of the distribution of enzyme-labeled cells reveals afferent amygdalar connections with the ipsilateral halves of the midline nucleus paraventricularis thalami and both the parvo- and magnocellular parts of the nucleus subparafascicularis in the dorsal thalamus, all the subdivisions of the midline nucleus centralis complex, the nucleus reuniens ventralis and the nucleus interventralis. The largest populations of enzyme-labeled cells in the hypothalamus are found to lie in the middle and posterior parts of the ipsilateral, lateral hypothalamus and the ventromedial hypothalamic nucleus, with scattered cells in the supramammillary and dorsomedial nuclei and the posterior hypothalamic area, Tsai's ventral tegmental area, the rostral and caudal subdivisions of the nucleus linearis in the midbrain and the dorsal raphe nucleus. The most conspicuous subdiencephalic source of amygdalar afferent connections is observed to be the pars lateralis of the nucleus parabrachialis in the dorsolateral pontine tegmentum, with a few labeled cells differentiated from pigmented cells in the locus coeruleus.

Altered central nervous system processing of baroreceptor input following hindlimb unloading in rats

NASA Technical Reports Server (NTRS)

Moffitt, J. A.; Schadt, J. C.; Hasser, E. M.

1999-01-01

The effect of cardiovascular deconditioning on central nervous system processing of baroreceptor afferent activity was evaluated following 14 days of hindlimb unloading (HU). Inactin-anesthetized rats were instrumented with catheters, renal sympathetic nerve electrodes, and aortic depressor nerve electrodes for measurement of mean arterial pressure, heart rate, renal sympathetic nerve activity (RSNA), and aortic depressor nerve activity (ADNA). Baroreceptor and baroreflex functions were assessed during infusion of phenylephrine and sodium nitroprusside. Central processing of baroreceptor afferent input was evaluated by linear regression relating RSNA to ADNA. The maximum baroreflex-elicited increase in RSNA was significantly reduced in HU rats (122 +/- 3.8 vs. 144 +/- 4.9% of baseline RSNA), whereas ADNA was not altered. The slope (-0.18 +/- 0.04 vs. -0.40 +/- 0.04) and y-intercept (121 +/- 3.2 vs. 146 +/- 4.3) of the linear regression relating increases in efferent RSNA to decreases in afferent ADNA during hypotension were significantly reduced in HU rats. There were no differences during increases in arterial pressure. Results demonstrate that the attenuation in baroreflex-mediated increases in RSNA following HU is due to changes in central processing of baroreceptor afferent information rather than aortic baroreceptor function.

Intrapulmonary receptors in the Tegu lizard: II. Functional characteristics and localization;.

PubMed

Scheid, P; Kuhlmann, W D; Fedde, M R

1977-02-01

Intrapulmonary receptors identified in the Tegu lizard by single-unit vagal recording (Fedde et al., 1977) were subjected to a number of stimuli and localized within the lung. Some carbon dioxide receptors could follow periodic changes in intrapulmonary CO2 concentrations as rapidly as 1.3 Hz; No oxygen sensitivity was observed with this receptor type, and halothane markedly depressed the discharge frequency. In response to intravenously injected acetazolamide they increased their discharge frequency and became almost totally insensitive to CO2, suggesting molecular per se is not the direct controller of receptor discharge; These receptors show many of the functional characteristics described for those in the avian lung. Afferent activity from both CO2 and mechanoreceptors could be elicited by electrically stimulating the lung surface. The CO2 receptors appeared to be organized in a receptive field covering more than 1 cm2 of lung surface, multiple receptors being innervated by a single afferent fiber. Activity in afferent fibers from mechanoreceptors could be evoked from only one distinct spot on the lung surface. Conduction velocities of afferent fibers from CO2 receptors ranged from 1 to 3 m-sec-1; from mechanoreceptors, from 1.9 to 5.2 m-sec-1.

Modulation of the masseteric reflex by gastric vagal afferents.

PubMed

Pettorossi, V E

1983-04-01

Several investigations have shown that the vagal nerve can affect the reflex responses of the masticatory muscles acting at level either of trigeminal motoneurons or of the mesencephalic trigeminal nucleus (MTN). The present experiments have been devoted to establish the origin of the vagal afferent fibres involved in modulating the masseteric reflex. In particular, the gastric vagal afferents were taken into consideration and selective stimulations of such fibres were performed in rabbit. Conditioning electrical stimulation of truncus vagalis ventralis (TVV) reduced the excitability of the MTN cells as shown by a decrease of the antidromic response recorded from the semilunar ganglion and elicited by MTN single-shock electrical stimulation. Sympathetic and cardiovascular influences were not involved in these responses. Mechanical stimulation of gastric receptors, by means of gastric distension, clearly diminished the amplitude of twitch tension of masseteric reflex and inhibited the discharge frequency of proprioceptive MTN units. The effect was phasic and depended upon the velocity of distension. Thus the sensory volleys originating from rapid adapting receptors reach the brain stem through vagal afferents and by means of a polysynaptic connection inhibits the masseteric reflex at level of MTN cells.

Dual-afferent sensory input training for voluntary movement after stroke: A pilot randomized controlled study.

PubMed

Bae, Seahyun; Kim, Kyung-Yoon

2017-01-01

Stimulation through afferent sensory input is necessary to improve voluntary functional movement in stroke patients. Dual-afferent sensory input, which combines electromyography-triggered functional electric stimulation (ETFES) and action observation, was investigated to determine its effects on voluntary movements in stroke patients. This study was conducted on 18 patients with left hemiplegia diagnosed between 6 and 24 months prior. The 9 subjects in the dual-afferent sensory input (DASI) group underwent ETFES with action observation training for 4 weeks (20 min/d, 5 d/wk), while the 9 control group subjects underwent functional electric stimulation (FES) for the same duration. The outcome measures were the movement-related cortical potential (MRCP), H-reflex, electromyography (EMG), and balance. The control and DASI groups showed significant increases in MRCP, muscle activity, and balance, while H-reflex was significantly decreased. MRCP and balance showed significant differences between DASI and control groups. DASI stimulates voluntary movement in patients, causes rapid activation of the cerebral cortex, and reduces excessive excitation of spinal motor neurons. Therefore, DASI, which stimulates voluntary movement, has a greater effect on brain activation in stroke patients.

Putative roles of neuropeptides in vagal afferent signaling

PubMed Central

de Lartigue, Guillaume

2014-01-01

The vagus nerve is a major pathway by which information is communicated between the brain and peripheral organs. Sensory neurons of the vagus are located in the nodose ganglia. These vagal afferent neurons innervate the heart, the lung and the gastrointestinal tract, and convey information about peripheral signals to the brain important in the control of cardiovascular tone, respiratory tone, and satiation, respectively. Glutamate is thought to be the primary neurotransmitter involved in conveying all of this information to the brain. It remains unclear how a single neurotransmitter can regulate such an extensive list of physiological functions from a wide range of visceral sites. Many neurotransmitters have been identified in vagal afferent neurons and have been suggested to modulate the physiological functions of glutamate. Specifically, the anorectic peptide transmitters, cocaine and amphetamine regulated transcript (CART) and the orexigenic peptide transmitters, melanin concentrating hormone (MCH) are differentially regulated in vagal afferent neurons and have opposing effects on food intake. Using these two peptides as a model, this review will discuss the potential role of peptide transmitters in providing a more precise and refined modulatory control of the broad physiological functions of glutamate, especially in relation to the control of feeding. PMID:24650553

Subdiaphragmatic vagotomy increases the sensitivity of lumbar Aδ primary afferent neurons along with voltage-dependent potassium channels in rats.

PubMed

Furuta, Sadayoshi; Watanabe, Lisa; Doi, Seira; Horiuchi, Hiroshi; Matsumoto, Kenjiro; Kuzumaki, Naoko; Suzuki, Tsutomu; Narita, Minoru

2012-02-01

Subdiaphragmatic vagal dysfunction causes chronic pain. To verify whether this chronic pain is accompanied by enhanced peripheral nociceptive sensitivity, we evaluated primary afferent neuronal excitability in subdiaphragmatic vagotomized (SDV) rats. SDV rats showed a decrease in the electrical stimuli-induced hind limb-flexion threshold at 250 Hz, but showed no similar effect at 5 or 2000 Hz, which indicated that lumbar primary afferent Aδ sensitivity was enhanced in SDV rats. The whole-cell patch-clamp technique also revealed the hyper-excitability of acutely dissociated medium-sized lumbar dorsal root ganglion (DRG) neurons isolated from SDV rats. The contribution of changes in voltage-dependent potassium (Kv) channels was assessed, and transient A-type K(+) (I(A) ) current density was apparently decreased. Moreover, Kv4.3 immunoreactivity in medium-sized DRG neurons was significantly reduced in SDV rats compared to sham. These results indicate that SDV causes hyper-excitability of lumbar primary Aδ afferent neurons, which may be induced along with suppressing I(A) currents via the decreased expression of Kv4.3. Thus, peripheral Aδ neuroplasticity may contribute to the chronic lower limb pain caused by SDV. Copyright © 2011 Wiley Periodicals, Inc.

Common neural structures activated by epidural and transcutaneous lumbar spinal cord stimulation: Elicitation of posterior root-muscle reflexes

PubMed Central

Freundl, Brigitta; Binder, Heinrich; Minassian, Karen

2018-01-01

Epidural electrical stimulation of the lumbar spinal cord is currently regaining momentum as a neuromodulation intervention in spinal cord injury (SCI) to modify dysregulated sensorimotor functions and augment residual motor capacity. There is ample evidence that it engages spinal circuits through the electrical stimulation of large-to-medium diameter afferent fibers within lumbar and upper sacral posterior roots. Recent pilot studies suggested that the surface electrode-based method of transcutaneous spinal cord stimulation (SCS) may produce similar neuromodulatory effects as caused by epidural SCS. Neurophysiological and computer modeling studies proposed that this noninvasive technique stimulates posterior-root fibers as well, likely activating similar input structures to the spinal cord as epidural stimulation. Here, we add a yet missing piece of evidence substantiating this assumption. We conducted in-depth analyses and direct comparisons of the electromyographic (EMG) characteristics of short-latency responses in multiple leg muscles to both stimulation techniques derived from ten individuals with SCI each. Post-activation depression of responses evoked by paired pulses applied either epidurally or transcutaneously confirmed the reflex nature of the responses. The muscle responses to both techniques had the same latencies, EMG peak-to-peak amplitudes, and waveforms, except for smaller responses with shorter onset latencies in the triceps surae muscle group and shorter offsets of the responses in the biceps femoris muscle during epidural stimulation. Responses obtained in three subjects tested with both methods at different time points had near-identical waveforms per muscle group as well as same onset latencies. The present results strongly corroborate the activation of common neural input structures to the lumbar spinal cord—predominantly primary afferent fibers within multiple posterior roots—by both techniques and add to unraveling the basic mechanisms underlying electrical SCS. PMID:29381748