Spencer, Nick J; Kyloh, Melinda; Duffield, Michael
In mammals, sensory stimuli in visceral organs, including those that underlie pain perception, are detected by spinal afferent neurons, whose cell bodies lie in dorsal root ganglia (DRG). One of the major challenges in visceral organs has been how to identify the different types of nerve endings of spinal afferents that transduce sensory stimuli into action potentials. The reason why spinal afferent nerve endings have been so challenging to identify is because no techniques have been available, until now, that can selectively label only spinal afferents, in high resolution. We have utilized an anterograde tracing technique, recently developed in our laboratory, which facilitates selective labeling of only spinal afferent axons and their nerve endings in visceral organs. Mice were anesthetized, lumbosacral DRGs surgically exposed, then injected with dextran-amine. Seven days post-surgery, the large intestine was removed. The characteristics of thirteen types of spinal afferent nerve endings were identified in detail. The greatest proportion of nerve endings was in submucosa (32%), circular muscle (25%) and myenteric ganglia (22%). Two morphologically distinct classes innervated myenteric ganglia. These were most commonly a novel class of intraganglionic varicose endings (IGVEs) and occasionally rectal intraganglionic laminar endings (rIGLEs). Three distinct classes of varicose nerve endings were found to innervate the submucosa and circular muscle, while one class innervated internodal strands, blood vessels, crypts of lieberkuhn, the mucosa and the longitudinal muscle. Distinct populations of sensory endings were CGRP-positive. We present the first complete characterization of the different types of spinal afferent nerve endings in a mammalian visceral organ. The findings reveal an unexpectedly complex array of different types of primary afferent endings that innervate specific layers of the large intestine. Some of the novel classes of nerve endings identified
Undem, Bradley J; Carr, Michael J
Afferent nerves in the airways serve to regulate breathing pattern, cough, and airway autonomic neural tone. Pharmacologic agents that influence afferent nerve activity can be subclassified into compounds that modulate activity by indirect means (e.g. bronchial smooth muscle spasmogens) and those that act directly on the nerves. Directly acting agents affect afferent nerve activity by interacting with various ion channels and receptors within the membrane of the afferent terminals. Whether by direct or indirect means, most compounds that enter the airspace will modify afferent nerve activity, and through this action alter airway physiology. PMID:11686889
Enríquez-Denton, M; Manjarrez, E; Rudomin, P
Two to twelve weeks after crushing a muscle nerve, still before the damaged afferents reinnervate the muscle receptors, conditioning stimulation of group I fibers from flexor muscles depolarizes the damaged afferents [M. Enriquez, I. Jimenez, P. Rudomin, Changes in PAD patterns of group I muscle afferents after a peripheral nerve crush. Exp. Brain Res., 107 (1996), 405-420]. It is not known, however, if this primary afferent depolarization (PAD) is indeed related to presynaptic inhibition. We now show in the cat that 2-12 weeks after crushing the medial gastrocnemius nerve (MG), conditioning stimulation of group I fibers from flexors increases the excitability of the intraspinal terminals of both the intact lateral gastrocnemius plus soleus (LGS) and of the previously damaged MG fibers ending in the motor pool, because of PAD. The PAD is associated with the depression of the pre- and postsynaptic components of the extracellular field potentials (EFPs) evoked in the motor pool by stimulation of either the intact LGS or of the previously damaged MG nerves. These observations indicate, in contrast to what has been reported for crushed cutaneous afferents [K.W. Horch, J.W. Lisney, Changes in primary afferent depolarization of sensory neurones during peripheral nerve regeneration in the cat, J. Physiol., 313 (1981), 287-299], that shortly after damaging their peripheral axons, the synaptic efficacy of group I spindle afferents remains under central control. Presynaptic inhibitory mechanisms could be utilized to adjust the central actions of muscle afferents not fully recovered from peripheral lesions.
Baird, Richard A.; Schuff, N. R.
Vestibular nerve afferents innervating the bullfrog utriculus differ in their response dynamics and sensitivity to natural stimulation. They also supply hair cells that differ markedly in hair bundle morphology. To examine the peripheral innervation patterns of individual utricular afferents more closely, afferent fibers were labeled by the extracellular injection of horseradish peroxidase (HRP) into the vestibular nerve after sectioning the vestibular nerve medial to Scarpa's ganglion to allow the degeneration of sympathetic and efferent fibers. The peripheral arborizations of individual afferents were then correlated with the diameters of their parent axons, the regions of the macula they innervate, and the number and type of hair cells they supply. The utriculus is divided by the striola, a narrow zone of distinctive morphology, into media and lateral parts. Utiricular afferents were classified as striolar or extrastriolar according to the epithelial entrance of their parent axons and the location of their terminal fields. In general, striolar afferents had thicker parent axons, fewer subepithelial bifurcations, larger terminal fields, and more synaptic endings than afferents in extrstriolar regions. Afferents in a juxtastriolar zone, immediately adjacent to the medial striola, had innervation patterns transitional between those in the striola and more peripheral parts of the medial extrastriola. moast afferents innervated only a single macular zone. The terminal fields of striolar afferents, with the notable exception of a few afferents with thin parent axons, were generally confined to one side of the striola. Hair cells in the bullfrog utriculus have perviously been classified into four types based on hair bundle morphology. Afferents in the extrastriolar and juxtastriolar zones largely or exclusively innervated Type B hair cells, the predominant hair cell type in the utricular macula. Striolar afferents supplied a mixture of four hair cell types, but largely
Bolton, P S; Kerman, I A; Woodring, S F; Yates, B J
It is well established that the vestibular system influences the sympathetic nervous system and the respiratory system; presumably, vestibulosympathetic and vestibulorespiratory responses participate in maintaining stable blood pressure and blood oxygenation during movement and changes in posture. Many brainstem neurons that generate vestibulospinal reflexes integrate signals from the labyrinth and neck muscles to distinguish between head movements on a stable body and whole body movements. In the present study, responses were recorded from the splanchnic (sympathetic), hypoglossal (inspiratory) and abdominal (expiratory) nerves during stimulation of the C2 dorsal root ganglion or C2 or C3 nerve branches innervating dorsal neck muscles. Stimulation of neck afferents using low current intensities, in many cases less than twice the threshold for producing an afferent volley recordable from the cord dorsum, elicited changes in sympathetic and respiratory nerve activity. These data suggest that head rotation on a stable body would elicit both cervical and vestibular inputs to respiratory motoneurons and sympathetic preganglionic neurons. The effects of cervical afferent stimulation on abdominal, splanchnic and hypoglossal nerve activity were not abolished by transection of the brainstem caudal to the vestibular nuclei; thus, pathways in addition to those involving the vestibular nuclei are involved in relaying cervical inputs to sympathetic preganglionic neurons and respiratory motoneurons. Transection of the C1-3 dorsal roots enhanced responses of the splanchnic and abdominal nerves to pitch head rotations on a fixed body but diminished responses of the hypoglossal nerve. Thus, neck and vestibular afferent influences on activity of respiratory pump muscles and sympathetic outflow appear to be antagonistic, so that responses will occur during whole body movements but not head movements on a stationary trunk. In contrast, neck and vestibular influences on tongue
EVERILL, B.; KOCSIS, J. D.
Whole-cell patch-clamp techniques were used to study the effects of nerve growth factor on voltage-dependent potassium conductance in normal and axotomized identified large cutaneous afferent dorsal root ganglion neurons (48–50 μm diameter) many of which probably give rise to myelinated Aβ fibers. K-currents were isolated by blocking Na- and Ca-currents with appropriate ion replacement and channel blockers. Separation of current components was achieved on the basis of response to variation in conditioning voltage. Cutaneous afferents were labeled by the retrograde marker hydroxy-stilbamide (FluoroGold) which was injected into the skin of the foot. The sciatic nerve was either ligated or crushed with fine forceps five to seven days later. Neurons were dissociated 14–17 days after injury. The cut ends of the sciatic nerves were positioned into polyethylene tubes, which were connected to mini-osmotic pumps filled with either nerve growth factor or sterile saline. Control neurons displayed a prominent sustained K-current and the transient potassium currents “A” and “D”. Nerve ligation, which blocks target reconnection resulted in near 50% reduction of total outward current; isolated sustained K-current and transient A-current were reduced by a comparable amount. Nerve crush, which allows regeneration to peripheral targets and exposure of the regenerating nerve to the distal nerve segment, resulted in a small reduction in sustained K-current but no reduction in transient A-current compared to controls. Levels of transient A-current and sustained K-current were maintained at control levels after nerve growth factor treatment. These results indicate that the large reduction in transient A-current, and in sustained K-current, observed in cutaneous afferent cell bodies after nerve ligation is prevented by application of nerve growth factor. PMID:11008179
Jänig, Wilfrid; Grossmann, Lydia; Gorodetskaya, Natalia
Crush lesion of a skin nerve is followed by sprouting of myelinated (A) and unmyelinated (C) afferent fibers into the distal nerve stump. Here, we investigate quantitatively both ongoing activity and activity evoked by mechanical or thermal stimulation of the nerve in 43 A- and 135 C-fibers after crush lesion of the sural nerve using neurophysiological recordings in anesthetized rats. The discharge patterns in the injured afferent nerve fibers and in intact (control) afferent nerve fibers were compared. (1) Almost all (98%) A-fibers were mechanosensitive, some of them exhibited additionally weak cold/heat sensitivity; 7% had ongoing activity. (2) Three patterns of physiologically evoked activity were present in the lesioned C-fibers: (a) C-fibers with type 1 cold sensitivity (low cold threshold, inhibition on heating, high level of ongoing and cold-evoked activity; 23%): almost all of them were mechanoinsensitive and 40% of them were additionally heat-sensitive; (b) C-fibers with type 2 cold sensitivity (high cold threshold, low level of ongoing and cold-evoked activity; 23%). All of them were excited by mechanical and/or heat stimuli; (c) cold-insensitive C-fibers (54%), which were heat- and/or mechanosensitive. (3) The proportions of C-fibers exhibiting these three patterns of discharge to physiological stimuli were almost identical in the population of injured C-fibers and in a population of 91 intact cutaneous C-fibers. 4. Ongoing activity was present in 56% of the lesioned C-fibers. Incidence and rate of ongoing activity were the same in the populations of lesioned and intact type 1 cold-sensitive C-fibers. The incidence (but not rate) of ongoing activity was significantly higher in lesioned type 2 cold-sensitive and cold insensitive C-fibers than in the corresponding populations of intact C-fibers (42/93 fibers vs. 11/72 fibers).
Undem, Bradley J; Carr, Michael J
The best available data support the hypothesis that there are at least two types of vagal nerves responsible for initiating coughing reflexes. One type of nerve conducts action potentials in the A-range and is characterized by rapidly adapting responses to mechanical probing or acidification of the large airway epithelium. Stimulation of these nerves can evoke cough in unconscious experimental animals and humans. These nerves are important in immediate cough evoked by aspiration and as such perform a critical role in airway defense. The other type of primary afferent nerve involved in cough is the vagal C-fiber. Inhalation of selective C-fiber stimulants leads to cough only in conscious animals. In clinical studies, inhalation of a low concentration of a C-fiber stimulant causes an irritating, itchy urge-to-cough sensation that mimics the urge-to-cough sensations associated with respiratory tract infection, post-infection, gastroesophageal reflux disorders, and inflammatory airway diseases. Here we discuss the recent advances in sensory neurobiology that allow for the targeting of vagal C-fibers for novel antitussive therapy. No attempts are made to be all-inclusive with respect to the numerous possible molecular targets being considered to accomplish this goal. Rather, two general strategies are discussed: decreasing generator potential amplitude and decreasing the efficiency by which a generator potential evokes action-potential discharge. For the first category we focus on two targets, transient receptor potential vanilloid 1 and transient receptor potential A1. For the latter category we focus on recent advances in voltage-gated sodium (Na(V)) channel biology.
Gorodetskaya, Natalia; Constantin, Cristina; Jänig, Wilfrid
Spontaneous activity, and mechanical and thermal sensitivity were investigated in regenerating afferent nerve fibers within 4-21 days post sural nerve lesion (crush or transection and resuturing) in anaesthetized rats. About 33-40% of the myelinated (A) and 22-27% of the unmyelinated (C) fibers excited by electrical nerve stimulation exhibited at least one of these ectopic discharge properties. In total 177 A- and 169 C-fibers with ectopic activity were analysed. Most A-fibers (161/177) were mechanosensitive. Spontaneous activity (median 1 imp/s) was present in 23/177 and thermosensitivity in 14/177 A-fibers (13 of them being activated by heat stimuli). Almost all A-fibers (159/177) exhibited only one type of ectopic discharge property. Most C-fibers (94/169) were thermosensitive responding either to cold (n = 45) or to heat stimuli (n = 33) or to both (n = 16). Eighty-four of 169 C-fibers were spontaneously active (median 0.3 imp/s) and 75/169 C-fibers were mechanosensitive. Both the proportion and the discharge rate of spontaneously active C-fibers were significantly higher after crush than after section and resuturing of the nerve. About 60% of the C-fibers (101/169) had only one ectopic discharge property and 40% two or three. In conclusion, regenerating cutaneous afferent A- and C-fibers may develop mechano- and/or thermosensitivity as well as spontaneous activity. We suggest that spontaneous and evoked ectopic activity in regenerating cutaneous afferents are a function of the intrinsic functional properties of these neurons and of the interaction between the regenerating nerve fibers and non-neural cells during Wallerian degeneration in the nerve distal to the nerve lesion.
Foss, Jason D; Wainford, Richard D; Engeland, William C; Fink, Gregory D; Osborn, John W
Renal denervation has been shown to lower arterial pressure in some hypertensive patients, yet it remains unclear whether this is due to ablation of afferent or efferent renal nerves. To investigate the role of afferent renal nerves in arterial pressure regulation, previous studies have used methods that disrupt both renal and nonrenal afferent signaling. The present study was conducted to develop and validate a technique for selective ablation of afferent renal nerves that does not disrupt other afferent pathways. To do this, we adapted a technique for sensory denervation of the adrenal gland by topical application of capsaicin and tested the hypothesis that exposure of the renal nerves to capsaicin (renal-CAP) causes ablation of afferent but not efferent renal nerves. Renal-CAP had no effect on renal content of the efferent nerve markers tyrosine hydroxylase and norepinephrine; however, the afferent nerve marker, calcitonin gene-related peptide was largely depleted from the kidney 10 days after intervention, but returned to roughly half of control levels by 7 wk postintervention. Moreover, renal-CAP abolished the cardiovascular responses to acute pharmacological stimulation of afferent renal nerves. Renal-CAP rats showed normal weight gain, as well as cardiovascular and fluid balance regulation during dietary sodium loading. To some extent, renal-CAP did blunt the bradycardic response and increase the dipsogenic response to increased salt intake. Lastly, renal-CAP significantly attenuated the development of deoxycorticosterone acetate-salt hypertension. These results demonstrate that renal-CAP effectively causes selective ablation of afferent renal nerves in rats.
Booth, Lindsea C.; May, Clive N.; Yao, Song T.
Renal nerves contain afferent, sensory and efferent, sympathetic nerve fibers. In heart failure (HF) there is an increase in renal sympathetic nerve activity (RSNA), which can lead to renal vasoconstriction, increased renin release and sodium retention. These changes are thought to contribute to renal dysfunction, which is predictive of poor outcome in patients with HF. In contrast, the role of the renal afferent nerves remains largely unexplored in HF. This is somewhat surprising as there are multiple triggers in HF that have the potential to increase afferent nerve activity, including increased venous pressure and reduced kidney perfusion. Some of the few studies investigating renal afferents in HF have suggested that at least the sympatho-inhibitory reno-renal reflex is blunted. In experimentally induced HF, renal denervation, both surgical and catheter-based, has been associated with some improvements in renal and cardiac function. It remains unknown whether the effects are due to removal of the efferent renal nerve fibers or afferent renal nerve fibers, or a combination of both. Here, we review the effects of HF on renal efferent and afferent nerve function and critically assess the latest evidence supporting renal denervation as a potential treatment in HF. PMID:26483699
Booth, Lindsea C; May, Clive N; Yao, Song T
Renal nerves contain afferent, sensory and efferent, sympathetic nerve fibers. In heart failure (HF) there is an increase in renal sympathetic nerve activity (RSNA), which can lead to renal vasoconstriction, increased renin release and sodium retention. These changes are thought to contribute to renal dysfunction, which is predictive of poor outcome in patients with HF. In contrast, the role of the renal afferent nerves remains largely unexplored in HF. This is somewhat surprising as there are multiple triggers in HF that have the potential to increase afferent nerve activity, including increased venous pressure and reduced kidney perfusion. Some of the few studies investigating renal afferents in HF have suggested that at least the sympatho-inhibitory reno-renal reflex is blunted. In experimentally induced HF, renal denervation, both surgical and catheter-based, has been associated with some improvements in renal and cardiac function. It remains unknown whether the effects are due to removal of the efferent renal nerve fibers or afferent renal nerve fibers, or a combination of both. Here, we review the effects of HF on renal efferent and afferent nerve function and critically assess the latest evidence supporting renal denervation as a potential treatment in HF.
Niijima, Akira; Jiang, Zheng-Yao; Daunton, Nancy G.; Fox, Robert A.
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.
Nishihara, Katsushi; Nozawa, Yoshihisa; Nakano, Motoko; Ajioka, Hirofusa; Matsuura, Naosuke
Capsaicin sensitive afferent nerves play an important role in gastric mucosal defensive mechanisms. Capsaicin stimulates afferent nerves and enhances the release of calcitonin gene-related peptide (CGRP), which seems to be the predominant neurotransmitter of spinal afferents in the rat stomach, exerting many pharmacological effects by a direct mechanism or indirectly through second messengers such as nitric oxide (NO). Lafutidine is a new type of anti-ulcer drug, possessing both an antisecretory effect, exerted via histamine H2 receptor blockade, and gastroprotective activities. Studies with certain antagonists or chemical deafferentation techniques suggest the gastroprotective actions of lafutidine to be mediated by capsaicin sensitive afferent nerves, but this is an assumption based on indirect techniques. In order to explain the direct relation of lafutidine to afferent nerves, we conducted the following studies. We determined CGRP and NO release from rat stomach and specific [3H]-resiniferatoxin (RTX) binding to gastric vanilloid receptor subtype 1 (VR1), which binds capsaicin, using EIA, a microdialysis system and a radioreceptor assay, respectively. Lafutidine enhanced both CGRP and NO release from the rat stomach induced by a submaximal dose of capsaicin, but had no effect on specific [3H]-RTX and capsaicin binding to VR1. In conclusion, our findings demonstrate that lafutidine modulates the activity of capsaicin sensitive afferent nerves in the rat stomach, which may be a key mechanism involved in its gastroprotective action. PMID:11906962
Enríquez, M; Jiménez, I; Rudomin, P
In the anesthetized cat we have analyzed the changes in primary afferent depolarization (PAD) evoked in single muscle spindle and tendon organ afferents at different times after their axons were crushed in the periphery and allowed to regenerate. Medial gastrocnemius (MG) afferents were depolarized by stimulation of group I fibers in the posterior biceps and semitendinosus nerve (PBSt), as soon as 2 weeks after crushing their axons in the periphery, in some cases before they could be activated by physiological stimulation of muscle receptors. Two to twelve weeks after crushing the MG nerve, stimulation of the PBSt produced PAD in all MG fibers reconnected with presumed muscle spindles and tendon organs. The mean amplitude of the PAD elicited in afferent fibers reconnected with muscle spindles was increased relative to values obtained from Ia fibers in intact (control) preparations, but remained essentially the same in fibers reconnected with tendon organs. Quite unexpectedly, we found that, between 2 and 12 weeks after crushing the MG nerve, stimulation of the bulbar reticular formation (RF) produced PAD in most afferent fibers reconnected with muscle spindle afferents. The mean amplitude of the PAD elicited in these fibers was significantly increased relative to the PAD elicited in muscle spindle afferents from intact preparations (from 0.08 +/- 0.4 to 0.47 +/- 0.34 mV). A substantial recovery was observed between 6 months and 2.5 years after the peripheral nerve injury. Stimulation of the sural (SU) nerve produced practically no PAD in muscle spindles from intact preparations, and this remained so in those afferents reconnected with muscle spindles impaled 2-12 weeks after the nerve crush. The mean amplitude of the PAD produced in afferent fibers reconnected with tendon organs by stimulation of the PBSt nerve and of the bulbar RF remained essentially the same as the PAD elicited in intact afferents. However, SU nerve stimulation produced a larger PAD in afferents
Fox, M T; Reynolds, G W; Scott, I; Simcock, D C; Simpson, H V
Heavy burdens of the abomasal nematode, Ostertagia (Telodorsagia) circumcincta, in growing lambs result in a reduction in liveweight gain due largely to a drop in voluntary feed intake. The present study investigated: (1) the role of subdiaphragmatic vagal and non-vagal visceral afferent nerves in mediating a reduction in voluntary feed intake, using subdiaphragmatic vagal deafferentation (vagotomy) either alone or in combination with coeliac-superior mesenteric ganglionectomy (vagotomy and sympathectomy); and (2) the association between appetite, abomasal pH, selected blood values (amidated gastrin (G-17-amide), glycine-extended gastrin (G-17-Gly), pepsinogen and leptin) and worm burden, in sheep experimentally infected with 100,000 O. circumcincta infective larvae per os. Neither vagotomy alone nor vagotomy and sympathectomy in combination adversely affected the establishment or course of development of the parasite burden, when compared with a control group subject to sham surgery. Furthermore, neither surgical procedure prevented the drop in appetite seen 5-10 days post-infection, although combined vagotomy and sympathectomy did reduce voluntary feed intake prior to the start of the study. Ostertagia infection resulted in a significant increase in abomasal pH in all three groups, which was accompanied by an increase in blood G-17-amide and in G-17-Gly, the latter reported for the first time in parasitized ruminants. There were no significant differences in blood leptin, also reported for the first time in parasitized sheep, either between groups or in comparison with pre-infection levels, though weak negative correlations were established between blood leptin and appetite from day 5 to the end of the study in all three groups and a positive correlation with blood G-17-amide in the control group over the same period. These data suggest that neither intact subdiaphragmatic vagal afferent nerves or coeliac-superior mesenteric ganglion fibres, nor changes in
Alvarez, Francisco J.; Bullinger, Katie L.; Titus, Haley E.; Nardelli, Paul; Cope, Timothy C.
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
Schiller, Alicia M; Pellegrino, Peter R; Zucker, Irving H
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.
Schiller, Alicia M.; Pellegrino, Peter R.; Zucker, Irving H.
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
Bombardi, C; Chiocchetti, R; Brunetti, O; Grandis, A; Lucchi, M L; Bortolami, R
The central distribution of intradental afferent nerve fibers was investigated by combining electron microscopic observations with a selective method for inducing degeneration of the A delta- and C-type afferent fibers. Degenerating terminals were found on the proprioceptive mesencephalic trigeminal neurons and on dendrites in the neuropil of the trigeminal motor nucleus after application of capsaicin to the rat's lower incisor tooth pulp. The results give anatomical evidence of new sites of central projection of intradental A delta- and C-type fibers whereby the nociceptive information from the tooth pulp can affect jaw muscle activity.
Just, S; Heppelmann, B
The aim of the present study was to examine the effect of electrical saphenous nerve stimulation (14 V, 1-10 Hz) on the mechanosensitivity of rat knee joint afferents. The responses to passive joint rotations at defined torque were recorded from slowly conducting knee joint afferent nerve fibres (0.6-20.0 m/s). After repeated nerve stimulation with 1 Hz, the mechanosensitivity of about 79% of the units was significantly affected. The effects were most prominent at a torque close to the mechanical threshold. In about 46% of the examined nerve fibres a significant increase was obtained, whereas about 33% reduced their mechanosensitivity. The sensitisation was prevented by an application of 5 microM phentolamine, an alpha-adrenergic receptor blocker, together with a neuropeptide Y receptor blocker. An inhibition of N-type Ca(2+) channels by an application of 1 microM omega-conotoxin GVIA caused comparable changes of the mechanosensitivity during the electrical stimulation. Electrical nerve stimulation with higher frequencies resulted in a further reduction of the mean response to joint rotations. After stimulation with 10 Hz, there was a nearly complete loss of mechanosensitivity.In conclusion, antidromic electrical nerve stimulation leads to a frequency dependent transient decrease of the mechanosensitivity. A sensitisation was only obtained at 1 Hz, but this effect may be based on the influence of sympathetic nerve fibres.
Madden, Christopher J.; Santos da Conceicao, Ellen Paula; Morrison, Shaun F.
ABSTRACT In urethane/α-chloralose anesthetized rats, electrical stimulation of cervical vagal afferent fibers inhibited the increases in brown adipose tissue sympathetic nerve activity and brown adipose tissue thermogenesis evoked by cold exposure, by nanoinjection of the GABAA receptor antagonist, bicuculline, in the dorsomedial hypothalamus, and by nanoinjection of N-methyl-D-aspartate in the rostral raphe pallidus. Vagus nerve stimulation-evoked inhibition of brown adipose tissue sympathetic nerve activity was prevented by blockade of ionotropic glutamate receptors in the termination site of vagal afferents in the nucleus of the solitary tract, and by nanoinjection of GABAA receptor antagonists in the rostral raphe pallidus. In conclusion, the brown adipose tissue sympathoinhibitory effect of cervical afferent vagal nerve stimulation is mediated by glutamatergic activation of second-order sensory neurons in the nucleus of the solitary tract and by a GABAergic inhibition of brown adipose tissue sympathetic premotor neurons in the rostral raphe pallidus, but does not require GABAergic inhibition of the brown adipose tissue sympathoexcitatory neurons in the dorsomedial hypothalamus. PMID:28349097
Bernhard, C. G.; Granit, Ragnar
Rapid local cooling of mammalian nerve sets up a discharge which is preceded by a local temperature potential, the cooled region being electronegative relative to a normal portion of the nerve. Heating the nerve locally above its normal temperature similarly makes the heated region electronegative relative to a region at normal temperature, and again a discharge is set up from the heated region. These local temperature potentials, set up by the nerve itself, are held to serve as "generator potentials" and the mechanism found is regarded as the prototype for temperature end organs. PMID:19873460
Mingin, Gerald C; Heppner, Thomas J; Tykocki, Nathan R; Erickson, Cuixia Shi; Vizzard, Margaret A; Nelson, Mark T
Social stress has been implicated as a cause of urinary bladder hypertrophy and dysfunction in humans. Using a murine model of social stress, we and others have shown that social stress leads to bladder overactivity. Here, we show that social stress leads to bladder overactivity, increased bladder compliance, and increased afferent nerve activity. In the social stress paradigm, 6-wk-old male C57BL/6 mice were exposed for a total of 2 wk, via barrier cage, to a C57BL/6 retired breeder aggressor mouse. We performed conscious cystometry with and without intravesical infusion of the TRPV1 inhibitor capsazepine, and measured pressure-volume relationships and afferent nerve activity during bladder filling using an ex vivo bladder model. Stress leads to a decrease in intermicturition interval and void volume in vivo, which was restored by capsazepine. Ex vivo studies demonstrated that at low pressures, bladder compliance and afferent activity were elevated in stressed bladders compared with unstressed bladders. Capsazepine did not significantly change afferent activity in unstressed mice, but significantly decreased afferent activity at all pressures in stressed bladders. Immunohistochemistry revealed that TRPV1 colocalizes with CGRP to stain nerve fibers in unstressed bladders. Colocalization significantly increased along the same nerve fibers in the stressed bladders. Our results support the concept that social stress induces TRPV1-dependent afferent nerve activity, ultimately leading to the development of overactive bladder symptoms.
Heppner, Thomas J.; Tykocki, Nathan R.; Erickson, Cuixia Shi; Vizzard, Margaret A.; Nelson, Mark T.
Social stress has been implicated as a cause of urinary bladder hypertrophy and dysfunction in humans. Using a murine model of social stress, we and others have shown that social stress leads to bladder overactivity. Here, we show that social stress leads to bladder overactivity, increased bladder compliance, and increased afferent nerve activity. In the social stress paradigm, 6-wk-old male C57BL/6 mice were exposed for a total of 2 wk, via barrier cage, to a C57BL/6 retired breeder aggressor mouse. We performed conscious cystometry with and without intravesical infusion of the TRPV1 inhibitor capsazepine, and measured pressure-volume relationships and afferent nerve activity during bladder filling using an ex vivo bladder model. Stress leads to a decrease in intermicturition interval and void volume in vivo, which was restored by capsazepine. Ex vivo studies demonstrated that at low pressures, bladder compliance and afferent activity were elevated in stressed bladders compared with unstressed bladders. Capsazepine did not significantly change afferent activity in unstressed mice, but significantly decreased afferent activity at all pressures in stressed bladders. Immunohistochemistry revealed that TRPV1 colocalizes with CGRP to stain nerve fibers in unstressed bladders. Colocalization significantly increased along the same nerve fibers in the stressed bladders. Our results support the concept that social stress induces TRPV1-dependent afferent nerve activity, ultimately leading to the development of overactive bladder symptoms. PMID:26224686
Zimmermann, Katharina; Hein, Alexander; Hager, Ulrich; Kaczmarek, Jan Stefan; Turnquist, Brian P; Clapham, David E; Reeh, Peter W
This protocol details methods to identify and record from cutaneous primary afferent axons in an isolated mammalian skin–saphenous nerve preparation. The method is based on extracellular recordings of propagated action potentials from single-fiber receptive fields. Cutaneous nerve endings show graded sensitivities to various stimulus modalities that are quantified by adequate and controlled stimulation of the superfused skin with heat, cold, touch, constant punctate pressure or chemicals. Responses recorded from single-fibers are comparable with those obtained in previous in vivo experiments on the same species. We describe the components and the setting-up of the basic equipment of a skin–nerve recording station (few days), the preparation of the skin and the adherent saphenous nerve in the mouse (15–45 min) and the isolation and recording of neurons (approximately 1–3 h per recording). In addition, stimulation techniques, protocols to achieve single-fiber recordings, issues of data acquisition and action potential discrimination are discussed in detail. PMID:19180088
Lundgren, Ove; Jodal, Mats; Jansson, Madeleine; Ryberg, Anders T.; Svensson, Lennart
Background The maintenance of the intestinal epithelium is of great importance for the survival of the organism. A possible nervous control of epithelial cell renewal was studied in rats and mice. Methods Mucosal afferent nerves were stimulated by exposing the intestinal mucosa to capsaicin (1.6 mM), which stimulates intestinal external axons. Epithelial cell renewal was investigated in the jejunum by measuring intestinal thymidine kinase (TK) activity, intestinal 3H-thymidine incorporation into DNA, and the number of crypt cells labeled with BrdU. The influence of the external gut innervation was minimized by severing the periarterial nerves. Principal Findings Luminal capsaicin increased all the studied variables, an effect nervously mediated to judge from inhibitory effects on TK activity or 3H-thymidine incorporation into DNA by exposing the mucosa to lidocaine (a local anesthetic) or by giving four different neurotransmitter receptor antagonists i.v. (muscarinic, nicotinic, neurokinin1 (NK1) or calcitonin gene related peptide (CGRP) receptors). After degeneration of the intestinal external nerves capsaicin did not increase TK activity, suggesting the involvement of an axon reflex. Intra-arterial infusion of Substance P (SP) or CGRP increased intestinal TK activity, a response abolished by muscarinic receptor blockade. Immunohistochemistry suggested presence of M3 and M5 muscarinic receptors on the intestinal stem/progenitor cells. We propose that the stem/progenitor cells are controlled by cholinergic nerves, which, in turn, are influenced by mucosal afferent neuron(s) releasing acetylcholine and/or SP and/or CGRP. In mice lacking the capsaicin receptor, thymidine incorporation into DNA and number of crypt cells labeled with BrdU was lower than in wild type animals suggesting that nerves are important also in the absence of luminal capsaicin, a conclusion also supported by the observation that atropine lowered thymidine incorporation into DNA by 60% in control
Boada, M Danilo; Gutierrez, Silvia; Aschenbrenner, Carol A; Houle, Timothy T; Hayashida, Ken-Ichiro; Ririe, Douglas G; Eisenach, James C
Chronic pain after nerve injury is often accompanied by hypersensitivity to mechanical stimuli, yet whether this reflects altered input, altered processing, or both remains unclear. Spinal nerve ligation or transection results in hypersensitivity to mechanical stimuli in skin innervated by adjacent dorsal root ganglia, but no previous study has quantified the changes in receptive field properties of these neurons in vivo. To address this, we recorded intracellularly from L4 dorsal root ganglion neurons of anesthetized young adult rats, 1 wk after L5 partial spinal nerve ligation (pSNL) or sham surgery. One week after pSNL, hindpaw mechanical withdrawal threshold in awake, freely behaving animals was decreased in the L4 distribution on the nerve-injured side compared with sham controls. Electrophysiology revealed that high-threshold mechanoreceptive cells of A-fiber conduction velocity in L4 were sensitized, with a seven-fold reduction in mechanical threshold, a seven-fold increase in receptive field area, and doubling of maximum instantaneous frequency in response to peripheral stimuli, accompanied by reductions in after-hyperpolarization amplitude and duration. Only a reduction in mechanical threshold (minimum von Frey hair producing neuronal activity) was observed in C-fiber conduction velocity high-threshold mechanoreceptive cells. In contrast, low-threshold mechanoreceptive cells were desensitized, with a 13-fold increase in mechanical threshold, a 60% reduction in receptive field area, and a 40% reduction in instantaneous frequency to stimulation. No spontaneous activity was observed in L4 ganglia, and the likelihood of recording from neurons without a mechanical receptive field was increased after pSNL. These data suggest massively altered input from undamaged sensory afferents innervating areas of hypersensitivity after nerve injury, with reduced tactile and increased nociceptive afferent response. These findings differ importantly from previous preclinical
Gutierrez, Silvia; Aschenbrenner, Carol A.; Houle, Timothy T.; Hayashida, Ken-ichiro; Ririe, Douglas G.; Eisenach, James C.
Chronic pain after nerve injury is often accompanied by hypersensitivity to mechanical stimuli, yet whether this reflects altered input, altered processing, or both remains unclear. Spinal nerve ligation or transection results in hypersensitivity to mechanical stimuli in skin innervated by adjacent dorsal root ganglia, but no previous study has quantified the changes in receptive field properties of these neurons in vivo. To address this, we recorded intracellularly from L4 dorsal root ganglion neurons of anesthetized young adult rats, 1 wk after L5 partial spinal nerve ligation (pSNL) or sham surgery. One week after pSNL, hindpaw mechanical withdrawal threshold in awake, freely behaving animals was decreased in the L4 distribution on the nerve-injured side compared with sham controls. Electrophysiology revealed that high-threshold mechanoreceptive cells of A-fiber conduction velocity in L4 were sensitized, with a seven-fold reduction in mechanical threshold, a seven-fold increase in receptive field area, and doubling of maximum instantaneous frequency in response to peripheral stimuli, accompanied by reductions in after-hyperpolarization amplitude and duration. Only a reduction in mechanical threshold (minimum von Frey hair producing neuronal activity) was observed in C-fiber conduction velocity high-threshold mechanoreceptive cells. In contrast, low-threshold mechanoreceptive cells were desensitized, with a 13-fold increase in mechanical threshold, a 60% reduction in receptive field area, and a 40% reduction in instantaneous frequency to stimulation. No spontaneous activity was observed in L4 ganglia, and the likelihood of recording from neurons without a mechanical receptive field was increased after pSNL. These data suggest massively altered input from undamaged sensory afferents innervating areas of hypersensitivity after nerve injury, with reduced tactile and increased nociceptive afferent response. These findings differ importantly from previous preclinical
Delivopoulos, Evangelos; Chew, Daniel J; Minev, Ivan R; Fawcett, James W; Lacour, Stéphanie P
In this paper we present a compliant neural interface designed to record bladder afferent activity. We developed the implant's microfabrication process using multiple layers of silicone rubber and thin metal so that a gold microelectrode array is embedded within four parallel polydimethylsiloxane (PDMS) microchannels (5 mm long, 100 μm wide, 100 μm deep). Electrode impedance at 1 kHz was optimized using a reactive ion etching (RIE) step, which increased the porosity of the electrode surface. The electrodes did not deteriorate after a 3 month immersion in phosphate buffered saline (PBS) at 37 °C. Due to the unique microscopic topography of the metal film on PDMS, the electrodes are extremely compliant and can withstand handling during implantation (twisting and bending) without electrical failure. The device was transplanted acutely to anaesthetized rats, and strands of the dorsal branch of roots L6 and S1 were surgically teased and inserted in three microchannels under saline immersion to allow for simultaneous in vivo recordings in an acute setting. We utilized a tripole electrode configuration to maintain background noise low and improve the signal to noise ratio. The device could distinguish two types of afferent nerve activity related to increasing bladder filling and contraction. To our knowledge, this is the first report of multichannel recordings of bladder afferent activity.
Yamakawa, Kentaro; Rajendran, Pradeep S.; Takamiya, Tatsuo; Yagishita, Daigo; So, Eileen L.; Mahajan, Aman; Shivkumar, Kalyanam
Vagal nerve stimulation (VNS) has been shown to have antiarrhythmic effects, but many of these benefits were demonstrated in the setting of vagal nerve decentralization. The purpose of this study was to evaluate the role of afferent fiber activation during VNS on efferent control of cardiac hemodynamic and electrophysiological parameters. In 37 pigs a 56-electrode sock was placed over the ventricles to record local activation recovery intervals (ARIs), a surrogate of action potential duration. In 12 of 37 animals atropine was given systemically. Right and left VNS were performed under six conditions: both vagal trunks intact (n = 25), ipsilateral right (n = 11), ipsilateral left (n = 14), contralateral right (n = 7), contralateral left (n = 10), and bilateral (n = 25) vagal nerve transection (VNTx). Unilateral VNTx significantly affected heart rate, PR interval, Tau, and global ARIs. Right VNS after ipsilateral VNTx had augmented effects on hemodynamic parameters and increase in ARI, while subsequent bilateral VNTx did not significantly modify this effect (%change in ARI in intact condition 2.2 ± 0.9% vs. ipsilateral VNTx 5.3 ± 1.7% and bilateral VNTx 5.3 ± 0.8%, P < 0.05). Left VNS after left VNTx tended to increase its effects on hemodynamics and ARI response (P = 0.07), but only after bilateral VNTx did these changes reach significance (intact 1.1 ± 0.5% vs. ipsilateral VNTx 3.6 ± 0.7% and bilateral VNTx 6.6 ± 1.6%, P < 0.05 vs. intact). Contralateral VNTx did not modify VNS response. The effect of atropine on ventricular ARI was similar to bilateral VNTx. We found that VNS activates afferent fibers in the ipsilateral vagal nerve, which reflexively inhibit cardiac parasympathetic efferent electrophysiological and hemodynamic effects. PMID:26371172
Lauweryns, J M; Van Lommel, A
This study on the innervation of rabbit intrapulmonary neuroepithelial bodies (NEB) was undertaken to obtain more information about the detailed ultrastructure of morphologically afferent and efferent intracorpuscular NEB nerve endings, the extent to which they are in cytoplasmic continuity with one another, and the structure of the synaptic junctions they form with the NEB corpuscular cells. As in earlier studies, NEB exhibit intracorpuscular nerve endings containing predominantly either mitochondria (morphologically afferent) or synaptic vesicles (morphologically efferent). Both types of nerve endings form synaptic junctions with the NEB corpuscular cells, arranged so that a NEB corpuscular cell is the presynaptic element and the nerve ending the postsynaptic element. This arrangement implies that NEB can transmit nerve impulses to the central nervous system, thus arguing in favour of their hypothetical neuroreceptor function. Moreover, on serial sections, the morphologically afferent and efferent intracorpuscular nerve endings are often found in cytoplasmic continuity. Hence, transduction of stimuli in the NEB implies concomitant efferent modulation of the NEB corpuscular cells. In conclusion, intrapulmonary NEB apparently function as neuroreceptors that are locally modulated by axon reflexes. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 6 (cont.) Fig. 6 (cont.) Fig. 6 PMID:3654362
Nassenstein, Christina; Kwong, Kevin; Taylor-Clark, Thomas; Kollarik, Marian; Macglashan, Donald M; Braun, Armin; Undem, Bradley J
Transient receptor potential (TRP) A1 and TRPM8 are ion channels that have been localized to afferent nociceptive nerves. These TRP channels may be of particular relevance to respiratory nociceptors in that they can be activated by various inhaled irritants and/or cold air. We addressed the hypothesis that mouse vagal sensory nerves projecting to the airways express TRPA1 and TRPM8 and that they can be activated via these receptors. Single cell RT-PCR analysis revealed that TRPA1 mRNA, but not TRPM8, is uniformly expressed in lung-labelled TRPV1-expressing vagal sensory neurons. Neither TRPA1 nor TRPM8 mRNA was expressed in TRPV1-negative neurons. Capsaicin-sensitive, but not capsaicin-insensitive, lung-specific neurons responded to cinnamaldehyde, a TRPA1 agonist, with increases in intracellular calcium. Menthol, a TRPM8 agonist, was ineffective at increasing cellular calcium in lung-specific vagal sensory neurons. Cinnamaldehyde also induced TRPA1-like inward currents (as measured by means of whole cell patch clamp recordings) in capsaicin-sensitive neurons. In an ex vivo vagal innervated mouse lung preparation, cinnamaldehyde evoked action potential discharge in mouse vagal C-fibres with a peak frequency similar to that observed with capsaicin. Cinnamaldehyde inhalation in vivo mimicked capsaicin in eliciting strong central-reflex changes in breathing pattern. Taken together, our results support the hypothesis that TRPA1, but not TRPM8, is expressed in vagal sensory nerves innervating the airways. TRPA1 activation provides a mechanism by which certain environmental stimuli may elicit action potential discharge in airway afferent C-fibres and the consequent nocifensor reflexes.
Foss, Jason D.; Fink, Gregory D.
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
Rudomin, P; Jiménez, I; Chávez, D
In the anaesthetized cat, the acute section of the saphenous (Saph) and/or the superficial peroneal (SP) nerves was found to produce a long-lasting increase of the field potentials generated in the dorsal horn by stimulation of the medial branch of the sural (mSU) nerve. This facilitation was associated with changes in the level of the tonic primary afferent depolarization (PAD) of the mSU intraspinal terminals. The mSU afferent fibres projecting into Rexed's laminae III–IV were subjected to a tonic PAD that was reduced by the acute section of the SP and/or the Saph nerves. The mSU afferents projecting deeper into the dorsal horn (Rexed's laminae V–VI) were instead subjected to a tonic PAD that was increased after Saph and SP acute nerve section. A differential control of the synaptic effectiveness of the low-threshold cutaneous afferents according to their sites of termination within the dorsal horn is envisaged as a mechanism that allows selective processing of sensory information in response to tactile and nociceptive stimulation or during the execution of different motor tasks. PMID:23478136
Rudomin, P; Jiménez, I; Chávez, D
In the anaesthetized cat, the acute section of the saphenous (Saph) and/or the superficial peroneal (SP) nerves was found to produce a long-lasting increase of the field potentials generated in the dorsal horn by stimulation of the medial branch of the sural (mSU) nerve. This facilitation was associated with changes in the level of the tonic primary afferent depolarization (PAD) of the mSU intraspinal terminals. The mSU afferent fibres projecting into Rexed's laminae III-IV were subjected to a tonic PAD that was reduced by the acute section of the SP and/or the Saph nerves. The mSU afferents projecting deeper into the dorsal horn (Rexed's laminae V-VI) were instead subjected to a tonic PAD that was increased after Saph and SP acute nerve section. A differential control of the synaptic effectiveness of the low-threshold cutaneous afferents according to their sites of termination within the dorsal horn is envisaged as a mechanism that allows selective processing of sensory information in response to tactile and nociceptive stimulation or during the execution of different motor tasks.
Undem, Bradley J; Oh, Eun Joo; Lancaster, Eric; Weinreich, Daniel
The effect of reducing extracellular calcium concentration ([Ca(2+)](o)) on vagal afferent excitability was analyzed in a guinea pig isolated vagally innervated trachea-bronchus preparation. Afferent fibers were characterized as either having low-threshold, rapidly adapting mechanosensors (Adelta fibers) or nociceptive-like phenotypes (Adelta and C fibers). The nociceptors were derived from neurons within the jugular ganglia, whereas the low-threshold mechanosensors were derived from neurons within the nodose ganglia. Reducing [Ca(2+)](o) did not affect the excitability of the low-threshold mechanosensors in the airway. By contrast, reducing [Ca(2+)](o) selectively increased the excitability of airway nociceptors as manifested by a substantive increase in action potential discharge in response to mechanical stimulation, and in a subset of fibers, by overtly evoking action potential discharge. This increase in the excitability of nociceptors was not mimicked by a combination of omega-conotoxin and nifedipine or tetraethylammonium. Whole cell patch recordings from airway-labeled and unlabeled neurons in the vagal jugular ganglia support the hypothesis that [Ca(2+)](o) inhibits a nonselective cation conductance in vagal nociceptors that may serve to regulate excitability of the nerve terminals within the airways.
Bessou, P; Joffroy, M; Pagès, B
1. The background activity was observed in gamma and alpha efferent fibres and in group I and II fibres innervating the muscle gastrocnemius lateralis or medialis. The reflex effects of ipsilateral and contralateral sural nerve stimulations on the muscle efferents were analysed together with their consequences upon the afferents of the same muscle. The observations were made in the decerebrated cat without opening the neural loops between the muscle and the spinal cord.2. The multi-unit discharges of each category of fibres were obtained, on line, by an original electronic device (Joffroy, 1975, 1980) that sorted the action potentials from the whole electrical activity of a small branch of gastrocnemius lateralis or medialis nerve according to the direction and velocity of propagation of the potentials.3. The small nerve may be regarded as a representative sample of different functional groups of fibres conducting faster than 12 m.sec(-1) and supplying gastrocnemius muscles.4. Some gamma efferents were always tonically firing except when a transient flaccid state developed. Usually the alpha efferents were silent, probably because the muscle was fixed close to the minimal physiological length.5. Separate and selective stimulations of Abeta, Adelta and C fibres of ipsilateral and contralateral sural nerve showed that each group could induce the excitation of gamma neurones. The reciprocal inhibition period of alpha efferents during a flexor reflex was only once accompanied by a small decrease in gamma-firing.6. The reflex increase of over-all frequency of gamma efferents resulted from an increased firing rate of tonic gamma neurones and from the recruitment of gamma neurones previously silent. When the gamma efferents in the small nerve naturally occurred in two subgroups, the slower-conducting subgroup (mainly composed of tonic gamma axons) was activated before the faster-conducting subgroup (mostly composed by gamma axons with no background discharge). Some rare
Weber, W E
Phantom pain, a form of neuropathic pain, is caused by damage to somatosensible afferent nerve fibres in the peripheral or central nervous system. Often, the pain cannot be satisfactorily treated with nonsteroidal anti-inflammatory drugs. Dependent on the underlying mechanism the pain is treated with either antidepressants (for more or less continuous pain) or anti-epileptics (for paroxysmal pain). Of the antidepressants, the tricyclic antidepressants are the best studied and most prescribed. The activity of new drugs, such as the selective serotonin reuptake inhibitor paroxetine as well as venlafaxine, has yet to be clearly shown. Of the anti-epileptics, carbamazepine and phenytoin are the most prescribed. New drugs which provide greater pain relief than the placebo are oxcarbazepine, gabapentine and lamotrigine. Other effective drugs for phantom pain are: gamma-butyric acid agonists (baclofen), opiates (morphine preparations with a regulated release; phentanyl patch), the N-methyl-D-aspartate receptor antagonist amantadine, transdermally administered clonidine and locally applied lidocaine.
Humenick, A; Chen, B N; Wiklendt, L; Spencer, N J; Zagorodnyuk, V P; Dinning, P G; Costa, M; Brookes, S J H
Spinal sensory neurons innervate many large blood vessels throughout the body. Their activation causes the hallmarks of neurogenic inflammation: vasodilatation through the release of the neuropeptide calcitonin gene-related peptide and plasma extravasation via tachykinins. The same vasodilator afferent neurons show mechanical sensitivity, responding to crushing, compression or axial stretch of blood vessels – responses which activate pain pathways and which can be modified by cell damage and inflammation. In the present study, we tested whether spinal afferent axons ending on branching mesenteric arteries (‘vascular afferents’) are sensitive to increased intravascular pressure. From a holding pressure of 5 mmHg, distension to 20, 40, 60 or 80 mmHg caused graded, slowly adapting increases in firing of vascular afferents. Many of the same afferent units showed responses to axial stretch, which summed with responses evoked by raised pressure. Many vascular afferents were also sensitive to raised temperature, capsaicin and/or local compression with von Frey hairs. However, responses to raised pressure in single, isolated vessels were negligible, suggesting that the adequate stimulus is distortion of the arterial arcade rather than distension per se. Increasing arterial pressure often triggered peristaltic contractions in the neighbouring segment of intestine, an effect that was mimicked by acute exposure to capsaicin (1 μm) and which was reduced after desensitisation to capsaicin. These results indicate that sensory fibres with perivascular endings are sensitive to pressure-induced distortion of branched arteries, in addition to compression and axial stretch, and that they contribute functional inputs to enteric motor circuits. PMID:26010893
Xu, Bo; Zheng, Hong; Liu, Xuefei; Patel, Kaushik P
Renal denervation for the treatment of hypertension has proven to be successful; however, the underlying mechanism/s are not entirely clear. To determine if preautonomic neurons in the paraventricular nucleus (PVN) respond to afferent renal nerve (ARN) stimulation, extracellular single-unit recording was used to investigate the contribution of the rostral ventrolateral medulla (RVLM)-projecting PVN (PVN-RVLM) neurons to the response elicited during stimulation of ARN. In 109 spontaneously active neurons recorded in the PVN of anesthetized rats, 25 units were antidromically activated from the RVLM. Among these PVN-RVLM neurons, 84% (21/25) were activated by ARN stimulation. The baseline discharge rate was significantly higher in these neurons than those PVN-RVLM neurons not activated by ARN stimulation (16%, 4/25). The responsiveness of these neurons to baroreflex activation induced by phenylephrine and activation of cardiac sympathetic afferent reflex (CSAR) was also examined. Almost all of the PVN neurons that responded to ARN stimulation were sensitive to baroreflex (95%) and CSAR (100%). The discharge characteristics for nonevoked neurons (not activated by RVLM antidromic stimulation) showed that 23% of these PVN neurons responded to ARN stimulation. All the PVN neurons that responded to ARN stimulation were activated by N-methyl-D-aspartate, and these responses were attenuated by the glutamate receptor blocker AP5. These experiments demonstrated that sensory information originating in the kidney is integrated at the level of preautonomic neurons within the PVN, providing a novel mechanistic insight for use of renal denervation in the modulation of sympathetic outflow in disease states such as hypertension and heart failure.
Djilas, Milan; Azevedo-Coste, Christine; Guiraud, David; Yoshida, Ken
In this study, we explored the feasibility of estimating muscle length in passive conditions by interpreting nerve responses from muscle spindle afferents recorded with thin-film longitudinal intrafascicular electrodes. Afferent muscle spindle response to passive stretch was recorded in ten acute rabbit experiments. A newly proposed first-order model of muscle spindle response to passive sinusoidal muscle stretch manages to capture the relationship between afferent neural firing rate and muscle length. We demonstrate that the model can be used to track random motion trajectories with bandwidth from 0.1 to 1 Hz over a range of 4 mm with a muscle length estimation error of 0.3 mm (1.4 degrees of joint angle). When estimation is performed using four-channel ENG there is a 50% reduction in estimate variation, compared to using single-channel recordings.
Banks, R W; Hulliger, M; Saed, H H; Stacey, M J
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
Wilkinson, Katherine A; Kloefkorn, Heidi E; Hochman, Shawn
We utilized an in vitro adult mouse extensor digitorum longus (EDL) nerve-attached preparation to characterize the responses of muscle spindle afferents to ramp-and-hold stretch and sinusoidal vibratory stimuli. Responses were measured at both room (24°C) and muscle body temperature (34°C). Muscle spindle afferent static firing frequencies increased linearly in response to increasing stretch lengths to accurately encode the magnitude of muscle stretch (tested at 2.5%, 5% and 7.5% of resting length [Lo]). Peak firing frequency increased with ramp speeds (20% Lo/sec, 40% Lo/sec, and 60% Lo/sec). As a population, muscle spindle afferents could entrain 1:1 to sinusoidal vibrations throughout the frequency (10-100 Hz) and amplitude ranges tested (5-100 µm). Most units preferentially entrained to vibration frequencies close to their baseline steady-state firing frequencies. Cooling the muscle to 24°C decreased baseline firing frequency and units correspondingly entrained to slower frequency vibrations. The ramp component of stretch generated dynamic firing responses. These responses and related measures of dynamic sensitivity were not able to categorize units as primary (group Ia) or secondary (group II) even when tested with more extreme length changes (10% Lo). We conclude that the population of spindle afferents combines to encode stretch in a smoothly graded manner over the physiological range of lengths and speeds tested. Overall, spindle afferent response properties were comparable to those seen in other species, supporting subsequent use of the mouse genetic model system for studies on spindle function and dysfunction in an isolated muscle-nerve preparation.
Cha, S W; Tan, C K
This study seeks to extend the observations of previous studies of projection of primary afferent fibres from the forelimb nerves and muscles to the external cuneate nucleus (ECN) of mammals using a neurotoxic lectin, Ricinus communis agglutinin (RCA) to achieve chemical ganglionectomy of the dorsal root ganglia. Following intraneural injection of RCA into the three main forelimb nerves, namely the radial, ulnar and median nerves, terminal degeneration of the primary afferent fibres in the ECN was studied under the light microscope by means of the Fink-Heimer method. The results show that the primary afferent fibres from these three nerves project to the medial part of the ECN. The field of terminal degeneration take a crescentic form. The projection from the median nerve was most dorsally located whereas that from the radial nerve was the most ventral with extensive overlaps between them. Of the three nerves, the projection from the radial nerve was the most dense. Rostrocaudally, the three nerves also show extensive overlaps. The rostrocaudal extent of maximum terminal degeneration was greatest for the radial nerve and least for the median nerve. Analysis of variance showed that these differences were statistically significant. This suggests that the radial nerve has the most extensive projection to the ECN and the median nerve the least.
Torigoe, Yasuhiro; Cernucan, Roxana D.; Nishimoto, Jo Ann S.; Blanks, Robert H. I.
As a part of the study of the vestibular-autonomic pathways involved in motion sickness, the location and the morphology of preganglionic sympathetic neurons (PSNs) projecting via the greater splanchnic nerve were examined. Retrograde labeling of neurons was obtained by application of horseradish peroxidase to the cut end of the greater splanchnic nerve. Labeled PSNs were found, ipsilaterally, within the T1 to T11 spinal cord segments, with the highest density of neurons in T6. Most PSNs were located within the intermediolateral column, but a significant portion also occurred within the lateral funiculus, the intercalated region, and the central autonomic area; the proportion of labeling between the four regions depended on the spinal cord segment.
Tai, Changfeng; Chen, Mang; Shen, Bing; Wang, Jicheng; Liu, Hailong; Roppolo, James R; de Groat, William C
Bladder reflexes evoked by stimulation of pudendal afferent nerves (PudA-to-Bladder reflex) were studied in normal and chronic spinal cord injured (SCI) adult cats to examine the reflex plasticity. Physiological activation of pudendal afferent nerves by tactile stimulation of the perigenital skin elicits an inhibitory PudA-to-Bladder reflex in normal cats, but activates an excitatory reflex in chronic SCI cats. However, in both normal and chronic SCI cats electrical stimulation applied to the perigenital skin or directly to the pudendal nerve induces either inhibitory or excitatory PudA-to-Bladder reflexes depending on stimulation frequency. An inhibitory response occurs at 3-10 Hz stimulation, but becomes excitatory at 20-30 Hz. The inhibitory reflex activated by electrical stimulation significantly (P<0.05) increases the bladder capacity to about 180% of control capacity in normal and chronic SCI cats. The excitatory reflex significantly (P<0.05) reduces bladder capacity to about 40% of control capacity in chronic SCI cats, but does not change bladder capacity in normal cats. Electrical stimulation of pudendal afferent nerves during slow bladder filling elicits a large amplitude bladder contraction comparable to the contraction induced by distension alone. A bladder volume about 60% of bladder capacity was required to elicit this excitatory reflex in normal cats; however, in chronic SCI cats a volume less than 20% of bladder capacity was sufficient to unmask an excitatory response. This study revealed the co-existence of both inhibitory and excitatory PudA-to-Bladder reflex pathways in cats before and after chronic SCI. However our data combined with published electrophysiological data strongly indicates that the spinal circuitry for both the excitatory and inhibitory PudA-to-Bladder reflexes undergoes a marked reorganization after SCI.
Unno, Tatsuya; Hashimoto, Mitsuyasu; Arai, Shoichi; Kurosawa, Mieko
Radiotherapy for malignant tumours often elicits anorexia or loss of appetite as an adverse effect. However, the mechanism for this is poorly understood. The present study was undertaken to investigate if visceral afferents are responsible for reduction of food intake following X-ray irradiation. Rats were exposed bilaterally to X-ray (10 MV) irradiation with total doses of 1.5, 3 and 6 Gy, using a high-energy electron linear accelerator at a dose rate of 4.9 Gy min(-1) X-ray irradiation of the whole body, abdomen or head with doses of 1.5, 3 and 6 Gy reduced food intake in a dose-dependent manner. The reduction of food intake after X-ray irradiation of the whole body or abdomen was significantly greater than when only the head was irradiated. Reduction of food intake was observed for the first 4 days after 6 Gy X-ray irradiation of the abdomen, while it was observed only on the first day after the same 6-Gy irradiation of the abdomen in animals whose small-diameter afferents were ablated by capsaicin pre-treatment. These results suggested that the abdominal afferent nerves at least contribute to the reduction of food intake observed on second to fourth days after 6-Gy abdominal irradiation. Taken together, the present evidence suggests that the reduction of food intake following X-ray irradiation of the whole body or the abdomen is partly mediated via abdominal afferent nerves. Moreover, the results of X-ray irradiation to the head suggest that X-ray irradiation directly influences the central nervous system to reduce food intake.
Zagorodnyuk, Vladimir P; Kyloh, Melinda; Brookes, Simon J; Nicholas, Sarah J; Spencer, Nick J
The functional role of the different classes of visceral afferents that innervate the large intestine is poorly understood. Recent evidence suggests that low-threshold, wide-dynamic-range rectal afferents play an important role in the detection and transmission of visceral pain induced by noxious colorectal distension in mice. However, it is not clear which classes of spinal afferents are activated during naturally occurring colonic motor patterns or during intense contractions of the gut smooth muscle. We developed an in vitro colorectum preparation to test how the major classes of rectal afferents are activated during spontaneous colonic migrating motor complex (CMMC) or pharmacologically induced contraction. During CMMCs, circular muscle contractions increased firing in low-threshold, wide-dynamic-range muscular afferents and muscular-mucosal afferents, which generated a mean firing rate of 1.53 ± 0.23 Hz (n = 8) under isotonic conditions and 2.52 ± 0.36 Hz (n = 17) under isometric conditions. These low-threshold rectal afferents were reliably activated by low levels of circumferential stretch induced by increases in length (1-2 mm) or load (1-3 g). In a small proportion of cases (5 of 34 units), some low-threshold muscular and muscular-mucosal afferents decreased their firing rate during the peak of the CMMC contractions. High-threshold afferents were never activated during spontaneous CMMC contractions or tonic contractions induced by bethanechol (100 μM). High-threshold rectal afferents were only activated by intense levels of circumferential stretch (10-20 g). These results show that, in the rectal nerves of mice, low-threshold, wide-dynamic-range muscular and muscular-mucosal afferents are excited during contraction of the circular muscle that occurs during spontaneous CMMCs. No activation of high-threshold rectal afferents was detected during CMMCs or intense contractile activity in naïve mouse colorectum.
Gonçalves da Silva Leite, Janaina; Costa Cavalcante, Maria Luzete; Fechine-Jamacaru, Francisco Vagnaldo; de Lima Pompeu, Margarida Maria; Leite, José Alberto Dias; Nascimento Coelho, Dulce Maria; Rabelo de Freitas, Marcos
Sensory receptors are distributed throughout the oral cavity, pharynx, and larynx. Laryngeal sensitivity is crucial for maintaining safe swallowing, thus avoiding silent aspiration. Morphologic description of different receptor types present in larynx vary because of the study of many different species, from mouse to humans. The most commonly sensory structures described in laryngeal mucosa are free nerve endings, taste buds, muscle spindles, glomerular and corpuscular receptors. This study aimed at describing the morphology and the distribution of nerve endings in premature newborn glottic region. Transversal serial frozen sections of the whole vocal folds of three newborns were analyzed using an immuno-histochemical process with a pan-neuronal marker anti-protein gene product 9.5 (PGP 9.5). Imaging was done using a confocal laser microscope. Nerve fiber density in vocal cord was calculated using panoramic images in software Morphometric Analysis System v1.0. Some sensory structures, i.e. glomerular endings and intraepithelial free nerve endings were found in the vocal cord mucosa. Muscle spindles, complex nerve endings (Meissner-like, spherical, rectangular and growing) spiral-wharves nerve structures were identified in larynx intrinsic muscles. Nervous total mean density in vocal cord was similar in the three newborns, although they had different gestational age. The mean nerve fiber density was higher in the posterior region than anterior region of vocal cord. The present results demonstrate the occurrence of different morphotypes of sensory corpuscles and nerve endings premature newborn glottic region and provide information on their sensory systems.
Booth, Lindsea C; Nishi, Erika E; Yao, Song T; Ramchandra, Rohit; Lambert, Gavin W; Schlaich, Markus P; May, Clive N
Previous studies indicate that catheter-based renal denervation reduces blood pressure and renal norepinephrine spillover in human resistant hypertension. The effects of this procedure on afferent sensory and efferent sympathetic renal nerves, and the subsequent degree of reinnervation, have not been investigated. We therefore examined the level of functional and anatomic reinnervation at 5.5 and 11 months after renal denervation using the Symplicity Flex catheter. In normotensive anesthetized sheep (n=6), electric stimulation of intact renal nerves increased arterial pressure from 99±3 to 107±3 mm Hg (afferent response) and reduced renal blood flow from 198±16 to 85±20 mL/min (efferent response). In a further group (n=6), immediately after denervation, renal sympathetic nerve activity was absent and the responses to electric stimulation were abolished. At 11 months after denervation (n=5), renal sympathetic nerve activity and the responses to electric stimulation were at normal levels. Immunohistochemical staining for renal efferent (tyrosine hydroxylase) and renal afferent nerves (calcitonin gene-related peptide), as well as renal norepinephrine levels, was normal 11 months after denervation. Findings at 5.5 months after denervation were similar (n=5). In summary, catheter-based renal denervation effectively ablated the renal afferent and efferent nerves in normotensive sheep. By 11 months after denervation the functional afferent and efferent responses to electric stimulation were normal. Reinnervation at 11 months after denervation was supported by normal anatomic distribution of afferent and efferent renal nerves. In view of this evidence, the mechanisms underlying the prolonged hypotensive effect of catheter-based renal denervation in human resistant hypertension need to be reassessed.
Kim, Kyu-Sung; Minor, Lloyd B; Della Santina, Charles C; Lasker, David M
In mammals, vestibular-nerve afferents that innervate only type I hair cells (calyx-only afferents) respond nearly in phase with head acceleration for high-frequency motion, whereas afferents that innervate both type I and type II (dimorphic) or only type II (bouton-only) hair cells respond more in phase with head velocity. Afferents that exhibit irregular background discharge rates have a larger phase lead re-head velocity than those that fire more regularly. The goal of this study was to investigate the cause of the variation in phase lead between regular and irregular afferents at high-frequency head rotations. Under the assumption that externally applied galvanic currents act directly on the nerve, we derived a transfer function describing the dynamics of a semicircular canal and its hair cells through comparison of responses to sinusoidally modulated head velocity and currents. Responses of all afferents were fit well with a transfer function with one zero (lead term). Best-fit lead terms describing responses to current for each group of afferents were similar to the lead term describing responses to head velocity for regular afferents (0.006 s + 1). This finding indicated that the pre-synaptic and synaptic inputs to regular afferents were likely to be pure velocity transducers. However, the variation in phase lead between regular and irregular afferents could not be explained solely by the ratio of type I to II hair cells (Baird et al 1988), suggesting that the variation was caused by a combination of pre- (type of hair cell) and post-synaptic properties.
Grossmann, Lydia; Gorodetskaya, Natalia; Teliban, Alina; Baron, Ralf; Jänig, Wilfrid
Cutaneous C-fiber afferents show two distinct types of cold sensitivity corresponding to non-noxious and noxious cold sensations. Here, responses to cold stimulation of afferent fibers regenerating in the rat sural nerve were studied in vivo 7-14 days after nerve crush and compared with responses to mechanical and heat stimulation. The physiological stimuli were applied to the sural nerve at or distal to the lesion site. Ectopic activity was evoked in 43% of 98 A-fibers (all mechanosensitive; a few additionally weakly thermosensitive). Ectopic activity was evoked in 127 (49.2%) of 258 electrically identified C-fibers by the physiological stimuli. Eight C-fibers were spontaneously active only. Of the 127 C-fibers, 46% had one of two distinct response patterns to cooling: (1) type 1 cold-sensitive C-fibers (n=29) had a high rate of activity at 28 degrees C on the nerve surface and showed graded responses to cooling with maximal discharge rates of 11.5+/-1.1 imp/s. This activity was completely inhibited by heating, while 12/29 fibers were also excited at high threshold (median 48 degrees C) by heating. Only one type 1 cold-sensitive C-fiber was mechanosensitive. (2) Type 2 cold-sensitive C-fibers (n=29) were silent or showed a low rate of activity at 28 degrees C, had a high threshold (median 5 degrees C) and low maximal discharge rates (2.4+/-0.4 imp/s) to cooling. They were also heat-sensitive (n=25) and/or mechanosensitive (n=20). These C-fibers were, apart from their cold sensitivity, functionally indistinguishable from C-fibers with mechano- and/or heat sensitivity only. Thus regenerating cutaneous C-fibers show two types of cold sensitivity similar to those observed in intact skin: fibers of one group are predominantly sensitive to cooling, whereas the others are polymodal.
Chen, Tai-Yuan; Yang, Yi-Chin; Sha, Ya-Na; Chou, Jiun-Rou
This study employed a rat model of sciatic nerve injury to investigate the effects of postoperative low-power far-infrared (FIR) radiation therapy on nerve repair following end-to-end neurorrhaphy. The rat models were divided into the following 3 groups: (1) nerve injury without FIR biostimulation (NI/sham group); (2) nerve injury with FIR biostimulation (NI/FIR group); and (3) noninjured controls (normal group). Walking-track analysis results showed that the NI/FIR group exhibited significantly higher sciatic functional indices at 8 weeks after surgery (P < 0.05) compared with the NI/sham group. The decreased expression of CD4 and CD8 in the NI/FIR group indicated that FIR irradiation modulated the inflammatory process during recovery. Compared with the NI/sham group, the NI/FIR group exhibited a significant reduction in muscle atrophy (P < 0.05). Furthermore, histomorphometric assessment indicated that the nerves regenerated more rapidly in the NI/FIR group than in the NI/sham group; furthermore, the NI/FIR group regenerated neural tissue over a larger area, as well as nerve fibers of greater diameter and with thicker myelin sheaths. Functional recovery, inflammatory response, muscular reinnervation, and histomorphometric assessment all indicated that FIR radiation therapy can accelerate nerve repair following end-to-end neurorrhaphy of the sciatic nerve. PMID:25722734
Xiao, Bo; Zanoun, Rami R.; Carvell, George E.; Washington, Kia M.
The rodent whisker/trigeminal system, characterized by high spatial and temporal resolution, provides an experimental model for developing new therapies for improving sensory functions of damaged peripheral nerves. Here, we use controlled whisker stimulation and single-unit recordings of trigeminal ganglion cells to examine in detail the nature and time course of functional recovery of mechanoreceptive afferents following nerve transection with microsurgical repair of the infraorbital nerve (ION) branch of the trigeminal nerve in adult rats. Response measures include rapid vs. slow adaptation, firing rate, interspike intervals, latency, and angular (directional) tuning. Whisker-evoked responses, readily observable by 3 wk post-transection, recover progressively for at least the next 5 wk. All cells in transected animals, as in control cases, responded to deflections of single whiskers only, but topography within the ganglion was clearly disrupted. The time course and extent of recovery of quantitative response measures were receptor dependent. Cells displaying slowly adapting (SA) properties recovered more quickly than rapidly adapting (RA) populations, and for some response measures—notably evoked firing rates—closely approached or attained control levels by 8 wk post-transection. Angular tuning of RA cells was slightly better than control units, whereas SA tuning did not differ from control values. Nerve conduction times and refractory periods, examined separately using electrical stimulation of the ION, were slower than normal in all transected animals and poorly reflected recovery of whisker-evoked response latencies and interspike intervals. Results underscore the need for multiple therapeutic strategies that target different aspects of functional restitution following peripheral nerve injury. PMID:26792886
Napadow, Vitaly; Edwards, Robert R; Cahalan, Christine M; Mensing, George; Greenbaum, Seth; Valovska, Assia; Li, Ang; Kim, Jieun; Maeda, Yumi; Park, Kyungmo; Wasan, Ajay D.
Objective Previous Vagus Nerve Stimulation (VNS) studies have demonstrated anti-nociceptive effects, and recent non-invasive approaches; termed transcutaneous-VNS, or t-VNS, have utilized stimulation of the auricular branch of the vagus nerve in the ear. The dorsal medullary vagal system operates in tune with respiration, and we propose that supplying vagal afferent stimulation gated to the exhalation phase of respiration can optimize t-VNS. Design counterbalanced, crossover study. Patients patients with chronic pelvic pain (CPP) due to endometriosis in a specialty pain clinic. Interventions/Outcomes We evaluated evoked pain analgesia for Respiratory-gated Auricular Vagal Afferent Nerve Stimulation (RAVANS) compared with Non-Vagal Auricular Stimulation (NVAS). RAVANS and NVAS were evaluated in separate sessions spaced at least one week apart. Outcome measures included deep tissue pain intensity, temporal summation of pain, and anxiety ratings, which were assessed at baseline, during active stimulation, immediately following stimulation, and 15 minutes after stimulus cessation. Results RAVANS demonstrated a trend for reduced evoked pain intensity and temporal summation of mechanical pain, and significantly reduced anxiety in N=15 CPP patients, compared to NVAS, with moderate to large effect sizes (eta2>0.2). Conclusion Chronic pain disorders such as CPP are in great need of effective, non-pharmacological options for treatment. RAVANS produced promising anti-nociceptive effects for QST outcomes reflective of the noted hyperalgesia and central sensitization in this patient population. Future studies should evaluate longer-term application of RAVANS to examine its effects on both QST outcomes and clinical pain. PMID:22568773
Djilas, Milan; Azevedo-Coste, Christine; Guiraud, David; Yoshida, Ken
Afferent muscle spindle activity in response to passive muscle stretch was recorded in vivo using thin-film longitudinal intrafascicular electrodes. A neural spike detection and classification scheme was developed for the purpose of separating activity of primary and secondary muscle spindle afferents. The algorithm is based on the multiscale continuous wavelet transform using complex wavelets. The detection scheme outperforms the commonly used threshold detection, especially with recordings having low signal-to-noise ratio. Results of classification of units indicate that the developed classifier is able to isolate activity having linear relationship with muscle length, which is a step towards online model-based estimation of muscle length that can be used in a closed-loop functional electrical stimulation system with natural sensory feedback.
Chen, Guoqing; Larson, Jeffrey A.; Ogagan, P. Dafe; Shen, Bing; Wang, Jicheng; Roppolo, James R.; de Groat, William C.; Tai, Changfeng
Purpose To determine if transcutaneous electrical stimulation of somatic afferent nerves in the foot of cats can induce a post-stimulation increase in bladder capacity. Materials and Methods In α-chloralose anesthetized cats (N=12) electrical stimulation (5 Hz) was applied to the skin of the hind foot for two periods of 30 minutes via dual pad electrodes attached on the plantar and dorsal surfaces (combination 1-2) or at two sites on the plantar surface (combination 1-3). The post-stimulation effect was examined by performing repeated CMGs following 30 minute stimulation. In the control group (N=12) the isovolumetric contractions were allowed to continue during each 30 minute period without stimulation. Results Stimulation inhibited isovolumetric rhythmic bladder contractions. The bladder capacity was not increased after the first 30 minute foot stimulation via electrode combination 1-2, but was significantly increased 47.5±2.9% after the second 30 minute stimulation via electrode combination 1-3. After inducing the post-stimulation effect, the foot stimulation applied during CMGs via electrode combinations 1-2 or 1-3 elicited a further increase in bladder capacity (23.26±17.64% and 20.07±18.59% respectively). Conclusions This study shows that the transcutaneous plantar electrical stimulation of somatic afferent nerves in the foot can induce a post-stimulation increase in bladder capacity, suggesting that an intermittent stimulation pattern rather than a continuous stimulation might be effective in clinical applications to treat overactive bladder symptoms. PMID:22099982
Johnson, R D; Munson, J B
1. In cats, we studied the physiological properties of regenerating sprouts of muscle afferent fibers and compared them with sprouts from cutaneous afferent fibers. 2. Muscle nerves to the triceps surae and cutaneous sural nerves were axotomized in the popliteal fossa, and the proximal ends were inserted into nerve cuffs. Six days later, we recorded action potentials from single Groups I and II muscle and mostly Group II cutaneous afferents driven by mechanostimulation of the cuff. 3. Most muscle afferent sprouts (91%) had a regular slowly adapting discharge in response to sustained mechanical displacement of the cuff, particularly to sustained stretch stimuli, whereas most cutaneous afferents (92%) did not. Muscle afferents were more likely to have a spontaneous discharge and afterdischarge. 4. Group II muscle afferent sprouts had lower stretch thresholds and a higher incidence of spontaneous discharge compared with Group I fiber sprouts, whereas Group I fibers had a higher incidence of high-frequency afterdischarge to mechanical stimuli. 5. We conclude that, 6 days after axotomy, regenerating sprouts of muscle afferents, particularly Group II afferents, have become mechanosensitive in the absence of a receptor target and exhibit physiological properties similar to those found when innervating their native muscle but significantly different from sprouts of cutaneous afferents. Expression of these native muscle afferent firing patterns after the inappropriate reinnervation of hairy skin may be due to inherent properties of the muscle afferent fiber.
Boyd, I A; Kalu, K U
1. Compound action potentials were recorded from certain muscle and cutaneous nerves in normal and chronically de-efferentated hind limbs of cats during stimulation of the appropriate dorsal spinal roots, 2. The peaks for groups I, II and III in the compound action potential were correlated with the corresponding peaks in the fibre-diameter histograms of the same de-efferentated nerve after processing it for light microscopy. 3. The scaling factor (ratio of conduction velocity in m/sec to total diameter in micrometer) was not constant for all sizes of fibre nor did it increase progressively with fibre size. Evidence is presented that a logarithmic relation between conduction velocity and fibre diameter is not appropriate. 4. In muscle nerves the scaling factor for fibres fixed by glutaraldehyde perfusion and embedded in Epon was 5.7 for group I afferent fibres and 4.6 for myelinated fibres in both group II and group III. 5. In cutaneous nerves the scaling factor was 5.6 for large fibres (group I or Abeta) and 4.6 for small fibres (group III or Adelta). 6. The scaling factor for group I fibres is the same as was found previously for alpha-efferent fibres, and that for groups II and III is the same as for gamma-efferent fibres (Boyd & Davey, 1968). 7. The possibility that there is a clear discontinuity in scaling factor between fibres in groups I and alpha, and those in other functional groups, is discussed. 8. It is concluded that there must be some structural feature of alpha and group I fibres which differs from that of smaller myelinated fibres. It is likely that a difference in the relative thickness of the myelin sheath is involved and possibly also in the conductances responsible for generating the action potential. Images Plate 1 PMID:458657
Appenteng, K; O'Donovan, M J; Somjen, G; Stephens, J A; Taylor, A
1. By spike-triggered averaging of intracellular synaptic noise it has been shown in pentobarbitone anaesthetized cats that jaw elevator muscle spindle afferents with their cell bodies in the mid-brain have a relatively weak monosynaptic projection to masseter and temporalis motoneurones. 2. Extending the spike-triggered averaging method to recording extracellular excitatory field potentials it has been shown that virtually all the spindles do project monosynaptically to the motoneurone pool. It is concluded that the general weakness of the projection is due to its restriction to a small proportion of the motoneurones, possibly those concerned most with tonic postural functions. 3. The shape of individual intracellular e.p.s.p.s together with the spatial distribution of extracellular excitatory potential fields provide some evidence for a dentrically weighted distribution of the synapses. 4. Evidence is presented that both primary- and secondary-type spindle afferents project monosynaptically, the secondary effects being some 71% of the strength of the primary ones. PMID:149860
Appenteng, K; O'Donovan, M J; Somjen, G; Stephens, J A; Taylor, A
1. By spike-triggered averaging of intracellular synaptic noise it has been shown in pentobarbitone anaesthetized cats that jaw elevator muscle spindle afferents with their cell bodies in the mid-brain have a relatively weak monosynaptic projection to masseter and temporalis motoneurones. 2. Extending the spike-triggered averaging method to recording extracellular excitatory field potentials it has been shown that virtually all the spindles do project monosynaptically to the motoneurone pool. It is concluded that the general weakness of the projection is due to its restriction to a small proportion of the motoneurones, possibly those concerned most with tonic postural functions. 3. The shape of individual intracellular e.p.s.p.s together with the spatial distribution of extracellular excitatory potential fields provide some evidence for a dentrically weighted distribution of the synapses. 4. Evidence is presented that both primary- and secondary-type spindle afferents project monosynaptically, the secondary effects being some 71% of the strength of the primary ones.
Sántha, P; Jancsó, G
Choleratoxin B subunit-binding thick myelinated, A-fibre and unmyelinated, capsaicin-sensitive nociceptive C-fibre primary afferent fibres terminate in a strict topographic and somatotopic manner in the spinal cord dorsal horn. Injection of choleratoxin B subunit-horseradish peroxidase conjugate into injured but not intact peripheral nerves produced transganglionic labelling of primary afferents not only in the deeper layers (Rexed's laminae III-IV), but also in the substantia gelatinosa (Rexed's laminae II) of the spinal dorsal horn. This was interpreted in terms of a sprouting response of the Abeta-myelinated afferents and suggested a contribution to the pathogenesis of neuropathic pain [Nature 355 (1992) 75; J Comp Neurol 360 (1995) 121]. By utilising the selective neurotoxic effect of capsaicin, we examined the role of C-fibre sensory ganglion neurons in the mechanism of this phenomenon. Elimination of these particular, capsaicin-sensitive C-fibre afferents by prior intrathecal or systemic capsaicin treatment inhibited transganglionic labelling by the choleratoxin B subunit-horseradish peroxidase conjugate of the substantia gelatinosa evoked by chronic sciatic nerve section. More importantly, prior perineural capsaicin treatment of the transected nerve proximal to the anticipated site of injection of choleragenoid 12 hours later prevented the labelling of the substantia gelatinosa, but not that of the deeper layers. Electron microscopic examination of the dorsal roots revealed no significant difference in the proportion of labelled myelinated fibres relating to the intact (54.4+/-5.5%) and the transected (62.4+/-5.4%) sciatic nerves. In contrast, the proportion of labelled unmyelinated dorsal root axons relating to the transected, but not the intact nerves showed a significant, six-fold increase after sciatic nerve transection (intact: 4.9+/-1.3%; transected: 35+/-6.7%). These observations indicate that peripheral nerve lesion-induced transganglionic labelling
Zheng, Ji-Hong; Song, Xue-Jun
We provide new evidence demonstrating that peripheral nerve injury produces profound alterations in synaptic input to dorsal horn neurons mediated by non-nociceptive sensory neurons, and activation of neurokinin-1 receptor may be involved in the enhanced synaptic response and thus contribute to the tactile allodynia. Our results show that Abeta-fiber-evoked field potential significantly increased in the first postoperative week and decreased thereafter while maximal mechanical allodynia was exhibited. The neurokinin-1 receptor antagonist L703,606 significantly reduced Abeta-fiber-evoked field potential in nerve-injured but not in sham-operated animals. The non-N-methyl-D-aspartate receptor antagonist CNQX inhibited Abeta-fiber-evoked field potential in both nerve-injured and sham-operated rats, while the N-methyl-D-aspartate receptor antagonist MK-801 did not affect Abeta-fiber-evoked field potential in either CCI or sham-operated animals.
Minev, Ivan R.; Chew, Daniel J.; Delivopoulos, Evangelos; Fawcett, James W.; Lacour, Stéphanie P.
Neuroprostheses interfaced with transected peripheral nerves are technological routes to control robotic limbs as well as convey sensory feedback to patients suffering from traumatic neural injuries or degenerative diseases. To maximize the wealth of data obtained in recordings, interfacing devices are required to have intrafascicular resolution and provide high signal-to-noise ratio (SNR) recordings. In this paper, we focus on a possible building block of a three-dimensional regenerative implant: a polydimethylsiloxane (PDMS) microchannel electrode capable of highly sensitive recordings in vivo. The PDMS 'micro-cuff' consists of a 3.5 mm long (100 µm × 70 µm cross section) microfluidic channel equipped with five evaporated Ti/Au/Ti electrodes of sub-100 nm thickness. Individual electrodes have average impedance of 640 ± 30 kΩ with a phase angle of -58 ± 1 degrees at 1 kHz and survive demanding mechanical handling such as twisting and bending. In proof-of-principle acute implantation experiments in rats, surgically teased afferent nerve strands from the L5 dorsal root were threaded through the microchannel. Tactile stimulation of the skin was reliably monitored with the three inner electrodes in the device, simultaneously recording signal amplitudes of up to 50 µV under saline immersion. The overall SNR was approximately 4. A small but consistent time lag between the signals arriving at the three electrodes was observed and yields a fibre conduction velocity of 30 m s-1. The fidelity of the recordings was verified by placing the same nerve strand in oil and recording activity with hook electrodes. Our results show that PDMS microchannel electrodes open a promising technological path to 3D regenerative interfaces.
Lu, Jian; Xing, Jihong; Li, Jianhua
Arterial blood pressure and heart rate responses to static contraction of the hindlimb muscles are greater in rats whose femoral arteries were previously ligated than in control rats. Also, the prior findings demonstrate that nerve growth factor (NGF) is increased in sensory neurons-dorsal root ganglion (DRG) neurons of occluded rats. However, the role for endogenous NGF in engagement of the augmented sympathetic and pressor responses to stimulation of mechanically and/or metabolically sensitive muscle afferent nerves during static contraction after femoral artery ligation has not been specifically determined. In the present study, both afferent nerves and either of them were activated by muscle contraction, passive tendon stretch, and arterial injection of lactic acid into the hindlimb muscles. Data showed that femoral occlusion-augmented blood pressure response to contraction was significantly attenuated by a prior administration of the NGF antibody (NGF-Ab) into the hindlimb muscles. The effects of NGF neutralization were not seen when the sympathetic nerve and pressor responses were evoked by stimulation of mechanically sensitive muscle afferent nerves with tendon stretch in occluded rats. In addition, chemically sensitive muscle afferent nerves were stimulated by lactic acid injected into arterial blood supply of the hindlimb muscles after the prior NGF-Ab, demonstrating that the reflex muscle responses to lactic acid were significantly attenuated. The results of this study further showed that NGF-Ab attenuated an increase in acid-sensing ion channel subtype 3 (ASIC3) of DRG in occluded rats. Moreover, immunohistochemistry was employed to examine the number of C-fiber and A-fiber DRG neurons. The data showed that distribution of DRG neurons with different thin fiber phenotypes was not notably altered when NGF was infused into the hindlimb muscles. However, NGF increased expression of ASIC3 in DRG neurons with C-fiber but not A-fiber. Overall, these data
Lesniak, Daine R.; Gerling, Gregory J.
In effort to mimic the sensitivity and efficient information transfer of natural tactile afferents, recent work has combined force transducers and computational models of mechanosensitive afferents. Sensor durability, another feature important to sensor design, might similarly capitalize upon biological rules. In particular, gains in sensor durability might leverage insight from the compound end organ of the slowly adapting type I afferent, especially its multiple sites of spike initiation that reset each other. This work develops models of compound spiking sensors using a computational network of transduction functions and leaky integrate and fire models (together a spike encoder, the software element of a compound spiking sensor), informed by the output of an existing force transducer (hardware sensing elements of a compound spiking sensor). Individual force transducer failures are simulated with and without resetting between spike encoders to test the importance of both resetting and configuration on system durability. The results indicate that the resetting of adjacent spike encoders, upon the firing of a spike by any one, is an essential mechanism to maintain a stable overall response in the midst of transducer failure. Furthermore, results suggest that when resetting is enabled, the durability of a compound sensor is maximized when individual transducers are paired with spike encoders and multiple, paired units are employed. To explore these ideas more fully, use cases examine the design of a compound sensor to either reach a target lifetime with a set probability or determine how often to schedule maintenance to control the probability of failure. PMID:25705703
Kopp, Ulla C; Cicha, Michael Z; Smith, Lori A; Ruohonen, Saku; Scheinin, Mika; Fritz, Nicolas; Hökfelt, Tomas
Activation of efferent renal sympathetic nerve activity (ERSNA) increases afferent renal nerve activity (ARNA), which then reflexively decreases ERSNA via activation of the renorenal reflexes to maintain low ERSNA. The ERSNA-ARNA interaction is mediated by norepinephrine (NE) that increases and decreases ARNA by activation of renal α(1)-and α(2)-adrenoceptors (AR), respectively. The ERSNA-induced increases in ARNA are suppressed during a low-sodium (2,470 ± 770% s) and enhanced during a high-sodium diet (5,670 ± 1,260% s). We examined the role of α(2)-AR in modulating the responsiveness of renal sensory nerves during low- and high-sodium diets. Immunohistochemical analysis suggested the presence of α(2A)-AR and α(2C)-AR subtypes on renal sensory nerves. During the low-sodium diet, renal pelvic administration of the α(2)-AR antagonist rauwolscine or the AT1 receptor antagonist losartan alone failed to alter the ARNA responses to reflex increases in ERSNA. Likewise, renal pelvic release of substance P produced by 250 pM NE (from 8.0 ± 1.3 to 8.5 ± 1.6 pg/min) was not affected by rauwolscine or losartan alone. However, rauwolscine+losartan enhanced the ARNA responses to reflex increases in ERSNA (4,680 ± 1,240%·s), and renal pelvic release of substance P by 250 pM NE, from 8.3 ± 0.6 to 14.2 ± 0.8 pg/min. During a high-sodium diet, rauwolscine had no effect on the ARNA response to reflex increases in ERSNA or renal pelvic release of substance P produced by NE. Losartan was not examined because of low endogenous ANG II levels in renal pelvic tissue during a high-sodium diet. Increased activation of α(2)-AR contributes to the reduced interaction between ERSNA and ARNA during low-sodium intake, whereas no/minimal activation of α(2)-AR contributes to the enhanced ERSNA-ARNA interaction under conditions of high sodium intake.
Cicha, Michael Z.; Smith, Lori A.; Ruohonen, Saku; Scheinin, Mika; Fritz, Nicolas; Hökfelt, Tomas
Activation of efferent renal sympathetic nerve activity (ERSNA) increases afferent renal nerve activity (ARNA), which then reflexively decreases ERSNA via activation of the renorenal reflexes to maintain low ERSNA. The ERSNA-ARNA interaction is mediated by norepinephrine (NE) that increases and decreases ARNA by activation of renal α1-and α2-adrenoceptors (AR), respectively. The ERSNA-induced increases in ARNA are suppressed during a low-sodium (2,470 ± 770% s) and enhanced during a high-sodium diet (5,670 ± 1,260% s). We examined the role of α2-AR in modulating the responsiveness of renal sensory nerves during low- and high-sodium diets. Immunohistochemical analysis suggested the presence of α2A-AR and α2C-AR subtypes on renal sensory nerves. During the low-sodium diet, renal pelvic administration of the α2-AR antagonist rauwolscine or the AT1 receptor antagonist losartan alone failed to alter the ARNA responses to reflex increases in ERSNA. Likewise, renal pelvic release of substance P produced by 250 pM NE (from 8.0 ± 1.3 to 8.5 ± 1.6 pg/min) was not affected by rauwolscine or losartan alone. However, rauwolscine+losartan enhanced the ARNA responses to reflex increases in ERSNA (4,680 ± 1,240%·s), and renal pelvic release of substance P by 250 pM NE, from 8.3 ± 0.6 to 14.2 ± 0.8 pg/min. During a high-sodium diet, rauwolscine had no effect on the ARNA response to reflex increases in ERSNA or renal pelvic release of substance P produced by NE. Losartan was not examined because of low endogenous ANG II levels in renal pelvic tissue during a high-sodium diet. Increased activation of α2-AR contributes to the reduced interaction between ERSNA and ARNA during low-sodium intake, whereas no/minimal activation of α2-AR contributes to the enhanced ERSNA-ARNA interaction under conditions of high sodium intake. PMID:21106912
Samii, Madjid; Koerbel, Andrei; Safavi-Abbasi, Sam; Di Rocco, Federico; Samii, Amir; Gharabaghi, Alireza
Increasing rates of facial and cochlear nerve preservation after vestibular schwannoma surgery have been achieved in the last 30 years. However, the management of a partially or completely damaged facial nerve remains an important issue. In such a case, several immediate or delayed repair techniques have been used. On the basis of recent studies of successful end-to-side neurorrhaphy, the authors applied this technique in a patient with an anatomically preserved but partially injured facial nerve during vestibular schwannoma surgery. The authors interposed a sural nerve graft to reinforce the facial nerve whose partial anatomical continuity had been preserved. On follow-up examinations 18 months after surgery, satisfactory cosmetic results for facial nerve function were observed. The end-to-side interposed nerve graft appears to be a reasonable alternative in cases of partial facial nerve injury, and might be a future therapeutic option for other cranial nerve injuries.
González, H; Jiménez, I; Rudomin, P
The effects of the brainstem reticular formation on the intraspinal excitability of low threshold cutaneous and muscle afferents were studied in the frog neuraxis isolated together with the right hindlimb nerves. Stimulation of low threshold fibers (less than two times threshold) in cutaneous nerves produced short latency, negative field potentials in the ipsilateral dorsal neuropil (200-400 microns depth) that reversed to positivity at deeper regions (500-700 microns). Stimulation of low threshold fibers (less than two times threshold) in muscle nerves produced, instead, negative response that acquired their maximum amplitude in the ventral neuropil (700-900 microns depth). These electrophysiological findings suggest, in agreement with observations in the cat, that low threshold cutaneous and muscle afferents end at different sites in the spinal cord. Intraspinal microstimulation applied within the dorsal neuropil produced antidromic responses in low threshold cutaneous afferents that were increased in size following stimulation of the dorsal or ventral roots, as well as of the brainstem reticular formation. This increase in excitability is interpreted as being due to primary afferent depolarization (PAD) of the intraspinal terminals of cutaneous fibers. Antidromic responses recorded in muscle nerves following intraspinal stimulation within the ventral neuropil were also increased following conditioning stimulation of adjacent dorsal or ventral roots. However, stimulation of the bulbar reticular formation produced practically no changes in the antidromic responses, but was able to inhibit the PAD of low threshold muscle afferents elicited by stimulation of the dorsal or ventral roots. It is suggested that the PAD of low threshold cutaneous and muscle afferents is mediated by independent sets of interneurons. Reticulospinal fibers would have excitatory connections with the interneurons mediating the PAD of cutaneous fibers and inhibitory connections with the
Oyamatsu, Hiroshi; Koga, Daisuke; Igarashi, Michihiro; Shibata, Minoru; Ushiki, Tatsuo
Histological changes were observed in peripheral nerves following end-to-side nerve coaptation to determine the effects of perineurial opening and deliberate donor nerve injury during surgery. Twenty rats were randomised into four groups as follows: group 1, end-to-side nerve coaptation without perineurial opening; group 2, end-to-side nerve coaptation with simple perineurial opening; group 3, end-to-side nerve coaptation with partial crush injury after perineurial opening; group 4, end-to-side nerve coaptation with partial neurotomy after perineurial opening. Seven days after coaptation of the musculocutaneous (recipient) nerve to the ulnar (donor) nerve, the nerves were immunohistochemically analysed using antibodies against neurofilament-H (RT97) and phosphorylated GAP-43 (p-GAP-43). The former labels all axons, including regenerating axons and degenerated axonal debris, while the latter only labels regenerating axons. Results demonstrated no regenerating nerves in the recipient nerve of group 1. In group 2, because nerve herniation from the perineurial opening partially injured donor nerve fibres, some regenerating axons extended proximally and distally along the partially injured fibres in the donor nerve; some of these regenerating axons also extended into the recipient nerve via the perineurial opening. In groups 3 and 4, thin regenerating axons were more prominent in recipient and donor nerves compared with group 2. Statistical evaluation revealed increased efficacy of perineurial opening and deliberate donor nerve injury in end-to-side nerve coaptation, suggesting that partial nerve fibre herniation with partial axonotmesis or neurotomesis was important for effective axonal regeneration in end-to-side nerve coaptation.
Cao, Dong-Yuan; You, Hao-Jun; Zhao, Yan; Guo, Yuan; Wang, Hui-Sheng; Arendt-Nielsen, Lars; Wang, Hui-Ling; Zhang, Qi
The aim of the present study was to investigate the role of peripheral ionotropic glutamate receptors in the process of signal transmission between adjacent different peripheral sensory nerves. The T9 and T10 cutaneous branches of spinal dorsal rami were dissociated and cut proximally in pentobarbital anesthetized rats. Eighty-seven single afferents from T10 nerve filaments were recorded and characterized by assessing their spontaneous activities. Following 30 s antidromic electrical stimulation (intensity: 1 mA; duration: 0.5 ms; frequency: 20 Hz) of T9 cutaneous branches, the spontaneous activities of Abeta, Adelta and C fibers of T10 nerve were significantly enhanced from 2.00+/-0.34, 2.42+/-0.33, and 2.19+/-0.32 impulses/min to 4.31+/-0.58, 5.22+/-0.55, and 5.27+/-0.69 impulses/min, respectively (n=29 for each type, P<0.05). These enhanced spontaneous discharges of T10 nerve were significantly blocked by local treatment of its receptive field with either N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 or non-NMDA receptor antagonist DNQX (0.1 mM, 10 microl for each drug) (P<0.05). These results suggest that peripheral ionotropic glutamate receptors are involved in the activation of peripheral nerves following the antidromic stimulation of adjacent afferents from different spinal segments. We further provide the direct evidence that neurotransmitters released from adjacent peripheral nerves may also contribute to the occurrence of allodynia as well as secondary hyperalgesia during the pathological nociception.
Beta-Bungarotoxin(beta-BT) was applied to chick embryos at 3-day intervals beginning on the 4th day of incubation to see the effect of chronically and massively applied beta-BT, and to investigate the hair cell-nerve relationship in the developing inner ear by electron microscopy. On the 10th day of incubation, nerve terminals had achieved contact with differentiating hair cells, but the acoustico-vestibular ganglion cells of treated animals were decreased in number to one-third of those of the control. By the 14th day, most of the ganglion cells degenerated and disappeared, and only a few nerve terminals were seen in the neuroepithelium. At this time, most of the hair cells lacked synaptic contacts with nerve terminals; but their presynaptic specialization remained intact and they showed evidence of continuing differentiation. On the 17th day, the acoustico-vestibular ganglion cells were completely absent. All the hair cells were devoid of afferent and efferent innervation but were fully differentiated on the 21st day. Beta-BT was found to have a similar destructive effect on cultured spinal ganglion cells. The present study shows that beta-BT kills acoustico-vestibular and spinal nerve cells when applied chronically and massively during development. Furthermore, the differentiation of hair cells proceeds normally, and their presynaptic specializations are maintained when nerve terminals are absent during later developmental stages. PMID:856835
Rudomin, P; Lomelí, J
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
Flock, A; Russell, I
1. Intracellular recordings were made from morphologically identified hair cells in the lateral line canal organs of the burbot Lota lota. 2. I.p.s.p.s were recorded from hair cells when the efferent fibres were excited by electrical stimulation of the lateral line nerve. The i.p.s.p.s were abolished when the fish was injected with immobilizing concentration of Flaxedil which is known to block the efferent synapses. 3. The i.p.s.p.s are accompanied by a decrease in the resistance of the hair cell membrane and an increase in the intracellular receptor potential. 4. Spontaneous and mechanically evoked e.p.s.p.s which were recorded intracellularly from the post-synaptic afferent nerve terminals were reduced in amplitude for the duration of the i.p.s.p. Images A, B C PMID:948076
Schmidhammer, R; Nógrádi, A; Szabó, A; Redl, H; Hausner, T; van der Nest, D G; Millesi, H
End-to-end nerve repair is a widely used and successful experimental microsurgical technique via which a denervated nerve stump is supplied with reinnervating motor or sensory axons. On the other hand, questions are still raised as concerns the reliability and usefulness of the end-to-side coaptation technique. This study had the aim of the reinnervation of the denervated forearm flexor muscles in baboons through the use of an end-to-side coaptation technique and the synergistic action of the radial nerve. The median and ulnar nerves were transected, and the motor branch of the radial nerve supplying the extensor carpi radialis muscles (MBECR) was used as an axon donor for the denervated superficial forearm flexors. A nerve graft was connected to the axon donor nerve through end-to-side coaptation, while at the other end of the graft an end-to-end connection was established so as to reinnervate the motor branch of the forearm flexors. Electrophysiological investigations and functional tests indicated successful reinnervation of the forearm flexors and recovery of the flexor function. The axon counts in the nerve segments proximal (1038+/-172 S.E.M.) and distal (1050+/-116 S.E.M.) to the end-to-side coaptation site and in the nerve graft revealed that motor axon collaterals were given to the graft without the loss or appreciable misdirection of the axons in the MBECR nerve distal to the coaptation site. The nerve graft was found to contain varying, but satisfactory numbers of axons (269+/-59 S.E.M.) which induced morphological reinnervation of the end-plates in the flexor muscles. Accordingly, we have provided evidence that end-to-side coaptation can be a useful technique when no free donor nerve is available. This technique is able to induce limited, but still useful reinnervation for the flexor muscles, thereby producing a synergistic action of the flexor and extensor muscles which allows the hand to achieve a basic gripping function.
Oğün, Tunç C; Ozdemir, Mustafa; Senaran, Hakan; Ustün, Mehmet E
After a few reports on end-to-side nerve repair at the beginning of the last century, the technique was put aside until its recent reintroduction. The authors present their results in three patients with median nerve defects that were between 15 and 22 cm long and treated using end-to-side median-to-ulnar neurorrhaphy through an epineurial window. The follow-up times were between 32 and 38 months. Sensory evaluation involved superficial touch, pinprick, and two-point discrimination tests. Motor evaluation was completed by assessing the presence of opposition and by palpating the abductor pollicis brevis muscle. Sensory recovery was observed in all patients in the median nerve dermatome, and motor recovery was absent, except in Case 1. End-to-side nerve repair can be a viable alternative to nerve grafting in patients with long gaps between the ends of the injured nerve.
Núñez, R; Gross, G H; Sachs, B D
Cell number, size, and somatotopic arrangement within the spinal ganglia of the cells of origin of the rat dorsal penile nerve (DPN), and their spinal cord projections, were studied by loading the proximal stump of the severed DPN with horseradish peroxidase (HRP). The DPN sensory cells were located entirely in the sixth lumbar (L6) dorsal root ganglia (DRG), in which a mean of 468 +/- 78 cells per side were observed, measuring 26.7 +/- 0.8 microns in their longest axis (range 10-65 microns) and distributed apparently randomly within the ganglia. Within the spinal cord, no retrograde label was found, i.e., no motoneurons were labeled, indicating that in the rat the DPN is formed exclusively of sensory nerve fibers. Although labeled fibers entered the cord only through L6, transganglionically transported HRP was evident in all spinal segments examined, i.e., T13-S2. Labeled fibers projected along the inner edge of the dorsal horn (medial pathway) throughout their extensive craniosacral distribution. However, laminar distribution varied with spinal segment. In the dorsal horn, terminals or preterminal axons were found in the dorsal horn marginal zone (lamina I), the substantia gelatinosa (lamina II), the nucleus proprius (laminae III and IV--the most consistent projection), Clarke's column (lamina VI), and the dorsal gray commissure. In the ventral horn, terminals were found in lamina VII and lamina IX. Label apposed to cell somas and dendrites in lamina VII may represent direct primary afferent projections onto sympathetic autonomic neurons. In lamina IX, labeled terminals delineated the somas and dendrites of cells that appeared to be motoneurons. This is the first description of an apparently monosynaptic contact onto motoneurons by a primary afferent of nonmuscle origin.
Rein, Susanne; Manthey, Suzanne; Zwipp, Hans; Witt, Andreas
The aim of this study was to analyse the pattern of sensory nerve endings and blood vessels around the sinus tarsi. The superficial and deep parts of the fat pads at the inferior extensor retinaculum (IER) as well as the subtalar joint capsule inside the sinus tarsi from 13 cadaver feet were dissected. The distribution of the sensory nerve endings and blood vessels were analysed in the resected specimens as the number per cm(2) after staining with haematoxylin-eosin, S100 protein, low-affinity neurotrophin receptor p75, and protein gene product 9.5 using the classification of Freeman and Wyke. Free nerve endings were the predominant sensory ending (P < 0.001). Ruffini and Golgi-like endings were rarely found and no Pacini corpuscles were seen. Significantly more free nerve endings (P < 0.001) and blood vessels (P = 0.01) were observed in the subtalar joint capsule than in the superficial part of the fat pad at the IER. The deep part of the fat pad at the IER had significantly more blood vessels than the superficial part of the fat pad at the IER (P = 0.012). Significantly more blood vessels than free nerve endings were seen in all three groups (P < 0.001). No significant differences in distribution were seen in terms of right or left side, except for free nerve endings in the superficial part of the fat pad at the IER (P = 0.003). A greater number of free nerve endings correlated with a greater number of blood vessels. The presence of sensory nerve endings between individual fat cells supports the hypothesis that the fat pad has a proprioceptive role monitoring changes and that it is a source of pain in sinus tarsi syndrome due to the abundance of free nerve endings.
Afferent Fiber Remodeling in the Somatosensory Thalamus of Mice as a Neural Basis of Somatotopic Reorganization in the Brain and Ectopic Mechanical Hypersensitivity after Peripheral Sensory Nerve Injury
Yagasaki, Yuki; Katayama, Yoko
Abstract Plastic changes in the CNS in response to peripheral sensory nerve injury are a series of complex processes, ranging from local circuit remodeling to somatotopic reorganization. However, the link between circuit remodeling and somatotopic reorganization remains unclear. We have previously reported that transection of the primary whisker sensory nerve causes the abnormal rewiring of lemniscal fibers (sensory afferents) on a neuron in the mouse whisker sensory thalamus (V2 VPM). In the present study, using transgenic mice whose lemniscal fibers originate from the whisker sensory principle trigeminal nucleus (PrV2) are specifically labeled, we identified that the transection induced retraction of PrV2-originating lemniscal fibers and invasion of those not originating from PrV2 in the V2 VPM. This anatomical remodeling with somatotopic reorganization was highly correlated with the rewiring of lemniscal fibers. Origins of the non-PrV2-origin lemniscal fibers in the V2 VPM included the mandibular subregion of trigeminal nuclei and the dorsal column nuclei (DCNs), which normally represent body parts other than whiskers. The transection also resulted in ectopic receptive fields of V2 VPM neurons and extraterritorial pain behavior on the uninjured mandibular region of the face. The anatomical remodeling, emergence of ectopic receptive fields, and extraterritorial pain behavior all concomitantly developed within a week and lasted more than three months after the transection. Our findings, thus, indicate a strong linkage between these plastic changes after peripheral sensory nerve injury, which may provide a neural circuit basis underlying large-scale reorganization of somatotopic representation and abnormal ectopic sensations.
Schuelert, Niklas; Just, Stefan; Kuelzer, Raimund; Corradini, Laura; Gorham, Louise C J; Doods, Henri
Somatostatin (SST) is a peptide hormone that regulates the endocrine system and affects neurotransmission via interaction with G protein-coupled SST receptors and inhibition of the release of different hormones. The aim of this study was to investigate whether the analgesic properties of the selective SSTR4 agonist J-2156 are mediated via peripheral and/or spinal receptors. Effect on mechanical hyperalgesia in the Complete Freund׳s Adjuvant (CFA) model was measured after intraperitoneal application of J-2156. Electrophysiological neuronal recordings were conducted 24 h after injection of CFA or vehicle into the paw of Wistar rats. Mechanosensitivity of peripheral afferents of the saphenous nerve as well as of spinal wide dynamic range (WDR) and nociceptive-specific (NS) neurons were measured after systemic or spinal application of J-2156. In CFA animals J-2156 dose dependently reduced hyperalgesia in behavioral studies. The minimal effective dose was 0.1 mg/kg. Mechanosensitivity of peripheral afferents and spinal neurons was significantly reduced by J-2156. NS neurons were dose dependently inhibited by J-2156 while in WDR neurons only the highest concentration of 100 µM had an effect. In sham controls, J-2156 had no effect on neuronal activity. We demonstrated that J-2156 dose-dependently reduces peripheral and spinal neuronal excitability in the CFA rat model without affecting physiological pain transmission. Given the high concentration of the compound required to inhibit spinal neurons, it is unlikely that the behavioral effect seen in CFA model is mediated centrally. Overall these data demonstrated that the analgesic effect of J-2156 is mediated mainly via peripheral SST4 receptors.
Göransson, Harry; Taskinen, Hanna-Stiina; Paavilainen, Pasi; Vahlberg, Tero; Röyttä, Matias
Background: The present study was conducted to find out a tool to enable improved functional recovery with proximal nerve injury. In this experimental study, nerve regeneration was compared between side-to-side (STS), end-to-side (ETS), and end-to-end repairs. Methods: The walk track analysis was used as an outcome of functional recovery. Nerve regeneration was studied with morphometry and histology 6 or 26 weeks postoperatively. Results: All 3 repair techniques showed regeneration of the nerve. From 12 weeks onward, the functional results of the 3 intervention groups were significantly better compared with the unrepaired control group. End-to-end repair was significantly better when compared with the STS and ETS groups. At 26 weeks, the functional and morphometric results and histologic findings did not differ between the STS and ETS groups. The functional results correlated with the morphometric findings in all groups. Conclusions: STS neurorrhaphy showed nerve regeneration, and the end results did not differ from clinically widely used ETS repair. Further studies are warranted to optimize the neurorrhaphy technique and examine possible applications of STS repair in peripheral nerve surgery. PMID:28293523
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
Boyle, R.; Goldberg, J. M.; Highstein, S. M.
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
Shin, T; Maeyama, T; Morikawa, I; Umezaki, T
In this investigation, particular attention was paid to elucidate the laryngeal reflex mechanism of protective closure and the sensory function of the larynx during deglutition. For this purpose, three different experimental procedures were adopted: (1) subglottal pressure of felines was measured during deglutition using a pressure transducer; (2) subglottal pressure of human beings was measured during deglutition using a pressure transducer; and (3) afferent discharges from superior and recurrent laryngeal nerves of felines were recorded. The following conclusions appear justified. (1) Feline and human subglottal pressure during deglutition showed the following pattern. The pressure rises with onset of deglutition, temporarily drops during laryngeal elevation, rises again during the downward movement of the larynx, and drops again at the end of the glutition. This pattern was not affected by the resection of the unilateral recurrent laryngeal nerve. (2) The superior laryngeal nerve is involved in the sensory function of the pharynx, larynx, and trachea. At least two types of afferent discharges from superficial and internal sensory nerves are suspected. Afferent discharges from the recurrent laryngeal nerves in the larynx and trachea are not as distinct as those of the superior laryngeal nerve, and this seems to correspond with various changes in the thorax. During deglutition, afferent discharges were recorded from superior to recurrent laryngeal nerves.
Vaughan, Sydney K; Kemp, Zachary; Hatzipetros, Theo; Vieira, Fernando; Valdez, Gregorio
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that primarily targets the motor system. Although much is known about the effects of ALS on motor neurons and glial cells, little is known about its effect on proprioceptive sensory neurons. This study examines proprioceptive sensory neurons in mice harboring mutations associated with ALS, in SOD1(G93A) and TDP43(A315T) transgenic mice. In both transgenic lines, we found fewer proprioceptive sensory neurons containing fluorescently tagged cholera toxin in their soma five days after injecting this retrograde tracer into the tibialis anterior muscle. We asked whether this is due to neuronal loss or selective degeneration of peripheral nerve endings. We found no difference in the total number and size of proprioceptive sensory neuron soma between symptomatic SOD1(G93A) and control mice. However, analysis of proprioceptive nerve endings in muscles revealed early and significant alterations at Ia/II proprioceptive nerve endings in muscle spindles before the symptomatic phase of the disease. Although these changes occur alongside those at α-motor axons in SOD1(G93A) mice, Ia/II sensory nerve endings degenerate in the absence of obvious alterations in α-motor axons in TDP43(A315T) transgenic mice. We next asked whether proprioceptive nerve endings are similarly affected in the spinal cord and found that nerve endings terminating on α-motor neurons are affected during the symptomatic phase and after peripheral nerve endings begin to degenerate. Overall, we show that Ia/II proprioceptive sensory neurons are affected by ALS-causing mutations, with pathological changes starting at their peripheral nerve endings.
Sekizawa, S; Tsubone, H; Hishida, N; Kuwahara, M; Sugano, S
This study was aimed at characterizing the superior laryngeal nerve (SLN) afferent activities under four different respiratory conditions, i.e., tracheostomy breathing (TB), upper airway breathing (UAB), tracheal occlusion (TO) and upper airway occlusion (UAO), and investigating respiratory changes in response to transmural pressures applied to the larynx in anesthetized Shiba goats. The activity recorded from the whole SLN increased at both inspiration and expiration during TB, UAB and TO, while an expiratory augmentation accompanied by an inspiratory inhibition was found during UAO. Based on recordings from 109 thin filament-preparations, 47 units were identified as 'drive' receptors, 31 as 'pressure' receptors (22 'positive' and 9 'negative' pressure receptors), and the rest 31 as 'non-modulated type' of receptors. The posterior cricoarytenoid (PCA) muscle activity showed a clear inspiratory modulation during UAB and was significantly enhanced by negative pressure applied to the isolated upper airway, where such an augmented activity was abolished by bilateral section of the SLN. No significant changes were found in the respiratory cycle during application of negative pressures to the larynx. The respiratory modulation of the SLN in Shiba goats was essentially identical to that reported for rabbits, rats and guinea pigs, but not in dogs. The reflex response of the upper airway muscles to the laryngeal pressure changes in Shiba goats were found to be less noticeable than in rabbits and dogs.
Brumovsky, Pablo Rodolfo; Feng, Bin; Xu, Linjing; McCarthy, Carly Jane; Gebhart, G F
Studies in humans and rodents suggest that colon inflammation promotes urinary bladder hypersensitivity and, conversely, that cystitis contributes to colon hypersensitivity, events referred to as cross-organ sensitization. To investigate a potential peripheral mechanism, we examined whether cystitis alters the sensitivity of pelvic nerve colorectal afferents. Male C57BL/6 mice were treated with cyclophosphamide (CYP) or saline, and the mechanosensitive properties of single afferent fibers innervating the colorectum were studied with an in vitro preparation. In addition, mechanosensitive receptive endings were exposed to an inflammatory soup (IS) to study sensitization. Urinary bladder mechanosensitive afferents were also tested. We found that baseline responses of stretch-sensitive colorectal afferents did not differ between treatment groups. Whereas IS excited a proportion of colorectal afferents CYP treatment did not alter the magnitude of this response. However, the number of stretch-sensitive fibers excited by IS was increased relative to saline-treated mice. Responses to IS were not altered by CYP treatment, but the proportion of IS-responsive fibers was increased relative to saline-treated mice. In bladder, IS application increased responses of muscular afferents to stretch, although no differences were detected between saline- and CYP-treated mice. In contrast, their chemosensitivity to IS was decreased in the CYP-treated group. Histological examination revealed no changes in colorectum and modest edema and infiltration in the urinary bladder of CYP-treated mice. In conclusion, CYP treatment increased mechanical sensitivity of colorectal muscular afferents and increased the proportion of chemosensitive colorectal afferents. These data support a peripheral contribution to cross-organ sensitization of pelvic organs.
Sonner, Patrick M; Ladle, David R
Sensory feedback is critical for normal locomotion and adaptation to external perturbations during movement. Feedback provided by group Ia afferents influences motor output both directly through monosynaptic connections and indirectly through spinal interneuronal circuits. For example, the circuit responsible for reciprocal inhibition, which acts to prevent co-contraction of antagonist flexor and extensor muscles, is driven by Ia afferent feedback. Additionally, circuits mediating presynaptic inhibition can limit Ia afferent synaptic transmission onto central neuronal targets in a task-specific manner. These circuits can also be activated by stimulation of proprioceptive afferents. Rodent locomotion rapidly matures during postnatal development; therefore, we assayed the functional status of reciprocal and presynaptic inhibitory circuits of mice at birth and compared responses with observations made after 1 wk of postnatal development. Using extracellular physiological techniques from isolated and hemisected spinal cord preparations, we demonstrate that Ia afferent-evoked reciprocal inhibition is as effective at blocking antagonist motor neuron activation at birth as at 1 wk postnatally. In contrast, at birth conditioning stimulation of muscle nerve afferents failed to evoke presynaptic inhibition sufficient to block functional transmission at synapses between Ia afferents and motor neurons, even though dorsal root potentials could be evoked by stimulating the neighboring dorsal root. Presynaptic inhibition at this synapse was readily observed, however, at the end of the first postnatal week. These results indicate Ia afferent feedback from the periphery to central spinal circuits is only weakly gated at birth, which may provide enhanced sensitivity to peripheral feedback during early postnatal experiences.
Fukuoka, T; Miyoshi, K; Noguchi, K
Tetrodotoxin-sensitive (TTX-s) spontaneous activity is recorded from the dorsal roots after peripheral nerve injury. Primary sensory neurons in the dorsal root ganglion (DRG) express multiple TTX-s voltage-gated sodium channel α-subunits (Navs). Since Nav1.3 increases, whereas all other Navs decrease, in the DRG neurons after peripheral nerve lesion, Nav1.3 is proposed to be critical for the generation of these spontaneous discharges and the contributions of other Navs have been ignored. Here, we re-evaluate the changes in expression of three other TTX-s Navs, Nav1.1, Nav1.6 and Nav1.7, in the injured 5th lumbar (L5) primary afferent components following L5 spinal nerve ligation (SNL) using in situ hybridization histochemistry and immunohistochemistry. While the overall signal intensities for these Nav mRNAs decreased, many injured DRG neurons still expressed these transcripts at clearly detectable levels. All these Nav proteins accumulated at the proximal stump of the ligated L5 spinal nerve. The immunostaining patterns of Nav1.6 and Nav1.7 associated with the nodes of Ranvier were maintained in the ipsilateral L5 dorsal root. Interestingly, putative proprioceptive neurons characterized by α3 Na+/K+ ATPase-immunostaining specifically lacked Nav1.7 mRNA in naïve DRG but displayed de novo expression of this transcript following SNL. Nav1.7-immunoreactive fibers were significantly increased in the ipsilateral gracile nucleus where central axonal branches of the injured A-fiber afferents terminated. These data indicate that multiple TTX-s channel subunits could contribute to the generation and propagation of the spontaneous discharges in the injured primary afferents. Specifically, Nav1.7 may cause some functional changes in sensory processing in the gracile nucleus after peripheral nerve injury.
Blocks of osmium-fixed human digital skin, representing a total area of 5 sq mm, were cut serially parallel to the skin surface starting with the epidermis for electron microscopical studies. At intervals, single 1-mu sections were taken and used for recording the microtopography of the receptor organs at various levels. Graphic reconstructions of 28 nerve endings were made. It was found that the digital skin accommodated up to 80 dermal papillae and three to four sweat duct orifices per square millimeter. Each papilla contained one to three fenestrated capillary loops. More than 60% of all papillae contained free nerve endings, sometimes up to five in a single papilla. As a result, up to 100 free nerve endings were counted per square millimeter. Intraepidermal endings were also present, one to five per square millimeter. No endings of any kind were found within the boundary zones between the papillary ridges and in the immediate vicinity of the sweat ducts. The origin of a free ending was marked by the perikaryon of a modified Schwann cell, which constituted the terminal cell of the Schwann sheath. The perikaryon was situated at the base of the dermal papilla, while its distal process provided the cytoplasmic sheath to the axon terminals and their branches. Sometimes two endings merged into a single receptor organ. The terminal Schwann cell frequently served as a rallying point of endings. Three morphological kinds of free endings were observed: open endings, beaded endings, and plain endings. The intraepidermal endings were the derivatives of the plain endings. The free endings in the digital skin had essentially vertical distribution. Each ending covered a minute surface area of skin in a punctate pattern. This is in contrast to the mode of distribution of the free (penicillate) endings of the human hairy skin. Each penicillus covers a large horizontal skin area and overlaps that of their neighbors.
Peripheral nerves possess the capacity of self-regeneration after traumatic injury but the extent of regeneration is often poor and may benefit from exogenous factors that enhance growth. The use of cellular systems is a rational approach for delivering neurotrophic factors at the nerve lesion site, and in the present study we investigated the effects of enwrapping the site of end-to-end rat sciatic nerve repair with an equine type III collagen membrane enriched or not with N1E-115 pre-differentiated neural cells. After neurotmesis, the sciatic nerve was repaired by end-to-end suture (End-to-End group), end-to-end suture enwrapped with an equine collagen type III membrane (End-to-EndMemb group); and end-to-end suture enwrapped with an equine collagen type III membrane previously covered with neural cells pre-differentiated in vitro from N1E-115 cells (End-to-EndMembCell group). Along the postoperative, motor and sensory functional recovery was evaluated using extensor postural thrust (EPT), withdrawal reflex latency (WRL) and ankle kinematics. After 20 weeks animals were sacrificed and the repaired sciatic nerves were processed for histological and stereological analysis. Results showed that enwrapment of the rapair site with a collagen membrane, with or without neural cell enrichment, did not lead to any significant improvement in most of functional and stereological predictors of nerve regeneration that we have assessed, with the exception of EPT which recovered significantly better after neural cell enriched membrane employment. It can thus be concluded that this particular type of nerve tissue engineering approach has very limited effects on nerve regeneration after sciatic end-to-end nerve reconstruction in the rat. PMID:20149260
Ikeda, Ryo; Cha, Myeounghoon; Ling, Jennifer; Jia, Zhanfeng; Coyle, Dennis; Gu, Jianguo G
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 Ca(2+)-action potentials in Merkel cells, which drive Aβ-afferent nerve endings to fire slowly adapting impulses. We further demonstrate that Piezo2 and Ca(2+)-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.
Silinsky, E M; Watanabe, M; Redman, R S; Qiu, R; Hirsh, J K; Hunt, J M; Solsona, C S; Alford, S; MacDonald, R C
1. The requirement for extracellular Ca2+ in the process of evoked acetylcholine (ACh) release by nerve impulses was tested at endplates in frog skeletal muscle. Ca(2+)-containing lipid vesicles (Ca2+ liposomes) were used to elevate cytoplasmic Ca2+ concentrations under conditions in which Ca2+ entry from the extracellular fluid was prevented. 2. In an extracellular solution containing no added Ca2+ and 1 mM Mg2+ ('Ca(2+)-free' solution), Ca2+ liposomes promoted the synchronous release of ACh quanta, reflected electrophysiologically as endplate potentials (EPPs), in response to temporally isolated nerve impulses. 3. Motor nerve stimulation generated EPPs during superfusion with Ca2+ liposomes in Ca(2+)-free solutions containing the Ca2+ channel blocker Co2+ (1 mM), and the Ca2+ chelator EGTA (2 mM). As a physiological control for Ca2+ leakage from the liposomes to the extracellular fluid, the effect of Ca2+ liposomes on asynchronous evoked ACh release mediated by Ba2+ was examined. In contrast to the effects of 0.2-0.3 mM extracellular Ca2+, which generated EPPs but antagonized Ba(2+)-mediated asynchronous ACh release, Ca2+ liposomes generated EPPs but did not reduce asynchronous release mediated by Ba2+. The effects of Ca2+ liposomes were thus not due to leakage of Ca2+ from the liposome to the extracellular fluid. 4. Morphological studies using fluorescently labelled liposomes in conjunction with a confocal microscope demonstrate that lipid is transferred from the liposomes to nerve endings and liposomal contents are delivered to the nerve terminal cytoplasm. 5. The results suggest that when intracellular Ca2+ is elevated using liposomes as a vehicle, evoked ACh release can occur in the absence of Ca2+ entry via Ca2+ channels. Images Figure 5 Figure 6 PMID:7738845
Quevedo, J; Eguibar, J R; Lomeli, J; Rudomin, P
A technique was developed to measure, in the anesthetized and paralyzed cat under artificial ventilation, changes of excitability to intraspinal stimulation simultaneously in two different afferent fibers or in two collaterals of the same afferent fiber. Intraspinal stimulation reduced the threshold of single muscle afferent fibers ending in the intermediate nucleus. This effect was seen with strengths below those required to activate the afferent fiber tested (1.5-12 microA), occurred at a short latency (1.5-2.0 ms), reached a maximum between 15 and 30 ms, and lasted up to 100 ms. The effects produced by graded stimulation applied at the shortest conditioning-testing stimulus time intervals increased by fixed steps, suggesting recruitment of discrete elements, most likely of last-order interneurons mediating primary afferent depolarization (PAD). The short-latency increases in excitability produced by the weakest effective intraspinal stimuli were usually detected only in the collateral closest to the stimulating micropipette, indicating that the stimulated interneurons mediating PAD have spatially restricted actions. The short-latency PAD produced by intraspinal stimuli, as well as the PAD produced by stimulation of the posterior biceps and semitendinosus (PBSt) nerve or by stimulation of the bulbar reticular formation (RF), was depressed 19-30 min after the i.v. injection of 0.5 mg/kg of picrotoxin, suggesting that all these effects were mediated by GABAergic mechanisms. The PAD elicited by stimulation of muscle and/or cutaneous nerves was depressed following the i.v. injection of (-)-baclofen, whereas the PAD elicited in the same collateral by stimulation of the RF was baclofen-resistant. The short-latency PAD produced by intraspinal stimulation was not always depressed by i.v. injections of (-)-baclofen. Baclofen-sensitive and baclofen-resistant monosynaptic PADs could be produced in different collaterals of the same afferent fiber. The results suggest that
Gandevia, S C; Wilson, L; Cordo, P J; Burke, D
1. This study was designed to determine whether cutaneous receptors in the hand exert reflex effects on fusimotor neurones innervating relaxed muscles. Recordings were made from fifty-four muscle spindle afferents in the radial nerve while the arm was held relaxed in a supporting frame. Cutaneous afferents were activated by trains of stimuli at non-noxious levels to the superficial radial nerve or to the palmar surface of the fingers. 2. For the population of muscle spindle afferents, the mean discharge rate was 7.1 +/- 6.4 Hz (range 0-24 Hz). Thirty-three per cent had no background discharge, and this occurred significantly more often in finger extensors than wrist extensors. 3. Trains of cutaneous stimuli produced no change in the discharge rates of the majority of spindle endings irrespective of whether the spindle afferent had a background discharge or was given one by muscle stretch. However, with two of forty afferents, the stimuli produced an increase in discharge at latencies of 135 and 155 ms. 4. With a further fourteen muscle spindle endings, the dynamic responses to stretch were measured 100-400 ms after the trains of cutaneous stimuli. For four spindle afferents there was a statistically significant change in the dynamic response to stretch occurring at conditioned-stretch intervals of 100-200 ms. For two afferents the dynamic response decreased by 17 and 26% and for two others it increased by about 24 and 37%. 5. While these results support the view that the level of background fusimotor drive is low in the relaxed state, they suggest that there is some dynamic fusimotor drive to completely relaxed muscles operating on the human hand, and that this drive can be altered reflexly by cutaneous afferent inputs from the hand. Images Figure 4 PMID:7837105
Guo, Yuan; Yao, Fan-Rong; Cao, Dong-Yuan; Pickar, Joel G; Zhang, Qi; Wang, Hui-Sheng; Zhao, Yan
To investigate the effect of somatostatin on the cross-excitation between adjacent primary afferent terminals in the rats, we recorded single unit activity from distal cut ends of dorsal cutaneous branches of the T10 and T12 spinal nerves in response to antidromic stimulation of the distal cut end of the T11 dorsal root in the presence and absence of somatostatin and its receptor antagonist applied to the receptive field of the recorded nerve. Afferent fibers were classified based upon their conduction velocity. Mean mechanical thresholds decreased and spontaneous discharge rates increased significantly in C and Adelta but not Abeta fibers of the T10 and T12 spinal nerves in both male and female rats following antidromic electrical stimulation (ADES) of the dorsal root from adjacent spinal segment (DRASS) indicating cross-excitation of thin fiber afferents. The cross-excitation was not significantly different between male and female rats. Microinjection of somatostatin into the receptive field of recorded units inhibited the cross-excitation. This inhibitory effect, in turn, was reversed by the somatostation receptor antagonist cyclo-somatostatin (c-SOM). Application of c-SOM alone followed by ADES of DRASS significantly decreased the mechanical thresholds and increased the discharge rates of C and Adelta fibers, indicating that endogenous release of somatostatin plays a tonic inhibitory role on the cross-excitation between peripheral nerves. These results suggest that somatostatin could inhibit the cross-excitation involved in peripheral hyperalgesia and have a peripheral analgesic effect.
Ng, Kheng-Seong; Brookes, Simon J.; Montes-Adrian, Noemi A.; Mahns, David A.
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
Lomelí, J; Castillo, L; Linares, P; Rudomin, P
In anesthetized and paralyzed cats under artificial respiration, we examined the extent to which primary afferent depolarization (PAD) might affect invasion of action potentials in intraspinal axonal and/or terminal branches of single muscle afferents. To this end, one stimulating micropipette was placed at the L6 spinal level within the intermediate or motor nucleus, and another one at the L3 level, in or close to Clarke's column. Antidromically conducted responses produced in single muscle afferents by stimulation at these two spinal levels were recorded from fine lateral gastrocnemius nerve filaments. In all fibers examined, stimulation of one branch, with strengths producing action potentials, increased the intraspinal threshold of the other branch when applied at short conditioning testing stimulus intervals (<1.5-2.0 ms), because of the refractoriness produced by the action potentials invading the tested branch. Similar increases in the intraspinal threshold were found in branches showing tonic PAD and also during the PAD evoked by stimulation of group I afferent fibers in muscle nerves. It is concluded that during tonic or evoked PAD, axonal branches in the dorsal columns and myelinated terminals of muscle afferents ending deep in the L6 and L3 segmental levels continue to be invaded by action potentials. These findings strengthen the view that presynaptic inhibition of muscle afferents produced by activation of GABAergic mechanisms is more likely to result from changes in the synaptic effectiveness of the afferent terminals than from conduction failure because of PAD.
Orlov, S.N.; Pokudin, N.I.; Kravstov, G.M.; Postnov, Yu.V.; Okun', I.M.; Shukanova, N.A.; Rakovich, A.A.; Aksentsev, S.L.; Konev, S.V.
The frequency of neurotransmitter release from the synaptic vesicles of nerve endings by exocytosis depends primarily on the free calcium concentration in the cytoplasm which is controlled by calcium transporting and calcium binding systems. In this paper, in an attempt to determine the state of these systems in primary hypertension and the effects of neurotransmitter release on the increased resistance in the peripheral circulatory system, the authors study the exchange, uptake, and concentration of calcium 45 cations by synaptosomes.
Rudomin, P; Lomelí, J; Quevedo, J
We examined primary afferent depolarization (PAD) in the anesthetized cat elicited in 109 pairs of intraspinal collaterals of single group I afferents from the gastrocnemius nerve, one of the pair ending in the L3 segment, around the Clarke's column nuclei, and the other in the L6 segment within the intermediate zone. Tests for refractoriness were made to assess whether the responses produced by intraspinal stimulation in the L3 and L6 segments were due to activation of collaterals of the same afferent fiber. PAD in each collateral was estimated by independent computer-controlled measurement of the intraspinal current required to maintain a constant probability of antidromic firing. In most fibers, stimulation of the ipsilateral posterior biceps and semitendinosus (PBSt) nerve with trains of pulses maximal for group I afferents had a qualitatively similar effect but produced a larger PAD in the L6 than in the L3 collaterals. Stimulation of cutaneous nerves (sural and superficial peroneus) with single pulses and of the posterior articular nerve, the ipsilateral reticular formation, nucleus raphe magnus and contralateral motor cortex with trains of pulses often had qualitatively different effects. They could produce PAD and/or facilitate the PBSt-induced PAD in one collateral, and produce PAH and/or inhibit the PAD in the other collateral. These patterns could be changed in a differential manner by sensory or supraspinal conditioning stimulation. In summary, the present investigation suggests that the segmental and ascending collaterals of individual afferents are not fixed routes for information transmission, but parts of dynamic systems in which information transmitted to segmental reflex pathways and to Clarke's column neurons by common sources can be decoupled by sensory and descending inputs and funneled to specific targets according to the motor tasks to be performed.
Silinsky, E M; Solsona, C S
1. The effects of adenosine (50 microM) and 2-chloroadenosine (1-25 microM) were studied on Ca2+ currents in frog motor nerve endings. 2. Ca2+ currents associated with the synchronous, neurally evoked release of acetylcholine (ACh) were measured using either perineural or patch recording methods. Tetraethylammonium and/or 3,4-diaminopyridine were employed to block K+ currents. 3. Ca2+ currents were depressed by omega-conotoxin (1.5-2.5 microM), Cd2+ (100 microM-2 mM), Co2+ (500 microM-5 mM) or by a reduction of the extracellular calcium concentration. Such currents were also observed when Sr2+ was substituted for Ca2+. Both ACh release and Ca2+ currents at motor nerve endings have been reported to be insensitive to 1,4-dihydropyridine antagonists in this species. 4. Adenosine receptor agonists did not affect Ca2+ currents at concentrations that produced maximal inhibition of ACh release. 5. The effects of adenosine receptor agonists were examined on asynchronous K(+)-dependent ACh release under conditions in which the Ca2+ concentration gradient is likely to be reversed (Ca(2+)-free Ringer solution containing 1 mM EGTA). ACh release was measured by monitoring the frequency of occurrence of miniature endplate potentials (MEPPs). In Ca(2+)-free solutions containing 1 mM EGTA, high K+ depolarization caused a decrease in MEPP frequency, presumably because it elicits the efflux of Ca2+ from the nerve ending via membrane Ca2+ channels in a reverse Ca2+ gradient. 6. The Ca2+ channel blocker Co2+, which blocks the exit of Ca2+ from the nerve ending, increased the frequency of MEPPs in a concentration-dependent manner in a reverse Ca2+ gradient. 7. Adenosine or 2-chloroadenosine inhibited ACh release in a reverse Ca2+ gradient. 8. The results suggest that blockade of Ca2+ entry is not responsible for the inhibitory effects of adenosine at frog motor nerve endings. PMID:1338459
Broad, R M; McDonald, T J; Brodin, E; Cook, M A
A perifused preparation of guinea pig myenteric nerve varicosities (synaptosomes) was used to determine the characteristics of evoked tachykinin release and the inhibition of such release by adenosine analogues. Release of substance P-like immunoreactivity (SP-LI) and neurokinin A-like immunoreactivity (NKA-LI) was evoked by elevated extracellular [K+] in a reversible and repeatable manner. This release was completely abolished in the absence of extracellular Ca2+. Perifusion in the presence of 5'-N-ethylcarboxamidoadenosine (NECA), a nonselective A1/A2 adenosine receptor agonist, decreased K(+)-evoked release of SP-LI and NKA-LI compared with that in the absence of the nucleoside. Similar decrements in peptide release were obtained with N6-cyclopentyl adenosine (CPA), a selective A1 agonist, and 2-[p-(2-carboxyethyl)]phenethylamino-5'-N-ethyl-carboxamidoadenosi ne (CGS 21680), a selective A2 agonist. Response to all nucleosides was graded. Potency order of adenosine analogues was CPA greater than NECA much greater than CGS 21680. Inhibition due to the nucleosides was diminished in the presence of the highly selective A1-receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) while perifusion in the presence of DPCPX alone did not alter evoked release of either peptide. These findings provide direct measurements of inhibitory effects of adenine nucleosides on the release, from enteric nerve endings, of endogenous neuromediators SP and NKA. The findings also directly demonstrate the presence of functional adenosine receptors of the A1 subtype on enteric nerve endings coupled negatively to release of tachykinins. The presence of A2 receptors on enteric nerve endings is neither supported nor excluded.
Yuryev, Mikhail; Khiroug, Leonard
Visualization of individual cutaneous nerve endings has previously relied on laborious procedures of tissue excision, fixation, sectioning and staining for light or electron microscopy. We present a method for non-invasive, longitudinal two-photon microscopy of single nerve endings within the skin of anesthetized transgenic mice. Besides excellent signal-to-background ratio and nanometer-scale spatial resolution, this method offers time-lapse ``movies'' of pathophysiological changes in nerve fine structure over minutes, hours, days or weeks. Structure of keratinocytes and dermal matrix is visualized simultaneously with nerve endings, providing clear landmarks for longitudinal analysis. We further demonstrate feasibility of dissecting individual nerve fibers with infra-red laser and monitoring their degradation and regeneration. In summary, our excision-free optical biopsy technique is ideal for longitudinal microscopic analysis of animal skin and skin innervations in vivo and can be applied widely in preclinical models of chronic pain, allergies, skin cancers and a variety of dermatological disorders.
Up-regulation of brain-derived neurotrophic factor is regulated by extracellular signal-regulated protein kinase 5 and by nerve growth factor retrograde signaling in colonic afferent neurons in colitis
Yu, Sharon J; Grider, John R; Gulick, Melisa A; Xia, Chun-mei; Shen, Shanwei; Qiao, Li-Ya
Brain-derived neurotrophic factor (BDNF) plays an essential role in sensory neuronal activation in response to visceral inflammation. Here we report that BDNF up-regulation in the primary afferent neurons in the dorsal root ganglia (DRG) in a rat model of colitis is mediated by the activation of endogenous extracellular signal-regulated protein kinases (ERK) 5 and by nerve growth factor (NGF) retrograde signaling. At 7 days of colitis, the expression level of BDNF is increased in conventional neuronal tracing dye Fast Blue labeled primary afferent neurons project to the distal colon. In these neurons, the phosphorylation (activation) level of ERK5 is also increased. In contrast, the level of phospho-ERK1/2 is not changed in the DRG during colitis. Prevention of the ERK5 activation in vivo with an intrathecal application of the MEK inhibitor PD98059 significantly attenuates the colitis-induced increases in BDNF expression in the DRG. Further studies show that BDNF up-regulation in the DRG is triggered by NGF retrograde signaling which also involves activation of the MEK/ERK pathways. Application of exogenous NGF exclusively to the compartment containing DRG nerve terminals in an ex vivo ganglia-nerve preparation has markedly increased the BDNF expression level in the DRG neuronal cell body that is placed in a different compartment; this BDNF elevation is attenuated by U0126, PD98059 and a specific ERK5 inhibitor BIX02188. These results demonstrate the mechanisms and pathways by which BDNF expression is elevated in primary sensory neurons following visceral inflammation that is mediated by increased activity of ERK5 and is likely to be triggered by the elevated NGF level in the inflamed viscera. PMID:22921460
Mercado, Francisco; López, Iván; Ortega, Aida; Almanza, Angélica; Soto, Enrique; Vega, Rosario
Vestibular-afferent neurons innervate hair cells from the sensory epithelia of vestibular end-organs and their action-potential discharge dynamics are driven by linear and angular accelerations of the head. The electrical activity of the vestibular-afferent neurons depends on their intrinsic properties and on the synaptic input from hair cells and from the terminals of the efferent system. Here we report that vestibular-afferent neurons of the rat are immunoreactive to RFamide-related peptides, and that the stronger signal comes from calyx-shaped neuron dendrites, with no signal detected in hair cells or supporting cells. The whole-cell voltage clamp recording of isolated afferent neurons showed that they express robust acid-sensing ionic currents (ASICs). Extracellular multiunit recordings of the vestibular nerve in a preparation in vitro of the rat inner ear showed that the perfusion of FMRFamide (a snail ortholog of this family of neuropeptides) exerts an excitatory effect on the afferent-neurons spike-discharge rate. Because the FMRFamide cannot activate the ASIC but reduces its desensitization generating a more robust current, its effect indicates that the ASIC are tonically active in the vestibular-afferent neurons and modulated by RFamide-like peptides.
Bugajski, Andrzej; Gil, Krzysztof
Obesity and its complications constitute an important health problem in growing number of people. Behavioral and pharmacological treatment is not much effective and surgical treatment carries too many threats. Promising method to be used is pharmacological or electric manipulation of vagus nerves. Regulation of food intake and energy utilization is a complex process regulated by centers in hypothalamus and brainstem which are receiving information from the peripheral via afferent neural pathways and sending peripherally adequate instructions by efferent neural pathways. In these signals conduction an important role plays vagus nerve. Additionally central nervous system stays under influence of endocrine, paracrine and neuroendocrine signals taking part in these regulations, functioning directly onto the centre or on the afferent neural endings. 80-90% fibers of vagus nerve are afferent fibers, so their action is mainly afferent, but possible contribution of the efferent fibers cannot be excluded. Efferent stimulation induces motility and secretion in the intestinal tract. Afferent unmyelinated C-type fibres of the vagus nerve are more sensitive and easily electrically stimulated. Information from vagus nerve is transmitted to nucleus tractus solitarius, which has projections to nucleus arcuate of the medio-basal hypothalamus, involved in the control of feeding behavior. It is suggested, that interaction onto the vagus nerve (stimulation or blocking) can be an alternative for other ways of obesity treatment. Through the manipulation of the vagus nerve activity the goal is achieved by influence on central nervous system regulating the energy homeostasis.
Thomas, David M; Walker, Paul D; Benjamins, Joyce A; Geddes, Timothy J; Kuhn, Donald M
Methamphetamine intoxication causes long-lasting damage to dopamine nerve endings in the striatum. The mechanisms underlying this neurotoxicity are not known but oxidative stress has been implicated. Microglia are the major antigen-presenting cells in brain and when activated, they secrete an array of factors that cause neuronal damage. Surprisingly, very little work has been directed at the study of microglial activation as part of the methamphetamine neurotoxic cascade. We report here that methamphetamine activates microglia in a dose-related manner and along a time course that is coincident with dopamine nerve ending damage. Prevention of methamphetamine toxicity by maintaining treated mice at low ambient temperature prevents drug-induced microglial activation. MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), which damages dopamine nerve endings and cell bodies, causes extensive microglial activation in striatum as well as in the substantia nigra. In contrast, methamphetamine causes neither microglial activation in the substantia nigra nor dopamine cell body damage. Dopamine transporter antagonists (cocaine, WIN 35,428 [(-)-2-beta-carbomethoxy-3-beta-(4-fluorophenyl)tropane 1,5-naphthalenedisulfonate], and nomifensine), selective D1 (SKF 82958 [(+/-)-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide]), D2 (quinpirole), or mixed D1/D2 receptor agonists (apomorphine) do not mimic the effect of methamphetamine on microglia. Hyperthermia, a prominent and dangerous clinical response to methamphetamine intoxication, was also ruled out as the cause of microglial activation. Together, these data suggest that microglial activation represents an early step in methamphetamine-induced neurotoxicity. Other neurochemical effects resulting from methamphetamine-induced overflow of DA into the synapse, but which are not neurotoxic, do not play a role in this response.
Lawrence, Gary; Wang, Jiafu; Chion, C K N Kwo; Aoki, K Roger; Dolly, J Oliver
The unique ability of a family of botulinum neurotoxins to block neuroexocytosis specifically-by selective interaction with peripheral cholinergic nerve endings, endocytotic uptake, translocation to the cytosol, and enzymic cleavage of essential proteins-underlies their increasing therapeutic applications. Although clinical use of type A is most widespread due to its prolonged inactivation of the synaptosomal-associated protein of 25 kDa, botulinum neurotoxin E cleaves this same target but at a different bond and exhibits faster onset of neuromuscular paralysis. Herein, insights were gained into the different dynamics of action of types A and E toxins, which could help in designing variants with new pharmacological profiles. Natural and recombinant type E dichain forms showed similar proteolytic and neuromuscular paralytic activities. The neuroparalysis induced by type E toxin was accelerated between 21 and 35 degrees C and attenuated by bafilomycin A1. Temperature elevation also revealed an unanticipated bipartite dose response indicative of two distinct internalization processes, one being independent of temperature and the other dependent. Although elevating the temperature also hastened intoxication by type A, a second uptake mechanism was not evident. Increasing the frequency of nerve stimulation raised the uptake of type E via both processes, but the enhanced trafficking through the temperature-dependent pathway was only seen at 35 degrees C. These novel observations reveal that two membrane retrieval mechanisms are operative at motor nerve terminals which type E toxin exploits to gain entry via an acidification-dependent step, whereas A uses only one.
When skin temperature falls below a set-point, mammals experience "cold in the skin" and exhibit heat-seeking behaviors for error correction. Physiological thermostats should perform the behavioral thermoregulation, and it is important to identify the thermostats. A classical model of the sensory system states that thermoreceptors (e.g., thermoTRPs) in skin nerve endings are sensors that transform temperature into the firing rate codes that are sent to the brain, where the codes are decoded as "cold" by a labeled line theory. However, the view that the temperature code is transformed into "cold" (not temperature) is conflicting. Another model states that a thermostat exists in the brain based on the view that a skin thermo-receptor is a sensor. However, because animals have no knowledge of the principle of temperature measurement, the brain is unable to measure skin temperature with a thermometer calibrated based on a code table of each sensor in the skin. Thus, these old models cannot identify the thermostats. We have proposed a new model in which temperature receptors in a nerve ending are molecules of the thermostats. When skin temperature falls below a set-point, these molecules as a whole induce impulses as command signals sent to the brain, where these impulses activate their target neurons for "cold" and heat-seeking behaviors for error correction. Our study challenges the famous models that sensory receptor is a sensor and the brain is a code processor.
Gosselink, K. L.; Grindeland, R. E.; Roy, R. R.; Zhong, H.; Bigbee, A. J.; Grossman, E. J.; Edgerton, V. R.
There are forms of growth hormone (GH) in the plasma and pituitary of the rat and in the plasma of humans that are undetected by presently available immunoassays (iGH) but can be measured by bioassay (bGH). Although the regulation of iGH release is well documented, the mechanism(s) of bGH release is unclear. On the basis of changes in bGH and iGH secretion in rats that had been exposed to microgravity conditions, we hypothesized that neural afferents play a role in regulating the release of these hormones. To examine whether bGH secretion can be modulated by afferent input from skeletal muscle, the proximal or distal ends of severed hindlimb fast muscle nerves were stimulated ( approximately 2 times threshold) in anesthetized rats. Plasma bGH increased approximately 250%, and pituitary bGH decreased approximately 60% after proximal nerve trunk stimulation. The bGH response was independent of muscle mass or whether the muscles were flexors or extensors. Distal nerve stimulation had little or no effect on plasma or pituitary bGH. Plasma iGH concentrations were unchanged after proximal nerve stimulation. Although there may be multiple regulatory mechanisms of bGH, the present results demonstrate that the activation of low-threshold afferents from fast skeletal muscles can play a regulatory role in the release of bGH, but not iGH, from the pituitary in anesthetized rats.
A brief account is given of the scientific career of Walter Ernest Dixon, and of the importance of his work and his influence for the development of Pharmacology in England. It is suggested that the Memorial Lecture may appropriately deal with some matter of new interest, from one of the fields of research in which Dixon himself was active. Special mention is made of his work with Brodie on the physiology and pharmacology of the bronchioles and the pulmonary blood-vessels, as probably showing the beginning of Dixon's interest in the actions of the alkaloids and organic bases which reproduce the effects of autonomic nerves.An account is given of Dixon's early interest in the suggestion, first made by Elliott, that autonomic nerves transmit their effects by releasing, at their endings, specific substances, which reproduce their actions; and of his attempt to obtain experimental support for this conception. After the War it was established by the experiments of O. Loewi; and it is now generally recognized that parasympathetic effects are so transmitted by release of acetylcholine, sympathetic effects by that of a substance related to adrenaline.Very recent evidence indicates that acetylcholine, by virtue of its other ("nicotine-like") action, also acts as transmitter of activity at synapses in autonomic ganglia, and from motor nerve to voluntary muscle.The terms "cholinergic" and "adrenergic" have been introduced to describe nerve-fibres which transmit their actions by the release at their endings of acetylcholine, and of a substance related to adrenaline, respectively. It is shown that Langley and Anderson's evidence, long available, as to the kinds of peripheral efferent fibres which can replace one another in regeneration, can be summarized by the statement, that cholinergic can replace cholinergic fibres, and that adrenergic can replace adrenergic fibres; but that fibres of different chemical function cannot replace one another. The bearing of this new evidence on
De Robertis, Eduardo; de Iraldi, Amanda Pellegrino
The pineal body of white normal rats, 1.5 to 3 months old, was studied under the electron microscope. A single type of parenchymal cell—the pinealocyte—is recognized as the main component of the tissue, and some of the structural characteristics of the nucleus and cytoplasm are described. The main morphological characteristic of the pinealocytes is represented by club-shaped perivascular expansions connected to the cell by thin pedicles. They are found lying in a large, clear space surrounding the blood capillaries. The name plurivesicular secretory processes is proposed, to emphasize the main structural feature and the probable function of these cellular expansions. A tubulofibrillar component is mainly found in the pedicle, and within the expansion there are numerous small mitochondria and densily packed vesicles of about 425 A. Two types of vesicles, one with a homogeneous content and another with a very dense osmium deposit, are described. Between the two types there are intermediary forms. In these processes, mitochondria show profound changes which may lead to complete vacuolization. The significance of this plurivesicular secretory component is discussed in the light of recent work on the biogenic amines of the pineal body and preliminary experiments showing the release of the vesicles containing dense granules after treatment with reserpine. These vesicles are interpreted as the site of storage of some of the biogenic amines. Bundles of unmyelinated nerve fibers and endings on large blood vessels which also contain a plurivesicular content are described and tentatively interpreted as adrenergic nerve terminals. PMID:13720811
Andresen, Michael C; Hofmann, Mackenzie E; Fawley, Jessica A
Cranial primary afferent sensory neurons figure importantly in homeostatic control of visceral organ systems. Of the two broad classes of visceral afferents, the role of unmyelinated or C-type class remains poorly understood. This review contrasts key aspects of peripheral discharge properties of C-fiber afferents and their glutamate transmission mechanisms within the solitary tract nucleus (NTS). During normal prevailing conditions, most information arrives at the NTS through myelinated A-type nerves. However, most of visceral afferent axons (75-90%) in NTS are unmyelinated, C-type axons. Centrally, C-type solitary tract (ST) afferent terminals have presynaptic transient receptor potential vanilloid type 1 (TRPV1) receptors. Capsaicin activation of TRPV1 blocks phasic or synchronous release of glutamate but facilitates release of glutamate from a separate pool of vesicles. This TRPV1-operated pool of vesicles is active at normal temperatures and is responsible for actively driving a 10-fold higher release of glutamate at TRPV1 compared with TRPV1- terminals even in the absence of afferent action potentials. This novel TRPV1 mechanism is responsible for an additional asynchronous release of glutamate that is not present in myelinated terminals. The NTS is rich with presynaptic G protein-coupled receptors, and the implications of TRPV1-operated glutamate offer unique targets for signaling in C-type sensory afferent terminals from neuropeptides, inflammatory mediators, lipid metabolites, cytokines, and cannabinoids. From a homeostatic view, this combination could have broad implications for integration in chronic pathological disturbances in which the numeric dominance of C-type endings and TRPV1 would broadly disturb multisystem control mechanisms.
Dux, M; Jancsó, G
A new technique based on the phenomenon of vascular labelling has been devised for the direct visualisation of overlapping innervation territories of cutaneous nerves. The saphenous, peroneal and sural nerves on one side in anaesthetised rats were exposed, cut centrally and successively stimulated antidromically to induce a neurogenic inflammatory response after an intravenous injection of either a 1% colloidal silver solution or a suspension of 3% Monastral Blue B. Light microscopic examination of transparent preparations of the dorsal hindpaw skin revealed labelled blood vessels of different colours which represented cutaneous territories served by different nerves. Blood vessels labelled with both substances were regarded as areas of overlapping innervation. Such areas were typically localised along the border of adjacent innervation territories. In addition, distinct areas exhibiting double-labelled blood vessels were regularly encountered in regions separate from this border zone. Areas of interest were drawn with the aid of a camera lucida and measured by means of a computerised system. The results indicate a significant, although topographically variable, degree of overlap of these cutaneous innervation areas. This new technique offers a possibility to explore the importance of normally existing overlap in the reinnervation of a denervated skin area by collateral nerve sprouting.
Kollarik, M; Carr, M J; Ru, F; Ring, C J A; Hart, V J; Murdock, P; Myers, A C; Muroi, Y; Undem, B J
Vagal afferent fibres innervating thoracic structures such as the respiratory tract and oesophagus are diverse, comprising several subtypes of functionally distinct C-fibres and A-fibres. Both morphological and functional studies of these nerve subtypes would be advanced by selective, effective and long-term transduction of vagal afferent neurons with viral vectors. Here we addressed the hypothesis that vagal sensory neurons can be transduced with adeno-associated virus (AAV) vectors in vivo, in a manner that would be useful for morphological assessment of nerve terminals, using enhanced green fluorescent protein (eGFP), as well as for the selective knock-down of specific genes of interest in a tissue-selective manner. We found that a direct microinjection of AAV vectors into the vagal nodose ganglia in vivo leads to selective, effective and long-lasting transduction of the vast majority of primary sensory vagal neurons without transduction of parasympathetic efferent neurons. The transduction of vagal neurons by pseudoserotype AAV2/8 vectors in vivo is sufficiently efficient such that it can be used to functionally silence TRPV1 gene expression using short hairpin RNA (shRNA). The eGFP encoded by AAV vectors is robustly transported to both the central and peripheral terminals of transduced vagal afferent neurons allowing for bright imaging of the nerve endings in living tissues and suitable for structure–function studies of vagal afferent nerve endings. Finally, the AAV2/8 vectors are efficiently taken up by the vagal nerve terminals in the visceral tissue and retrogradely transported to the cell body, allowing for tissue-specific transduction. PMID:20736420
Haacke, U; Sturm, G; Süwer, V; Wesemann, W; Wildenhahn, G
Nerve endings isolated from rat brain accumulate exogenous serotonin and dopamine. Both biogenic amines are released from nerve endings as well by means of electrical stimulation with rectangular pulses of alternating polarity as by incubation with 5 X 10(-4) to 5 X 10(-5) M solutions of the adamantane derivatives 1-aminoadamantane hydrochloride (D 1) and 1-amino-3,5-dimethyladamantane hydrochloride (memantine, D 145). The electrically stimulated liberation is small but is significantly increased after simultaneous incubation of the nerve endings with subthreshold concentrations of 1-aminoadamantanes (5X10(-6) to 5X10(-5) M). The reuptake of released serotonin is noncompetitively inhibited by 1-aminoadamantanes. Also in blood platelets frequently used as model cells of the nerve endings the serotonin uptake is inhibited by small concentrations of D 145, 10(-5) to 2X10(-4) M. High concentrations of D 145- greater than 2X10(-3) M, induce the "release-reaction", the simultaneous liberation of serotonin, ATP, and ADP. In the concentration range of 2X10(-4) to 2X10(-3) M D 145 only serotonin is set free.
Bonanno, G; Fassio, A; Severi, P; Ruelle, A; Raiteri, M
Fenfluramine is the most widely used anorexigenic drug in humans. In animal experiments d-fenfluramine has been shown to act as a potent releaser of brain serotonin [5-hydroxytryptamine (5-HT)]. Here we have investigated the effects of d-fenfluramine on the release of [3H]5-HT from isolated nerve endings of human neocortex. The drug elicited release of unmetabolized [3H]5-HT, and this effect was concentration dependent. However, the mechanism of release seems to differ profoundly depending on the concentrations of d-fenfluramine used. At 5 microM, the release of [3H]5-HT was blocked by the 5-HT transporter inhibitor fluoxetine and was Ca2+ independent and insensitive to the human autoreceptor 5-HT1D agonist sumatriptan. The release of [3H]5-HT elicited by 0.5 microM d-fenfluramine was similarly blocked by fluoxetine, but it was strongly Ca2+ dependent and sensitive to sumatriptan. It is suggested that, at relatively high concentrations, d-fenfluramine largely diffuses into serotonergic terminals and causes release of 5-HT through the 5-HT carrier working in the inside-outside direction; at relatively low concentrations d-fenfluramine enters the terminals through the 5-HT transporter but elicits release of 5-HT by an exocytotic-like mechanism.
Reynders, Ana; Mantilleri, Annabelle; Malapert, Pascale; Rialle, Stéphanie; Nidelet, Sabine; Laffray, Sophie; Beurrier, Corinne; Bourinet, Emmanuel; Moqrich, Aziz
Summary Cutaneous C-unmyelinated MRGPRD+ free nerve endings and C-LTMRs innervating hair follicles convey two opposite aspects of touch sensation: a sensation of pain and a sensation of pleasant touch. The molecular mechanisms underlying these diametrically opposite functions are unknown. Here, we used a mouse model that genetically marks C-LTMRs and MRGPRD+ neurons in combination with fluorescent cell surface labeling, flow cytometry, and RNA deep-sequencing technology (RNA-seq). Cluster analysis of RNA-seq profiles of the purified neuronal subsets revealed 486 and 549 genes differentially expressed in MRGPRD-expressing neurons and C-LTMRs, respectively. We validated 48 MRGPD- and 68 C-LTMRs-enriched genes using a triple-staining approach, and the Cav3.3 channel, found to be exclusively expressed in C-LTMRs, was validated using electrophysiology. Our study greatly expands the molecular characterization of C-LTMRs and suggests that this particular population of neurons shares some molecular features with Aβ and Aδ low-threshold mechanoreceptors. PMID:25683706
Eguibar, J R; Quevedo, J; Rudomin, P
This study was primarily aimed at investigating the selectivity of the cortico-spinal actions exerted on the pathways mediating primary afferent depolarization (PAD) of muscle spindle and tendon organ afferents ending within the intermediate nucleus at the L6-L7 segmental level. To this end we analyzed, in the anesthetized cat, the effects produced by electrical stimulation of sensory nerves and of the cerebral cortex on (a) the intraspinal threshold of pairs of single group I afferent fibers belonging to the same or to different hindlimb muscles and (b) the intraspinal threshold of two collaterals of the same muscle afferent fiber. Afferent fibers were classified in three categories, according to the effects produced by stimulation of segmental nerves and of the cerebral cortex. Twenty-five of 40 fibers (62.5%) were depolarized by stimulation of group I posterior biceps and semitendinosus (PBSt) or tibialis (Tib) fibers, but not by stimulation of the cerebral cortex or of cutaneous and joint nerves, which instead inhibited the PBSt- or Tib-induced PAD (type A PAD pattern, usually seen in Ia fibers). The remaining 15 fibers (37.5%) were all depolarized by stimulation of the PBSt or Tib nerves and the cerebral cortex. Stimulation of cutaneous and joint nerves produced PAD in 10 of those 15 fibers (type B PAD pattern) and inhibited the PBSt- or Tib-induced PAD in the 5 remaining fibers (type C PAD pattern). Fibers with a type B or C PAD pattern are likely to be Ib. Not all sites in the cerebral cortex inhibited with the same effectiveness the segmentally induced PAD of group I fibers with a type A PAD pattern. With the weakest stimulation of the cortical surface, the most effective sites that inhibited the PAD of individual fibers were surrounded by less effective sites, scattered all along the motor cortex (area 4gamma and 6) and sensory cortex (areas 3, 2 and 1), far beyond the area of projection of group I fibers from the hindlimb. With higher strengths of
Different Mode of Afferents Determines the Frequency Range of High Frequency Activities in the Human Brain: Direct Electrocorticographic Comparison between Peripheral Nerve and Direct Cortical Stimulation
Kobayashi, Katsuya; Matsumoto, Riki; Matsuhashi, Masao; Usami, Kiyohide; Shimotake, Akihiro; Kunieda, Takeharu; Kikuchi, Takayuki; Mikuni, Nobuhiro; Miyamoto, Susumu; Fukuyama, Hidenao; Takahashi, Ryosuke; Ikeda, Akio
Physiological high frequency activities (HFA) are related to various brain functions. Factors, however, regulating its frequency have not been well elucidated in humans. To validate the hypothesis that different propagation modes (thalamo-cortical vs. cortico-coritcal projections), or different terminal layers (layer IV vs. layer II/III) affect its frequency, we, in the primary somatosensory cortex (SI), compared HFAs induced by median nerve stimulation with those induced by electrical stimulation of the cortex connecting to SI. We employed 6 patients who underwent chronic subdural electrode implantation for presurgical evaluation. We evaluated the HFA power values in reference to the baseline overriding N20 (earliest cortical response) and N80 (late response) of somatosensory evoked potentials (HFASEP(N20) and HFASEP(N80)) and compared those overriding N1 and N2 (first and second responses) of cortico-cortical evoked potentials (HFACCEP(N1) and HFACCEP(N2)). HFASEP(N20) showed the power peak in the frequency above 200 Hz, while HFACCEP(N1) had its power peak in the frequency below 200 Hz. Different propagation modes and/or different terminal layers seemed to determine HFA frequency. Since HFACCEP(N1) and HFA induced during various brain functions share a similar broadband profile of the power spectrum, cortico-coritcal horizontal propagation seems to represent common mode of neural transmission for processing these functions. PMID:26087042
Different Mode of Afferents Determines the Frequency Range of High Frequency Activities in the Human Brain: Direct Electrocorticographic Comparison between Peripheral Nerve and Direct Cortical Stimulation.
Kobayashi, Katsuya; Matsumoto, Riki; Matsuhashi, Masao; Usami, Kiyohide; Shimotake, Akihiro; Kunieda, Takeharu; Kikuchi, Takayuki; Mikuni, Nobuhiro; Miyamoto, Susumu; Fukuyama, Hidenao; Takahashi, Ryosuke; Ikeda, Akio
Physiological high frequency activities (HFA) are related to various brain functions. Factors, however, regulating its frequency have not been well elucidated in humans. To validate the hypothesis that different propagation modes (thalamo-cortical vs. cortico-coritcal projections), or different terminal layers (layer IV vs. layer II/III) affect its frequency, we, in the primary somatosensory cortex (SI), compared HFAs induced by median nerve stimulation with those induced by electrical stimulation of the cortex connecting to SI. We employed 6 patients who underwent chronic subdural electrode implantation for presurgical evaluation. We evaluated the HFA power values in reference to the baseline overriding N20 (earliest cortical response) and N80 (late response) of somatosensory evoked potentials (HFA(SEP(N20)) and HFA(SEP(N80))) and compared those overriding N1 and N2 (first and second responses) of cortico-cortical evoked potentials (HFA(CCEP(N1)) and HFA(CCEP(N2))). HFA(SEP(N20)) showed the power peak in the frequency above 200 Hz, while HFA(CCEP(N1)) had its power peak in the frequency below 200 Hz. Different propagation modes and/or different terminal layers seemed to determine HFA frequency. Since HFA(CCEP(N1)) and HFA induced during various brain functions share a similar broadband profile of the power spectrum, cortico-coritcal horizontal propagation seems to represent common mode of neural transmission for processing these functions.
Parra, Andres; Gonzalez-Gonzalez, Omar; Gallar, Juana; Belmonte, Carlos
Dry eye disease (DED) is a multifactorial disorder affecting the composition and volume of tears. DED causes ocular surface dryness, cooling, and hyperosmolality, leading ultimately to corneal epithelium damage and reduced visual performance. Ocular discomfort is the main clinical symptom in DED. However, the peripheral neural source of such unpleasant sensations is still unclear. We analyzed in excised, superfused mouse eyes, the effect of NaCl-induced hyperosmolality (325-1005 mOsm·kg(-1)) on corneal cold thermoreceptor and polymodal nociceptor nerve terminal impulse (NTI) activity. Osmolality elevations at basal corneal temperature (33.6°C) linearly increased the ongoing NTI frequency of cold thermoreceptors, at a mean rate of 0.34 imp·s(-1)/10 mOsm. This frequency increase became significant with osmolality values greater than 340 mOsm. Comparison of cold thermoreceptor activity increase induced by a dynamic temperature reduction of 1.8°C under iso- and hyperosmolal (360-mOsm) conditions provided evidence that more than 50% of the increased firing response was attributable to hyperosmolality. Comparatively, activation of corneal polymodal nociceptor endings by hyperosmolal solutions started with values of 600 mOsm and greater. Sensitization of polymodal nociceptors by continuous perfusion with an "inflammatory soup" (bradykinin, histamine, prostaglandin E2 [PGE2], serotonin, and adenosine triphosphate [ATP]) did not enhance their activation by hyperosmolal solutions. High osmolality also altered the firing pattern and shape of cold and polymodal NTIs, possibly reflecting disturbances in local membrane currents. Results strongly suggest that tear osmolality elevations in the range observed in DED predominantly excite cold thermoreceptors, supporting the hypothesis that dryness sensations experienced by these patients are due, at least in part, to an augmented activity of corneal cold thermoreceptors.
Di Prisco, Silvia; Olivero, Guendalina; Merega, Elisa; Bonfiglio, Tommaso; Marchi, Mario; Pittaluga, Anna
Previous studies had shown that the HIV-1 capsidic glycoprotein gp120 (strain IIIB) modulates presynaptic release-regulating NMDA receptors on noradrenergic and glutamatergic terminals. This study aims to assess whether the chemokine CXC4 receptors (CXCR4s) has a role in the gp120-mediated effects. The effect of CXCL12, the endogenous ligand at CXCR4, on the NMDA-mediated releasing activity was therefore investigated. Rat hippocampal synaptosomes were preloaded with [(3)H]noradrenaline ([(3)H]NA) or [(3)H]D-aspartate ([(3)H]D-Asp) and acutely exposed to CXCL12, to NMDA or to both agonists. CXCL12, inactive on its own, facilitated the NMDA-evoked tritium release. The NMDA antagonist MK-801 abolished the NMDA/CXCL12-evoked tritium release of both radiolabelled tracers, while the CXCR4 antagonist AMD 3100 halved it, suggesting that rat hippocampal nerve endings possess presynaptic release-regulating CXCR4 receptors colocalized with NMDA receptors. Accordingly, Western blot analysis confirmed the presence of CXCR4 proteins in synaptosomal plasmamembranes. In both synaptosomal preparations, CXCL12-induced facilitation of NMDA-mediated release was dependent upon PLC-mediated src-induced events leading to mobilization of Ca(2+) from intraterminal IP3-sensitive stores Finally, the gp120-induced facilitation of NMDA-mediated release of [(3)H]NA and [(3)H]D-Asp was prevented by AMD 3100. We propose that CXCR4s are functionally coupled to NMDA receptors in rat hippocampal noradrenergic and glutamatergic terminals and account for the gp120-induced modulation of the NMDA-mediated central effects. The NMDA/CXCR4 cross-talk could have a role in the neuropsychiatric symptoms often observed in HIV-1 positive patients.
Gladden, M H; Matsuzaki, H
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
The nerve fiber distribution in the epidermis of the hairless rat skin was studied light microscopically by means of zinc iodide-osmium tetroxide staining. Two different morphological types of free nerve fiber endings could be detected: clusters of relatively thick nerve fibers stretched up through the spinous layer up to the granular layer sending off terminal branches. In addition, many solitary thin varicose nerve fibers were seen within the epidermis. The observed discrepancies in nerve fiber diameters appeared to be larger than those reported for human intraepidermal nerve fibers in recent immunohistochemical studies. Moreover, dendritic cells, most probably representing Langerhans cells, could be selectively stained. These cells appeared to be in a close location to thin varicose nerve fibers. Both types of demonstrated free nerve endings have to be functionally connected with different sensoric functions. Possibly, a subpopulation of the thin nerve fibers might possess primarily a nociceptive task, whereas the thick ones have most probably to be regarded as mechanoreceptive. The nerve fibers innervating dendritic cells appear to be identical to the peptidergic ones which may regulate the antigen-presenting capacity of these cells. Due to its selectivity for intraepidermal nerve fibers, the used method might supplement immunohistochemical procedures in a helpful manner.
Thomas, David M; Angoa Pérez, Mariana; Francescutti-Verbeem, Dina M; Shah, Mrudang M; Kuhn, Donald M
Methamphetamine (METH) is a neurotoxic drug of abuse that damages the dopamine (DA) neuronal system in a highly delimited manner. The brain structure most affected by METH is the striatum where long-term DA depletion and microglial activation are maximal. Endogenous DA has been implicated as a critical participant in METH-induced neurotoxicity, most likely as a substrate for non-enzymatic oxidation by METH-generated reactive oxygen species. The striatum is also extensively innervated by serotonin (5HT) nerve endings and this neurochemical system is modified by METH in much the same manner as seen in DA nerve endings (i.e., increased release of 5HT, loss of function in tryptophan hydroxylase and the serotonin transporter, long-term depletion of 5HT stores). 5HT can also be modified by reactive oxygen species to form highly reactive species that damage neurons but its role in METH neurotoxicity has not been assessed. Increases in 5HT levels with 5-hydroxytryptophan do not change METH-induced neurotoxicity to the DA nerve endings as revealed by reductions in DA, tyrosine hydroxylase and dopamine transporter levels. Partial reductions in 5HT with p-chlorophenylalanine are without effect on METH toxicity, despite the fact that p-chlorophenylalanine largely prevents METH-induced hyperthermia. Mice lacking the gene for brain tryptophan hydroxylase 2 are devoid of brain 5HT and respond to METH in the same manner as wild-type controls, despite showing enhanced drug-induced hyperthermia. Taken together, the present results indicate that endogenous 5HT does not appear to play a role in METH-induced damage to DA nerve endings of the striatum.
Angoa-Pérez, Mariana; Kane, Michael J; Briggs, Denise I; Francescutti, Dina M; Sykes, Catherine E; Shah, Mrudang M; Thomas, David M; Kuhn, Donald M
Mephedrone (4-methylmethcathinone) is a β-ketoamphetamine stimulant drug of abuse with close structural and mechanistic similarities to methamphetamine. One of the most powerful actions associated with mephedrone is the ability to stimulate dopamine (DA) release and block its re-uptake through its interaction with the dopamine transporter (DAT). Although mephedrone does not cause toxicity to DA nerve endings, its ability to serve as a DAT blocker could provide protection against methamphetamine-induced neurotoxicity like other DAT inhibitors. To test this possibility, mice were treated with mephedrone (10, 20, or 40 mg/kg) prior to each injection of a neurotoxic regimen of methamphetamine (four injections of 2.5 or 5.0 mg/kg at 2 h intervals). The integrity of DA nerve endings of the striatum was assessed through measures of DA, DAT, and tyrosine hydroxylase levels. The moderate to severe DA toxicity associated with the different doses of methamphetamine was not prevented by any dose of mephedrone but was, in fact, significantly enhanced. The hyperthermia caused by combined treatment with mephedrone and methamphetamine was the same as seen after either drug alone. Mephedrone also enhanced the neurotoxic effects of amphetamine and 3,4-methylenedioxymethamphetamine on DA nerve endings. In contrast, nomifensine protected against methamphetamine-induced neurotoxicity. As mephedrone increases methamphetamine neurotoxicity, the present results suggest that it interacts with the DAT in a manner unlike that of other typical DAT inhibitors. The relatively innocuous effects of mephedrone alone on DA nerve endings mask a potentially dangerous interaction with drugs that are often co-abused with it, leading to heightened neurotoxicity.
Angoa-Pérez, Mariana; Kane, Michael J.; Briggs, Denise I.; Francescutti, Dina M.; Sykes, Catherine E.; Shah, Mrudang M.; Thomas, David M.; Kuhn, Donald M.
Mephedrone (4-methylmethcathinone) is a β-ketoamphetamine stimulant drug of abuse with close structural and mechanistic similarities to methamphetamine. One of the most powerful actions associated with mephedrone is the ability to stimulate dopamine (DA) release and block its reuptake through its interaction with the dopamine transporter (DAT). Although mephedrone does not cause toxicity to DA nerve endings, its ability to serve as a DAT blocker could provide protection against methamphetamine-induced neurotoxicity like other DAT inhibitors. To test this possibility, mice were treated with mephedrone (10, 20 or 40 mg/kg) prior to each injection of a neurotoxic regimen of methamphetamine (4 injections of 2.5 or 5.0 mg/kg at 2 hr intervals). The integrity of DA nerve endings of the striatum was assessed through measures of DA, DAT and tyrosine hydroxylase levels. The moderate to severe DA toxicity associated with the different doses of methamphetamine was not prevented by any dose of mephedrone but was, in fact, significantly enhanced. The hyperthermia caused by combined treatment with mephedrone and methamphetamine was the same as seen after either drug alone. Mephedrone also enhanced the neurotoxic effects of amphetamine and MDMA on DA nerve endings. In contrast, nomifensine protected against methamphetamine-induced neurotoxicity. Because mephedrone increases methamphetamine neurotoxicity, the present results suggest that it interacts with the DAT in a manner unlike that of other typical DAT inhibitors. The relatively innocuous effects of mephedrone alone on DA nerve endings mask a potentially dangerous interaction with drugs that are often co-abused with it, leading to heightened neurotoxicity. PMID:23205838
Rudomin, P; Lomelí, J; Quevedo, J
We compared in the anesthetized cat the effects of reversible spinalization by cold block on primary afferent depolarization (PAD) and primary afferent hyperpolarization (PAH) elicited in pairs of intraspinal collaterals of single group I afferents from the gastrocnemius nerve, one of the pairs ending in the L3 segment, around the Clarke's column nuclei, and the other in the L6 segment within the intermediate zone. PAD in each collateral was estimated by independent computer-controlled measurement of the intraspinal current required to maintain a constant probability of antidromic firing. The results indicate that the segmental and ascending collaterals of individual afferents are subjected to a tonic PAD of descending origin affecting in a differential manner the excitatory and inhibitory actions of cutaneous and joint afferents on the pathways mediating the PAD of group I fibers. The PAD-mediating networks appear to function as distributed systems whose output will be determined by the balance of the segmental and supraspinal influences received at that moment. It is suggested that the descending differential modulation of PAD enables the intraspinal arborizations of the muscle afferents to function as dynamic systems, in which information transmitted to segmental reflex pathways and to Clarke's column neurons by common sources can be decoupled by sensory and descending inputs, and funneled to specific targets according to the motor tasks to be performed.
The first recordings of vagal afferent nerve fibre activity were performed by Paintal in the early 1950s. In these experiments, he showed that phenyldiguanide (later recognized as a 5-HT3 receptor agonist) stimulated the firing of C-fibres innervating the intestine. In the following years, ample physiological and psychological studies have demonstrated the importance of afferent information arising from the gut in the regulation of gastrointestinal function and behaviour. Many stimuli are capable of eliciting these functional effects and of stimulating afferent fibre discharge, including mechanical, chemical, nutrient- and immune-derived stimuli. Studies in the last 10 years have begun to focus on the precise sensory transduction mechanisms by which these visceral primary afferent nerve terminals are activated and, like the contribution by Zhu et al. in this issue of The Journal of Physiology, are revealing some novel and exciting findings.
Li, Bai-Yan; Feng, Bin; Tsu, Hwa Y; Schild, John H
Sensory information arising from visceral organ systems is encoded into action potential trains that propagate along afferent fibers to target nuclei in the central nervous system. These information streams range from tight patterns of action potentials that are well synchronized with the sensory transduction event to irregular, patternless discharge with no clear correlation to the sensory input. In general terms these afferent pathways can be divided into unmyelinated and myelinated fiber types. Our laboratory has a long standing interest in the functional differences between these two types of afferents in terms of the preprocessing of sensory information into action potential trains (synchrony, frequency, duration, etc.), the reflexogenic consequences of this sensory input to the central nervous system and the ionic channels that give rise to the electrophysiological properties of these unique cell types. The aim of this study was to determine whether there were any functional differences in the somatic action potential characteristics of unmyelinated and myelinated vagal afferents in response to different rates of sensory nerve stimulation. Our results showed that activity and frequency-dependent widening of the somatic action potential was quite prominent in unmyelinated but not myelinated vagal afferents. Spike broadening often leads to increased influx of Ca(2+) ions that has been associated with a diverse range of modulatory mechanisms both at the cell body and central synaptic terminations (e.g. increased neurotransmitter release.) We conclude that our observations are indicative of fundamentally different mechanisms for neural integration of sensory information arising from unmyelinated and myelinated vagal afferents.
Nikol'skiĭ, E E; Bukharaeva, E A; Samigullin, D V; Gaĭnulov, R Kh
Apart from the fact that the gradient of the velocity of the AP propagation along the nerve terminal and the intensity of secretion do exist, the kinetics of a quanta transmitter release may also be revealed in different parts of the terminal. The velocity of the propagation and the minimum sympatric delay tend to diminish along with moving away from the myelinated part of axon, whereas the synchronicity of the quanta release rises. The distinctions in the time course of secretion in different parts of the terminal were amplified when the calcium ion concentration in the medium was enhanced. The observed peculiarities of the secretion kinetics in different regions of nerve ending seem to compensate for diminishing of the amplitude of multiquantal endplate current.
Marasco, Paul D; Tsuruda, Pamela R; Bautista, Diana M; Julius, David; Catania, Kenneth C
Talpid moles are small insectivores that live in dark underground tunnels. They depend heavily on touch to navigate and find food. Most species have an array of complex epidermal sensory structures called Eimer's organs that cover the tip of the nose. In this study, the anatomy of Eimer's organ was examined in the coast mole and star-nosed mole by using the fluorescent styryl pyridinium dye AM1-43 and immunocytochemical staining for neurofilament 200 and substance P. In addition, DiI was used to label neural components of Eimer's organ. AM1-43 labeled all of the Eimer's organ receptors after systemic injection, suggesting a role in mechanotransduction. Immunostaining with neurofilament 200 and substance P labeled distinct subtypes of sensory fibers. Substance P labeled a group of free nerve endings along the outer edge of Eimer's organ, indicating a nociceptive role for these fibers. In contrast, neurofilament 200 labeled a more central set of nerve endings, suggesting that these fibers function as low-threshold mechanoreceptors. By labeling subsets of trigeminal afferents distant from the receptor array with DiI, we revealed innervation patterns indicating that one afferent supplies the outer, substance P-positive set of free nerve endings, whereas several afferents differentially innervate the central free nerve endings. Our results suggest that the free nerve endings innervating Eimer's organ are largely mechanosensitive and may play an important role in the rapid sensory discrimination observed in these species.
(1) The study was performed to elucidate the effects of afferent vagal stimulation and distension of the digestive tract on the micturition reflex in 21 acute decerebrate dogs immobilized with gallamine. Electrical stimulation of the central cut end of the cervical vagus nerve with high voltage (17.5-25 V) and moderate frequency (10-50 Hz) elicited in most cases inhibition of the periodic bladder contractions and of outflows of the pelvic vesical branch which were induced by a sustained intravesical pressure of 10-15 cmH2O. Distension of the thoracic esophagus, the stomach, and the duodenum also induced inhibition of the bladder contractions and of the pelvic outflow to the bladder. Such inhibitions were abolished after bilateral cervical vagotomies except a few cases of distension of the duodenum. (2) Another series of experiments were undertaken to clear the effect of afferent vagal stimulation on the electrical activity of the pontine micturition center in 10 acute decerebrate dogs. By means of an extracellular glass microelectrode method, unitary discharges synchronized with the grouping discharges in the pelvic vesical branch with a rhythm of 2.2-2.5 Hz were recorded from the pontine micturition center in the dorsolateral pontine tegmentum. Such a type of discharges was detected in 6 of 59 units which discharged by afferent stimulation of the pelvic vesical branch. This type of discharges was inhibited by afferent vagal stimulation at the supradiaphragmatic level. From these results, it may be concluded that the afferent pathway of the bladder relaxation reflex induced by distension of the upper digestive tract is mainly involved in the vagal nerves, but in some cases of the strong distension of the duodenum, the pathway is in splanchnic nerves, and that inhibition of the bladder contraction after stimulation of vagal nerve is induced by suppression of the pontine micturition centers.
Yamauchi, Takao; Kachi, Takashi
Effects of sham-pinealectomy and pinealectomy on preganglionic nerve endings on adrenomedullary adrenaline cells were investigated electron microscopically. Adult male golden hamsters from the normal, sham-pinealectomy and pinealectomy groups maintained under 24 h light-dark cycle and constant temperature were used at 28 days after surgery. From conventional electron microscopic specimens, montage photographs made of the adrenaline cell region at a magnification of x 11,000 were used for qualitative and quantitative electron microscopic analyses in 14 animals in each experimental group. The preganglionic nerve endings were localized mainly in the following three sites: the basal lamina part, the follicular lumen-junctional intercellular part, and the adrenaline cell-invaginated part. In the latter two parts, nerve endings and fibers had no envelope frequently, and in the former two parts, nerve endings sometimes showed the invagination complex. The frequency of nerve endings was highest in the follicular lumen-intercellular part, next highest in the basal lamina part and lowest in the A cell-invaginated part. The frequency of nerve endings in the basal lamina part was lower in the pinealectomy group than in the sham-pinealectomy group (P < 0.021), and those in the other two parts showed opposite changes, more evidently in the A cell-invaginated part. Nerve ending profiles in the adrenaline cell-invaginated part--which displayed a more rounded shape--increased in size in the pinealectomy group (longer diameter: P < 0.04; shorter diameter: P < 0.05). In conclusion, preganglionic nerve endings in the adrenal medulla of the golden hamster show differential morphological changes following PX depending on the intracellular part of A cells.
Dinsmore, M; Han, J S; Fisher, J A; Chan, V W S; Venkatraghavan, L
Transorbital ultrasonographic measurement of the diameter of the optic nerve sheath is a non-invasive, bed-side examination for detecting raised intracranial pressure. However, the ability of the optic nerve sheath diameter to predict acute changes in intracranial pressures remains unknown. The aim of this study was to examine the dynamic changes of the optic nerve sheath diameter in response to mild fluctuations in cerebral blood volume induced by changes in end-tidal carbon dioxide. We studied 11 healthy volunteers. End-tidal carbon dioxide was controlled by a model-based prospective end-tidal targeting system (RespirAct™). The volunteers' end-tidal carbon dioxide was targeted and maintained for 10 min each at normocapnia (baseline); hypercapnia (6.5 kPa); normocapnia (baseline 1); hypocapnia (3.9 kPa) and on return to normocapnia (baseline 2). A single investigator repeatedly measured the optic nerve sheath diameter for 10 min at each level of carbon dioxide. With hypercapnia, there was a significant increase in optic nerve sheath diameter, with a mean (SD) increase from baseline 4.2 (0.7) mm to 4.8 (0.8) mm; p < 0.001. On return to normocapnia, the optic nerve sheath diameter rapidly reverted back to baseline values. This study confirms dynamic changes in the optic nerve sheath diameter with corresponding changes in carbon dioxide, and their reversibly with normocapnia.
Dopico, Alejandro M; Widmer, Hélène; Wang, Gang; Lemos, José R; Treistman, Steven N
Large conductance, Ca2+-activated K+ (BK) channels were identified in freshly dissociated rat supraoptic neurones using patch clamp techniques. The single channel conductance of cell body BK channels, recorded from inside-out patches in symmetric 145 mM K+, was 246.1 pS, compared with 213 pS in nerve ending BK channels (P < 0.01). At low open probability (Po), the reciprocal of the slope in the ln(NPo)-voltage relationship (N, number of available channels in the patch) for cell body and nerve ending channels were similar: 11 vs. 14 mVper e-fold change in NPo, respectively. At 40 mV, the [Ca2+]i producing half-maximal activation was 273 nM, as opposed to > 1.53 μM for the neurohypophysial channel, indicating the higher Ca2+ sensitivity of the cell body isochannel. Cell body BK channels showed fast kinetics (open time constant, 8.5 ms; fast closed time constant, 1.6 and slow closed time constant, 12.7 ms), identifying them as ‘type I’ isochannels, as opposed to the slow gating (type II) of neurohypophysial BK channels. Cell body BK activity was reduced by 10 nM charybdotoxin (NPo, 37 % of control), or 10 nM iberiotoxin (NPo, 5 % of control), whereas neurohypophysial BK channels are insensitive to charybdotoxin at concentrations as high as 360 nM. Whilst blockade of nerve ending BK channels markedly slowed the repolarization of evoked single spikes, blockade of cell body channels was without effect on repolarization of evoked single spikes. Ethanol reversibly increased neurohypophysial BK channel activity (EC50, 22 mM; maximal effect, 100 mM). In contrast, ethanol (up to 100 mM) failed to increase cell body BK channel activity. In conclusion, we have characterized BK channels in supraoptic neuronal cell bodies, and demonstrated that they display different electrophysiological and pharmacological properties from their counterparts in the nerve endings. PMID:10432342
Yoshizawa, Hidekazu; Senda, Daiki; Natori, Yuhei; Tanaka, Rica; Mizuno, Hiroshi; Hayashi, Ayato
Axonal regeneration relies on support from proliferating host Schwann cells (SCs), and previous studies on acellular nerve allografts (ANGs) suggest that axons can regenerate into ANGs within a limited distance. Numerous studies have demonstrated that the supplementation of ANGs with exogenous factors, such as cultured SCs, stem cells, and growth factors, promote nerve regeneration in ANGs. However, there are several problems associated with their utilization. In this study, we investigated whether end-to-side (ETS) neurorrhaphy, which is an axonal provider, could be useful as an SC provider to support axonal elongation in ANGs. We found that ETS neurorrhaphy effectively promoted SC migration into ANGs when an epineurium window combined with partial neurectomy was performed, and the effectiveness increased when it was applied bilaterally. When we transplanted ANGs containing migrated SCs via ETS neurorrhaphy (hybrid ANGs) to the nerve gap, hybrid ANGs increased the number of regenerated axons and facilitated rapid axonal elongation, particularly when ETS neurorrhaphy was applied to both edges of the graft. This approach may represent a novel application of ETS neurorrhaphy and lead to the development of hybrid ANGs, making ANGs more practical in a clinical setting. PMID:27907118
Trulsson, M; Essick, G K
Intraneural microneurography and microstimulation were performed on single afferent axons in the inferior alveolar and lingual nerves innervating the face, teeth, labial, or oral mucosa. Using natural mechanical stimuli, 35 single mechanoreceptive afferents were characterized with respect to unit type [fast adapting type I (FA I), FA hair, slowly adapting type I and II (SA I and SA II), periodontal, and deep tongue units] as well as size and shape of the receptive field. All afferents were subsequently microstimulated with pulse trains at 30 Hz lasting 1.0 s. Afferents recordings whose were stable thereafter were also tested with single pulses and pulse trains at 5 and 60 Hz. The results revealed that electrical stimulation of single FA I, FA hair, and SA I afferents from the orofacial region can evoke a percept that is spatially matched to the afferent's receptive field and consistent with the afferent's response properties as observed on natural mechanical stimulation. Stimulation of FA afferents typically evoked sensations that were vibratory in nature; whereas those of SA I afferents were felt as constant pressure. These afferents terminate superficially in the orofacial tissues and seem to have a particularly powerful access to perceptual levels. In contrast, microstimulation of single periodontal, SA II, and deep tongue afferents failed to evoke a sensation that matched the receptive field of the afferent. These afferents terminate more deeply in the tissues, are often active in the absence of external stimulation, and probably access perceptual levels only when multiple afferents are stimulated. It is suggested that the spontaneously active afferents that monitor tension in collagen fibers (SA II and periodontal afferents) may have the role to register the mechanical state of the soft tissues, which has been hypothesized to help maintain the body's representation in the central somatosensory system.
Lennerz, J K M; Dentsch, C; Bernardini, N; Hummel, T; Neuhuber, W L; Reeh, P W
Emerging evidence indicates a nociceptive role of vagal afferents. A distinct oesophageal innervation in the rat, with muscular and mucosal afferents travelling predominantly in the recurrent (RLN) and superior laryngeal nerve (SLN), respectively, enabled characterization of mucosal afferents with nociceptive properties, using novel isolated oesophagus–nerve preparations. SLN and RLN single-fibre recordings identified 55 and 14 units, respectively, with none conducting faster than 8.7 m s−1. Mucosal response characteristics in the SLN distinguished mechanosensors (n= 13), mechanosensors with heat sensitivity (18) from those with cold sensitivity (19) and a mechanoinsensitive group (5). The mechanosensitive fibres, all slowly adapting, showed a unimodal distribution of mechanical thresholds (1.4–128 mN, peak ∼5.7 mN). No difference in response characteristics of C and Aδ fibres was encountered. Mucosal proton stimulation (pH 5.4 for 3 min), mimicking gastro-oesophageal reflux disease (GORD), revealed in 31% of units a desensitizing response that peaked around 20 s and faded within 60 s. Cold stimulation (15°C) was proportionally encoded but the response showed slow adaptation. In contrast, the noxious heat (48°C) response showed no obvious adaptation with discharge rates reflecting the temperature's time course. Polymodal (69%) mucosal units, > 30% proton sensitive, were found in each fibre category and were considered nociceptors; they are tentatively attributed to vagal nerve endings type I, IV and V, previously morphologically described. All receptive fields were mapped and the distribution indicates that the posterior upper oesophagus may serve as a ‘cutbank’, detecting noxious matters, ingested or regurgitated, and triggering nocifensive reflexes such as bronchoconstriction in GORD. PMID:17478536
Two types of mechanoreceptor have been found in the articular capsule of the knee joint of the domestic cat--Ruffini corpuscles and Pacinian corpuscles. Ruffini corpuscles are situated in the stratum fibrosum and consist of 2 to 6 cylinders. Each cylinder is made up of an afferent axon (diameter 3-4 micrometer), its swellings and terminal processes, Schwann cells enveloping the nerve swellings and terminal processes, endoneural connective tissue and a perineural capsule. The perineural capsule is incomplete in Ruffini corpuscles. The Pacinian corpuscles are 20 to 40 micrometer wide and 150-250 micrometer long. They are situated in groups of up to five at the boundary between the stratum synoviale and the stratum fibrosum. The afferent axon is myelinated (diameter 3-5 micrometer). Its terminal portion is inside the inner bulb which is formed of modified Schwann cells. Each corpuscle is enveloped by a perineural capsule (4-8 layers). The ultrastructure of the Pacinian corpuscles is compared with the ultrastructure of the skin receptors in the cat. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6 PMID:604339
Babes, Alexandru; Ciobanu, Alexandru Cristian; Neacsu, Cristian; Babes, Ramona-Madalina
Temperature sensing is a crucial feature of the nervous system, enabling organisms to avoid physical danger and choose optimal environments for survival. TRPM8 (Transient Receptor Potential Melastatin type 8) belongs to a select group of ion channels which are gated by changes in temperature, are expressed in sensory nerves and/or skin cells and may be involved in temperature sensing. This channel is activated by a moderate decrease in temperature, with a threshold of approximately 25 °C in heterologous expression systems, and by a variety of natural and synthetic compounds, including menthol. While the physiological role of TRPM8 as a transducer of gentle cooling is widely accepted, its involvement in acute noxious cold sensing in healthy tissues is still under debate. Although accumulating evidence indicates that TRPM8 is involved in neuropathic cold allodynia, in some animal models of nerve injury peripheral and central activation of TRPM8 is followed by analgesia. A variety of inflammatory mediators, including bradykinin and prostaglandin E(2), modulate TRPM8 by inhibiting the channel and shifting its activation threshold to colder temperatures, most likely counteracting the analgesic action of TRPM8. While important progress has been made in unraveling the biophysical features of TRPM8, including the revelation of its voltage dependence, the precise mechanism involved in temperature sensing by this channel is still not completely understood. This article will review the current status of knowledge regarding the (patho)physiological role(s) of TRPM8, its modulation by inflammatory mediators, the signaling pathways involved in this regulation, and the biophysical properties of the channel.
Tezel, Gülgün; Luo, Cheng; Yang, Xiangjun
PURPOSE This study aimed to determine the association between advanced glycation end products (AGEs) and glaucoma based on the known synergism between oxidative stress with AGEs and the evidence of oxidative stress during glaucomatous neurodegeneration. METHODS The extent and cellular localization of immunolabeling for AGEs and their receptor, RAGE, were determined in histologic sections of the retina and optic nerve head obtained from 38 donor eyes with glaucoma and 30 eyes from age-matched donors without glaucoma. RESULTS The extent of AGE and RAGE immunolabeling was greater in older than in younger donor eyes. However, compared with age-matched controls, an enhanced accumulation of AGEs and an up-regulation of RAGE were detectable in the glaucomatous retina and optic nerve head. Although some retinal ganglion cells (RGCs) and glia exhibited intracellular immunolabeling for AGEs, increased AGE immunolabeling in glaucomatous eyes was predominantly extracellular and included laminar cribriform plates in the optic nerve head. Some RAGE immunolabeling was detectable on RGCs; however, increased RAGE immunolabeling in glaucomatous eyes was predominant on glial cells, primarily Müller cells. CONCLUSIONS Given that the generation of AGEs is an age-dependent event, increased AGE accumulation in glaucomatous tissues supports that an accelerated aging process accompanies neurodegeneration in glaucomatous eyes. One of the potential consequences of AGE accumulation in glaucomatous eyes appears to be its contribution to increased rigidity of the lamina cribrosa. The presence of RAGE on RGCs and glia also makes them susceptible to AGE-mediated events through receptor-mediated signaling, which may promote cell death or dysfunction during glaucomatous neurodegeneration. PMID:17325164
Silver, Randi B; Poonwasi, Kumar S; Seyedi, Nahid; Wilson, Sandy J; Lovenberg, Timothy W; Levi, Roberto
Activation of presynatic histamine H(3) receptors (H(3)R) down-regulates norepinephrine exocytosis from cardiac sympathetic nerve terminals, in both normal and ischemic conditions. Analogous to the effects of alpha(2)-adrenoceptors, which also act prejunctionally to inhibit norepinephrine release, H(3)R-mediated antiexocytotic effects could result from a decreased Ca(2+) influx into nerve endings. We tested this hypothesis in sympathetic nerve terminals isolated from guinea pig heart (cardiac synaptosomes) and in a model human neuronal cell line (SH-SY5Y), which we stably transfected with human H(3)R cDNA (SH-SY5Y-H(3)). We found that reducing Ca(2+) influx in response to membrane depolarization by inhibiting N-type Ca(2+) channels with omega-conotoxin (omega-CTX) greatly attenuated the exocytosis of [(3)H]norepinephrine from both SH-SY5Y and SH-SY5Y-H(3) cells, as well as the exocytosis of endogenous norepinephrine from cardiac synaptosomes. Similar to omega-CTX, activation of H(3)R with the selective H(3)R-agonist imetit also reduced both the rise in intracellular Ca(2+) concentration (Ca(i)) and norepinephrine exocytosis in response to membrane depolarization. The selective H(3)R antagonist thioperamide prevented this effect of imetit. In the parent SH-SY5Y cells lacking H(3)R, imetit affected neither the rise in Ca(i) nor [(3)H]norepinephrine exocytosis, demonstrating that the presence of H(3)R is a prerequisite for a decrease in Ca(i) in response to imetit and that H(3)R activation modulates norepinephrine exocytosis by limiting the magnitude of the increase in Ca(i). Inasmuch as excessive norepinephrine exocytosis is a leading cause of cardiac dysfunction and arrhythmias during acute myocardial ischemia, attenuation of norepinephrine release by H(3)R agonists may offer a novel therapeutic approach to this condition.
Sitges, María; Aldana, Blanca I; Chiu, Luz M; Nekrassov, Vladimir
The effects of two classic antiepileptic drugs (carbamazepine and phenytoin), a potential antiepileptic (vinpocetine) and a monoamine-oxidase inhibitor (clorgyline) on the simultaneous changes (detected by HPLC) on Glu, Asp, dopamine and DOPAC inside and outside striatal isolated nerve endings were investigated. Under resting conditions phenytoin, carbamazepine and clorgyline increased dopamine release. Phenytoin and clorgyline increased internal dopamine and decreased DOPAC formation. Carbamazepine decreased internal dopamine and practically did not change DOPAC formation. Glu and Asp release was unchanged. Neurotransmitter release induced by the Na+ channel opener veratridine was reduced by all the antiepileptic drugs tested, except phenytoin which, like clorgyline, facilitated veratridine-induced dopamine release. We conclude that besides the antagonism exerted by carbamazepine, phenytoin and vinpocetine on excitatory neurotransmitters release triggered by Na+ channel activation, that might importantly contribute to their anticonvulsant action, they exert different actions on striatal dopamine distribution, that might explain their different side effect profiles.
Hara, H.; Chen, X.; Hartsfield, J. F.; Hara, J.; Martin, D.; Fermin, C. D.
Neurons from the vestibular (VG) and the statoacoustic (SAG) ganglion of the chick (Gallus domesticus) were evaluated histologically and morphometrically. Embryos at stages 34 (E8 days), 39 (E13 days) and 44 (E18 days) were sacrificed and temporal bones microdissected. Specimens were embedded in JB-4 methacrylate plastic, and stained with a mixture of 0.2% toluidine blue (TB) and 0.1% basic Fuschin in 25% ethanol or with a mixture of 2% TB and 1% paraphenylenediamine (PDA) for axon and myelin measurement study. Images of the VIIIth nerve were produced by a V150 (R) color imaging system and the contour of 200-300 neuronal bodies (perikarya) was traced directly on a video screen with a mouse in real time. The cross-sectional area of VG perikarya was 67.29 micrometers2 at stage 34 (E8), 128.46 micrometers2 at stage 39 (E13) and 275.85 micrometers2 at stage 44 (E18). The cross-sectional area of SAG perikarya was 62.44 micrometers2 at stage 34 (E8), 102.05 micrometers2 at stage 39 (E13) and 165.02 micrometers2 at stage 44 (E18). A significant cross-sectional area increase of the VG perikarya between stage 39 (E13) and stage 44 (E18) was determined. We randomly measured the cross-sectional area of myelin and axoplasm of hatchling afferent nerves, and found a correspondence between axoplasmic and myelin cross-sectional area in the utricular, saccular and semicircular canal nerve branches of the nerve. The results suggest that the period between stage 34 (E8) and 39 (E13) is a critical period for afferent neuronal development. Physiological and behavioral vestibular properties of developing and maturing hatchlings may change accordingly. The results compliment previous work by other investigators and provide valuable anatomical measures useful to correlate physiological data obtained from stimulation of the whole nerve or its parts.
Rudomín, P; Leonard, R B; Willis, W D
1. Excitability changes in primary afferents and inhibitory interactions in evoked spinal cord activity were investigated in unanesthetized stingrays (Dasyatis subina) with high cervical spinal transections. 2. Primary afferent excitability increases following a conditioning stimulus to an adjacent segmental nerve were demonstrated with the Wall (31) technique. 3. Stimulation of A-alpha,beta and A-delta afferent fibers produced excitability increases in both A-alpha,beta and delta-fibers of the adjacent segment. 4. The excitability increase had a latency of about 10 ms, it peaked around 25 ms, and the change lasted more than 100 ms. 5. The central afferent volley in A-alpha,beta fibers and the N1- and late negative waves due to postsynaptic activity of dorsal horn interneurons were reduced by conditioning volleys in adjacent afferent nerves. The time course of the inhibition paralleled that of the excitability increases in afferent terminal arborizations, suggesting that the depression of postsynaptic activity is, at least in part, due to presynaptic inhibition. 6. Reduction of evoked discharges and excitatory postsynaptic potentials was observed in recordings from interneurons with a time course similar to that of the primary afferent depolarization (PAD). 7. Conditioning volleys in afferents of adjacent peripheral nerves produced facilitation or inhibition of segmental reflexes.
Takhtfooladi, Mohammad Ashrafzadeh; Sharifi, Davood
This study aimed at evaluating the effects of red and blue light-emitting diodes (LED) and low-level laser (LLL) on the regeneration of the transected sciatic nerve after an end-to-end neurorrhaphy in rabbits. Forty healthy mature male New Zealand rabbits were randomly assigned into four experimental groups: control, LLL (680 nm), red LED (650 nm), and blue LED (450 nm). All animals underwent the right sciatic nerve neurotmesis injury under general anesthesia and end-to-end anastomosis. The phototherapy was initiated on the first postoperative day and lasted for 14 consecutive days at the same time of the day. On the 30th day post-surgery, the animals whose sciatic nerves were harvested for histopathological analysis were euthanized. The nerves were analyzed and quantified the following findings: Schwann cells, large myelinic axons, and neurons. In the LLL group, as compared to other groups, an increase in the number of all analyzed aspects was observed with significance level (P < 0.05). This finding suggests that postoperative LLL irradiation was able to accelerate and potentialize the peripheral nerve regeneration process in rabbits within 14 days of irradiation.
Edelmayer, Rebecca M.; Le, Larry N.; Yan, Jin; Wei, Xiaomei; Nassini, Romina; Materazzi, Serena; Preti, Delia; Appendino, Giovanni; Geppetti, Pierangelo; Dodick, David W.; Vanderah, Todd W.; Porreca, Frank; Dussor, Gregory
Activation of transient receptor potential ankyrin-1 (TRPA1) on meningeal nerve endings has been suggested to contribute to environmental irritant-induced headache but this channel may also contribute to other forms of headache such as migraine. The preclinical studies described here examined functional expression of TRPA1 on dural afferents and investigated whether activation of TRPA1 contributes to headache-like behaviors. Whole-cell patch-clamp recordings were performed in vitro using two TRPA1 agonists, mustard oil (MO) and the environmental irritant umbellulone (UMB), on dural-projecting trigeminal ganglion neurons. Application of MO and UMB to dural afferents produced TRPA1-like currents in approximately 42% and 38% of cells, respectively. Using an established in vivo behavioral model of migraine-related allodynia, dural application of MO and UMB produced robust time-related tactile facial and hindpaw allodynia that was attenuated by pretreatment with the TRPA1 antagonist HC-030031. Additionally, MO or UMB were applied to the dura and exploratory activity was monitored for 30 minutes using an automated open-field activity chamber. Dural MO and UMB decreased the number of vertical rearing episodes and the time spent rearing in comparison to vehicle treated animals. This change in activity was prevented in rats pretreated with HC-030031 as well as sumatriptan, a clinically effective anti-migraine agent. These data indicate that TRPA1 is expressed on a substantial fraction of dural afferents and activation of meningeal TRPA1 produces behaviors consistent with those seen in patients during migraine attacks. Further, they suggest that activation of meningeal TRPA1 via endogenous or exogenous mechanisms can lead to afferent signaling and headache. PMID:22809691
Edelmayer, Rebecca M; Le, Larry N; Yan, Jin; Wei, Xiaomei; Nassini, Romina; Materazzi, Serena; Preti, Delia; Appendino, Giovanni; Geppetti, Pierangelo; Dodick, David W; Vanderah, Todd W; Porreca, Frank; Dussor, Gregory
Activation of transient receptor potential ankyrin-1 (TRPA1) on meningeal nerve endings has been suggested to contribute to environmental irritant-induced headache, but this channel may also contribute to other forms of headache, such as migraine. The preclinical studies described here examined functional expression of TRPA1 on dural afferents and investigated whether activation of TRPA1 contributes to headache-like behaviors. Whole-cell patch-clamp recordings were performed in vitro with 2 TRPA1 agonists, mustard oil (MO), and the environmental irritant umbellulone (UMB) on dural-projecting trigeminal ganglion neurons. Application of MO and UMB to dural afferents produced TRPA1-like currents in approximately 42% and 38% of cells, respectively. By means of an established in vivo behavioral model of migraine-related allodynia, dural application of MO and UMB produced robust time-related tactile facial and hind paw allodynia that was attenuated by pretreatment with the TRPA1 antagonist HC-030031. Additionally, MO or UMB were applied to the dura, and exploratory activity was monitored for 30min with an automated open-field activity chamber. Dural MO and UMB decreased the number of vertical rearing episodes and the time spent rearing in comparison to vehicle-treated animals. This change in activity was prevented in rats pretreated with HC-030031 as well as sumatriptan, a clinically effective antimigraine agent. These data indicate that TRPA1 is expressed on a substantial fraction of dural afferents, and activation of meningeal TRPA1 produces behaviors consistent with those observed in patients during migraine attacks. Further, they suggest that activation of meningeal TRPA1 via endogenous or exogenous mechanisms can lead to afferent signaling and headache.
Duran-Jimenez, Beatriz; Dobler, Darin; Moffatt, Sarah; Rabbani, Naila; Streuli, Charles H.; Thornalley, Paul J.; Tomlinson, David R.; Gardiner, Natalie J.
OBJECTIVE The goal of this study was to characterize glycation adducts formed in both in vivo extracellular matrix (ECM) proteins of endoneurium from streptozotocin (STZ)-induced diabetic rats and in vitro by glycation of laminin and fibronectin with methylglyoxal and glucose. We also investigated the impact of advanced glycation end product (AGE) residue content of ECM on neurite outgrowth from sensory neurons. RESEARCH DESIGN AND METHODS Glycation, oxidation, and nitration adducts of ECM proteins extracted from the endoneurium of control and STZ-induced diabetic rat sciatic nerve (3–24 weeks post-STZ) and of laminin and fibronectin that had been glycated using glucose or methylglyoxal were examined by liquid chromatography with tandem mass spectrometry. Methylglyoxal-glycated or unmodified ECM proteins were used as substrata for dissociated rat sensory neurons as in vitro models of regeneration. RESULTS STZ-induced diabetes produced a significant increase in early glycation Nε-fructosyl-lysine and AGE residue contents of endoneurial ECM. Glycation of laminin and fibronectin by methylglyoxal and glucose increased glycation adduct residue contents with methylglyoxal-derived hydroimidazolone and Nε-fructosyl-lysine, respectively, of greatest quantitative importance. Glycation of laminin caused a significant decrease in both neurotrophin-stimulated and preconditioned sensory neurite outgrowth. This decrease was prevented by aminoguanidine. Glycation of fibronectin also decreased preconditioned neurite outgrowth, which was prevented by aminoguanidine and nerve growth factor. CONCLUSIONS Early glycation and AGE residue content of endoneurial ECM proteins increase markedly in STZ-induced diabetes. Glycation of laminin and fibronectin causes a reduction in neurotrophin-stimulated neurite outgrowth and preconditioned neurite outgrowth. This may provide a mechanism for the failure of collateral sprouting and axonal regeneration in diabetic neuropathy. PMID:19720799
Jiang, Wen; Kirkup, Anthony J; Grundy, David
Acute intestinal ischaemia stimulates visceral afferent nerves but the mechanisms responsible for this excitation are not fully understood. Mast cells may participate in this process as they are known to signal to mesenteric afferents during intestinal anaphylaxis and contribute to early inflammation and neuronal damage in response to cerebral ischaemia. We therefore hypothesised that mast cells are early responders to acute intestinal ischaemia and their activation initiates rapid signalling to the CNS via the excitation of mesenteric afferents. Primary afferent firing was recorded from a mesenteric nerve bundle supplying a segment of jejunum in anaesthetized adult rats. Acute focal ischaemia was produced by clamping theme senteric vessels for 8 min, and reperfusion followed removal of the vessel clip. Two episodes of ischaemia–reperfusion (I–R) separated by a 30 min interval were performed. Drugs or their vehicles were administered 10 min before the 2nd I–R episode. Ischaemia caused a reproducible, intense and biphasic afferent firing that was temporally dissociated from the concomitantly triggered complex pattern of intestinal motor activity. The L-type calcium channel blocker, nifedipine, significantly attenuated this afferent firing by a mechanism independent of its action on intestinal tone. Ischaemia-induced afferent firing was also abrogated by the mast cell stabilizer, doxantrazole, and the H1 histamine receptor antagonist, pyrilamine. In contrast, the nicotinic receptor antagonist, hexamethonium, and the N-type calcium channel toxin, ω-conotoxin GVIA, each reduced the ischaemia-evoked motor inhibition but not the concurrent afferent discharge. Similarly, the cyclooxygenase inhibitor, naproxen, had no effect on the ischaemic afferent response but reduced the intestinal tone shortly from the onset of ischaemia to the early period of reperfusion. These data support a critical role for mast cell-derived histamine in the direct chemoexcitation of
Nikol'kii, E E; Bukharaeva, E A; Samigullin, D V; Gainulo, R Kh
Experiments were performed on neuromuscular preparations from frogs, in which three extracellular microelectrodes were used to record nerve ending currents and single-quantum endplate currents simultaneously from the proximal, central, and distal parts of single synaptic contacts. The rate of propagation of excitation across terminals was measured. along with the minimum synaptic delay, the intensity. and the degree of synchronicity of the secretion of transmitter quanta in different parts of the nerve ending, and the relationships between these factors and the calcium ion concentration in the medium. These studies showed that along with gradients in the rate of conduction of excitation and the intensity of secretion in different parts of the ending. there were also differences in the kinetics of the release of transmitter quanta. As the distance from the end of the myelinated part of the axon increased, the rate of conduction of the nerve impulse and the duration of the synaptic delay decreased, while the synchronicity of the release of quanta increased. Increases in the calcium concentration in the medium produced greater increases in the synchronicity of transmitter quantum release in the distal parts of the synapse than in the proximal parts. Mathematical modeling of multiple-quantum endplate currents showed that the characteristics of the kinetics of the secretion process observed here in different parts of the nerve ending represent a factor which partially compensates for the decrease in the amplitude and extending of the duration of the leading front of the multiple-quantum endplate current which are associated with the low rate of conduction of excitation across the nerve ending. The contribution of this compensation increases as the intensity of secretion of transmitter quanta increases in the distal parts of the synaptic contact.
Dickman, J. D.; Fang, Q.
The question of whether a differential distribution of vestibular afferent information to central nuclear neurons is present in pigeons was studied using neural tracer compounds. Discrete tracing of afferent fibers innervating the individual semicircular canal and otolith organs was produced by sectioning individual branches of the vestibular nerve that innervate the different receptor organs and applying crystals of horseradish peroxidase, or a horseradish peroxidase/cholera toxin mixture, or a biocytin compound for neuronal uptake and transport. Afferent fibers and their terminal distributions within the brainstem and cerebellum were visualized subsequently. Discrete areas in the pigeon central nervous system that receive primary vestibular input include the superior, dorsal lateral, ventral lateral, medial, descending, and tangential vestibular nuclei; the A and B groups; the intermediate, medial, and lateral cerebellar nuclei; and the nodulus, the uvula, and the paraflocculus. Generally, the vertical canal afferents projected heavily to medial regions in the superior and descending vestibular nuclei as well as the A group. Vertical canal projections to the medial and lateral vestibular nuclei were observed but were less prominent. Horizontal canal projections to the superior and descending vestibular nuclei were much more centrally located than those of the vertical canals. A more substantial projection to the medial and lateral vestibular nuclei was seen with horizontal canal afferents compared to vertical canal fibers. Afferents innervating the utricle and saccule terminated generally in the lateral regions of all vestibular nuclei in areas that were separate from the projections of the semicircular canals. In addition, utricular fibers projected to regions in the vestibular nuclei that overlapped with the horizontal semicircular canal terminal fields, whereas saccular afferents projected to regions that received vertical canal fiber terminations. Lagenar
Patel, Yogi A.; Saxena, Tarun; Bellamkonda, Ravi V.; Butera, Robert J.
Efferent activation of the cervical vagus nerve (cVN) dampens systemic inflammatory processes, potentially modulating a wide-range of inflammatory pathological conditions. In contrast, afferent cVN activation amplifies systemic inflammatory processes, leading to activation of the hypothalamic-pituitary-adrenal (HPA) axis, the sympathetic nervous system through the greater splanchnic nerve (GSN), and elevation of pro-inflammatory cytokines. Ideally, to clinically implement anti-inflammatory therapy via cervical vagus nerve stimulation (cVNS) one should selectively activate the efferent pathway. Unfortunately, current implementations, in animal and clinical investigations, activate both afferent and efferent pathways. We paired cVNS with kilohertz electrical stimulation (KES) nerve block to preferentially activate efferent pathways while blocking afferent pathways. Selective efferent cVNS enhanced the anti-inflammatory effects of cVNS. Our results demonstrate that: (i) afferent, but not efferent, cVNS synchronously activates the GSN in a dose-dependent manner; (ii) efferent cVNS enabled by complete afferent KES nerve block enhances the anti-inflammatory benefits of cVNS; and (iii) incomplete afferent KES nerve block exacerbates systemic inflammation. Overall, these data demonstrate the utility of paired efferent cVNS and afferent KES nerve block for achieving selective efferent cVNS, specifically as it relates to neuromodulation of systemic inflammation. PMID:28054557
Lysakowski, Anna; Gaboyard-Niay, Sophie; Calin-Jageman, Irina; Chatlani, Shilpa; Price, Steven D; Eatock, Ruth Anne
Many primary vestibular afferents form large cup-shaped postsynaptic terminals (calyces) that envelope the basolateral surfaces of type I hair cells. The calyceal terminals both respond to glutamate released from ribbon synapses in the type I cells and initiate spikes that propagate to the afferent's central terminals in the brainstem. The combination of synaptic and spike initiation functions in these unique sensory endings distinguishes them from the axonal nodes of central neurons and peripheral nerves, such as the sciatic nerve, which have provided most of our information about nodal specializations. We show that rat vestibular calyces express an unusual mix of voltage-gated Na and K channels and scaffolding, cell adhesion, and extracellular matrix proteins, which may hold the ion channels in place. Protein expression patterns form several microdomains within the calyx membrane: a synaptic domain facing the hair cell, the heminode abutting the first myelinated internode, and one or two intermediate domains. Differences in the expression and localization of proteins between afferent types and zones may contribute to known variations in afferent physiology.
Birznieks, Ingvars; Wheat, Heather E; Redmond, Stephen J; Salo, Lauren M; Lovell, Nigel H; Goodwin, Antony W
Torsional loads are ubiquitous during everyday dextrous manipulations. We examined how information about torque is provided to the sensorimotor control system by populations of tactile afferents. Torsional loads of different magnitudes were applied in clockwise and anticlockwise directions to a standard central site on the fingertip. Three different background levels of contact (grip) force were used. The median nerve was exposed in anaesthetized monkeys and single unit responses recorded from 66 slowly adapting type-I (SA-I) and 31 fast adapting type-I (FA-I) afferents innervating the distal segments of the fingertips. Most afferents were excited by torque but some were suppressed. Responses of the majority of both afferent types were scaled by torque magnitude applied in one or other direction, with the majority of FA-I afferent responses and about half of SA-I afferent responses scaled in both directions. Torque direction affected responses in both afferent types, but more so for the SA-I afferents. Latencies of the first spike in FA-I afferent responses depended on the parameters of the torque. We used a Parzen window classifier to assess the capacity of the SA-I and FA-I afferent populations to discriminate, concurrently and in real-time, the three stimulus parameters, namely background normal force, torque magnitude and direction. Despite the potentially confounding interactions between stimulus parameters, both the SA-I and the FA-I populations could extract torque magnitude accurately. The FA-I afferents signalled torque magnitude earlier than did the SA-I afferents, but torque direction was extracted more rapidly and more accurately by the SA-I afferent population. PMID:20142274
Burke, R E; Rudomin, P; Vyklický, L; Zajac, F E
1. The reflex effects of pulses of intense radiant heat applied to the skin of the central plantar pad have been studied in unanaesthetized (decerebrate) spinal cats.2. Pad heat pulses produced flexion of the ipsilateral hind limb and increased ipsilateral flexor monosynaptic reflexes, due to post-synaptic excitation of flexor alpha motoneurones. These effects were accompanied by reduction of extensor monosynaptic reflexes and post-synaptic inhibition of extensor motoneurones.3. Ipsilateral (and contralateral) pad heat pulses consistently evoked negative dorsal root potentials (DRPs) as well as increased excitability of both cutaneous and group Ib muscle afferent terminals. The excitability of group Ia afferents was sometimes also increased during pad heat pulses, but to a lesser extent.4. Pad heat pulses produced negative DRPs in preparations in which positive DRP components could be demonstrated following electrical stimulation of both skin and muscle nerves.5. The motor and primary afferent effects of heat pulses always accompanied one another, beginning after the pad surface temperature had reached rather high levels (usually 48-55 degrees C).6. Negative DRPs increased excitability of cutaneous and group Ib afferents, and motoneurone activation produced by pad heat pulses was essentially unmodified when conduction in large myelinated afferents from the central plantar pad was blocked by cooling the posterior tibial nerve trunk.7. It is concluded that adequate noxious activation of cutaneous afferents of small diameter produces primary afferent depolarization in a variety of large diameter afferent fibres, as well as post-synaptic effects in alpha motoneurones.
Burke, R. E.; Rudomin, P.; Vyklický, L.; Zajac, F. E.
1. The reflex effects of pulses of intense radiant heat applied to the skin of the central plantar pad have been studied in unanaesthetized (decerebrate) spinal cats. 2. Pad heat pulses produced flexion of the ipsilateral hind limb and increased ipsilateral flexor monosynaptic reflexes, due to post-synaptic excitation of flexor alpha motoneurones. These effects were accompanied by reduction of extensor monosynaptic reflexes and post-synaptic inhibition of extensor motoneurones. 3. Ipsilateral (and contralateral) pad heat pulses consistently evoked negative dorsal root potentials (DRPs) as well as increased excitability of both cutaneous and group Ib muscle afferent terminals. The excitability of group Ia afferents was sometimes also increased during pad heat pulses, but to a lesser extent. 4. Pad heat pulses produced negative DRPs in preparations in which positive DRP components could be demonstrated following electrical stimulation of both skin and muscle nerves. 5. The motor and primary afferent effects of heat pulses always accompanied one another, beginning after the pad surface temperature had reached rather high levels (usually 48-55° C). 6. Negative DRPs increased excitability of cutaneous and group Ib afferents, and motoneurone activation produced by pad heat pulses was essentially unmodified when conduction in large myelinated afferents from the central plantar pad was blocked by cooling the posterior tibial nerve trunk. 7. It is concluded that adequate noxious activation of cutaneous afferents of small diameter produces primary afferent depolarization in a variety of large diameter afferent fibres, as well as post-synaptic effects in alpha motoneurones. PMID:5575337
Kuhn, Donald M; Francescutti-Verbeem, Dina M; Thomas, David M
Methamphetamine (METH) intoxication leads to persistent damage of dopamine (DA) nerve endings of the striatum. Recently, we and others have suggested that the neurotoxicity associated with METH is mediated by extensive microglial activation. DA itself has been shown to play an obligatory role in METH neurotoxicity, possibly through the formation of quinone species. We show presently that DA-quinones (DAQ) cause a time-dependent activation of cultured microglial cells. Microarray analysis of the effects of DAQ on microglial gene expression revealed that 101 genes were significantly changed in expression, with 73 genes increasing and 28 genes decreasing in expression. Among those genes differentially regulated by DAQ were those often associated with neurotoxic conditions including inflammation, cytokines, chemokines, and prostaglandins. In addition, microglial genes associated with a neuronally protective phenotype were among those that were downregulated by DAQ. These results implicate DAQ as one species that could cause early activation of microglial cells in METH intoxication, manifested as an alteration in the expression of a broad biomarker panel of genes. These results also link oxidative stress, chemical alterations in DA to its quinone, and microglial activation as part of a cascade of glial-neuronal crosstalk that can amplify METH-induced neurotoxicity.
Pardo, José V
The vagus nerve stimulation (VNS) device is used not only to treat refractory seizure disorders but also mood disorders; the latter indication received CE Mark approval in 2001 and Food and Drug Administration approval in 2005. Original estimates for the end of battery life (EOBL) were approximately 6-10 years. Many neuropsychiatric patients have or will soon face EOBL. A patient with severe, life-threatening, treatment-resistant bipolar disorder underwent 9 years of stable remission following 20 months of adjunctive VNS. The device ceased operation at EOBL. Because of logistical issues, re-initiation of VNS was delayed over several months. The patient relapsed with depression, mania and mixed states, and regained remission 17 months after device replacement. This case dictates prudence in managing stable patients in remission with VNS. If the device malfunctions, urgent surgical replacement is warranted with subsequent rapid titration to previous parameters as tolerated. Several months' delay may trigger relapse and prove difficult to re-establish remission.
Butera, C; Guerriero, R; Amadio, S; Ungaro, D; Tesfaghebriel, H; Bianchi, F; Comi, G; Del Carro, U
Botulinum toxin type-A is currently thought to be effective and safe for hemifacial spasm (HFS). The pre-synaptic block of acetylcholine release at the neuromuscular junction induces depression of orbicularis oculi muscle compound motor action potential (CMAP). The aim of our study was to evaluate at what extent end-plate functional recovery is possible even in botulinum toxin treatments lasting up to 15 years. We examined 81 outpatients with primary HFS (mean treatment duration = 7.2 ± 4.2 years) who underwent neurophysiologic study, once clinical effect of the previous treatment had vanished. The mean CMAP amplitude, mean rectified amplitude of response 1 (R1) of the blink reflex and area of response 2 (R2) of treated orbicularis oculi muscle were measured in comparison to the controlateral side. Mean amplitude of the above mentioned parameters was slightly lower (about 20%; p < 0.001) in the treated side at the end of the follow-up period (4.7 ± 1.7 months). The CMAP amplitude reduction weakly correlated with the interval from last treatment, while other neurophysiologic parameters did not change due to treatment duration or total toxin amount. Our study demonstrates that botulinum toxin affects compound motor action potential and blink-reflex responses for at least 4-5 months in HFS patients. The residual block is slight and does not increase with repeated injections after several years of treatment. Our study, beside confirming the long-term efficacy of botulinum toxin treatment for HFS, provides neurophysiologic evidence that therapeutic effect may be obtained without hindering the regenerative potential of the nerve-muscle complex.
Bailey, Aaron Z.; Mi, Yiqun P.; Nelson, Aimee J.
Background Short-latency afferent inhibition (SAI) results when somatosensory afferent input inhibits the corticospinal output from primary motor cortex (M1). The present study examined SAI in the flexor carpi radialis (FCR) muscle in individuals with spinal cord injury (SCI) and uninjured controls. Methods Short-latency afferent inhibition (SAI) was evoked by stimulating the median nerve at the elbow at intervals of 15, 20 and 25 ms in advance of a transcranial magnetic stimulation (TMS) pulse over M1. SAI was tested with the FCR at rest and also during ~20% of maximum voluntary contraction. Corticospinal output was assessed through measuring both motor thresholds and motor evoked potential (MEP) recruitment curves. The afferent volley was assessed via the N20–P25 amplitude of the somatosensory evoked potential (SEP) and the amplitude of sensory nerve action potentials (SNAP) recorded over the median nerve at the elbow. Results SAI is reduced in SCI in both the contracted and non-contracted FCR muscle. MEP recruitment curves and thresholds were decreased in SCI only in the active state and not the resting state. N20–P25 amplitude was similar between groups in both the resting and active states although SNAP was significantly reduced in SCI at rest. Conclusions We conclude that reduced SAI in SCI is likely attributed to neuroplasticity altering the intrinsic M1 circuitry mediating SAI and/or reduced afferent input traversing a direct thalamocortical route to M1. These data provide a new avenue of research aimed at identifying therapeutic approaches to alter SAI to improve upper limb function in individuals with SCI. PMID:28123808
Jankowska, E; Riddell, J S
1. Properties of dorsal horn interneurones that process information from group II muscle afferents in the sacral segments of the spinal cord have been investigated in the cat using both intracellular and extracellular recording. 2. The interneurones were excited by group II muscle afferents and cutaneous afferents but not by group I muscle afferents. They were most effectively excited by group II afferents of the posterior biceps, semitendinosus, triceps surae and quadriceps muscle nerves and by cutaneous afferents running in the cutaneous femoris, pudendal and sural nerves. The earliest synaptic actions were evoked monosynaptically and were very tightly locked to the stimuli. 3. EPSPs evoked monosynaptically by group II muscle afferents and cutaneous afferents of the most effective nerves were often cut short by disynaptic IPSPs. As a consequence of this negative feedback the EPSPs gave rise to single or double spike potentials and only a minority of interneurones responded with repetitive discharges. However, the neurones that did respond repetitively did so at a very high frequency of discharges (0.8-1.2 ms intervals between the first 2-3 spikes). 4. Sacral dorsal horn group II interneurones do not appear to act directly upon motoneurones because: (i) these interneurones are located outside the area within which last order interneurones have previously been found and (ii) the latencies of PSPs evoked in motoneurones by stimulation of the posterior biceps and semitendinosus, cutaneous femoris and pudendal nerves (i.e. the main nerves providing input to sacral interneurones) are compatible with a tri- but not with a disynaptic coupling. Spatial facilitation of EPSPs and IPSPs following synchronous stimulation of group II and cutaneous afferents of these nerves shows, however, that sacral interneurones may induce excitation or inhibition of motoneurones via other interneurones. 5. Comparison of the properties of group II interneurones in the sacral segments with
Hermes, Sam M.; Andresen, Michael C.; Aicher, Sue A.
The vagus nerve is dominated by afferent fibers that convey sensory information from the viscera to the brain. Most vagal afferents are unmyelinated, slow-conducting C-fibers, while a smaller portion are myelinated, fast-conducting A-fibers. Vagal afferents terminate in the nucleus tractus solitarius (NTS) in the dorsal brainstem and regulate autonomic and respiratory reflexes, as well as ascending pathways throughout the brain. Vagal afferents form glutamatergic excitatory synapses with postsynaptic NTS neurons that are modulated by a variety of channels. The organization of vagal afferents with regard to fiber type and channels is not well understood. In the present study, we used tract tracing methods to identify distinct populations of vagal afferents to determine if key channels are selectively localized to specific groups of afferent fibers. Vagal afferents were labeled with isolectin B4 (IB4) or cholera toxin B (CTb) to detect unmyelinated and myelinated afferents, respectively. We find that TRPV1 channels are preferentially found in unmyelinated vagal afferents identified with IB4, with almost half of all IB4 fibers showing co-localization with TRPV1. These results agree with prior electrophysiological findings. In contrast, we found that the ATP-sensitive channel P2X3 is found in a subset of both myelinated and unmyelinated vagal afferent fibers. Specifically, 18% of IB4 and 23% of CTb afferents contained P2X3. The majority of CTb-ir vagal afferents contained neither channel. Since neither channel was found in all vagal afferents, there are likely further degrees of heterogeneity in the modulation of vagal afferent sensory input to the NTS beyond fiber type. PMID:26706222
More than 30 years ago, Frank and Fuortes proposed that the synaptic effectiveness of muscle spindle afferents associated with spinal motoneurones could be diminished by the activation of nerves from flexor muscles. Since that time, research has focused on disclosing the mode of operation and the spinal pathways involved in this presynaptic inhibitory control. Initially, it was assumed that the same last-order interneurones mediated presynaptic inhibition of both muscle spindle and tendon organ afferent fibres. More recent evidence indicates that the synaptic effectiveness of these two groups of afferents is controlled by separate sets of GABAergic interneurones synapsing directly with the intraspinal terminals of the afferent fibres. This unique arrangement allows for selective control of the information on muscle length or muscle tension, despite the convergence of muscle spindle and tendon organ afferents on second-order interneurones.
Marqueste, Tanguy; Alliez, Jean-Roch; Alluin, Olivier; Jammes, Yves; Decherchi, Patrick
Numerous studies have been devoted to the regeneration of the motor pathway toward a denervated muscle after nerve injury. However, the regeneration of sensory muscle endings after repair by self-anastomosis are little studied. In previous electrophysiological studies, our laboratory showed that the functional characteristics of tibialis anterior muscle afferents are differentially affected after injury and repair of the peroneal nerve with and without chronic electrostimulation. The present study focuses on the axonal regeneration of mechano- (fibers I and II) and metabosensitive (fibers III and IV) muscle afferents by evaluating the recovery of their response to different test agents after nerve injury and repair by self-anastomosis during 10 wk of treadmill running (LSR). Data were compared with control animals (C), animals with nerve lesion and suture (LS), and animals with lesion, suture, and chronic muscle rehabilitation by electrostimulation (LSE) with a biphasic current modulated in pulse duration and frequency, eliciting a pattern mimicking the activity delivered by the nerve to the muscle. Compared with the C group, results indicated that 1) muscle weight was smaller in LS and LSR groups, 2) the fatigue index was greater in the LS group and smaller in the LSE group, 3) metabosensibility remained altered in the LS and LSE groups, and 4) mechanosensitivity presented a large increase of the activation pattern in the LS and LSE groups. Our data indicated that chronic muscle electrostimulation partially favors the recovery of muscle properties (i.e., muscle weight and twitch response were close to the C group) and that rehabilitation by treadmill running also efficiently induced a better functional muscle afferent recovery (i.e., the discharge pattern was similar to the C group). The effectiveness of the chronic electromyostimulation and the treadmill exercise on afferent recovery is discussed with regard to parameters listed above.
Burke, D; Gandevia, S C; McKeon, B; Skuse, N F
In order to demonstrate interactions between cutaneous and muscle afferent volleys in the ascending somatosensory pathways, different nerves of the lower limb were stimulated together in a conditioning-test paradigm, the changes in the earliest component of the cerebral potential evoked by the test stimulus being taken to indicate such an interaction. It was first confirmed that the cerebral potential evoked by stimulation of the posterior tibial nerve at the ankle is derived from muscle afferents in the mixed nerve and has shorter latencies than the cerebral potential evoked by purely cutaneous volleys in the sural nerve (see Burke et al. 1981). Complete suppression of the cerebral potential evoked by stimulation of muscle or cutaneous afferents was produced by conditioning volleys in a different nerve or in a different fascicle of the same nerve. The major factors determining the degree of suppression were found to be the relative sizes of the conditioning and test volleys and their timing, rather than whether the volleys were of cutaneous or muscular origin. It is concluded that the transmission of cutaneous or muscle afferent volleys to cortex can be profoundly altered in normal subjects by conditioning activity. The possibility that normal background afferent activity can similarly modify afferent transmission has implications for diagnostic studies, particularly when they are performed under non-standard conditions, such as in the operating theatre or intensive care unit. It is also concluded that, although a subject may perceive cutaneous paraesthesiae when the posterior tibial nerve is stimulated at the ankle, there may be no cutaneous component to the evoked cerebral potential.
Iwasaki, Yusaku; Yada, Toshihiko
Some gastrointestinal and pancreatic hormones are potently secreted by meal intake and reduce food intake, therefore these hormones play a role in the meal-evoked satiety peptides. Previous reports have demonstrated that peripheral administration of these gastrointestinal or pancreatic hormones decrease feeding and the anorectic effects are abolished by lesions of vagal afferent nerves using surgical or chemical protocols, indicative of the involvement of the vagal afferents. Vagal afferent nerves link between several peripheral organs and the nucleus tractus solitarius of the brainstem. The present review focuses on cholecystokinin, peptide YY(3-36), pancreatic polypeptide, and nesfatin-1 released from endocrine cells of the gut and pancreas. These hormonal peptides directly act on and increase cytosolic Ca(2+) in vagal afferent nodose ganglion neurons and finally suppress food intake via vagal afferents. Therefore, peripheral terminals of vagal afferents could sense gastrointestinal and pancreatic hormones and regulate food intake. Here, we review how the vagal afferent neurons sense a variety of gastrointestinal and pancreatic hormones and discuss its physiological significance in regulation of feeding.
The synaptic effectiveness of sensory fibers ending in the spinal cord of vertebrates can be centrally controlled by means of specific sets of GABAergic interneurons that make axo-axonic synapses with the terminal arborizations of the afferent fibers. In the steady state, the intracellular concentration of chloride ions in these terminals is higher than that predicted from a passive distribution, because of an active transport mechanism. Following the release of GABA by spinal interneurons and activation of GABA(A) receptors in the afferent terminals, there is an outwardly directed efflux of chloride ions that produces primary afferent depolarization (PAD) and reduces transmitter release (presynaptic inhibition). Studies made by intrafiber recording of PAD, or by measuring changes in the intraspinal threshold of single afferent terminals (which is reduced during PAD), have further indicated that muscle and cutaneous afferents have distinctive, but modifiable PAD patterns in response to segmental and descending stimuli. This has suggested that PAD and presynaptic inhibition in the various types of afferents is mediated by separate sets of last-order GABAergic interneurons. Direct activation, by means of intraspinal microstimulation, of single or small groups of last-order PAD-mediating interneurons shows that the monosynaptic PAD elicited in Ia and Ib afferents can remain confined to some sets of the intraspinal collaterals and not spread to nearby collaterals. The local character of PAD allows cutaneous and descending inputs to selectively inhibit the PAD of segmental and ascending intraspinal collaterals of individual muscle spindle afferents. It thus seems that the intraspinal branches of the sensory fibers are not hard wired routes that diverge excitation to spinal neurons, but are instead dynamic pathways that can be centrally controlled to address information to selected neuronal targets. This feature appears to play an important role in the selection of
Jiménez, I; Rudomin, P; Solodkin, M; Vyklicky, L
In the cat spinal cord, primary afferent depolarization (PAD) of group Ia fibers of extensor muscles is produced by high-frequency stimulation (100 Hz) of group I muscle flexor afferents without significant increases in extracellular potassium. On the other hand, the PAD produced by stimulation of mixed and pure cutaneous nerves correlates well with increases in potassium ions. We conclude that the PAD produced by group I muscle afferents results from the activation of specific pathways making axo-axonic synapses with the Ia fiber terminals. The PAD of Ia fibers resulting from activation of cutaneous nerves involves instead unspecific accumulation of potassium ions.
Lee, M T; O'Donovan, M J
We have examined the organization of muscle afferent projections to motoneurons in the lumbosacral spinal cord of chick embryos between stage 37, when muscle afferents first reach the motor nucleus, and stage 44, which is just before hatching. Connectivity between afferents and motoneurons was assessed by stimulating individual muscle nerves and recording the resulting motoneuron synaptic potentials intracellularly or electrotonically from other muscle nerves. Most of the recordings were made in the presence of DL-2-amino-5-phosphonovaleric acid (APV), picrotoxin, and strychnine to block long-latency excitatory and inhibitory pathways. Activation of muscle afferents evoked slow, positive potentials in muscle nerves but not in cutaneous nerves. These potentials were abolished in 0 mM Ca2+, 2mM Mn2+ solutions, indicating that they were generated by the action of chemical synapses. The muscle nerve recordings revealed a wide-spread pattern of excitatory connections between afferents and motoneurons innervating six different thigh muscles, which were not organized according to synergist-antagonist relationships. This pattern of connectivity was confirmed using intracellular recording from identified motoneurons, which allowed the latency of the responses to be determined. Short-latency potentials in motoneurons were produced by activation of homonymous afferents and the heteronymous afferents innervating the hip flexors sartorius and anterior iliotibialis. Stimulation of anterior iliotibialis afferents also resulted in some short-latency excitatory postsynaptic potentials (EPSPs) in motoneurons innervating the knee extensor femorotibialis, though other connections were of longer latency. Afferents from the adductor, a hip extensor, did not evoke short-latency EPSPs in any of these three types of motoneurons. Short-latency, but not long-latency EPSPs, persisted during repetitive stimulation at 5 Hz, suggesting that they were mediated monosynaptically. Long
Dietz, V; Quintern, J; Berger, W
The cerebral potentials (c.p.) evoked by electrical stimulation of the tibial nerve during stance and in the various phases of gait of normal subjects were compared with the c.p. and leg muscle e.m.g. responses evoked by perturbations of stance and gait. Over the whole step cycle of gait the c.p. evoked by an electrical stimulus were of smaller amplitude (3 microV and 9 microV, respectively) than that seen in the stance condition, and appeared with a longer latency (mean times to first positive peak: 63 and 43 ms, respectively). When the electrical stimulus was applied during stance after ischaemic blockade of group I afferents, the c.p. were similar to those evoked during gait. The c.p. evoked by perturbations were larger in amplitude than those produced by the electrical stimulus, but similar in latencies in both gait and stance (mean 26 microV and 40 microV; 65 ms and 42 ms, respectively) and configurations. The large gastrocnemius e.m.g. responses evoked by the stance and gait perturbations arose with a latency of 65 to 70 ms. Only in the stance condition was a smaller, shorter latency (40 ms) response seen. It is concluded that during gait the signals of group I afferents are blocked at both segmental and supraspinal levels which was tested by tibial nerve stimulation. It is suggested that the e.m.g. responses induced in the leg by gait perturbations are evoked by group II afferents and mediated via a spinal pathway. The c.p. evoked during gait most probably reflect the processing of this group II input by supraspinal motor centres for the coordination of widespread arm and trunk muscle activation, necessary to restablish body equilibrium.
Presentations and publications are: (1) an audiovisual summary web presentation on results from SLM-MIR avian experiments. A color presentation summarizing results from the SLM-MIR and STS-29 avian experiments; (2) color threshold and ratio of S 100B MAP5, NF68/200, GABA and GAD; (3) chicken (Gallus domesticus) inner ear afferents; (4) microgravity in the STS-29 Space Shuttle Discovery affected the vestibular system of chick embryos; (5) expression of S 100B in sensory and secretory cells of the vertebrate inner ear; (6) otoconia biogenesis, phylogeny, composition and functional attributes;(7) the glycan keratin sulfate in inner ear crystals; (8) elliptical-P cells in the avian perilymphatic interface of the tegmentum vasculosum; and (9) LAMP2c and S100B upregulation in brain stem after VIIIth nerve deafferentation.
Carrión, Daniela Calderón; Korkmaz, Yüksel; Cho, Britta; Kopp, Marion; Bloch, Wilhelm; Addicks, Klaus; Niedermeier, Wilhelm
The Merkel cell-neurite complex initiates the perception of touch and mediates Aβ slowly adapting type I responses. Lichen planus is a chronic inflammatory autoimmune disease with T-cell-mediated inflammation, whereas hyperkeratosis is characterized with or without epithelial dysplasia in the oral mucosa. To determine the effects of lichen planus and hyperkeratosis on the Merkel cell-neurite complex, healthy oral mucosal epithelium and lesional oral mucosal epithelium of lichen planus and hyperkeratosis patients were stained by immunohistochemistry (the avidin-biotin-peroxidase complex and double immunofluorescence methods) using pan cytokeratin, cytokeratin 20 (K20, a Merkel cell marker), and neurofilament 200 (NF200, a myelinated Aβ- and Aδ-nerve fibre marker) antibodies. NF200-immunoreactive (ir) nerve fibres in healthy tissues and in the lesional oral mucosa epithelium of lichen planus and hyperkeratosis were counted and statistically analysed. In the healthy oral mucosa, K20-positive Merkel cells with and without close association to the intraepithelial NF200-ir nerve fibres were detected. In the lesional oral mucosa of lichen planus and hyperkeratosis patients, extremely rare NF200-ir nerve fibres were detected only in the lamina propria. Compared with healthy tissues, lichen planus and hyperkeratosis tissues had significantly decreased numbers of NF200-ir nerve fibres in the oral mucosal epithelium. Lichen planus and hyperkeratosis were associated with the absence of Aβ-nerve endings in the oral mucosal epithelium. Thus, we conclude that mechanosensation mediated by the Merkel cell-neurite complex in the oral mucosal epithelium is impaired in lichen planus and hyperkeratosis.
Carrión, Daniela Calderón; Korkmaz, Yüksel; Cho, Britta; Kopp, Marion; Bloch, Wilhelm; Addicks, Klaus; Niedermeier, Wilhelm
The Merkel cell-neurite complex initiates the perception of touch and mediates Aβ slowly adapting type I responses. Lichen planus is a chronic inflammatory autoimmune disease with T-cell-mediated inflammation, whereas hyperkeratosis is characterized with or without epithelial dysplasia in the oral mucosa. To determine the effects of lichen planus and hyperkeratosis on the Merkel cell-neurite complex, healthy oral mucosal epithelium and lesional oral mucosal epithelium of lichen planus and hyperkeratosis patients were stained by immunohistochemistry (the avidin-biotin-peroxidase complex and double immunofluorescence methods) using pan cytokeratin, cytokeratin 20 (K20, a Merkel cell marker), and neurofilament 200 (NF200, a myelinated Aβ- and Aδ-nerve fibre marker) antibodies. NF200-immunoreactive (ir) nerve fibres in healthy tissues and in the lesional oral mucosa epithelium of lichen planus and hyperkeratosis were counted and statistically analysed. In the healthy oral mucosa, K20-positive Merkel cells with and without close association to the intraepithelial NF200-ir nerve fibres were detected. In the lesional oral mucosa of lichen planus and hyperkeratosis patients, extremely rare NF200-ir nerve fibres were detected only in the lamina propria. Compared with healthy tissues, lichen planus and hyperkeratosis tissues had significantly decreased numbers of NF200-ir nerve fibres in the oral mucosal epithelium. Lichen planus and hyperkeratosis were associated with the absence of Aβ-nerve endings in the oral mucosal epithelium. Thus, we conclude that mechanosensation mediated by the Merkel cell-neurite complex in the oral mucosal epithelium is impaired in lichen planus and hyperkeratosis. PMID:27025263
Johansson, R S; Vallbo, A B
1. Psychophysical thresholds were determined at 162 points in the glabrous skin area of the human hand when slowly rising, triangular indentations of controlled amplitudes were delivered with a small probe. The method of constant stimuli was used with either the two alternative forced choice or the yes-no procedure. It was found that the distribution of the psychophysical thresholds varied with the skin region. Thresholds from the volar aspect of the fingers and the peripheral parts of the palm were low and their distribution was unimodal with a median of 11.2 micrometers. In contrast, there was an over-representation of high thresholds when observations from the centre of the palm, the lateral aspects of the fingers and the regions of the creases were pooled, and the distribution was slightly bimodal with a median of 36.0 micrometers. 2. Nerve impulses were recorded from single fibres in the median nerve of human subjects with percutaneously inserted tungsten needle electrodes. The thresholds of 128 mechanosensitive afferent units in the glabrous skin area of the hand were determined when stimuli were delivered to partly the same points as stimulated for the assessment of the psychophysical thresholds. Of the four types of units present in this area the Pacinian corpuscle (PC) and rapidly adapting (RA) units had the lowest thresholds with medians of 9.2 and 13.8 micrometers, followed by the slowly adapting type I and slowly adapting type II units with medians of 56.5 and 33.1 micrometers. There was no indication of a difference between thresholds of units located in different skin areas. 3. In the region of low psychophysical thresholds there was good agreement between the thresholds of the rapidly adapting and Pacinian corpuscle units and the psychophysical thresholds, particularly at the lower ends of the samples. In the skin regions of high thresholds, on the other hand, practically all psychophysical thresholds were higher than the thresholds of the most
Edwards, I J; Lall, V K; Paton, J F; Yanagawa, Y; Szabo, G; Deuchars, S A; Deuchars, J
Sensory information arising from the upper neck is important in the reflex control of posture and eye position. It has also been linked to the autonomic control of the cardiovascular and respiratory systems. Whiplash associated disorders (WAD) and cervical dystonia, which involve disturbance to the neck region, can often present with abnormalities to the oromotor, respiratory and cardiovascular systems. We investigated the potential neural pathways underlying such symptoms. Simulating neck afferent activity by electrical stimulation of the second cervical nerve in a working heart brainstem preparation (WHBP) altered the pattern of central respiratory drive and increased perfusion pressure. Tracing central targets of these sensory afferents revealed projections to the intermedius nucleus of the medulla (InM). These anterogradely labelled afferents co-localised with parvalbumin and vesicular glutamate transporter 1 indicating that they are proprioceptive. Anterograde tracing from the InM identified projections to brain regions involved in respiratory, cardiovascular, postural and oro-facial behaviours--the neighbouring hypoglossal nucleus, facial and motor trigeminal nuclei, parabrachial nuclei, rostral and caudal ventrolateral medulla and nucleus ambiguus. In brain slices, electrical stimulation of afferent fibre tracts lateral to the cuneate nucleus monosynaptically excited InM neurones. Direct stimulation of the InM in the WHBP mimicked the response of second cervical nerve stimulation. These results provide evidence of pathways linking upper cervical sensory afferents with CNS areas involved in autonomic and oromotor control, via the InM. Disruption of these neuronal pathways could, therefore, explain the dysphagic and cardiorespiratory abnormalities which may accompany cervical dystonia and WAD.
Correia-de-Sá, P.; Ribeiro, J. A.
1. The effect of calcitonin gene-related peptide (CGRP) on [3H]-acetylcholine ([3H]-ACh) release from motor nerve endings and its interaction with presynaptic facilitatory A2a-adenosine and nicotinic acetylcholine receptors was studied on rat phrenic nerve-hemidiaphragm preparations loaded with [3H]-choline. 2. CGRP (100-400 nM) increased electrically evoked [3H]-ACh release from phrenic nerve endings in a concentration-dependent manner. 3. The magnitude of CGRP excitation increased with the increase of the stimulation pulse duration from 40 microseconds to 1 ms, keeping the frequency, the amplitude and the train length constants. With 1 ms pulses, the evoked [3H]-ACh release was more intense than with 40 microseconds pulse duration. 4. Both the nicotinic acetylcholine receptor agonist, 1,1-dimethyl-4-phenylpiperazinium, and the A2a adenosine receptor agonist, CGS 21680C, increased evoked [3H]-ACh release, but only CGS 21680C potentiated the facilitatory effect of CGRP. This potentiation was prevented by the A2a adenosine receptor antagonist, PD 115,199. 5. Adenosine deaminase prevented the excitatory effect of CGRP (400 nM) on [3H]-ACh release. This effect was reversed by the non-hydrolysable A2a-adenosine receptor agonist, CGS 21680C. 6. The nicotinic antagonist, tubocurarine, did not significantly change, whereas the A2-adenosine receptor antagonist, PD 115,199, blocked the CGRP facilitation. The A1-adenosine receptor antagonist, 1,3-dipropyl-8-cyclopentylxanthine, potentiated the CGRP excitatory effect. 7. The results suggest that the facilitatory effect of CGRP on evoked [3H]-ACh release from rat phrenic motor nerve endings depends on the presence of endogenous adenosine which tonically activates A2a-adenosine receptors.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8004402
Uchida, Sae; Kagitani, Fusako; Hotta, Harumi
Bleeding or rupture of the ovary often accompanies ovarian cysts and causes severe pain and autonomic responses such as hypotension. It would be expected that ovarian afferents contribute to cardiovascular responses induced by ovarian failure. The present study examined cardiovascular responses to noxious chemical stimulation of the ovary by bradykinin, an algesic substance released by tissue damage, and explored the role of ovarian afferents in the ovarian-cardiovascular responses in anesthetized rats. Non-pregnant adult rats were anesthetized with pentobarbital and artificially ventilated. The carotid artery was cannulated to monitor blood pressure and heart rate. Noxious chemical stimulation was achieved by applying a small piece of cotton soaked with bradykinin to the surface of the ovary for 30s. Application of bradykinin (10(-4) M) to the ovary decreased heart rate and blood pressure. These cardiovascular responses were not significantly influenced by severance of the vagal nerves or the superior ovarian nerve, but were abolished by severance of the ovarian nerve plexus (ONP). Application of bradykinin (10(-4) M) to the ovary evoked afferent activity of the ONP both in vivo and in vitro preparations. These results indicate that the decreases in heart rate and blood pressure following chemical noxious stimulation of the ovary with bradykinin are reflex responses, whose afferent nerve pathway is mainly through afferent fibers in the ONP.
Highstein, Stephen M.; Rabbitt, Richard D.; Holstein, Gay R.; Boyle, Richard D.
The vestibular semicircular canals are internal sensors that signal the magnitude, direction, and temporal properties of angular head motion. Fluid mechanics within the 3-canal labyrinth code the direction of movement and integrate angular acceleration stimuli over time. Directional coding is accomplished by decomposition of complex angular accelerations into 3 biomechanical components—one component exciting each of the 3 ampullary organs and associated afferent nerve bundles separately. For low-frequency angular motion stimuli, fluid displacement within each canal is proportional to angular acceleration. At higher frequencies, above the lower corner frequency, real-time integration is accomplished by viscous forces arising from the movement of fluid within the slender lumen of each canal. This results in angular velocity sensitive fluid displacements. Reflecting this, a subset of afferent fibers indeed report angular acceleration to the brain for low frequencies of head movement and report angular velocity for higher frequencies. However, a substantial number of afferent fibers also report angular acceleration, or a signal between acceleration and velocity, even at frequencies where the endolymph displacement is known to follow angular head velocity. These non-velocity-sensitive afferent signals cannot be attributed to canal biomechanics alone. The responses of non-velocity-sensitive cells include a mathematical differentiation (first-order or fractional) imparted by hair-cell and/or afferent complexes. This mathematical differentiation from velocity to acceleration cannot be attributed to hair cell ionic currents, but occurs as a result of the dynamics of synaptic transmission between hair cells and their primary afferent fibers. The evidence for this conclusion is reviewed below. PMID:15845995
Liu, Zhenyu; Hu, Youtian; Yu, Xiaoyun; Xi, Jiefeng; Fan, Xiaoming; Tse, Chung-Ming; Myers, Allen C; Pasricha, Pankaj J; Li, Xingde; Yu, Shaoyong
Transient receptor potential A1 (TRPA1) is a newly defined cationic ion channel, which selectively expresses in primary sensory afferent nerve, and is essential in mediating inflammatory nociception. Our previous study demonstrated that TRPA1 plays an important role in tissue mast cell activation-induced increase in the excitability of esophageal vagal nodose C fibers. The present study aims to determine whether prolonged antigen exposure in vivo sensitizes TRPA1 in a guinea pig model of eosinophilic esophagitis (EoE). Antigen challenge-induced responses in esophageal mucosa were first assessed by histological stains and Ussing chamber studies. TRPA1 function in vagal sensory neurons was then studied by calcium imaging and by whole cell patch-clamp recordings in 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI)-labeled esophageal vagal nodose and jugular neurons. Extracellular single-unit recordings were performed in vagal nodose and jugular C-fiber neuron subtypes using ex vivo esophageal-vagal preparations with intact nerve endings in the esophagus. Antigen challenge significantly increased infiltrations of eosinophils and mast cells in the esophagus. TRPA1 agonist allyl isothiocyanate (AITC)-induced calcium influx in nodose and jugular neurons was significantly increased, and current densities in esophageal DiI-labeled nodose and jugular neurons were also significantly increased in antigen-challenged animals. Prolonged antigen challenge decreased esophageal epithelial barrier resistance, which allowed intraesophageal-infused AITC-activating nodose and jugular C fibers at their nerve endings. Collectively, these results demonstrated that prolonged antigen challenge sensitized TRPA1 in esophageal sensory neurons and afferent C fibers. This novel finding will help us to better understand the molecular mechanism underlying esophageal sensory and motor dysfunctions in EoE.
Liu, Zhenyu; Hu, Youtian; Yu, Xiaoyun; Xi, Jiefeng; Fan, Xiaoming; Tse, Chung-Ming; Myers, Allen C.; Pasricha, Pankaj J.; Li, Xingde
Transient receptor potential A1 (TRPA1) is a newly defined cationic ion channel, which selectively expresses in primary sensory afferent nerve, and is essential in mediating inflammatory nociception. Our previous study demonstrated that TRPA1 plays an important role in tissue mast cell activation-induced increase in the excitability of esophageal vagal nodose C fibers. The present study aims to determine whether prolonged antigen exposure in vivo sensitizes TRPA1 in a guinea pig model of eosinophilic esophagitis (EoE). Antigen challenge-induced responses in esophageal mucosa were first assessed by histological stains and Ussing chamber studies. TRPA1 function in vagal sensory neurons was then studied by calcium imaging and by whole cell patch-clamp recordings in 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate (DiI)-labeled esophageal vagal nodose and jugular neurons. Extracellular single-unit recordings were performed in vagal nodose and jugular C-fiber neuron subtypes using ex vivo esophageal-vagal preparations with intact nerve endings in the esophagus. Antigen challenge significantly increased infiltrations of eosinophils and mast cells in the esophagus. TRPA1 agonist allyl isothiocyanate (AITC)-induced calcium influx in nodose and jugular neurons was significantly increased, and current densities in esophageal DiI-labeled nodose and jugular neurons were also significantly increased in antigen-challenged animals. Prolonged antigen challenge decreased esophageal epithelial barrier resistance, which allowed intraesophageal-infused AITC-activating nodose and jugular C fibers at their nerve endings. Collectively, these results demonstrated that prolonged antigen challenge sensitized TRPA1 in esophageal sensory neurons and afferent C fibers. This novel finding will help us to better understand the molecular mechanism underlying esophageal sensory and motor dysfunctions in EoE. PMID:25591867
Travo, Cécile; Saleur, Aurélie; Broussy, Audrey; Brugeaud, Aurore; Chabbert, Christian
ABSTRACT Damage to inner ear afferent terminals is believed to result in many auditory and vestibular dysfunctions. The sequence of afferent injuries and repair, as well as their correlation with vertigo symptoms, remains poorly documented. In particular, information on the changes that take place at the primary vestibular endings during the first hours following a selective insult is lacking. In the present study, we combined histological analysis with behavioral assessments of vestibular function in a rat model of unilateral vestibular excitotoxic insult. Excitotoxicity resulted in an immediate but transient alteration of the balance function that was resolved within a week. Concomitantly, vestibular primary afferents underwent a sequence of structural changes followed by spontaneous repair. Within the first two hours after the insult, a first phase of pronounced vestibular dysfunction coincided with extensive swelling of afferent terminals. In the next 24 h, a second phase of significant but incomplete reduction of the vestibular dysfunction was accompanied by a resorption of swollen terminals and fiber retraction. Eventually, within 1 week, a third phase of complete balance restoration occurred. The slow and progressive withdrawal of the balance dysfunction correlated with full reconstitution of nerve terminals. Competitive re-innervation by afferent and efferent terminals that mimicked developmental synaptogenesis resulted in full re-afferentation of the sensory epithelia. By deciphering the sequence of structural alterations that occur in the vestibule during selective excitotoxic impairment, this study offers new understanding of how a vestibular insult develops in the vestibule and how it governs the heterogeneity of vertigo symptoms. PMID:27483344
Carpenter, D. O.; Rudomin, P.
1. The organization of primary afferent depolarization (PAD) produced by excitation of peripheral sensory and motor nerves was studied in the frog cord isolated with hind limb nerves. 2. Dorsal root potentials from sensory fibres (DR-DRPs) were evoked on stimulation of most sensory nerves, but were largest from cutaneous, joint and flexor muscle afferents. With single shock stimulation the largest cutaneous and joint afferent fibres gave DR-DRPs, but potentials from muscle nerves resulted from activation of sensory fibres with thresholds to electrical stimulation higher than 1·2-1·5 times the threshold of the most excitable fibres in the nerve. This suggests that PAD from muscle afferents is probably due to excitation of extrafusal receptors. 3. Dorsal root potentials produced by antidromic activation of motor fibres (VR-DRPs) were larger from extensor muscles and smaller or absent from flexor muscles. The VR-DRPs were produced by activation of the lowest threshold motor fibres. 4. Three types of interactions were found between test and conditioning DRPs from the same or different nerves. With maximal responses occlusion was usually pronounced. At submaximal levels linear summation occurred. Near threshold the conditioning stimulus frequently resulted in a large facilitation of the test DRP. All three types of interactions were found with two DR-DRPs, two VR-DRPs or one DR-DRP and one VR-DRP. 5. The excitability of sensory nerve terminals from most peripheral nerves was increased during the DR-DRP. The magnitude of the excitability increase varied roughly with the magnitude of the DR-DRP evoked by the conditioning stimulus. 6. There was a marked excitability increase of cutaneous and extensor muscle afferent terminals during the VR-DRP. Flexor muscle afferent terminals often showed no excitability changes to ventral root stimulation. In those experiments where afferent terminals from flexor muscles did show an excitability increase, the effects were smaller than
Enríquez, M; Jiménez, I; Rudomin, P
The present investigation documents the patterns of primary afferent depolarization (PAD) of single, functionally identified muscle afferents from the medial gastrocnemius nerve in the intact, anesthetized cat. Classification of the impaled muscle afferents as from muscle spindles or from tendon organs was made according to several criteria, which comprised measurement of conduction velocity and electrical threshold of the peripheral axons, and the maximal frequency followed by the afferent fibers during vibration, as well as the changes in discharge frequency during longitudinal stretch, the projection of the afferent fiber to the motor pool, and, in unparalyzed preparations, the changes in afferent activity during a muscle twitch. In confirmation of a previous study, we found that most muscle spindle afferents (46.1-66.6%, depending on the combination of criteria utilized for receptor classification) had a type A PAD pattern. That is, they were depolarized by stimulation of group I fibers of the posterior biceps and semitendinosus (PBSt) nerve, but not by stimulation of cutaneous nerves (sural and superficial peroneus) or the bulbar reticular formation (RF), which in many cases inhibited the PBSt-induced PAD. In addition, we found a significant fraction of muscle spindle primaries that were depolarized by stimulation of group I PBSt fibers and also by stimulation of the bulbar RF. Stimulation of cutaneous nerves produced PAD in 9.1-31.2% of these fibers (type B PAD pattern) and no PAD in 8.2-15.4% (type C PAD pattern). In contrast to muscle spindle afferents, only the 7.7-15.4% of fibers from tendon organs had a type A PAD pattern, 23-46.1% had a type B and 50-61.5% a type C PAD pattern. These observations suggest that the neuronal circuitry involved in the control of the synaptic effectiveness of muscle spindles and tendon organs is subjected to excitatory as well as to inhibitory influences from cutaneous and reticulospinal fibers. As shown in the accompanying
Macefield, Vaughan G; Norcliffe-Kaufmann, Lucy; Gutiérrez, Joel; Axelrod, Felicia B; Kaufmann, Horacio
The Riley-Day syndrome is the most common of the hereditary sensory and autonomic neuropathies (Type III). Among the well-recognized clinical features are reduced pain and temperature sensation, absent deep tendon reflexes and a progressively ataxic gait. To explain the latter we tested the hypothesis that muscle spindles, or their afferents, are absent in hereditary sensory and autonomic neuropathy III by attempting to record from muscle spindle afferents from a nerve supplying the leg in 10 patients. For comparison we also recorded muscle spindles from 15 healthy subjects and from two patients with hereditary sensory and autonomic neuropathy IV, who have profound sensory disturbances but no ataxia. Tungsten microelectrodes were inserted percutaneously into fascicles of the common peroneal nerve at the fibular head. Intraneural stimulation within muscle fascicles evoked twitches at normal stimulus currents (10-30 µA), and deep pain (which often referred) at high intensities (1 mA). Microneurographic recordings from muscle fascicles revealed a complete absence of spontaneously active muscle spindles in patients with hereditary sensory and autonomic neuropathy III; moreover, responses to passive muscle stretch could not be observed. Conversely, muscle spindles appeared normal in patients with hereditary sensory and autonomic neuropathy IV, with mean firing rates of spontaneously active endings being similar to those recorded from healthy controls. Intraneural stimulation within cutaneous fascicles evoked paraesthesiae in the fascicular innervation territory at normal stimulus intensities, but cutaneous pain was never reported during high-intensity stimulation in any of the patients. Microneurographic recordings from cutaneous fascicles revealed the presence of normal large-diameter cutaneous mechanoreceptors in hereditary sensory and autonomic neuropathy III. Our results suggest that the complete absence of functional muscle spindles in these patients explains
Keen, Erica C.; Hudspeth, A. J.
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
Canning, Brendan J.; Merlo-Pich, Emilio; Woodcock, Ashley A.; Smith, Jaclyn A.
Rationale: Neuroplasticity of bronchopulmonary afferent neurons that respond to mechanical and chemical stimuli may sensitize the cough reflex. Afferent drive in cough is carried by the vagus nerve, and vagal afferent nerve terminals have been well defined in animals. Yet, both unmyelinated C fibers and particularly the morphologically distinct, myelinated, nodose-derived mechanoreceptors described in animals are poorly characterized in humans. To date there are no distinctive molecular markers or detailed morphologies available for human bronchopulmonary afferent nerves. Objectives: Morphologic and neuromolecular characterization of the afferent nerves that are potentially involved in cough in humans. Methods: A whole-mount immunofluorescence approach, rarely used in human lung tissue, was used with antibodies specific to protein gene product 9.5 (PGP9.5) and, for the first time in human lung tissue, 200-kD neurofilament subunit. Measurements and Main Results: We have developed a robust technique to visualize fibers consistent with autonomic and C fibers and pulmonary neuroendocrine cells. A group of morphologically distinct, 200-kD neurofilament-immunopositive myelinated afferent fibers, a subpopulation of which did not express PGP9.5, was also identified. Conclusions: PGP9.5-immunonegative nerves are strikingly similar to myelinated airway afferents, the cough receptor, and smooth muscle–associated airway receptors described in rodents. These have never been described in humans. Full description of human airway nerves is critical to the translation of animal studies to the clinical setting. PMID:25906337
Boyle, Richard; Highstein, Stephen M.; Carey, John P.; Xu, Jinping
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
Lysakowski, Anna; Gaboyard-Niay, Sophie; Calin-Jageman, Irina; Chatlani, Shilpa; Price, Steven D.; Eatock, Ruth Anne
Many primary vestibular afferents form large cup-shaped postsynaptic terminals (calyces) that envelope the basolateral surfaces of type I hair cells. The calyceal terminals both respond to glutamate released from ribbon synapses in the type I cells and initiate spikes that propagate to the afferent’s central terminals in the brainstem. The combination of synaptic and spike initiation functions in these unique sensory endings distinguishes them from the axonal nodes of central neurons and peripheral nerves, such as the sciatic nerve, which have provided most of our information about nodal specializations. We show that rat vestibular calyces express an unusual mix of voltage-gated Na and K channels and scaffolding, cell adhesion, and extracellular matrix proteins, which may hold the ion channels in place. Protein expression patterns form several microdomains within the calyx membrane: a synaptic domain facing the hair cell, the heminode abutting the first myelinated internode, and one or two intermediate domains. Differences in the expression and localization of proteins between afferent types and zones may contribute to known variations in afferent physiology. PMID:21734302
Moddel, G.; Best, B.; Ashby, P.
The differential nerve block produced by ischaemia has been used in an attempt to identify the afferent nerve fibres responsible for vibratory inhibition of the monosynaptic reflex in man. It is concluded that the inhibition arises mainly from receptors in the lower leg and is carried by myelinated afferent fibres larger than A-delta. PMID:599354
Anneken, John H; Angoa-Pérez, Mariana; Kuhn, Donald M
Methylone, 3,4-methylenedioxypyrovalerone (MDPV), and mephedrone are psychoactive ingredients of 'bath salts' and their abuse represents a growing public health care concern. These drugs are cathinone derivatives and are classified chemically as β-ketoamphetamines. Because of their close structural similarity to the amphetamines, methylone, MDPV, and mephedrone share most of their pharmacological, neurochemical, and behavioral properties. One point of divergence in their actions is the ability to cause damage to the CNS. Unlike methamphetamine, the β-ketoamphetamines do not damage dopamine (DA) nerve endings. However, mephedrone has been shown to significantly accentuate methamphetamine neurotoxicity. Bath salt formulations contain numerous different psychoactive ingredients, and individuals who abuse bath salts also coabuse other illicit drugs. Therefore, we have evaluated the effects of methylone, MDPV, mephedrone, and methamphetamine on DA nerve endings. The β-ketoamphetamines alone or in all possible two-drug combinations do not result in damage to DA nerve endings but do cause hyperthermia. MDPV completely protects against the neurotoxic effects of methamphetamine while methylone accentuates it. Neither MDPV nor methylone attenuates the hyperthermic effects of methamphetamine. The potent neuroprotective effects of MDPV extend to amphetamine-, 3,4-methylenedioxymethamphetamine-, and MPTP-induced neurotoxicity. These results indicate that β-ketoamphetamine drugs that are non-substrate blockers of the DA transporter (i.e., MDPV) protect against methamphetamine neurotoxicity, whereas those that are substrates for uptake by the DA transporter and which cause DA release (i.e., methylone, mephedrone) accentuate neurotoxicity. METH (a) enters DA nerve endings via the DAT, causes leakage of DA into the cytoplasm and then into the synapse via DAT-mediated reverse transport. Methylone (METHY) and mephedrone (MEPH; b), like METH, are substrates for the DAT but release
Quevedo, J; Eguibar, J R; Jiménez, I; Schmidt, R F; Rudomin, P
1. In the anesthetized and artificially ventilated cat, stimulation of the posterior articular nerve (PAN) with low strengths (1.2-1.4 x T) produced a small negative response (N1) in the cord dorsum of the lumbosacral spinal cord with a mean onset latency of 5.2 ms. Stronger stimuli (> 1.4 x T) produced two additional components (N2 and N3) with longer latencies (mean latencies 7.5 and 15.7 ms, respectively), usually followed by a slow positivity lasting 100-150 ms. With stimulus strengths above 10 x T there was in some experiments a delayed response (N4; mean latency 32 ms). 2. Activation of posterior knee joint nerve with single pulses and intensities producing N1 responses only, usually produced no dorsal root potentials (DRPs), or these were rather small. Stimulation with strengths producing N2 and N3 responses produced distinct DRPs. Trains of pulses were clearly more effective than single pulses in producing DRPs, even in the low-intensity range. 3. Cooling the thoracic spinal cord to block impulse conduction, increased the DRPs and the N3 responses produced by PAN stimulation without significantly affecting the N2 responses. Reversible spinalization also increased the DRPs produced by stimulation of cutaneous nerves. In contrast, the DRPs produced by stimulation of group I afferents from flexors were reduced. 4. Conditioning electrical stimulation of intermediate and high-threshold myelinated fibers in the PAN depressed the DRPs produced by stimulation of group I muscle and of cutaneous nerves. 5. Analysis of the intraspinal threshold changes of single Ia and Ib fibers has provided evidence that stimulation of intermediate and high threshold myelinated fibers in the posterior knee joint nerve inhibits the primary afferent depolarization (PAD) of Ia fibers, and may either produce PAD or inhibit the PAD in Ib fibers, in the same manner as stimulation of cutaneous nerves. In 7/16 group I fibers the inhibition of the PAD was increased during reversible
Gossard, J P; Bouyer, L; Rossignol, S
This study investigated the effects of antidromically conducted nerve impulses on the transmission of orthodromic volleys in primary afferents of the hindlimb in decerebrated paralyzed cats. Two protocols were used: (A) Single skin and muscle afferents (N=20) isolated from the distal part of cut dorsal rootlets (L7-S1) were recorded while stimulation was applied more caudally. The results showed that during the trains of three to 20 stimuli, the orthodromic firing frequency decreased or ceased, depending on the frequency of stimulation. Remarkably, subsequent to these trains, the occurrence of orthodromic spikes could be delayed for hundreds of ms (15/20 afferents) and sometimes stopped for several seconds (10/20 afferents). Longer stimulation trains, simulating antidromic bursts reported during locomotion, caused a progressive decrease, and a slow recovery of, orthodromic firing frequency (7/20 afferents), indicating a cumulative long-lasting depressing effect from successive bursts. (B) Identified stretch-sensitive muscle afferents were recorded intra-axonally and antidromic spikes were evoked by the injection of square pulses of current through the micropipette. In this case, one to three antidromic spikes were sufficient to delay the occurrence of the next orthodromic spike by more than one control inter-spike interval. If the control inter-spike interval was decreased by stretching the muscle, the delay evoked by antidromic spikes decreased proportionally. Overall, these findings suggest that antidromic activity could alter the mechanisms underlying spike generation in peripheral sensory receptors and modify the orthodromic discharges of afferents during locomotion.
Howland, Robert H
The vagus nerve is a major component of the autonomic nervous system, has an important role in the regulation of metabolic homeostasis, and plays a key role in the neuroendocrine-immune axis to maintain homeostasis through its afferent and efferent pathways. Vagus nerve stimulation (VNS) refers to any technique that stimulates the vagus nerve, including manual or electrical stimulation. Left cervical VNS is an approved therapy for refractory epilepsy and for treatment resistant depression. Right cervical VNS is effective for treating heart failure in preclinical studies and a phase II clinical trial. The effectiveness of various forms of non-invasive transcutaneous VNS for epilepsy, depression, primary headaches, and other conditions has not been investigated beyond small pilot studies. The relationship between depression, inflammation, metabolic syndrome, and heart disease might be mediated by the vagus nerve. VNS deserves further study for its potentially favorable effects on cardiovascular, cerebrovascular, metabolic, and other physiological biomarkers associated with depression morbidity and mortality.
Howland, Robert H.
The vagus nerve is a major component of the autonomic nervous system, has an important role in the regulation of metabolic homeostasis, and plays a key role in the neuroendocrine-immune axis to maintain homeostasis through its afferent and efferent pathways. Vagus nerve stimulation (VNS) refers to any technique that stimulates the vagus nerve, including manual or electrical stimulation. Left cervical VNS is an approved therapy for refractory epilepsy and for treatment resistant depression. Right cervical VNS is effective for treating heart failure in preclinical studies and a phase II clinical trial. The effectiveness of various forms of non-invasive transcutaneous VNS for epilepsy, depression, primary headaches, and other conditions has not been investigated beyond small pilot studies. The relationship between depression, inflammation, metabolic syndrome, and heart disease might be mediated by the vagus nerve. VNS deserves further study for its potentially favorable effects on cardiovascular, cerebrovascular, metabolic, and other physiological biomarkers associated with depression morbidity and mortality. PMID:24834378
Deuis, Jennifer R; Whately, Ella; Brust, Andreas; Inserra, Marco C; Asvadi, Naghmeh H; Lewis, Richard J; Alewood, Paul F; Cabot, Peter J; Vetter, Irina
Selective activation of peripheral κ opioid receptors (KORs) may overcome the dose-limiting adverse effects of conventional opioid analgesics. We recently developed a vicinal disulfide-stabilized class of peptides with subnanomolar potency at the KOR. The aim of this study was to assess the analgesic effects of one of these peptides, named conorphin-1, in comparison with the prototypical KOR-selective small molecule agonist U-50488, in several rodent pain models. Surprisingly, neither conorphin-1 nor U-50488 were analgesic when delivered peripherally by intraplantar injection at local concentrations expected to fully activate the KOR at cutaneous nerve endings. While U-50488 was analgesic when delivered at high local concentrations, this effect could not be reversed by coadministration with the selective KOR antagonist ML190 or the nonselective opioid antagonist naloxone. Instead, U-50488 likely mediated its peripheral analgesic effect through nonselective inhibition of voltage-gated sodium channels, including peripheral sensory neuron isoforms NaV1.8 and NaV1.7. Our study suggests that targeting the KOR in peripheral sensory nerve endings innervating the skin is not an alternative analgesic approach.
Witherspoon, J W; Smirnova, I V; McIff, T E
Consistency in gold chloride staining is essential for anatomical analysis of sensory nerve endings. The gold chloride stain for this purpose has been modified by many investigators, but often yields inconsistent staining, which makes it difficult to differentiate structures and to determine nerve ending distribution in large tissue samples. We introduce additional steps and major changes to the modified Gairns' protocol. We controlled the temperature and mixing rate during tissue staining to achieve consistent staining and complete solution penetration. We subjected samples to sucrose dehydration to improve cutting efficiency. We then exposed samples to a solution containing lemon juice, formic acid and paraformaldehyde to produce optimal tissue transparency with minimal tissue deformity. We extended the time for gold chloride impregnation 1.5 fold. Gold chloride was reduced in the labrum using 25% formic acid in water for 18 h and in the capsule using 25% formic acid in citrate phosphate buffer for 2 h. Citrate binds gold nanoparticles, which minimizes aggregation in the tissue. We stored samples in fresh ultrapure water at 4° C to slow reduction and to maintain color contrast in the tissue. Tissue samples were embedded in Tissue Tek and sectioned at 80 and 100 μm instead of using glycerin and teasing the tissue apart as in Gairns' modified gold chloride method. We attached sections directly to gelatin subbed slides after sectioning with a cryostat. The slides then were processed and coverslipped with Permount. Staining consistency was demonstrated throughout the tissue sections and neural structures were clearly identifiable.
Angoa-Pérez, Mariana; Kane, Michael J; Francescutti, Dina M; Sykes, Katherine E; Shah, Mrudang M; Mohammed, Abiy M; Thomas, David M; Kuhn, Donald M
Mephedrone (4-methylmethcathinone) is a β-ketoamphetamine with close structural analogy to substituted amphetamines and cathinone derivatives. Abuse of mephedrone has increased dramatically in recent years and has become a significant public health problem in the United States and Europe. Unfortunately, very little information is available on the pharmacological and neurochemical actions of mephedrone. In light of the proven abuse potential of mephedrone and considering its similarity to methamphetamine and methcathinone, it is particularly important to know if mephedrone shares with these agents an ability to cause damage to dopamine nerve endings of the striatum. Accordingly, we treated mice with a binge-like regimen of mephedrone (4 × 20 or 40 mg/kg) and examined the striatum for evidence of neurotoxicity 2 or 7 days after treatment. While mephedrone caused hyperthermia and locomotor stimulation, it did not lower striatal levels of dopamine, tyrosine hydroxylase or the dopamine transporter under any of the treatment conditions used presently. Furthermore, mephedrone did not cause microglial activation in striatum nor did it increase glial fibrillary acidic protein levels. Taken together, these surprising results suggest that mephedrone, despite its numerous mechanistic overlaps with methamphetamine and the cathinone derivatives, does not cause neurotoxicity to dopamine nerve endings of the striatum.
Angoa-Pérez, Mariana; Kane, Michael J.; Francescutti, Dina M.; Sykes, Katherine E.; Shah, Mrudang M.; Mohammed, Abiy M.; Thomas, David M.; Kuhn, Donald M.
Mephedrone (4-methylmethcathinone) is a β-ketoamphetamine with close structural analogy to substituted amphetamines and cathinone derivatives. Abuse of mephedrone has increased dramatically in recent years and has become a significant public health problem in the US and Europe. Unfortunately, very little information is available on the pharmacological and neurochemical actions of mephedrone. In light of the proven abuse potential of mephedrone and considering its similarity to methamphetamine and methcathinone, it is particularly important to know if mephedrone shares with these agents an ability to cause damage to dopamine nerve endings of the striatum. Accordingly, we treated mice with a binge-like regimen of mephedrone (4X 20 or 40 mg/kg) and examined the striatum for evidence of neurotoxicity 2 or 7 days after treatment. While mephedrone caused hyperthermia and locomotor stimulation, it did not lower striatal levels of dopamine, tyrosine hydroxylase or the dopamine transporter under any of the treatment conditions used presently. Furthermore, mephedrone did not cause microglial activation in striatum nor did it increase glial fibrillary acidic protein levels. Taken together, these surprising results suggest that mephedrone, despite its numerous mechanistic overlaps with methamphetamine and the cathinone derivatives, does not cause neurotoxicity to dopamine nerve endings of the striatum. PMID:22191803
Jiménez, I; Rudomin, P; Solodkin, M
The relative contribution of specific and unspecific (potassium) components involved in the generation of primary afferent depolarization (PAD) of cutaneous fibres was analyzed in the spinal cord of the anesthetized cat. To this end we examined the correlation between the intraspinal threshold changes of single afferent fibres in the sural nerve produced by segmental and descending inputs and the negative DC potential shifts produced by these same stimuli at the site of excitability testing, the latter taken as indicators of the changes in extracellular concentration of potassium ions. Stimulation of the ipsilateral brain-stem reticular formation and of the contralateral red nucleus with 100-200 Hz trains reduced very effectively the intraspinal threshold of sural nerve fibres ending in the dorsal horn practically without producing any negative DC potential shifts at the site of excitability testing. However, negative DC potential shifts were produced more ventrally, in the intermediate nucleus and/or motor nucleus. Stimulation of the sural and superficial peroneus nerves with pulses at 2 Hz and strengths below 2 xT, also reduced the intraspinal threshold of single SU fibres without producing significant DC potential changes at the site of excitability testing. On the other hand, 100 Hz trains with strengths above 2 xT produced negative DC potential shifts and a proportional reduction of the intraspinal threshold of the SU fibres. The PAD of sural fibres produced by stimulation of rubro-spinal and reticulo-spinal fibres as well as by stimulation of sensory nerves with low frequency trains was unaffected or slightly increased, by i.v. injection of strychnine (0.2 mg/kg), but was readily abolished 5-10 min after the i.v. injection of picrotoxin (2 mg/kg). The results suggest that activation of reticulo-spinal and rubro-spinal fibres, as well as stimulation of cutaneous nerves with low frequencies and low strengths, produce PAD of cutaneous fibres involving activation
Rudomín, P; Jiménez, I; Solodkin, M; Dueñas, S
The present series of investigations was aimed to disclose the possible sites of action of excitatory and inhibitory inputs on tho-interneuron pathway mediating the primary afferent depolarization (PAD) of group I afferents of extensor muscles in the cat spinal cord. To this end we compared the effects produced by stimulation of segmental and descending pathways on the PAD generated either by stimulation of group I fibers of flexor muscles or by intraspinal microstimulation. It was assumed that under the appropriate conditions the PAD produced by intraspinal microstimulation results from the activation of the last-order interneurons in the PAD pathway and may, therefore, allow detection pathway. The PAD of single group I afferent fibers was determined in barbiturate-anesthetized preparations by measuring the test stimulus current required to maintain a constant probability of antidromic firing. This was achieved by means of a feedback system that continuously adjusted the test stimulus current to the required values. The PAD of individual group Ia gastrocnemius soleus (GS) fibers that is produced by activation of the low-threshold afferents of the posterior biceps and semitendinosus nerve was found to be inhibited by conditioning stimulation of the relatively low-threshold cutaneous fibers and also by stimulation of supraspinal structures such as the ipsilateral brain stem reticular formation, the contralateral red nucleus, and the contralateral pyramidal tract. In contrast, the PAD of group Ia fibers produced by microstimulation applied in the intermediate nucleus could be inhibited only by stimulation of the brain stem reticular formation but not by stimulation of the other descending inputs presently tested or by stimulation of cutaneous nerves. PAD of group Ia fibers was produced also by microstimulation applied within the motor nucleus. However, in most fibers the resulting PAD could not be inhibited either by stimulation of the brain stem reticular formation
Correia, M. J.; Perachio, A. A.; Dickman, J. D.; Kozlovskaia, I. B.; Sirota, M. G.; Iakushin, S. B.; Beloozerova, I. N.
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.
Pinkham, Maximilian I; Barrett, Carolyn J
The chemosensitive cardiac vagal and sympathetic afferent reflexes are implicated in driving pathophysiological changes in sympathetic nerve activity (SNA) in cardiovascular disease states. This study investigated the impact of sex and ovarian hormones on the chemosensitive cardiac afferent reflex. Experiments were performed in anaesthetized, sinoaortic baroreceptor denervated male, female and ovariectomized female (OVX) Wistar rats with either intact cardiac innervation or bilateral vagotomy. To investigate the chemosensitive cardiac afferent reflexes renal SNA, heart rate (HR) and arterial pressure (AP) were recorded before and following application of capsaicin onto the epicardial surface of the left ventricle. Compared to males, ovary-intact females displayed similar cardiac afferent reflex mediated changes in renal SNA albeit with a reduced maximum sympathetic reflex driven increase in renal SNA. In females, ovariectomy significantly attenuated the cardiac vagal afferent reflex mediated inhibition of renal SNA (renal SNA decreased 2 ± 17% in OVX versus -50 ± 4% in ovary-intact females, P < 0.05) and augmented cardiac sympathetic afferent reflex mediated sympathoexcitation (renal SNA increased 91 ± 11% in OVX vs 62 ± 9% in ovary-intact females, P < 0.05) so that overall increases in reflex driven sympathoexcitation were significantly enhanced. Chronic estradiol replacement, but not progesterone replacement, begun at time of ovariectomy restored cardiac afferent reflex responses to be similar as ovary-intact females. Vagal denervation eliminated all group differences. The current findings show ovariectomy in female rats, mimicking menopause in women, results in greater chemosensitive cardiac afferent reflex driven sympathoexcitation and does so, at least partly, via the loss of estradiols actions on the cardiac vagal afferent reflex pathway.
Wang, Yutang; Seto, Sai-Wang; Golledge, Jonathan
Sympathetic nerve activity has been reported to be increased in both humans and animals with chronic heart failure. One of the mechanisms believed to be responsible for this phenomenon is increased systemic and cerebral angiotensin II signaling. Plasma angiotensin II is increased in humans and animals with chronic heart failure. The increase in angiotensin II signaling enhances sympathetic nerve activity through actions on both central and peripheral sites during chronic heart failure. Angiotensin II signaling is enhanced in different brain sites such as the paraventricular nucleus, the rostral ventrolateral medulla and the area postrema. Blocking angiotensin II type 1 receptors decreases sympathetic nerve activity and cardiac sympathetic afferent reflex when therapy is administered to the paraventricular nucleus. Injection of an angiotensin receptor blocker into the area postrema activates the sympathoinhibitory baroreflex. In peripheral regions, angiotensin II elevates both norepinephrine release and synthesis and inhibits norepinephrine uptake at nerve endings, which may contribute to the increase in sympathetic nerve activity seen in chronic heart failure. Increased circulating angiotensin II during chronic heart failure may enhance the sympathoexcitatory chemoreflex and inhibit the sympathoinhibitory baroreflex. In addition, increased circulating angiotensin II can directly act on the central nervous system via the subfornical organ and the area postrema to increase sympathetic outflow. Inhibition of angiotensin II formation and its type 1 receptor has been shown to have beneficial effects in chronic heart failure patients.
Bewick, Guy S.; Banks, Robert W.
A novel dissection and recording technique is described for optical monitoring staining and de-staining of lanceolate terminals surrounding hair follicles in the skin of the mouse pinna. The preparation is simple and relatively fast, reliably yielding extensive regions of multiple labeled units of living nerve terminals to study uptake and release of styryl pyridinium dyes extensively used in studies of vesicle recycling. Subdividing the preparations before labeling allows test vs. control comparisons in the same ear from a single individual. Helpful tips are given for improving the quality of the preparation, the labeling and the imaging parameters. This new system is suitable for assaying pharmacologically and mechanically-induced uptake and release of these vital dyes in lanceolate terminals in both wild-type and genetically modified animals. Examples of modulatory influences on labeling intensity are given. PMID:27077818
Bewick, Guy S; Banks, Robert W
A novel dissection and recording technique is described for optical monitoring staining and de-staining of lanceolate terminals surrounding hair follicles in the skin of the mouse pinna. The preparation is simple and relatively fast, reliably yielding extensive regions of multiple labeled units of living nerve terminals to study uptake and release of styryl pyridinium dyes extensively used in studies of vesicle recycling. Subdividing the preparations before labeling allows test vs. control comparisons in the same ear from a single individual. Helpful tips are given for improving the quality of the preparation, the labeling and the imaging parameters. This new system is suitable for assaying pharmacologically and mechanically-induced uptake and release of these vital dyes in lanceolate terminals in both wild-type and genetically modified animals. Examples of modulatory influences on labeling intensity are given.
Cabrera, Jorge Rubén; Viejo-Borbolla, Abel; Martinez-Martín, Nadia; Blanco, Soledad; Wandosell, Francisco; Alcamí, Antonio
Herpes simplex virus type 1 (HSV-1) and HSV-2 are highly prevalent viruses that cause a variety of diseases, from cold sores to encephalitis. Both viruses establish latency in peripheral neurons but the molecular mechanisms facilitating the infection of neurons are not fully understood. Using surface plasmon resonance and crosslinking assays, we show that glycoprotein G (gG) from HSV-2, known to modulate immune mediators (chemokines), also interacts with neurotrophic factors, with high affinity. In our experimental model, HSV-2 secreted gG (SgG2) increases nerve growth factor (NGF)-dependent axonal growth of sympathetic neurons ex vivo, and modifies tropomyosin related kinase (Trk)A-mediated signaling. SgG2 alters TrkA recruitment to lipid rafts and decreases TrkA internalization. We could show, with microfluidic devices, that SgG2 reduced NGF-induced TrkA retrograde transport. In vivo, both HSV-2 infection and SgG2 expression in mouse hindpaw epidermis enhance axonal growth modifying the termination zone of the NGF-dependent peptidergic free nerve endings. This constitutes, to our knowledge, the discovery of the first viral protein that modulates neurotrophins, an activity that may facilitate HSV-2 infection of neurons. This dual function of the chemokine-binding protein SgG2 uncovers a novel strategy developed by HSV-2 to modulate factors from both the immune and nervous systems. PMID:25611061
Andresen, Michael C; Peters, James H
Cranial nerve visceral afferents enter the brain stem to synapse on neurons within the solitary tract nucleus (NTS). The broad heterogeneity of both visceral afferents and NTS neurons makes understanding afferent synaptic transmission particularly challenging. To study a specific subgroup of second-order neurons in medial NTS, we anterogradely labeled arterial baroreceptor afferents of the aortic depressor nerve (ADN) with lipophilic fluorescent tracer (i.e., ADN+) and measured synaptic responses to solitary tract (ST) activation recorded from dye-identified neurons in medial NTS in horizontal brain stem slices. Every ADN+ NTS neuron received constant-latency ST-evoked excitatory postsynaptic currents (EPSCs) (jitter < 192 micros, SD of latency). Stimulus-recruitment profiles showed single thresholds and no suprathreshold recruitment, findings consistent with EPSCs arising from a single, branched afferent axon. Frequency-dependent depression of ADN+ EPSCs averaged approximately 70% for five shocks at 50 Hz, but single-shock failure rates did not exceed 4%. Whether adjacent ADN- or those from unlabeled animals, other second-order NTS neurons (jitters < 200 micros) had ST transmission properties indistinguishable from ADN+. Capsaicin (CAP; 100 nM) blocked ST transmission in some neurons. CAP-sensitive ST-EPSCs were smaller and failed over five times more frequently than CAP-resistant responses, whether ADN+ or from unlabeled animals. Variance-mean analysis of ST-EPSCs suggested uniformly high probabilities for quantal glutamate release across second-order neurons. While amplitude differences may reflect different numbers of contacts, higher frequency-dependent failure rates in CAP-sensitive ST-EPSCs may arise from subtype-specific differences in afferent axon properties. Thus afferent transmission within medial NTS differed by axon class (e.g., CAP sensitive) but was indistinguishable by source of axon (e.g., baroreceptor vs. nonbaroreceptor).
Hu, Zhipeng; Wang, Zhiwei; Wu, Hongbing; Yang, Zhimin; Jiang, Wanli; Li, Luocheng; Hu, Xiaoping
Object To test the hypothesis that angiotensin II (Ang II) could enhance noradrenaline (NA) release from sympathetic nerve endings of the aorta thus contributing to the up-regulation of matrix metalloproteinase 2 (MMP-2) during the formation of aortic dissection (AD). Methods Ang II, NA, MMP-2, MMP-9 of the aorta sample obtained during operation from aortic dissection patients were detected by High Performance Liquid Chromatography and ELISA and compared with controls. Isotope labelling method was used to test the impact of exogenous Ang II and noradrenaline on the NA release and MMP-2, MMP-9 expression on Sprague Dawley (SD) rat aorta rings in vitro. Two kidneys, one clip, models were replicated for further check of that impact in SD rats in vivo. Results The concentration of Ang II, MMP-2, 9 was increased and NA concentration was decreased in aorta samples from AD patients. Exogenous Ang II enhanced while exogenous NA restrained NA release from aortic sympathetic endings. The Ang II stimulated NA release and the following MMP-2 up-regulation could be weakened by Losartan and chemical sympathectomy. Beta blocker did not influence NA release but down-regulated MMP-2. Long term in vivo experiments confirmed that Ang II could enhance NA release and up-regulate MMP-2. Conclusions AD is initiated by MMP-2 overexpression as a result of increased NA release from sympathetic nervous endings in response to Ang II. This indicates an interaction of RAS and SAS during the formation of AD. PMID:24194850
Amirian, E Susan; Goodman, J Clay; New, Pamela; Scheurer, Michael E
Malignant peripheral nerve sheath tumors (MPNSTs) are rare soft tissue sarcomas that arise predominantly from Schwann cells. Despite the fact that MPNSTs have high local recurrence rates and are generally associated with poor prognosis, little is known about prognostic factors or effective clinical management for this tumor type. The purpose of this study was to describe the distributions of patient and tumor characteristics and to identify predictors of cause-specific survival among MPNST cases reported to SEER between 1973 and 2008. Patient and tumor characteristics were compared between pediatric and adult MPNST cases. Cox regression and tree-based survival analysis were used to examine factors associated with MPNST-related mortality separately among adults and children. A total of 1,315 MPNST cases were isolated from the 1973-2008 SEER dataset. Among pediatric cases, sex, race, and radiation therapy predicted MPNST survival, whereas among adults, tumor site, tumor grade, number of primary tumors, and tumor size were significant predictors. As tumor size at diagnosis/resection may be the only somewhat "modifiable" prognostic factor, future studies should aim to identify biological and social attributes associated with tumor size at diagnosis, separately among individuals with and without NF-1, in order to help identify earlier opportunities for clinical intervention.
Phillis, Benjamin D; Martin, Chris M; Kang, Daiwu; Larsson, Håkan; Lindström, Erik A; Martinez, Vicente; Blackshaw, L Ashley
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.
Witherspoon, J W; Smirnova, IV; McIff, TE
Consistency in gold chloride staining is essential for anatomical analysis of sensory nerve endings. The gold chloride stain for this purpose has been modified by many investigators, but often yields inconsistent staining, which makes it difficult to differentiate structures and to determine nerve ending distribution in large tissue samples. We introduce additional steps and major changes to the modified Gairns’ protocol. We controlled the temperature and mixing rate during tissue staining to achieve consistent staining and complete solution penetration. We subjected samples to sucrose dehydration to improve cutting efficiency. We then exposed samples to a solution containing lemon juice, formic acid and paraformaldehyde to produce optimal tissue transparency with minimal tissue deformity. We extended the time for gold chloride impregnation 1.5 fold. Gold chloride was reduced in the labrum using 25% formic acid in water for 18 h and in the capsule using 25% formic acid in citrate phosphate buffer for 2 h. Citrate binds gold nanoparticles, which minimizes aggregation in the tissue. We stored samples in fresh ultrapure water at 4° C to slow reduction and to maintain color contrast in the tissue. Tissue samples were embedded in Tissue Tek and sectioned at 80 and 100 μm instead of using glycerin and teasing the tissue apart as in Gairns’ modified gold chloride method. We attached sections directly to gelatin subbed slides after sectioning with a cryostat. The slides then were processed and coverslipped with Permount. Staining consistency was demonstrated throughout the tissue sections and neural structures were clearly identifiable. PMID:24476562
Rudomin, P; Hernández, E; Lomelí, J
The aim of this study was to examine the functional organization of the spinal neuronal networks activated by myelinated afferent fibers in the posterior articular nerve (PAN) of the anesthetized cat. Particular attention was given to the tonic and phasic GABAa inhibitory modulation of these networks. Changes in the synaptic effectiveness of the joint afferents were inferred from changes in the intraspinal focal potentials produced by electrical stimulation of the PAN. We found that conditioning stimulation of cutaneous nerves (sural, superficial peroneus and saphenous) and of the nucleus raphe magnus often inhibited, in a differential manner, the early and late components of the intraspinal focal potentials produced by stimulation of low and high threshold myelinated PAN afferents, respectively. The degree of the inhibition depended on the strength of both the conditioning and test stimuli and on the segmental level of recording. Conditioning stimulation of group I muscle afferents was less effective, but marked depression of the early and late focal potentials was produced by stimuli exceeding 5 xT. The i.v. injection of 1-2.5 mg/kg of picrotoxin, a GABAa blocker, had relatively minor effects on the early components of the PAN focal potentials, but was able to induce a significant increase of the late components. It also reduced the inhibitory effects of cutaneous and joint nerve conditioning on PAN focal responses. Conditioning autogenetic stimulation with high-frequency trains depressed the PAN focal potentials. The late components of the PAN responses remained depressed several minutes after discontinuing the conditioning train, even after picrotoxin administration. The present observations indicate that the neuronal networks activated by the low threshold PAN afferents show a relatively small post-activation depression and appear to be subjected to a minor tonic inhibitory GABAa control. In contrast, the pathways activated by stimulation of high threshold
Ellaway, P H; Davey, N J; Ferrell, W R; Baxendale, R H
Electrical stimulation of group II joint afferents of the posterior articular nerve (PAN) to the knee evoked short-latency facilitation and/or inhibition of the background discharge of gastrocnemius-soleus (GS) gamma-motoneurones in decerebrated spinal cats. The latencies of these responses were consistent with mediation via segmental oligosynaptic spinal pathways. In addition, a longer-latency facilitation was frequently observed. Mechanical non-noxious stimulation of the skin within the field of innervation of the sural nerve, on the lateral aspect of the heel, suppressed the short-latency facilitation, but not the inhibition or long-latency facilitation. Brief mechanical indentation of the posterior aspect of the knee joint capsule could elicit facilitation or inhibition of gamma-motoneurones. Facilitation, but not inhibition, was blocked by anaesthesia or section of the PAN. Both actions could be suppressed by mechanical stimulation of the heel. We conclude that GS gamma-motoneurones receive both facilitatory and inhibitory segmental inputs from group II articular afferents arising in the knee joint. Cutaneous afferents from the sural field exert a selective inhibitory influence over the facilitation of fusimotor discharge by articular afferents.
Hiebert, G W; Whelan, P J; Prochazka, A; Pearson, K G
1. In this investigation, we tested the hypothesis that muscle spindle afferents signaling the length of hind-leg flexor muscles are involved in terminating extensor activity and initiating flexion during walking. The hip flexor muscle iliopsoas (IP) and the ankle flexors tibialis anterior (TA) and extensor digitorum longus (EDL) were stretched or vibrated at various phases of the step cycle in spontaneously walking decerebrate cats. Changes in electromyogram amplitude, duration, and timing were then examined. The effects of electrically stimulating group I and II afferents in the nerves to TA and EDL also were examined. 2. Stretch of the individual flexor muscles (IP, TA, or EDL) during the stance phase reduced the duration of extensor activity and promoted the onset of flexor burst activity. The contralateral step cycle also was affected by the stretch, the duration of flexor activity being shortened and extensor activity occurring earlier. Therefore, stretch of the flexor muscles during the stance phase reset the locomotor rhythm to flexion ipsilaterally and extension contralaterally. 3. Results of electrically stimulating the afferents from the TA and EDL muscles suggested that different groups of afferents were responsible for the resetting of the step cycle. Stimulation of the TA nerve reset the locomotor step cycle when the stimulus intensity was in the group II range (2-5 xT). By contrast, stimulation of the EDL nerve generated strong resetting of the step cycle in the range of 1.2-1.4 xT, where primarily the group Ia afferents from the muscle spindles would be activated. 4. Vibration of IP or EDL during stance reduced the duration of the extensor activity by similar amounts to that produced by muscle stretch or by electrical stimulation of EDL at group Ia strengths. This suggests that the group Ia afferents from IP and EDL are capable of resetting the locomotor pattern generator. Vibration of TA did not affect the locomotor rhythm. 5. Stretch of IP or
Bangma, G C; ten Donkelaar, H
The origin of cerebellar afferents was studied in various types of reptiles, viz., the turtles Pseudemys scripta elegans and Testudo hermanni, the lizard Varanus exanthematicus, and the snake Python regius, with retrograde tracers (the enzyme horseradish peroxidase and the fluorescent tracer "Fast Blue"). Projections to the cerebellum were demonstrated from the nucleus of the basal optic root, the interstitial nucleus of the fasciculus longitudinalis medialis, the vestibular ganglion, and the vestibular nuclear complex, two somatosensory nuclei, viz., the descending nucleus of the trigeminal nerve and the nucleus of the dorsal funiculus, the nucleus of the solitary tract, the reticular formation, and throughout the spinal cord. A distinct bilateral projection to the cerebellum was found to arise in a nucleus previously called nucleus parvocellularis medialis (Ebbesson, '67). In the present study this cell mass is termed the perihypoglossal nuclear complex, considering its comparable position and fiber connections to the perihypoglossal nuclei in mammals. In all reptilian species studied a contralateral cerebellar projection of a cell mass located in the caudal brainstem adjacent to the nucleus raphes inferior was observed. It seems likely that this cell mass represents the reptilian homologue of the mammalian inferior olive. Most of the spinocerebellar fibers appeared to arise in neurons located in area VII-VIII of the gray matter. In this respect the origin of the spinocerebellar projection in reptiles resembles the origin of the rostral and ventral spinocerebellar tracts in mammals. No indications for the existence of a column of Clarke or a central cervical nucleus in the reptilian spinal cord were obtained. On comparison of the cerebellum afferents in reptiles with the known connections of the cerebellum in amphibians, birds, and mammals, a basic pattern of cerebellar afferent projections appears to exist in these vertebrate classes, including retinal
Dorn, Linda Josephine; Lappat, Annabelle; Neuhuber, Winfried; Scherer, Hans; Olze, Heidi; Hölzl, Matthias
Introduction Interdisciplinary research has contributed greatly to an improved understanding of the vestibular system. To date, however, very little research has focused on the vestibular system's somatosensory afferents. To ensure the diagnostic quality of vestibular somatosensory afferent data, especially the extra cranial afferents, stimulation of the vestibular balance system has to be precluded. Objective Sophisticated movements require intra- and extra cranial vestibular receptors. The study's objective is to evaluate an investigation concept for cervico-vestibular afferents with respect to clinical feasibility. Methods A dedicated chair was constructed, permitting three-dimensional trunk excursions, during which the volunteer's head remains fixed. Whether or not a cervicotonic provocation nystagmus (c-PN) can be induced with static trunk excursion is to be evaluated and if this can be influenced by cervical monophasic transcutaneous electrical nerve stimulation (c-TENS) with a randomized test group. 3D-video-oculography (VOG) was used to record any change in cervico-ocular examination parameters. The occurring nystagmuses were evaluated visually due to the small caliber of nystagmus amplitudes in healthy volunteers. Results The results demonstrate: no influence of placebo-controlled c-TENS on the spontaneous nystagmus; a significant increase of the vertical nystagmus on the 3D-trunk-excursion chair in static trunk flexion with cervical provocation in all young healthy volunteers (n = 49); and a significant difference between vertical and horizontal nystagmuses during static trunk excursion after placebo-controlled c-TENS, except for the horizontal nystagmus during trunk torsion. Conclusion We hope this cervicotonic investigation concept on the 3D trunk-excursion chair will contribute to new diagnostic and therapeutic perspectives on cervical pathologies in vestibular head-to-trunk alignment. PMID:28050208
Prasad, Sashank; Galetta, Steven L
The efficient organization of the human afferent visual system meets enormous computational challenges. Once visual information is received by the eye, the signal is relayed by the retina, optic nerve, chiasm, tracts, lateral geniculate nucleus, and optic radiations to the striate cortex and extrastriate association cortices for final visual processing. At each stage, the functional organization of these circuits is derived from their anatomical and structural relationships. In the retina, photoreceptors convert photons of light to an electrochemical signal that is relayed to retinal ganglion cells. Ganglion cell axons course through the optic nerve, and their partial decussation in the chiasm brings together corresponding inputs from each eye. Some inputs follow pathways to mediate pupil light reflexes and circadian rhythms. However, the majority of inputs arrive at the lateral geniculate nucleus, which relays visual information via second-order neurons that course through the optic radiations to arrive in striate cortex. Feedback mechanisms from higher cortical areas shape the neuronal responses in early visual areas, supporting coherent visual perception. Detailed knowledge of the anatomy of the afferent visual system, in combination with skilled examination, allows precise localization of neuropathological processes and guides effective diagnosis and management of neuro-ophthalmic disorders.
Phillips, Robert J.; Walter, Gary C.; Powley, Terry L.
Recent progress in understanding visceral afferents, some of it reviewed in the present issue, serves to underscore how little is known about the aging of the visceral afferents in the gastrointestinal (GI) tract. In spite of the clinical importance of the issue--with age, GI function often becomes severely compromised--only a few initial observations on age-related structural changes of visceral afferents are available. Primary afferent cell bodies in both the nodose ganglia and dorsal root ganglia lose Nissl material and accumulate lipofucsin, inclusions, aggregates, and tangles. Additionally, in changes that we focus on in the present review, vagal visceral afferent terminals in both the muscle wall and the mucosa of the GI tract exhibit age-related structural changes. In aged animals, both of the vagal terminal types examined, namely intraganglionic laminar endings and villus afferents, exhibit dystrophic or regressive morphological changes. These neuropathies are associated with age-related changes in the structural integrity of the target organs of the affected afferents, suggesting that local changes in trophic environment may give rise to the aging of GI innervation. Given the clinical relevance of GI tract aging, a more complete understanding both of how aging alters the innervation of the gut and of how such changes might be mitigated should be made research priorities. PMID:19665435
Lomelí, J; Quevedo, J; Linares, P; Rudomin, P
In the vertebrate spinal cord, the activation of GABA(gamma-amino-butyric acid)-releasing interneurons that synapse with intraspinal terminals of sensory fibres leading into the central nervous system (afferent fibres) produces primary afferent depolarization and presynaptic inhibition. It is not known to what extent these presynaptic mechanisms allow a selective control of information transmitted through specific sets of intraspinal branches of individual afferents. Here we study the local nature of the presynaptic control by measuring primary afferent depolarization simultaneously in two intraspinal collaterals of the same muscle spindle afferent. One of these collaterals ends at the L6-L7 segmental level in the intermediate nucleus, and the other ascends to segment L3 within Clarke's column, the site of origin of spinocerebellar neurons. Our results indicate that there are central mechanisms that are able to affect independently the synaptic effectiveness of segmental and ascending collaterals of individual muscle spindle afferents. Focal control of presynaptic inhibition thus allows the intraspinal branches of afferent fibres to function as a dynamic assembly that can be fractionated to convey information to selected neuronal targets. This may be a mechanism by which different spinal postsynaptic targets that are coupled by sensory input from a common source could be uncoupled.
Xing, Jihong; Lu, Jian; Li, Jianhua
Autonomic responses to activation of mechanically and metabolically sensitive muscle afferent nerves during static contraction are augmented in rats with femoral artery occlusion. Moreover, metabolically sensitive transient receptor potential cation channel subfamily A, member 1 (TRPA1) has been reported to contribute to sympathetic nerve activity (SNA) and arterial blood pressure (BP) responses evoked by static muscle contraction. Thus, in the present study, we examined the mechanisms by which afferent nerves' TRPA1 plays a role in regulating amplified sympathetic responsiveness due to a restriction of blood flow directed to the hindlimb muscles. Our data show that 24-72 h of femoral artery occlusion (1) upregulates the protein levels of TRPA1 in dorsal root ganglion (DRG) tissues; (2) selectively increases expression of TRPA1 in DRG neurons supplying metabolically sensitive afferent nerves of C-fiber (group IV); and (3) enhances renal SNA and BP responses to AITC (a TRPA1 agonist) injected into the hindlimb muscles. In addition, our data demonstrate that blocking TRPA1 attenuates SNA and BP responses during muscle contraction to a greater degree in ligated rats than those responses in control rats. In contrast, blocking TRPA1 fails to attenuate SNA and BP responses during passive tendon stretch in both groups. Overall, results of this study indicate that alternations in muscle afferent nerves' TRPA1 likely contribute to enhanced sympathetically mediated autonomic responses via the metabolic component of the muscle reflex under circumstances of chronic muscle ischemia.
Xing, Jihong; Lu, Jian; Li, Jianhua
Autonomic responses to activation of mechanically and metabolically sensitive muscle afferent nerves during static contraction are augmented in rats with femoral artery occlusion. Moreover, metabolically sensitive transient receptor potential cation channel subfamily A, member 1 (TRPA1) has been reported to contribute to sympathetic nerve activity (SNA) and arterial blood pressure (BP) responses evoked by static muscle contraction. Thus, in the present study, we examined the mechanisms by which afferent nerves' TRPA1 plays a role in regulating amplified sympathetic responsiveness due to a restriction of blood flow directed to the hindlimb muscles. Our data show that 24–72 h of femoral artery occlusion (1) upregulates the protein levels of TRPA1 in dorsal root ganglion (DRG) tissues; (2) selectively increases expression of TRPA1 in DRG neurons supplying metabolically sensitive afferent nerves of C-fiber (group IV); and (3) enhances renal SNA and BP responses to AITC (a TRPA1 agonist) injected into the hindlimb muscles. In addition, our data demonstrate that blocking TRPA1 attenuates SNA and BP responses during muscle contraction to a greater degree in ligated rats than those responses in control rats. In contrast, blocking TRPA1 fails to attenuate SNA and BP responses during passive tendon stretch in both groups. Overall, results of this study indicate that alternations in muscle afferent nerves' TRPA1 likely contribute to enhanced sympathetically mediated autonomic responses via the metabolic component of the muscle reflex under circumstances of chronic muscle ischemia. PMID:26441669
Stecina, Katinka; Quevedo, Jorge; McCrea, David A
Reflex actions of muscle afferents in hindlimb flexor nerves were examined on ipsilateral motoneurone activity recorded in peripheral nerves during midbrain stimulation-evoked fictive locomotion and during fictive scratch in decerebrate cats. Trains of stimuli (15-30 shocks at 200 Hz) were delivered during the flexion phase at intensities sufficient to activate both group I and II afferents (5 times threshold, T). In many preparations tibialis anterior (TA) nerve stimulation terminated ongoing flexion and reset the locomotor cycle to extension (19/31 experiments) while extensor digitorum longus (EDL) stimulation increased and prolonged the ongoing flexor phase activity (20/33 preparations). The effects of sartorius, iliopsoas and peroneus longus muscle afferent stimulation were qualitatively similar to those of EDL nerve. Resetting to extension was seen only with higher intensity stimulation (5T) while ongoing flexor activity was often enhanced at group I intensity (2T) stimulation. The effects of flexor nerve stimulation were qualitatively similar during fictive scratch. Reflex reversals were consistently observed in some fictive locomotor preparations. In those cases, EDL stimulation produced a resetting to extension and TA stimulation prolonged the ongoing flexion phase. Occasionally reflex reversals occurred spontaneously during only one of several stimulus presentations. The variable and opposite actions of flexor afferents on the locomotor step cycle indicate the existence of parallel spinal reflex pathways. A hypothetical organization of reflex pathways from flexor muscle afferents to the spinal pattern generator networks with competing actions of group I and group II afferents on the flexor and extensor portions of this central circuitry is proposed.
1. Stimulation of different hindlimb nerves in spontaneously walking premammillary cats was used in order to examine the effects of sensory input on the rhythmic motor output. 2. Stimulation of the tibial or sural nerve at low intensities caused the burst of activity in the triceps surae or semimembranosus to be prolonged if stimuli were given during the extension phase. When applied during the flexion phase, the same stimuli shortened the burst of activity in the pretibial flexors and induced an early onset of the extensor activity, except if stimuli were given at the very beginning of the flexion phase, when flexor burst prolongations or rebounds were observed instead. 3. These effects were related to activation of large cutaneous afferents in these nerves since the results could be duplicated by low-intensity stimulation of the tibial nerve at the ankle or by direct stimulation of the pad. 4. In contrast, activation of smaller afferents by high-intensity stimulation resulted prolongations of the flexor burst and/or shortenings of the extensor burst for stimuli applied before or during these bursts, respectively. 5. It was concluded that the large and small cutaneous afferents make, respectively, inhibitory and excitatory connections with the central structure involved in the generation of flexion during walking.
Kumagai, Hiroo; Oshima, Naoki; Matsuura, Tomokazu; Iigaya, Kamon; Imai, Masaki; Onimaru, Hiroshi; Sakata, Katsufumi; Osaka, Motohisa; Onami, Toshiko; Takimoto, Chie; Kamayachi, Tadashi; Itoh, Hiroshi; Saruta, Takao
Accentuated sympathetic nerve activity (SNA) is a risk factor for cardiovascular events. In this review, we investigate our working hypothesis that potentiated activity of neurons in the rostral ventrolateral medulla (RVLM) is the primary cause of experimental and essential hypertension. Over the past decade, we have examined how RVLM neurons regulate peripheral SNA, how the sympathetic and renin-angiotensin systems are correlated and how the sympathetic system can be suppressed to prevent cardiovascular events in patients. Based on results of whole-cell patch-clamp studies, we report that angiotensin II (Ang II) potentiated the activity of RVLM neurons, a sympathetic nervous center, whereas Ang II receptor blocker (ARB) reduced RVLM activities. Our optical imaging demonstrated that a longitudinal rostrocaudal column, including the RVLM and the caudal end of ventrolateral medulla, acts as a sympathetic center. By organizing and analyzing these data, we hope to develop therapies for reducing SNA in our patients. Recently, 2-year depressor effects were obtained by a single procedure of renal nerve ablation in patients with essential hypertension. The ablation injured not only the efferent renal sympathetic nerves but also the afferent renal nerves and led to reduced activities of the hypothalamus, RVLM neurons and efferent systemic sympathetic nerves. These clinical results stress the importance of the RVLM neurons in blood pressure regulation. We expect renal nerve ablation to be an effective treatment for congestive heart failure and chronic kidney disease, such as diabetic nephropathy.
Sensitivities to moderately intense stimuli representing four taste qualities to man were determined for 79 hamster chorda tympani fibers. Some fibers were very sensitive to sucrose, sodium chloride, or hydrochloric acid, but none were very sensitive to quinine. These sensitivities were not randomly distributed among fibers: the sucrose sensitivity was separated from and negatively correlated with the other sensitivities which were associated and positively correlated with each other. Moreover, there were a limited number of sensitivity patterns: (a) fibers responding best to sucrose responded second-best to salt, less to acid, not to quinine; (b) fibers responding best to salt either responded second-best to sucrose and not to acid or quinine; or second-best to acid, less to quinine, and not to sucrose; and (c) fibers responding best to acid responded second-best to salt, more to quinine, and less to sucrose than other fibers. Therefore, if four stimuli of different taste qualities are ordered from acceptable to unacceptable, neural response functions of most hamster chorda tympani taste fibers peak at one point. Sensitivities to nine other moderately intense stimuli which vary in quality to man were also determined for 46–49 of the fibers. Sensitivities to sweet stimuli were always associated with each other and separated from sensitivities to nonsweet stimuli. Sensitivities to nonsweet stimuli were all associated with each other; however, the strongest correlations were between sensitivities to stimuli of like quality, e.g., the three acids or the two sodium salts. PMID:4705639
Bent, Leah R; Lowrey, Catherine R
We have shown for the first time that single cutaneous afferents in the foot dorsum have significant reflex coupling to motoneurons supplying muscles in the upper limb, particularly posterior deltoid and triceps brachii. These observations strengthen what we know from whole nerve stimulation, that skin on the foot and ankle can contribute to the modulation of interlimb muscles in distant innervation territories. The current work provides evidence of the mechanism behind the reflex, where one single skin afferent can evoke a reflex response, rather than a population. Nineteen of forty-one (46%) single cutaneous afferents isolated in the dorsum or plantar surface of the foot elicited a significant modulation of muscle activity in the upper limb. Identification of single afferents in this reflex indicates the strength of the connection and, ultimately, the importance of foot skin in interlimb coordination. The median response magnitude was 2.29% of background EMG, and the size of the evoked response did not significantly differ among the four mechanoreceptor classes (P > 0.1). Interestingly, although the distribution of afferents types did not differ across the foot dorsum, there was a significantly greater coupling response from receptors located on the medial aspect of the foot dorsum (P < 0.01). Furthermore, the most consistent coupling with upper limb muscles was demonstrated by type I afferents (fast and slowly adapting). This work contributes to the current literature on receptor specificity, supporting the view that individual classes of cutaneous afferents may subserve specific roles in kinesthesia, reflexes, and tactile perception.
Raybould, Helen E; Glatzle, Jorg; Robin, Carla; Meyer, James H; Phan, Thomas; Wong, Helen; Sternini, Catia
Intestinal perfusion with carbohydrates inhibits gastric emptying via vagal and spinal capsaicin-sensitive afferent pathways. The aim of the present study was to determine the role of 1) 5-hydroxytryptamine (5-HT)(3) receptors (5-HT(3)R) in mediating glucose-induced inhibition of gastric emptying and 2) 5-HT(3)R expression in vagal and spinal afferents in innervating the duodenum. In awake rats fitted with gastric and duodenal cannulas, perfusion of the duodenum with glucose (50 and 100 mg) inhibited gastric emptying. Intestinal perfusion of mannitol inhibited gastric emptying only at the highest concentration (990 mosm/kgH(2)O). Pretreatment with the 5-HT(3)R antagonist tropisetron abolished both glucose- and mannitol-induced inhibition of gastric emptying. Retrograde labeling of visceral afferents by injection of dextran-conjugated Texas Red into the duodenal wall was used to identify extrinsic primary afferents. Immunoreactivity for 5-HT(3)R, visualized with an antibody directed to the COOH terminus of the rat 5-HT(3)R, was found in >80% of duodenal vagal and spinal afferents. These results show that duodenal extrinsic afferents express 5-HT(3)R and that the receptor mediates specific glucose-induced inhibition of gastric emptying. These findings support the hypothesis that enterochromaffin cells in the intestinal mucosa release 5-HT in response to glucose, which activates 5-HT(3)R on afferent nerve terminals to evoke reflex changes in gastric motility. The primary glucose sensors of the intestine may be mucosal enterochromaffin cells.
Wardman, Daniel L; Gandevia, Simon C; Colebatch, James G
Abstract We compared the brain areas that showed significant flow changes induced by selective stimulation of muscle and cutaneous afferents using fMRI BOLD imaging. Afferents arising from the right hand were studied in eight volunteers with electrical stimulation of the digital nerve of the index finger and over the motor point of the FDI muscle. Both methods evoked areas of significant activation cortically, subcortically, and in the cerebellum. Selective muscle afferent stimulation caused significant activation in motor-related areas. It also caused significantly greater activation within the contralateral precentral gyrus, insula, and within the ipsilateral cerebellum as well as greater areas of reduced blood flow when compared to the cutaneous stimuli. We demonstrated separate precentral and postcentral foci of excitation with muscle afferent stimulation. We conclude, contrary to the findings with evoked potentials, that muscle afferents evoke more widespread cortical, subcortical, and cerebellar activation than do cutaneous afferents. This emphasizes the importance, for studies of movement, of matching the kinematic aspects in order to avoid the results being confounded by alterations in muscle afferent activation. The findings are consistent with clinical observations of the movement consequences of sensory loss and may also be the basis for the contribution of disturbed sensorimotor processing to disorders of movement.
Wardman, Daniel L.; Gandevia, Simon C.; Colebatch, James G.
Abstract We compared the brain areas that showed significant flow changes induced by selective stimulation of muscle and cutaneous afferents using fMRI BOLD imaging. Afferents arising from the right hand were studied in eight volunteers with electrical stimulation of the digital nerve of the index finger and over the motor point of the FDI muscle. Both methods evoked areas of significant activation cortically, subcortically, and in the cerebellum. Selective muscle afferent stimulation caused significant activation in motor‐related areas. It also caused significantly greater activation within the contralateral precentral gyrus, insula, and within the ipsilateral cerebellum as well as greater areas of reduced blood flow when compared to the cutaneous stimuli. We demonstrated separate precentral and postcentral foci of excitation with muscle afferent stimulation. We conclude, contrary to the findings with evoked potentials, that muscle afferents evoke more widespread cortical, subcortical, and cerebellar activation than do cutaneous afferents. This emphasizes the importance, for studies of movement, of matching the kinematic aspects in order to avoid the results being confounded by alterations in muscle afferent activation. The findings are consistent with clinical observations of the movement consequences of sensory loss and may also be the basis for the contribution of disturbed sensorimotor processing to disorders of movement. PMID:24771687
Angel, M J; Guertin, P; Jiménez, T; McCrea, D A
1. Intracellular recording from extensor motoneurones in paralysed decerebrate cats was used to examine the distribution of short-latency non-monosynaptic excitation by group I afferents during fictive locomotion produced by stimulation of the mesencephalic locomotor region (MLR). 2. During the extension but not the flexion phase of fictive locomotion, stimulation of ankle extensor nerves at 1.2-2.0 times threshold evoked excitatory postsynaptic potentials (EPSPs) in motoneurones innervating hip, knee and ankle extensors. Disynaptic EPSPs were also evoked by selective activation of group Ia muscle spindle afferents by muscle stretch. 3. The central latencies of these group I-evoked EPSPs (mean, 1.55 ms) suggest their mediation by a disynaptic pathway with a single interneurone interposed between extensor group I afferents and extensor motoneurones. Disynaptic EPSPs were also evoked during periods of spontaneous locomotion following the cessation of MLR stimulation. 4. Hip extensor motoneurones received disynaptic EPSPs during extension following stimulation of both homonymous and ankle extensor nerves. Stimulation of hip extensor nerves did not evoke disynaptic EPSPs in ankle extensor motoneurones. 5. The appearance of disynaptic EPSPs during extension appears to result from cyclic disinhibition of an unidentified population of excitatory spinal interneurones and not postsynaptic voltage-dependent conductances in motoneurones or phasic presynaptic inhibition of group I afferents during flexion. 6. The reorganization of group I reflexes during fictive locomotion includes the appearance of disynaptic excitation of hip, knee and ankle extensor motoneurones. This excitatory reflex is one of the mechanisms by which group I afferents can enhance extensor activity and increase force production during stance. PMID:8865080
Drinkhill, M J; Moore, J; Hainsworth, R
1. Previous work has shown that increases in aortic root pressure result in reflex vasodilation, and that this response is likely to result mainly from stimulation of receptors in the coronary arteries, although contribution from left ventricular receptors was not excluded. This investigation was undertaken to resolve this question and to determine the afferent nerve fibres likely to be involved in this reflex. 2. In chloralose-anaesthetized dogs a perfusion circuit was used which allowed us to change the pressures in: (a) the aortic root, coronary arteries and the left ventricle; (b) aortic root and coronary arteries at constant ventricular pressure; and (c) the left ventricle with mean (although not pulse) aortic pressure constant. Electrophysiological recordings were made from slips dissected from the vagus nerve which responded with an increase in discharge to either combined increases in the pressures, or to aortic root injections of veratridine. 3. Recordings were made from twenty-one vagal afferents. On the basis of their conduction velocities, eleven were classified as non-myelinated and ten as myelinated. 4. Three non-myelinated afferents responded to veratridine injections only, three to both veratridine and combined aortic root and ventricular pressure changes, and five to pressure changes only. Responses to pressure occurred only when ventricular systolic pressure exceeded 30 kPa. 5. None of the myelinated afferents responded to veratridine. All showed increases in discharge to combined increases in mean aortic root, coronary arterial and left ventricular systolic pressures, which would be graded over a range similar to that which caused reflex changes. All were more sensitive to changes in mean coronary pressure than to changes in ventricular systolic pressure. 6. We conclude that myelinated vagal afferent nerve fibres, which respond predominantly to changes in mean coronary arterial pressure, are likely to be responsible for the vasodilation to the
Effect of Positive End-Expiratory Pressure on the Sonographic Optic Nerve Sheath Diameter as a Surrogate for Intracranial Pressure during Robot-Assisted Laparoscopic Prostatectomy: A Randomized Controlled Trial
Chin, Ji-Hyun; Kim, Wook-Jong; Lee, Joonho; Han, Yun A.; Lim, Jinwook; Hwang, Jai-Hyun; Cho, Seong-Sik
Background Positive end-expiratory pressure (PEEP) can increase intracranial pressure. Pneumoperitoneum and the Trendelenburg position are associated with an increased intracranial pressure. We investigated whether PEEP ventilation could additionally influence the sonographic optic nerve sheath diameter as a surrogate for intracranial pressure during pneumoperitoneum combined with the Trendelenburg position in patients undergoing robot-assisted laparoscopic prostatectomy. Methods After anesthetic induction, 38 patients were randomly allocated to a low tidal volume ventilation (8 ml/kg) without PEEP group (zero end-expiratory pressure [ZEEP] group, n = 19) or low tidal volume ventilation with 8 cmH2O PEEP group (PEEP group, n = 19). The sonographic optic nerve sheath diameter was measured prior to skin incision, 5 min and 30 min after pneumoperitoneum and the Trendelenburg position, and at the end of surgery. The study endpoint was the difference in the sonographic optic nerve sheath diameter 5 min after pneumoperitoneum and the Trendelenburg position between the ZEEP and PEEP groups. Results Optic nerve sheath diameters 5 min after pneumoperitoneum and the Trendelenburg position did not significantly differ between the groups [least square mean (95% confidence interval); 4.8 (4.6–4.9) mm vs 4.8 (4.7–5.0) mm, P = 0.618]. Optic nerve sheath diameters 30 min after pneumoperitoneum and the Trendelenburg position also did not differ between the groups [least square mean (95% confidence interval); 4.5 (4.3–4.6) mm vs 4.5 (4.4–4.6) mm, P = 0.733]. Conclusions An 8 cmH2O PEEP application under low tidal volume ventilation does not induce an increase in the optic nerve sheath diameter during pneumoperitoneum combined with the steep Trendelenburg position, suggesting that there might be no detrimental effects of PEEP on the intracranial pressure during robot-assisted laparoscopic prostatectomy. Trial Registration ClinicalTrial.gov NCT02516566 PMID:28107408
Rybak, Ilya A; Stecina, Katinka; Shevtsova, Natalia A; McCrea, David A
A computational model of the mammalian spinal cord circuitry incorporating a two-level central pattern generator (CPG) with separate half-centre rhythm generator (RG) and pattern formation (PF) networks has been developed from observations obtained during fictive locomotion in decerebrate cats. Sensory afferents have been incorporated in the model to study the effects of afferent stimulation on locomotor phase switching and step cycle period and on the firing patterns of flexor and extensor motoneurones. Here we show that this CPG structure can be integrated with reflex circuits to reproduce the reorganization of group I reflex pathways occurring during locomotion. During the extensor phase of fictive locomotion, activation of extensor muscle group I afferents increases extensor motoneurone activity and prolongs the extensor phase. This extensor phase prolongation may occur with or without a resetting of the locomotor cycle, which (according to the model) depends on the degree to which sensory input affects the RG and PF circuits, respectively. The same stimulation delivered during flexion produces a temporary resetting to extension without changing the timing of following locomotor cycles. The model reproduces this behaviour by suggesting that this sensory input influences the PF network without affecting the RG. The model also suggests that the different effects of flexor muscle nerve afferent stimulation observed experimentally (phase prolongation versus resetting) result from opposing influences of flexor group I and II afferents on the PF and RG circuits controlling the activity of flexor and extensor motoneurones. The results of modelling provide insights into proprioceptive control of locomotion. PMID:17008375
Nishimura, H; Johnson, R D; Munson, J B
1. This study investigates the relation between the peripheral innervation of low-threshold cutaneous afferents and the postsynaptic potentials elicited by electrical stimulation of those afferents. 2. In cats deeply anesthetized with pentobarbital sodium, cord dorsum potentials (CDPs) and postsynaptic potentials (PSPs) in spinal motoneurons were elicited by stimulation of the caudal cutaneous sural nerve (CCS), the lateral cutaneous sural nerve (LCS), and the medial gastrocnemius (MG) muscle nerve. We tested 1) unoperated cats, and cats in which CCS has been 2) chronically axotomized and ligated, 3) cut and self-reunited, 4) cut and cross-united with LCS, or 5) cut and cross-united with the MG. Terminal experiments were performed 3-36 mo after initial surgery. 3. In cats in which the CCS had been self-reunited or cross-united distally with LCS, tactile stimulation of the hairy skin normally innervated by the distal nerve activated afferents in the CCS central to the coaptation, indicating that former CCS afferents had regenerated into native or foreign skin, respectively. 4. In cats in which the CCS had been cross-united distally with the MG, both stretch and contraction of the MG muscle activated the former CCS afferents. 5. In unoperated cats, CDPs elicited by stimulation of CCS and of LCS exhibited a low-threshold N1 wave and a higher-threshold N2 wave. These waves were greatly delayed and appeared to merge after chronic axotomy of CCS. Regeneration of CCS into itself, into LCS, or into MG restored the normal latencies and configurations of these potentials. 6. In unoperated cats, stimulation of CCS, of LCS, and of MG each produced PSPs of characteristic configurations in the various subpopulations of motoneurons of the triceps surae. CDPs and PSPs elicited by the CCS cross-regenerated into LCS or MG were typical of those generated by the normal CCS, i.e., there was no evidence of respecification of central synaptic connections to bring accord between center
Lee, Lu-Yuan; Yu, Jerry
Sensory nerves innervating the lung and airways play an important role in regulating various cardiopulmonary functions and maintaining homeostasis under both healthy and disease conditions. Their activities conducted by both vagal and sympathetic afferents are also responsible for eliciting important defense reflexes that protect the lung and body from potential health-hazardous effects of airborne particulates and chemical irritants. This article reviews the morphology, transduction properties, reflex functions, and respiratory sensations of these receptors, focusing primarily on recent findings derived from using new technologies such as neural immunochemistry, isolated airway-nerve preparation, cultured airway neurons, patch-clamp electrophysiology, transgenic mice, and other cellular and molecular approaches. Studies of the signal transduction of mechanosensitive afferents have revealed a new concept of sensory unit and cellular mechanism of activation, and identified additional types of sensory receptors in the lung. Chemosensitive properties of these lung afferents are further characterized by the expression of specific ligand-gated ion channels on nerve terminals, ganglion origin, and responses to the action of various inflammatory cells, mediators, and cytokines during acute and chronic airway inflammation and injuries. Increasing interest and extensive investigations have been focused on uncovering the mechanisms underlying hypersensitivity of these airway afferents, and their role in the manifestation of various symptoms under pathophysiological conditions. Several important and challenging questions regarding these sensory nerves are discussed. Searching for these answers will be a critical step in developing the translational research and effective treatments of airway diseases.
Studer, U E; Spiegel, T; Casanova, G A; Springer, J; Gerber, E; Ackermann, D K; Gurtner, F; Zingg, E J
contrast medium back to the reservoir. Our results suggest that the combination of an ileal low-pressure reservoir together with an afferent tubular isoperistaltic limb is at least as good as an antireflux nipple valve. Moreover, the use of the afferent ileal limb makes it possible to resect the distal and often diseased ureters together with the paraureteric lymphatics at a safe distance from the bladder tumor. This avoids also distal ischemic ureteric stenosis and makes possible a simple end-to-side ureterointestinal anastomosis with a small complication rate.
Background The afferent projections from the auricular branch of the vagus nerve (ABVN) to the nucleus tractus solitaries (NTS) have been proposed as the anatomical basis for the increased parasympathetic tone seen in auriculo-vagal reflexes. As the afferent center of the vagus nerve, the NTS has been considered to play roles in the anticonvulsant effect of cervical vagus nerve stimulation (VNS). Here we proposed an “auriculo-vagal afferent pathway” (AVAP), by which transcutaneous auricular vagus nerve stimulation (ta-VNS) suppresses pentylenetetrazol (PTZ)-induced epileptic seizures by activating the NTS neurons in rats. Results The afferent projections from the ABVN to the NTS were firstly observed in rats. ta-VNS increased the first grand mal latency of the epileptic seizure and decreased the seizure scores in awake rats. Furthermore, when the firing rates of the NTS neurons decreased, epileptiform activity manifested as electroencephalogram (EEG) synchronization increased with 0.37±0.12 s delay in anaesthetized rats. The change of instantaneous frequency, mean frequency of the NTS neurons was negative correlated with the amplitude of the epileptic activity in EEG traces. ta-VNS significantly suppressed epileptiform activity in EEG traces via increasing the firing rates of the neurons of the NTS. In comparison with tan-VNS, the anticonvulsant durations of VNS and ta-VNS were significantly longer (P<0.01). There was no significant difference between the anticonvulsant durations of VNS and ta-VNS (P>0.05). The anticonvulsant effect of ta-VNS was weakened by reversible cold block of the NTS. Conclusions There existed an anatomical relationship between the ABVN and the NTS, which strongly supports the concept that ta-VNS has the potential for suppressing epileptiform activity via the AVAP in rats. ta-VNS will provide alternative treatments for neurological disorders, which can avoid the disadvantage of VNS. PMID:23927528
Vinay, L; Brocard, F; Fellippa-Marques, S; Clarac, F
Presynaptic inhibition of primary afferents can be evoked from at least three sources in the adult animal: 1) by stimulation of several supraspinal structures; 2) by spinal reflex action from sensory inputs; or 3) by the activity of spinal locomotor networks. The depolarisation in the intraspinal afferent terminals which is due, at least partly, to the activation of GABA(A) receptors may be large enough to reach firing threshold and evoke action potentials that are antidromically conducted into peripheral nerves. Little is known about the development of presynaptic inhibition and its supraspinal control during ontogeny. This article, reviewing recent experiments performed on the in vitro brainstem/spinal cord preparation of the neonatal rat, demonstrates that a similar organisation is present, to some extent, in the new-born rat. A spontaneous activity consisting of antidromic discharges can be recorded from lumbar dorsal roots. The discharges are generated by the underlying afferent terminal depolarizations reaching firing threshold. The number of antidromic action potentials increases significantly in saline solution with chloride concentration reduced to 50% of control. Bath application of the GABA(A) receptor antagonist, bicuculline (5-10 microM) blocks the antidromic discharges almost completely. Dorsal root discharges are therefore triggered by chloride-dependent GABA(A) receptor-mediated mechanisms; 1) activation of descending pathways by stimulation delivered to the ventral funiculus (VF) of the spinal cord at the C1 level; 2) activation of sensory inputs by stimulation of a neighbouring dorsal root; or 3) pharmacological activation of the central pattern generators for locomotion evokes antidromic discharges in dorsal roots. VF stimulation also inhibited the response to dorsal root stimulation. The time course of this inhibition overlapped with that of the dorsal root discharge suggesting that part of the inhibition of the monosynaptic reflex may be
Durbaba, R; Taylor, A; Ellaway, P H; Rawlinson, S
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.
Response properties of periodontal single afferents were investigated in cats with inflammatory irritant-induced pulpitis. A deep dentin cavity was prepared on the right mandibular canine in order to apply an inflammatory agent and small fiber excitant, allyl-isothiocyanate (mustard oil: MO), and single afferents innervating the canine periodontal mechanoreceptor were dissected from the mandibular nerve bundle by examining impulse responses while applying mechanical stimuli to the tip of the crown. Evoked impulses by mechanical stimuli were increased in number for 15 minutes with MO application to the pulp when compared with those with mineral oil. The mechanoreceptive thresholds of single nerve fibers were decreased after the MO application to the pulp when compared with those with mineral oil. These results suggest that the alteration of responses in the periodontal afferent fiber, or the peripheral sensitization, can be produced by MO-induced pulpal inflammation probably due to the axon reflex mechanism in the furcating branches of nerve fibers innervating both the tooth pulp and periodontal ligament.
Schessel, D A; Ginzberg, R; Highstein, S M
Intracellular records with glass microelectrodes filled with horseradish peroxidase (HRP) were taken from primary afferents of the horizontal semicircular canal in the lizard, Calotes versicolor. A coefficient of variation (CV) of the interspike intervals of spontaneous action potentials (APs) was calculated and correlated with the terminal morphologies of afferents within the canal crista. Irregular fibers with CV greater than 0.4 always correlated with a nerve chalice or calyx afferent terminal expansion surrounding one or more type I hair cells; more regular fibers with CV less than 0.4 always correlated with a dimorphic or bouton only terminal expansion of afferents. Afferents with a CV greater than 0.4 demonstrated miniature excitatory postsynaptic potentials (mEPSPs) that summated to initiate APs. APs were blocked by tetrodotoxin and mEPSP frequency was modulated by caloric stimulation. Cobalt application reversibly blocked mEPSPs. Electron microscopic examination of physiologically studied afferents with CV greater than 0.4 revealed synaptic profiles consisting of typical synaptic bodies and synaptic vesicles in the type I hair cell presynaptic to the nerve chalice. Examples of the interspike baseline in regular and irregular afferents suggest differential modes of impulse initiation in these two fiber types.
Chen, Yi; Wang, Yu; Chen, Lu; Sun, Chenyuo; English, Arthur W.; Wolpaw, Jonathan R.; Chen, Xiang Yang
Operant conditioning of the spinal stretch reflex or its electrical analog, the H-reflex, produces spinal cord plasticity and can thereby affect motoneuron responses to primary afferent input. To explore whether this conditioning can affect the functional outcome after peripheral nerve injury, we assessed the effect of up-conditioning soleus (SOL) H-reflex on SOL and tibialis anterior (TA) function after sciatic nerve transection and repair. Sprague-Dawley rats were implanted with EMG electrodes in SOL and TA and stimulating cuffs on the posterior tibial nerve. After control data collection, the sciatic nerve was transected and repaired and the rat was exposed for 120 days to continued control data collection (TC rats) or SOL H-reflex up-conditioning (TU rats). At the end of data collection, motoneurons that had reinnervated SOL and TA were labeled retrogradely. Putative primary afferent terminals (i.e., terminals containing vesicular glutamate transporter-1 (VGLUT1)) on SOL motoneurons were studied immunohistochemically. SOL (and probably TA) background EMG activity recovered faster in TU rats than in TC rats, and the final recovered SOL H-reflex was significantly larger in TU than in TC rats. TU and TC rats had significantly fewer labeled motoneurons and higher proportions of double-labeled motoneurons than untransected rats. VGLUT1 terminals were significantly more numerous on SOL motoneurons of TU than TC rats. Combined with the larger H-reflexes in TU rats, this anatomical finding supports the hypothesis that SOL H-reflex up-conditioning strengthened primary afferent reinnervation of SOL motoneurons. These results suggest that H-reflex up-conditioning may improve functional recovery after nerve injury and repair. PMID:21123559
Chen, Yi; Wang, Yu; Chen, Lu; Sun, Chenyou; English, Arthur W; Wolpaw, Jonathan R; Chen, Xiang Yang
Operant conditioning of the spinal stretch reflex or its electrical analog, the H-reflex, produces spinal cord plasticity and can thereby affect motoneuron responses to primary afferent input. To explore whether this conditioning can affect the functional outcome after peripheral nerve injury, we assessed the effect of up-conditioning soleus (SOL) H-reflex on SOL and tibialis anterior (TA) function after sciatic nerve transection and repair. Sprague Dawley rats were implanted with EMG electrodes in SOL and TA and stimulating cuffs on the posterior tibial nerve. After control data collection, the sciatic nerve was transected and repaired and the rat was exposed for 120 d to continued control data collection (TC rats) or SOL H-reflex up-conditioning (TU rats). At the end of data collection, motoneurons that had reinnervated SOL and TA were labeled retrogradely. Putative primary afferent terminals [i.e., terminals containing vesicular glutamate transporter-1 (VGLUT1)] on SOL motoneurons were studied immunohistochemically. SOL (and probably TA) background EMG activity recovered faster in TU rats than in TC rats, and the final recovered SOL H-reflex was significantly larger in TU than in TC rats. TU and TC rats had significantly fewer labeled motoneurons and higher proportions of double-labeled motoneurons than untransected rats. VGLUT1 terminals were significantly more numerous on SOL motoneurons of TU than TC rats. Combined with the larger H-reflexes in TU rats, this anatomical finding supports the hypothesis that SOL H-reflex up-conditioning strengthened primary afferent reinnervation of SOL motoneurons. These results suggest that H-reflex up-conditioning may improve functional recovery after nerve injury and repair.
Santana-Filho, Valter J; Davis, Greg J; Castania, Jaci A; Ma, Xiuying; Salgado, Helio C; Abboud, Francois M; Fazan, Rubens; Chapleau, Mark W
Activation of the sensory nerve endings of non-myelinated C-fiber afferents evokes release of autocrine/paracrine factors that cause localized vasodilation, neurogenic inflammation, and modulation of sensory nerve activity. The aims of this study were to determine the effect of antidromic electrical stimulation on afferent baroreceptor activity in vivo, and investigate the role of endogenous prostanoids and hydrogen peroxide (H2O2) in mediating changes in nerve activity. Baroreceptor activity was recorded from the left aortic depressor nerve (ADN) in anesthetized rats before and after stimulating the ADN for brief (5–20 s) periods. The rostral end of the ADN was crushed or sectioned beforehand to prevent reflex changes in blood pressure. Antidromic stimulation of ADN using parameters that activate both myelinated A-fibers and non-myelinated C-fibers caused pronounced and long-lasting (> 1 min) inhibition of baroreceptor activity (n = 9, P < 0.05), with the magnitude and duration of inhibition dependent on the duration of the stimulation period (n = 5). Baroreceptor activity was only transiently inhibited after selective stimulation of A-fibers. The inhibition of activity after antidromic stimulation of A and C fibers was prolonged after administration of the cyclooxygenase inhibitor indomethacin (5 mg/kg, IV, n = 7) and abolished after administration of PEG-catalase (104 units/kg, IV, n = 7), an enzyme that catalyzes the decomposition of H2O2 to water and oxygen. The results demonstrate a long-lasting inhibition of baroreceptor activity after antidromic stimulation of ADN and suggest that endogenous prostanoids and H2O2 oppose and mediate the inhibition, respectively. These mechanisms may contribute to rapid baroreceptor resetting during acute hypertension and be engaged during chronic baroreceptor activation therapy in patients with hypertension.
Lee, Bong Hyo; Bae, Jong Han; Kim, Kwang Joong; Steffensen, Scott C.; Leem, Joong Woo; Yang, Chae Ha; Kim, Hee Young
Administration of cocaine increases locomotor activity by enhancing dopamine transmission. To explore the peripheral mechanisms underlying acupuncture treatment for drug addiction, we developed a novel mechanical acupuncture instrument (MAI) for objective mechanical stimulation. The aim of this study was to evaluate whether acupuncture inhibition of cocaine-induced locomotor activity is mediated through specific peripheral nerves, the afferents from superficial or deep tissues, or specific groups of nerve fibers. Mechanical stimulation of acupuncture point HT7 with MAI suppressed cocaine-induced locomotor activity in a stimulus time-dependent manner, which was blocked by severing the ulnar nerve or by local anesthesia. Suppression of cocaine-induced locomotor activity was elicited after HT7 stimulation at frequencies of either 50 (for Meissner corpuscles) or 200 (for Pacinian corpuscles) Hz and was not affected by block of C/Aδ-fibers in the ulnar nerve with resiniferatoxin, nor generated by direct stimulation of C/Aδ-fiber afferents with capsaicin. These findings suggest that HT7 inhibition of cocaine-induced locomotor activity is mediated by A-fiber activation of ulnar nerve that originates in superficial and deep tissue. PMID:24260531
Ueno, Hiroaki; Nakazato, Masamitsu
The hypothalamus is a center of food intake and energy metabolism regulation. Information signals from peripheral organs are mediated through the circulation or the vagal afferent pathway and input into the hypothalamus, where signals are integrated to determine various behaviors, such as eating. Numerous appetite-regulating peptides are expressed in the central nervous system and the peripheral organs, and interact in a complex manner. Of such peptides, gut peptides are known to bind to receptors at the vagal afferent pathway terminal that extend into the mucosal layer of the digestive tract, modulate the electrical activity of the vagus nerve, and subsequently send signals to the solitary nucleus and furthermore to the hypothalamus. All peripheral peptides other than ghrelin suppress appetite, and they synergistically suppress appetite through the vagus nerve. In contrast, the appetite-enhancing peptide, ghrelin, antagonizes the actions of appetite-suppressing peptides through the vagus nerve, and appetite-suppressing peptides have attenuated effects in obesity as a result of inflammation in the vagus nerve. With greater understanding of the mechanism for food intake and energy metabolism regulation, medications that apply the effects of appetite-regulating peptides or implantable devices that electrically stimulate the vagus nerve are being investigated as novel treatments for obesity in basic and clinical studies.
Cox, Jane A; Lamora, Angela; Johnson, Stephen L; Voigt, Mark M
The formation of branchiomeric nerves (cranial nerves V, VII, IX and X) from their sensory, motor and glial components is poorly understood. The current model for cranial nerve formation is based on the Vth nerve, in which sensory afferents are formed first and must enter the hindbrain in order for the motor efferents to exit. Using transgenic zebrafish lines to discriminate between motor neurons, sensory neurons and peripheral glia, we show that this model does not apply to the remaining three branchiomeric nerves. For these nerves, the motor efferents form prior to the sensory afferents, and their pathfinding show no dependence on sensory axons, as ablation of cranial sensory neurons by ngn1 knockdown had no effect. In contrast, the sensory limbs of the IXth and Xth nerves (but not the Vth or VIIth) were misrouted in gli1 mutants, which lack hindbrain bmn, suggesting that the motor efferents are crucial for appropriate sensory axon projection in some branchiomeric nerves. For all four nerves, peripheral glia were the intermediate component added and had a critical role in nerve integrity but not in axon guidance, as foxd3 null mutants lacking peripheral glia exhibited defasciculation of gVII, gIX, and gX axons. The bmn efferents were unaffected in these mutants. These data demonstrate that multiple mechanisms underlie formation of the four branchiomeric nerves. For the Vth, sensory axons initiate nerve formation, for the VIIth the sensory and motor limbs are independent, and for the IXth/Xth the motor axons initiate formation. In all cases the glia are patterned by the initiating set of axons and are needed to maintain axon fasciculation. These results reveal that coordinated interactions between the three neural cell types in branchiomeric nerves differ according to their axial position.
Wild, Vanessa; Messlinger, Karl; Fischer, Michael J M
Endogenous NO and hydrogen sulfide form HNO, which causes CGRP release via TRPA1 channel activation in sensory nerves. In the present study, stimulation of intact trigeminal afferent neuron preparations with NO donors, Na2S or both was analyzed by measuring CGRP release as an index of mass activation. Combined stimulation was able to activate all parts of the trigeminal system and acted synergistic compared to stimulation with both substances alone. To investigate the contribution of both substances, we varied their ratio and tracked intracellular calcium in isolated neurons. Our results demonstrate that hydrogen sulfide is the rate-limiting factor for HNO formation. CGRP has a key role in migraine pathophysiology and HNO formation at all sites of the trigeminal system should be considered for this novel means of activation.
Shin, Hong Kee; Kim, Jin Hyuk
Whole bee venom (WBV)-induced pain model has been reported to be very useful for the study of pain. However, the major constituent responsible for the production of pain by WBV is not apparent. Intraplantar injection of WBV and melittin dramatically reduced mechanical threshold, and increased flinchings and paw thickness. In behavioral experiments, capsaicin pretreatment almost completely prevented WBV- and melittin-induced reduction of mechanical threshold and flinchings. Intraplantar injection of melittin increased discharge rate of dorsal horn neurons only with C fiber input from peripheral receptive field, which was completely blocked by topical application of capsaicin to sciatic nerve. These results suggest that both melittin and WBV induce nociceptive responses by selective activation of capsaicin-sensitive afferent fibers.
Kewin, Kevin; Jordan, Paivi M.; Cameron, Peter; Klapczynski, Marcin; McIntosh, J. Michael; Crooks, Peter A.; Dwoskin, Linda P.; Lysakowski, Anna
Electrical stimulation of vestibular efferent neurons rapidly excites the resting discharge of calyx/dimorphic (CD) afferents. In turtle, this excitation arises when acetylcholine (ACh), released from efferent terminals, directly depolarizes calyceal endings by activating nicotinic ACh receptors (nAChRs). Although molecular biological data from the peripheral vestibular system implicate most of the known nAChR subunits, specific information about those contributing to efferent-mediated excitation of CD afferents is lacking. We sought to identify the nAChR subunits that underlie the rapid excitation of CD afferents and whether they differ from α9α10 nAChRs on type II hair cells that drive efferent-mediated inhibition in adjacent bouton afferents. We recorded from CD and bouton afferents innervating the turtle posterior crista during electrical stimulation of vestibular efferents while applying several subtype-selective nAChR agonists and antagonists. The α9α10 nAChR antagonists, α-bungarotoxin and α-conotoxin RgIA, blocked efferent-mediated inhibition in bouton afferents while leaving efferent-mediated excitation in CD units largely intact. Conversely, 5-iodo-A-85380, sazetidine-A, varenicline, α-conotoxin MII, and bPiDDB (N,N-dodecane-1,12-diyl-bis-3-picolinium dibromide) blocked efferent-mediated excitation in CD afferents without affecting efferent-mediated inhibition in bouton afferents. This pharmacological profile suggested that calyceal nAChRs contain α6 and β2, but not α9, nAChR subunits. Selective blockade of efferent-mediated excitation in CD afferents distinguished dimorphic from calyx afferents by revealing type II hair cell input. Dimorphic afferents differed in having higher mean discharge rates and a mean efferent-mediated excitation that was smaller in amplitude yet longer in duration. Molecular biological data demonstrated the expression of α9 in turtle hair cells and α4 and β2 in associated vestibular ganglia. PMID:25716861
Herrera-Mundo, Nieves; Sitges, María
Vinpocetine is a neuroprotective drug that exerts beneficial effects on neurological symptoms and cerebrovascular disease. 3-nitropropionic acid (3-NPA) is a toxin that irreversibly inhibits succinate dehydrogenase, the mitochondrial enzyme that acts in the electron transport chain at complex II. In previous studies in striatum-isolated nerve endings (synaptosomes), we found that vinpocetine decreased dopamine (DA) at expense of its main metabolite 3,4-dihydroxyphenylacetic acid (DOPAC), and that 3-NPA increased DA, reactive oxygen species (ROS), DA-quinone products formation, and decreased DOPAC. Therefore, in this study, the possible effect of vinpocetine on 3-NPA-induced increase in DA, ROS, lipid peroxidation, and DA-quinone products formation in striatum synaptosomes were investigated, and compared with the effects of the antioxidant α-tocopherol. Results show that the increase in DA induced by 3-NPA was inhibited by both 25 μM vinpocetine and 50 μM α-tocopherol. Vinpocetine, as α-tocopherol, also inhibited 3-NPA-induced increase in ROS (as judged by DCF fluorescence), lipid peroxidation (as judged by TBA-RS formation), and DA-quinone products formation (as judged by the nitroblue tetrazolium reduction method). As in addition to the inhibition of complex II exerted by 3-NPA, 3-NPA increases DA-oxidation products that in turn can inhibit other sites of the respiratory chain, the drop in DA produced by vinpocetine and α-tocopherol may importantly contribute to their protective action from oxidative damage, particularly in DA-rich structures.
Pittaluga, A; Raiteri, M
Exposure of rat or human neocortical or hippocampal tissue to glutamate receptor agonists elicits as Ca(2+)-dependent, exocytotic-like release of previously accumulated [3H]noradrenaline through activation of both N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors colocalized on the noradrenergic axon terminals. Here we show that the NMDA (100 microM)-evoked release of [3H]noradrenaline from superfused thin layers of isolated rat hippocampal or cortical nerve endings was potentiated when the human immunodeficiency virus type 1 coat protein gp120 was added to the superfusion medium concomitantly with NMDA. The effect of gp120 (10 pM to 3 nM) on the 100 microM NMDA-evoked release of [3H]noradrenaline was concentration-dependent; the maximal effect (approximately 140% potentiation) was reached at 100 pM of gp120. The protein was inactive on its own. The [3H]noradrenaline release evoked by NMDA (100 microM)+gp120 (100 pM) was prevented by classical NMDA receptor antagonists, as well as by 10 microM memantine. Neither the release evoked by NMDA nor that elicited by NMDA+gp120 was sensitive to the nitric oxide synthase inhibitor NG-nitro-L-arginine, suggesting no involvement of nitric oxide. The [3H]noradrenaline release elicited by 100 microM AMPA was unaffected by gp120. The protein potentiated the release evoked by 100 microM glutamate; the effect of 100 pM gp120 was quantitatively identical to that of 1 microM glycine, with no apparent additivity between gp120 and glycine. The antagonism by 1 microM 7-chloro-kynurenic acid of the NMDA-induced [3H]noradrenaline release was reversed by glycine or gp120.(ABSTRACT TRUNCATED AT 250 WORDS)
Sitges, María; Chiu, Luz María; Nekrassov, Vladimir
The single and combined effects of carbamazepine and vinpocetine on the release of the excitatory amino acid neurotransmitter glutamate, on the rise in internal Na+ (Na(i), as determined with SBFI), and on the rise in internal Ca2+ (Ca(i), as determined with fura-2) induced by an increased permeability of presynaptic Na+ channels, with veratridine, or by an increased permeability of presynaptic Ca2+ channels with high K+, were investigated in isolated hippocampal nerve endings. The present study shows that carbamazepine and vinpocetine, both inhibit dose dependently the release of preloaded [3H]Glu induced by veratridine. However, carbamazepine is two orders of magnitude less potent than vinpocetine. The calculated IC(50)'s for carbamazepine and vinpocetine to inhibit veratridine-induced [3H]Glu release are 200 and 2 microM, respectively. Consistently 150 microM carbamazepine and 1.5 microM vinpocetine reduce the veratridine-induced rise in Na(i) in a similar extent. The single effects of carbamazepine and of vinpocetine on the presynaptic Na+ channel mediated responses, namely the rise in Na(i) and the release of Glu induced by veratridine, are additive. Responses that depend on the entrance of external Ca2+ via presynaptic Ca2+ channels, such as the release of [3H]Glu and the rise in Ca(i) induced by high K+, are insensitive to 300 microM carbamazepine and slightly reduced by 5 microM vinpocetine. It is concluded that the additive effects of carbamazepine, which is one of the most common antiepileptic drugs, and vinpocetine that besides its known neuroprotective action and antiepileptic potential is a memory enhancer, may perhaps be advantageous in the treatment of epileptic patients.
Riddell, J S; Hadian, M
The actions of group II muscle afferents projecting to the lower-lumbar (L6 and L7) segments of the cat spinal cord were investigated by recording the cord dorsum and focal synaptic field potentials evoked by electrical stimulation of hindlimb muscle nerves. Cord dorsum potentials recorded over the lower-lumbar segments were generally much smaller than those produced by group II afferents terminating within the midlumbar and sacral segments. Only group II afferents of tibialis posterior produced potentials with an amplitude (mean maximal amplitude 39 μV, n = 7) approaching that of potentials over other segments. Focal synaptic potentials (mean maximal amplitudes 135–200 μV) were evoked by group II afferents of the following muscle nerves, listed in order of effectiveness: quadriceps, tibialis posterior (throughout L6 and L7), gastrocnemius soleus, flexor digitorum longus, posterior biceps-semitendinosus and popliteus (mainly within L7). Field potentials were recorded in the dorsal horn (laminae IV–V) and also more ventrally in a region which included the lateral part of the intermediate zone (lateral to the large group I intermediate field potentials) and often extended into the ventral horn (laminae V–VII). The latencies of the group II potentials are considered compatible with the monosynaptic actions of the fastest conducting group II muscle afferents. The results are compared with morphological evidence on the pattern of termination of group II muscle afferents in the lower-lumbar segments and with previous descriptions of the actions of group II muscle afferents in midlumbar and sacral segments. PMID:10618155
González, H; Jiménez, I; Rudomin, P
1. In the isolated spinal cord and brainstem of the frog, stimulation of the brainstem (BS) with trains of 3-4 pulses at 60-400 Hz produced dorsal root potentials (DRPs). The lowest threshold sites eliciting DRPs were located at the level of the obex up to about 2.5 mm rostrally, 0.5-1.2 mm laterally, between 0.5 and 1.6 mm depth. This region corresponds to the bulbar reticular formation (RF). 2. Stimulation of the RF with strengths below those required to produce DRPs, very effectively inhibited the DRPs produced by stimulation of a neighboring dorsal root (DR-DRPs) as well as the DRPs produced by antidromic stimulation of the central end of motor nerves (VR-DRPs). The inhibition was detectable 20 ms after the first pulse of the conditioning train, attained maximal values between 50 and 100 ms and lasted more than 250 ms. 3. Stimulation of the bulbar RF increased the negative response (N1 response) produced in the motor pool by antidromic activation of motoneurons. The time course of the facilitation of the N1 response resembled that of the reticularly-induced inhibition of the VR-DRPs and DR-DRPs. 4. The present series of observations supports the existence of reticulo-spinal pathways that are able to inhibit the depolarization elicited in afferent fibers by stimulation of other afferent fibers or by antidromic activation of motor axons. This inhibition appears to be exerted on the PAD mediating interneurons and is envisaged as playing an important role in motor control.
Bruce, L. L.
Gravity is a critical factor in the normal development of the vestibular system, as prolonged prenatal exposures to either micro- or hypergravity will alter the pattern of projections from specific vestibular organs to specific targets in the vestibular nuclei. This study addresses the effect of gravity on the development of vestibulocerebellar projections. In adult rats the semicircular canal afferents project mainly to the cerebellar nodulus whereas the otolith maculae project mainly to the ventral uvula of the cerebellum. To determine if the distribution pattern of these afferents is altered by exposures to altered gravity, 10 pregnant rats were exposed to hypergravity (1.5g) from embryonic day 12 (before vestibular ganglion neurons contact vestibular nuclei) to embryonic day 21 (near the time when the vestibular system becomes functional). Controls were exposed to Earth's gravity but otherwise received the same treatment. At the end of the exposure the embryos were deeply anesthetized and fixed by transcardiac perfusion with 4% paraformaldehyde in 0.1 M phosphate buffer (pH7.4). Filter strips coated with DiI and PTIR were implanted into the saccule (gravistatic vestibular receptor) or into the posterior vertical canal (angular acceleration receptor), and allowed to diffuse for 2 weeks at 37°C. Then the brains were dissected and sectioned for fluorescent confocal imaging. Examination of the control cerebella revealed that the canal and otolith afferents have reached the nodulus and uvula, and axons extend into the internal granular, Purkinje, and molecular layers. Projections from the saccule and posterior vertical canal were partially segregated into their respective domains, the uvula and nodulus. In contrast, in hypergravity-exposed rat fetuses the saccule and posterior vertical canal projections were poorly segregated, and both organs contributed labeled fibers to all layers of the nodulus and uvula. This contrasts with the increased afferent segregation
Johansson, H; Sjölander, P; Sojka, P; Wadell, I
The aim of the present study was to investigate the extent to which skin receptors might influence the responses of primary muscle spindle afferents via reflex actions on the fusimotor system. The experiments were performed on 43 cats anaesthetized with alpha-chloralose. The alterations in fusimotor activity were assessed from changes in the responses of the muscle spindle afferents to sinusoidal stretching of their parent muscles (triceps surae and plantaris). The mean rate of firing and the modulation of the afferent response were determined. Control measurements were made in absence of any cutaneous stimulation. Tests were made (a) during physiological stimulation of skin afferents of the ipsilateral pad or of the contralateral hindlimb, or (b) during repetitive electrical stimulation of the sural nerve in the ipsilateral hindlimb, or of sural or superficial peroneal nerve in the contralateral hindlimb. Of the total number of 113 units tested with repetitive electrical stimulation of the ipsilateral sural nerve (at 20 Hz), 24.8% exhibited predominantly dynamic fusimotor reflexes, 5.3% mixed or predominantly static fusimotor reflexes. One unit studied in a preparation with intact spinal cord exhibited static reflexes at low stimulation intensities and dynamic ones at higher stimulation strengths. The remaining units (69%) were uninfluenced. When the receptor-bearing muscle was held at constant length and a train of stimuli (at 20 Hz) was applied to the ipsilateral sural nerve, the action potentials in the primary muscle spindle afferent could be stimulus-locked to the 3rd or 4th pulse in the train (and to the pulses following thereafter), with a latency of about 24 ms from the effective pulse. This 1:1 pattern of driving seemed to be mediated via static and/or dynamic fusimotor neurons. Natural stimulation influenced comparatively few units (3 of 65 units tested from the ipsilateral pad and 10 of 98 tested from the contralateral hindlimb), but when the effects
Tiwari, Ekta; Lemay, Michel A.; Braverman, Alan S.; Obeid, Iyad; Barbe, Mary F.; Ruggieri, Michael R.
Objective Surgical rerouting of neuronal pathways may allow functional reinnervation of the bladder. We aim to develop techniques to monitor afferent (sensory) nerve activity during bladder filling in normal intact bladders for eventual application to monitoring sensory reinnervation of the bladder following nerve transfer. Methods Electroneurogram recordings were performed in anesthetized rats under isoflurane (1–2% induction dose, inhalation) of: (I) sciatic nerves during stimulation of the hindpaw with Semmes-Weinstein monofilaments of varying forces (10–300 g); and (II) bladder nerves during bladder filling with infusion rate of 0.5 mL/min, in acute experiments. Bipolar cuff electrodes were wrapped around the sciatic nerve (n=7) and ureter (and associated bladder nerves) proximal to the bladder wall (n=7), to record sciatic and bladder nerve discharges, respectively. The sciatic nerve was transected between the spinal cord and the electrode, to eliminate efferent nerve signals and record afferent fibers discharge only with hindpaw stimulation. Whereas, recordings were made of the discharges of both afferent and efferent fibers from bladder nerves during bladder filling. All recordings were performed using a low noise amplifier (SR560, filtered 300 Hz–10 kHz, gain ×10k), sampled at 20 kHz using PowerLab software (AD Instruments) and displayed using LabChart software. Bladder pressure was also recorded during filling. Results Sciatic nerve recordings consistently showed increased afferent fibers discharge with increased size of monofilament used to stimulate the hindpaw, with the highest discharge observed with the 300 g monofilament and lowest with 10 g. In contrast, recording from bladder nerves showed that combined afferent and efferent discharges increased substantially in response to bladder filling in 2 of 7 rats, and increased moderately in 2 other rats. However, there was no response in the remaining rats, perhaps due to nerve damage during cuff
Meredith, Frances L.; Kirk, Matthew E.; Rennie, Katherine J.
Potassium-selective ion channels are important for accurate transmission of signals from auditory and vestibular sensory end organs to their targets in the central nervous system. During different gravity conditions, astronauts experience altered input signals from the peripheral vestibular system resulting in sensorimotor dysfunction. Adaptation to altered sensory input occurs, but it is not explicitly known whether this involves synaptic modifications within the vestibular epithelia. Future investigations of such potential plasticity require a better understanding of the electrophysiological mechanisms underlying the known heterogeneity of afferent discharge under normal conditions. This study advances this understanding by examining the role of the Kv1 potassium channel family in mediating action potentials in specialized vestibular afferent calyx endings in the gerbil crista and utricle. Pharmacological agents selective for different sub-types of Kv1 channels were tested on membrane responses in whole cell recordings in the crista. Kv1 channels sensitive to α-dendrotoxin and dendrotoxin-K were found to prevail in the central regions, whereas K+ channels sensitive to margatoxin, which blocks Kv1.3 and 1.6 channels, were more prominent in peripheral regions. Margatoxin-sensitive currents showed voltage-dependent inactivation. Dendrotoxin-sensitive currents showed no inactivation and dampened excitability in calyces in central neuroepithelial regions. The differential distribution of Kv1 potassium channels in vestibular afferents supports their importance in accurately relaying gravitational and head movement signals through specialized lines to the central nervous system. Pharmacological modulation of specific groups of K+ channels could help alleviate vestibular dysfunction on earth and in space. PMID:26082693
Fermin, C. D.; Martin, D. S.; Hara, H.
Afferents of chick embryos (Gallus domesticus) VIIIth nerve were examined at E3, E6, E9, E13, El7, and hatching (NH) for anti-S100 beta, anti-MAP5, anti-GABA, anti-GAD and anti-NF68/200 stain. Different ages were processed together to determine if the distribution of these antibodies changed during synaptogenesis and myelination. Color thresholding showed that saturation of pixels changed for S100 beta only 5%, for NF68/200 10%, and for MAP5, 10%, between E9-NH. Color ratio of NF68/200 over MAP5 was 1.00 at E13 and 0.25 at E16 and NH. S100 beta, GABA and GAD were co-expressed on nerve endings at the edge of the maculae and center of the cristae, whereas hair cells in the center of the maculae expressed either S100 beta or GABA, but not both. S100 beta/NF68/200 shared antigenic sites on the chalices, but NF68/200 expression was higher than S100 beta in the chalices at hatching. MAP5 was expressed in more neurons than NF68/200 at E11, whereas NF68/200 was more abundant than MAP5 at hatching. The results suggest that: 1) the immunoexpression of these neuronal proteins is modulated concomitantly with the establishment of afferent synapses and myelination; 2) S100 beta may serve a neurotrophic function in the chalices where it is co-expressed with the neurotransmitter GABA and its synthesizing enzyme GAD.
Roatta, S; Windhorst, U; Ljubisavljevic, M; Johansson, H; Passatore, M
Previous reports showed that sympathetic stimulation affects the activity of muscle spindle afferents (MSAs). The aim of the present work is to study the characteristics of sympathetic modulation of MSA response to stretch: (i) on the dynamic and static components of the stretch response, and (ii) on group Ia and II MSAs to evaluate potentially different effects. In anaesthetised rabbits, the peripheral stump of the cervical sympathetic nerve (CSN) was stimulated at 10 impulses s−1 for 45–90 s. The responses of single MSAs to trapezoidal displacement of the mandible were recorded from the mesencephalic trigeminal nucleus. The following characteristic parameters were determined from averaged trapezoidal responses: initial frequency (IF), peak frequency at the end of the ramp (PF), and static index (SI). From these, other parameters were derived: dynamic index (DI = PF - SI), dynamic difference (DD = PF - IF) and static difference (SD = SI - IF). The effects of CSN stimulation were also evaluated during changes in the state of intrafusal muscle fibre contraction induced by succinylcholine and curare. In a population of 124 MSAs, 106 units (85.4 %) were affected by sympathetic stimulation. In general, while changes in resting discharge varied among different units (Ia vs. II) and experimental conditions (curarised vs. non-curarised), ranging from enhancement to strong depression of firing, the amplitude of the response to muscle stretches consistently decreased. This was confirmed and detailed in a quantitative analysis performed on 49 muscle spindle afferents. In both the non-curarised (23 units) and curarised (26 units) condition, stimulation of the CSN reduced the response amplitude in terms of DD and SD, but hardly affected DI. The effects were equally present in both Ia and II units; they were shown to be independent from gamma drive and intrafusal muscle tone and not secondary to muscle hypoxia. Sympathetic action on the resting discharge (IF) was less
Roatta, S; Windhorst, U; Ljubisavljevic, M; Johansson, H; Passatore, M
Previous reports showed that sympathetic stimulation affects the activity of muscle spindle afferents (MSAs). The aim of the present work is to study the characteristics of sympathetic modulation of MSA response to stretch: (i) on the dynamic and static components of the stretch response, and (ii) on group Ia and II MSAs to evaluate potentially different effects. In anaesthetised rabbits, the peripheral stump of the cervical sympathetic nerve (CSN) was stimulated at 10 impulses s(-1) for 45-90 s. The responses of single MSAs to trapezoidal displacement of the mandible were recorded from the mesencephalic trigeminal nucleus. The following characteristic parameters were determined from averaged trapezoidal responses: initial frequency (IF), peak frequency at the end of the ramp (PF), and static index (SI). From these, other parameters were derived: dynamic index (DI = PF - SI), dynamic difference (DD = PF - IF) and static difference (SD = SI - IF). The effects of CSN stimulation were also evaluated during changes in the state of intrafusal muscle fibre contraction induced by succinylcholine and curare. In a population of 124 MSAs, 106 units (85.4 %) were affected by sympathetic stimulation. In general, while changes in resting discharge varied among different units (Ia vs. II) and experimental conditions (curarised vs. non-curarised), ranging from enhancement to strong depression of firing, the amplitude of the response to muscle stretches consistently decreased. This was confirmed and detailed in a quantitative analysis performed on 49 muscle spindle afferents. In both the non-curarised (23 units) and curarised (26 units) condition, stimulation of the CSN reduced the response amplitude in terms of DD and SD, but hardly affected DI. The effects were equally present in both Ia and II units; they were shown to be independent from gamma drive and intrafusal muscle tone and not secondary to muscle hypoxia. Sympathetic action on the resting discharge (IF) was less
Turner, Katherine J.; Hawkins, Thomas A.; Yáñez, Julián; Anadón, Ramón; Wilson, Stephen W.; Folgueira, Mónica
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
Reid, Adam J; Shawcross, Susan G; Hamilton, Alex E; Wiberg, Mikael; Terenghi, Giorgio
Novel approaches are required in peripheral nerve injury management because current surgical techniques, which do not address axotomy-induced neuronal death, lead to deficient sensory recovery. Sensory neuronal death has functional preference with cutaneous neurons dying in great numbers whilst muscle afferents survive axotomy. This offers the potential of comparing similar cell types that suffer distinct fates upon nerve injury. Here, a novel approach, combining in vivo rat nerve injury model with laser microdissection and quantitative real-time polymerase chain reaction, identifies crucial disparities in apoptotic gene expression attributable to subpopulations of differing sensory modalities and examines the response to N-acetylcysteine (NAC) therapy. We show that axotomised muscle afferent neurons survive injury due to a neuroprotective response which markedly downregulates Bax and caspase-3 mRNA. In contrast, axotomised cutaneous sensory neurons significantly upregulate caspase-3 and alter both Bcl-2 and Bax expression such that pro-apoptotic Bax predominates. N-Acetylcysteine (NAC) intervention promotes neuroprotection of cutaneous sensory neurons through considerable upregulation of Bcl-2 and downregulation of both Bax and caspase-3 mRNA. The data presented identifies differential activation of apoptotic genes in axotomised neuronal subpopulations. Furthermore, NAC therapy instigates apoptotic gene expression changes in axotomised neurons, thereby offering pharmacotherapeutic potential in the clinical treatment of nerve injury.
Slattery, James A; Page, Amanda J; Dorian, Camilla L; Brierley, Stuart M; Blackshaw, L Ashley
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
Clarke, Alex. M.; Michie, Patricia T.; Glue, Leonard C. T.
The experiments reported in this paper tested the hypothesis that the afferent potential elicited by a tendon tap in an isometrically recorded phasic stretch reflex can be detected in the surface EMG of normal humans when appropriate techniques are used. These techniques involved (1) training the subjects to relax mentally and physically so that the EMG was silent before and immediately after the diphasic MAP which reflects a highly synchronous discharge of afferent impulses from low threshold muscle stretch receptors after a tendon tap, and (2) using a data retrieval computer to summate stimulus-locked potentials in the EMG over a series of 16 samples using taps of uniform peak force and duration on the Achilles tendon to elicit the tendon jerk in the calf muscles. A discrete, diphasic potential (`A-wave') was recorded from EMG electrodes placed on the surface of the skin over the medial gastrocnemius muscle. The `A-wave' afferent potential had the opposite polarity to the corresponding efferent MAP. Under control conditions of relaxation the `A-wave' had a latency after the onset of the tap of 2 msec, the peak to peak amplitude was of the order of 5 μV and the duration was in the range of 6 to 10 msec. Further experiments were conducted to show that the `A-wave' (1) was not an artefact of the instrumentation used, (2) had a threshold at low intensities of stimulation, and (3) could be reliably augmented by using a Jendrassik manoeuvre compared with the potential observed during control (relaxation) conditions. The results support the conclusion that the `A-wave' emanates from the pool of muscle spindles which discharges impulses along group Ia nerve fibres in response to the phasic stretch stimulus because the primary ending of the spindles is known to initiate the stretch reflex and the spindles can be sensitized by fusimotor impulses so that their threshold is lowered as a result of a Jendrassik manoeuvre. The finding has important implications for the
Nagi, Saad S; Rubin, Troy K; Chelvanayagam, David K; Macefield, Vaughan G; Mahns, David A
Abstract 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
Rogasch, Nigel C; Burne, John A; Türker, Kemal S
A powerful early inhibition is seen in triceps surae after transcutaneous electrical stimulation of the Achilles tendon [tendon electrical stimulation (TES)]. The aim of the present study was to confirm results from surface electromyogram (SEMG) recordings that the inhibition is not wholly or partly due to stimulation of cutaneous afferents that may lie within range of the tendon electrodes. Because of methodological limitations, SEMG does not reliably identify the time course of inhibitory and excitatory reflex components. This issue was revisited here with an analysis of changes in single motor unit (SMU) firing rate [peristimulus frequencygram (PSF)] and probability [peristimulus time histogram (PSTH)] to reexamine the time course of inhibitory SMU events that follow purely cutaneous (superficial sural) nerve stimulation. Results were then compared with similar data from TES. When compared with the reflex response to TES, sural nerve stimulation resulted in a longer onset latency of the primary inhibition and a weaker effect on SMU firing probability and rate. PSF also revealed that decreased SMU firing rates persisted during the excitation phase in SEMG, suggesting that the initial inhibition was more prolonged than previously reported. In a further study, the transcutaneous SEMG Achilles tendon response was compared with that from direct intratendon stimulation with insulated needle electrodes. This method should attenuate the SEMG response if it is wholly or partly dependent on cutaneous afferents. However, subcutaneous stimulation of the tendon produced similar components in the SEMG, confirming that cutaneous afferents made little or no contribution to the initial inhibition following TES.
Wada, N; Kanda, Y; Takayama, R
Experiments were performed on 16 adult spinalized (L2) cats. Postsynaptic potentials (PSPs) produced by electrical stimulation of afferent nerves innervating foot pads were recorded from hindlimb motoneurons innervating the following hindlimb muscles: the posterior biceps and semitendinosus (PBSt), anterior biceps and semimembranosus (ABSm), lateral gastrocnemius and soleus (LGS), medial gastrocnemius (MG), plantaris (P1), tibialis anterior (TA), popliteus (Pop), flexor digitorum longus and flexor hallucis longus (FDHL) and peroneus longus (Per.l). The rate of occurrence of different types of PSPs (EPSPs, IPSPs and mixed PSPs), the size of the PSPs and their central latencies were analyzed for each group of motoneurons to identify the neural pathways from the afferents innervating foot pads to hindlimb motoneurons. The rates of occurrence of different types of PSPs did not depend on the foot pad stimulated in PBSt, ABSm and LGS motoneurons, but for other groups of motoneurons their rates of occurrence depended on the foot pad stimulated. It was often noted that the size of PSPs in the same motoneurons differed according to the foot pad stimulated. Measurements of the central latencies of the PSPs indicated that the shortest neural pathways for EPSPs and IPSPs were disynaptic (central latencies < 1.8 ms). The functional role of neuronal pathways from afferent nerves innervating foot pads to hindlimb motoneurons could be to maintain stability of the foot during different postural and motor activities.
Gelsema, A J; Bouman, L N; Karemaker, J M
The short-latency effect on heart rate of peripheral nerve stimulation was studied in decerebrate cats. Selective activation (17-40 microA, 100 Hz, 1 s long) of low-threshold fibers in the nerves to the triceps surae muscle yielded isometric contractions of maximal force that were accompanied by a cardiac cycle length shortening within 0.4 s from the start of stimulation. This effect was abolished by pharmacologically induced neuromuscular blockade. The cardiac cycle length shortening during paralysis reappeared after a 6- to 10-fold increase of the stimulation strength. Cutaneous (sural) nerve stimulation (15-25 microA, 100 Hz, 1 s long) elicited reflex contractions in the stimulated limb, which were also accompanied by a cardiac acceleration with similar latency. Paralysis prevented the reflex contractions and reduced the cardiac response in some cats and abolished it in others. The response reappeared in either case after a 5- to 10-fold increase of the stimulus strength. It is concluded that muscle nerve and cutaneous nerve activity both cause a similar cardiac acceleration with a latency of less than 0.4 s. The response to muscle nerve stimulation is elicited by activity in group III afferents. It is excluded that the cardiac response to nerve stimulation is secondary to a change in the respiratory pattern.
Background Depressive disorders are the most common form of mental disorders in community and health care settings. Unfortunately, the treatment of Major Depressive Disorder (MDD) is far from satisfactory. Vagus nerve stimulation (VNS) is a relatively new and promising physical treatment for depressive disorders. One particularly appealing element of VNS is the long-term benefit in mood regulation. However, because this intervention involves surgery, perioperative risks, and potentially significant side effects, this treatment has been limited to those patients with treatment-resistant depression who have failed medication trials and exhausted established somatic treatments for major depression, due to intolerance or lack of response. This double-blinded randomized clinical trial aims to overcome these limitations by introducing a novel method of stimulating superficial branches of the vagus nerve on the ear to treat MDD. The rationale is that direct stimulation of the afferent nerve fibers on the ear area with afferent vagus nerve distribution should produce a similar effect as classic VNS in reducing depressive symptoms without the burden of surgical intervention. Design One hundred twenty cases (60 males) of volunteer patients with mild and moderate depression will be randomly divided into transcutaneous vagus nerve stimulation group (tVNS) and sham tVNS group. The treatment period lasts 4 months and all clinical and physiological measurements are acquired at the beginning and the end of the treatment period. Discussion This study has the potential to significantly extend the application of VNS treatment for MDD and other disorders (including epilepsy, bipolar disorder, and morbid obesity), resulting in direct benefit to the patients suffering from these highly prevalent disorders. In addition, the results of this double-blinded clinical trial will shed new light on our understanding of acupuncture point specificity, and development of methodologies in clinical
Morita, I; Komatsuzaki, A; Kanda, T; Tatsuoka, H; Chiba, T
The human vestibular sensory epithelia of macula utriculi in 3 cases of acoustic neurinoma were examined by conventional and intermediate voltage electron microscopes. The apical part and the nerve terminals of hair cells were studied by means of a computer-aided three-dimensional (3-D) reconstruction technique. The sensory epithelia were fairly well preserved. Most type I and all type II hair cells appeared as those described in the other reports. However, some type I hair cells were incompletely surrounded by nerve calyces and received direct contacts from the efferent nerve endings. These type I hair cells were also innervated by a few neighbouring afferent nerve calyces. The stereocilia and the cuticular plate of type I hair cells differed from those of type II hair cells. The mean diameter of type I hair cell stereocilia was 488 +/- 59 nm and that of type II hair cells was 373 +/- 21 nm. The cuticular plate of type I hair cells resembled a cone and was about several times as thick as that of type II hair cells which was similar to a flat disc.
Jiménez, I; Rudomin, P; Solodkin, M
Intracellular recordings were made in the barbiturate-anesthetized cat from single afferent fibres left in continuity with the medial gastrocnemius muscle to document the transmembrane potential changes produced in functionally identified fibres by stimulation of sensory nerves and of the contralateral red nucleus (RN). Fifty five fibres from muscle spindles had conduction velocities above 70 m/s and were considered as from group Ia. Stimulation of group I afferent fibres of the posterior biceps and semitendinosus nerve (PBSt) produced primary afferent depolarization (PAD) in 30 (54%) Ia fibres. Stimulation of the sural (SU) nerve produced no transmembrane potential changes in 39 (71%) group Ia fibres and dorsal root reflex-like activity (DRRs) in 16 (29%) fibres. In 17 out of 28 group Ia fibres (60.7%) SU conditioning inhibited the PAD generated by stimulation of the PBSt nerve. Facilitation of the PBSt-induced PAD by SU conditioning was not seen. Repetitive stimulation of the RN had mixed effects: it produced PAD in 1 out of 8 fibres and inhibited the PAD induced by PBSt stimulation in 2 other fibres. Nine fibres connected to muscle spindles had conduction velocities below 70 m/s and were considered to be group II afferents. No PAD was produced in these fibres by SU stimulation but DRRs were generated in 5 of them. In 23 out of 31 fibres identified as from tendon organs group I PBSt volleys produced PAD. However, stimulation of the SU nerve produced PAD only in 3 out of 34 fibres, no transmembrane potential changes in 30 fibres and DRRs in 1 fibre. The effects of SU conditioning on the PAD produced by PBSt stimulation were tested in 19 Ib fibres and were inhibitory in 12 of them. In 9 of these fibres SU alone produced no transmembrane potential changes. Repetitive stimulation of the RN produced PAD in 3 out of 9 Ib fibres. SU conditioning inhibited the RN-induced PAD. The present findings support the existence of an alternative inhibitory pathway from cutaneous
Baudry, Stéphane; Maerz, Adam H; Enoka, Roger M
The present work investigated presynaptic modulation of Ia afferents in the extensor carpi radialis (ECR) when young and old adults exerted a wrist extension force either to support an inertial load (position control) or to achieve an equivalent constant torque against a rigid restraint (force control) at 5, 10, and 15% of the maximal force. H reflexes were evoked in the ECR by stimulating the radial nerve above the elbow. A conditioning stimulus was applied to the median nerve above the elbow to assess presynaptic inhibition of homonymous Ia afferents (D1 inhibition) or at the wrist (palmar branch) to assess the ongoing presynaptic inhibition of heteronymous Ia afferents that converge onto the ECR motor neuron pool (heteronymous Ia facilitation). The young adults had less D1 inhibition and greater heteronymous Ia facilitation during the position task (79 and 132.1%, respectively) compared with the force task (69.1 and 115.1%, respectively, P < 0.05). In contrast, the old adults exhibited no difference between the two tasks for either D1 inhibition ( approximately 72%) or heteronymous Ia facilitation ( approximately 114%). Contraction intensity did not influence the amount of D1 inhibition or heteronymous Ia facilitation for either group of subjects. The amount of antagonist coactivation was similar between tasks for young adults, whereas it was greater in the position task for old adults (P = 0.02). These data indicate that in contrast to young adults, old adults did not modulate presynaptic inhibition of Ia afferents when controlling the position of a compliant load but rather increased coactivation of the antagonist muscle.
Ferrington, D. G.; Rowe, Mark J.
1. Responses were recorded from individual tactile afferent fibres isolated by microdissection from the median nerve of pentobarbitone-anaesthetized neonatal kittens (1-5 days post-natal age). Experiments were also conducted on adult cats to permit precise comparisons between neonatal and adult fibres. 2. Neonatal fibres with receptive fields on the glabrous skin of the foot pads were classified into two broad groups, a slowly adapting class (40%) which responded throughout a 1 sec period of steady indentation and a rapidly adapting or dynamically sensitive class comprising 60% of units. Fibres in these two groups had overlapping conduction velocities in the range 4·3 to 7·5 m/sec and were believed to be the developing Group II afferents of the adult. 3. Neonatal slowly adapting fibres qualitatively resembled their adult counter-parts. They displayed graded stimulus-response relations which, over the steepest segment of the curves, had mean slopes of 15·7 impulses/100 μm of indentation. Plateau levels of response were often reached at amplitudes of skin indentation of < 0·5-0·7 mm. 4. Dynamically sensitive fibres with receptive fields on the glabrous skin were studied using sinusoidal cutaneous vibration which in the adult enables them to be divided into two distinct classes. However, in the neonate, they formed a continuum whether criteria of sensitivity or responsiveness were used. 5. In response to vibration neonatal fibres differed from adult ones according to the following quantitative indices: (i) sensitivity as measured by both absolute thresholds and thresholds for a 1: 1 pattern of response, both of which were higher in the neonate than in the adult at all frequencies > 50 Hz and differed by an order of magnitude at frequencies ≥ 200 Hz; (ii) responsiveness based on the mean impulse rate evoked at a fixed amplitude of cutaneous vibration; (iii) band width of vibratory sensitivity which in the neonate was confined to approximately 5-300 Hz whereas
Mandadi, Sravan; Hong, Peter; Tran, Michelle A; Bráz, Joao M; Colarusso, Pina; Basbaum, Allan I; Whelan, Patrick J
Compared to proprioceptive afferent collateral projections, less is known about the anatomical, neurochemical, and functional basis of nociceptive collateral projections modulating lumbar central pattern generators (CPG). Quick response times are critical to ensure rapid escape from aversive stimuli. Furthermore, sensitization of nociceptive afferent pathways can contribute to a pathological activation of motor circuits. We investigated the extent and role of collaterals of capsaicin-sensitive nociceptive sacrocaudal afferent (nSCA) nerves that directly ascend several spinal segments in Lissauer's tract and the dorsal column and regulate motor activity. Anterograde tracing demonstrated direct multisegmental projections of the sacral dorsal root 4 (S4) afferent collaterals in Lissauer's tract and in the dorsal column. Subsets of the traced S4 afferent collaterals expressed transient receptor potential vanilloid 1 (TRPV1), which transduces a nociceptive response to capsaicin. Electrophysiological data revealed that S4 dorsal root stimulation could evoke regular rhythmic bursting activity, and our data suggested that capsaicin-sensitive collaterals contribute to CPG activation across multiple segments. Capsaicin's effect on S4-evoked locomotor activity was potent until the lumbar 5 (L5) segments, and diminished in rostral segments. Using calcium imaging we found elevated calcium transients within Lissauer's tract and dorsal column at L5 segments when compared to the calcium transients only within the dorsal column at the lumbar 2 (L2) segments, which were desensitized by capsaicin. We conclude that lumbar locomotor networks in the neonatal mouse spinal cord are targets for modulation by direct multisegmental nSCA, subsets of which express TRPV1 in Lissauer's tract and the dorsal column. J. Comp. Neurol. 521:2870-2887, 2013. © 2013 Wiley Periodicals, Inc.
Martínez-Lorenzana, Guadalupe; Condés-Lara, Miguel; Rojas-Piloni, Gerardo
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
Taguchi, Toru; Tomotoshi, Kimihiko; Mizumura, Kazue
Ingestion of a poisonous mushroom, Clitocybe acromelalga, results in strong and long-lasting allodynia, burning pain, redness and swelling in the periphery of the body. Acromelic acid (ACRO), a kainate analogue isolated from the mushroom, is assumed to be involved in the poisoning. ACRO has two isomers, ACRO-A and ACRO-B. The potency of ACRO-A is a million times higher than that of ACRO-B for induction of allodynia when intrathecally administered in mice. The effect of ACRO on the primary afferents of somatic tissues remains largely unknown. The aim of the present study was to examine the effect of ACRO-A on the response behavior of unmyelinated afferents in the skeletal muscle. For this purpose single fiber recordings of C-afferents were made from rat extensor digitorum longus (EDL) muscle-common peroneal nerve preparations in vitro. Intramuscular injections of ACRO-A at three different concentrations (10(-12), 10(-10) and 10(-8)M, 5 microl over 5s) near the receptive field in the EDL muscle elicited excitation of C-afferents (12%, 50% and 44%, respectively). ACRO-A at the concentration of 10(-10)M induced the strongest excitation. The incidence of ACRO-A responsive fibers at the concentration of 10(-10) and 10(-8)M was significantly higher than that at 10(-12)M. The responses to mechanical and heat stimulations did not differ between ACRO-A sensitive and insensitive fibers. These results clearly demonstrated the powerful excitatory action of ACRO-A on mechanosensitive unmyelinated afferents in the rat skeletal muscle.
Braz, Joao M.; Skinner, Kate; Llewellyn-Smith, Ida J.; Basbaum, Allan I.
Protein kinase C γ (PKCγ), which is concentrated in interneurons of the inner part of lamina II of the dorsal horn, has been implicated in injury-induced allodynia, a condition wherein pain is produced by innocuous stimuli. Although it is generally assumed that these interneurons receive input from the nonpeptidergic, IB4-positive subset of nociceptors, the fact that PKCγ cells do not express Fos in response to noxious stimulation suggests otherwise. Here, we demonstrate that the terminal field of the nonpeptidergic population of nociceptors, in fact, lies dorsal to that of PKCγ interneurons. There was also no overlap between the PKCγ-expressing interneurons and the transganglionic tracer wheat germ agglutinin which, after sciatic nerve injection, labels all unmyelinated nociceptors. However, transganglionic transport of the β-subunit of cholera toxin, which marks the medium-diameter and large-diameter myelinated afferents that transmit non-noxious information, revealed extensive overlap with the layer of PKCγ interneurons. Furthermore, expression of a transneuronal tracer in myelinated afferents resulted in labeling of PKCγ interneurons. Light and electron microscopic double labeling further showed that the VGLUT1 subtype of vesicular glutamate transmitter, which is expressed in myelinated afferents, marks synapses that are presynaptic to the PKCγ interneurons. Finally, we demonstrate that a continuous non-noxious input, generated by walking on a rotarod, induces Fos in the PKCγ interneurons. These results establish that PKCγ interneurons are activated by myelinated afferents that respond to innocuous stimuli, which suggests that injury-induced mechanical allodynia is transmitted through a circuit that involves PKCγ interneurons and non-nociceptive, VGLUT1-expressing myelinated primary afferents. PMID:18685019
Arslantunali, D; Dursun, T; Yucel, D; Hasirci, N; Hasirci, V
Peripheral nerve injury is a worldwide clinical problem which could lead to loss of neuronal communication along sensory and motor nerves between the central nervous system (CNS) and the peripheral organs and impairs the quality of life of a patient. The primary requirement for the treatment of complete lesions is a tension-free, end-to-end repair. When end-to-end repair is not possible, peripheral nerve grafts or nerve conduits are used. The limited availability of autografts, and drawbacks of the allografts and xenografts like immunological reactions, forced the researchers to investigate and develop alternative approaches, mainly nerve conduits. In this review, recent information on the various types of conduit materials (made of biological and synthetic polymers) and designs (tubular, fibrous, and matrix type) are being presented. PMID:25489251
Willis, W D; Núnez, R; Rudomín, P
1. In cats anesthetized with sodium pentobarbital, recordings were made from dorsal root ganglion (DRG) cells having a peripheral process in the gastrocnemius-soleus (GS) nerve. The GS nerve was left in continuity with the muscle to allow identification of group Ia and Ib fibers by responses of the receptors to muscle stretch and contraction. The central processes of the DRG cells were activated antidromically by stimulation within the spinal cord so that changes in the excitability of the fibers could be examined following conditioning volleys in muscle and cutaneous nerves. 2. Recordings were made from 44 DRG cells. Of these, 15 were group Ia and 9 group Ib afferents of the GS nerve. 3. Of 15 Ia fibers, 12 were activated antidromically by stimulation in the motor nucleus, but no Ib fibers were discharged by such stimulation. Ib fibers could be antidromically activated by stimulation in the intermediate nucleus. 4. The central processes of the Ia DRG cells had slower conduction velocities than did the peripheral processes. 5. The thresholds to electrical stimulation of the peripheral processes of Ia and Ib fibers of the GS nerve showed considerable overlap. 6. All of the Ia DRG cells tested showed an increased excitability following conditioning volleys in the biceps-semitendinosus (BST) nerve. The increase in excitability was produced by the largest fibers of the BST nerve. 7. Stimulation of the sural (SU) or superficial peroneal (SP) cutaneous nerves also increased the excitability of some Ia fibers. However, other Ia fibers were unaffected, and in two cases the excitability was reduced. 8. The excitability of group Ib fibers was increased by conditioning volleys in the BST, SU, or SP nerves. 9. It is concluded that cutaneous volleys produce a mixture of primary afferent depolarization and primary afferent hyperpolarization in Ia fibers of anesthetized cats. Such converse actions probably cancel in excitability tests using population responses. 10. The
Strote, G; Bonow, I; Attah, S
A detailed morphological investigation of the anterior sensory organs, the nerve ring and a glomerulus-like structure in male Onchocerca volvulus was performed by means of electron microscopy. The 8 head papillae are arranged in the common 4 + 4 pattern of most filarial worms in circles around the mouth opening. The amphidial openings are found between the circles of inner and outer papillae on both sides of the mouth. Inside, several additional nerve axons are seen in the tissue of the anterior tip not related to one of the identified papillar structures. The inner and outer papillae exhibit a remarkably different fine structure, and are part of a complex system of at least 2 different receptor cell types at the anterior tip of the worm. The amphidial channel contains 8 modified cilia; accessory axons are associated with the cytoplasm of the sheath cell. The anterior nerve ring of male worms is located about 150 micrometers posterior from the outermost tip of the head region. It consists of several fibres coiled around the oesophagus. The comparison of the fine structure of the central nervous system did not show the expected morphological differences associated with the heterogeneous age distribution in the natural worm population. This was in contrast to previous findings with respect to tissues in different parts of the worm. The study also provides the first evidence that suggests the existence of an excretory organ in a filarial worm in the region of the anterior nerve ring. Paired glomerulus-like structures in the lateral chords and a canal formed by a projection of the basal zone of the cuticles were identified.
Glatzle, Jörg; Wang, Yuhua; Adelson, David W; Kalogeris, Theodore J; Zittel, Tilman T; Tso, Patrick; Wei, Jen-Yu; Raybould, Helen E
Nutrients in the intestine initiate changes in secretory and motor function of the gastrointestinal (GI) tract. The nature of the 'sensors' in the intestinal wall is not well characterized. Intestinal lipid stimulates the release of cholecystokinin (CCK) from mucosal entero-endocrine cells, and it is proposed that CCK activates CCK A receptors on vagal afferent nerve terminals. There is evidence that chylomicron components are involved in this lipid transduction pathway. The aim of the present study was to determine (1) the pathway mediating reflex inhibition of gastric motility and (2) activation of duodenal vagal afferents in response to chylomicrons. Mesenteric lymph was obtained from awake rats fitted with lymph fistulas during intestinal perfusion of lipid (Intralipid, 170 micromol h(-1), chylous lymph) or a dextrose and/or electrolyte solution (control lymph). Inhibition of gastric motility was measured manometrically in urethane-anaesthetized recipient rats in response to intra-arterial injection of lymph close to the upper GI tract. Chylous lymph was significantly more potent than control lymph in inhibiting gastric motility. Functional vagal deafferentation by perineural capsaicin or CCK A receptor antagonist (devazepide, 1 mg kg(-1), i.v.) significantly reduced chylous lymph-induced inhibition of gastric motility. The discharge of duodenal vagal afferent fibres was recorded from the dorsal abdominal vagus nerve in an in vitro preparation of the duodenum. Duodenal vagal afferent nerve fibre discharge was significantly increased by close-arterial injection of CCK (1-100 pmol) in 43 of 83 units tested. The discharge of 88% of CCK-responsive fibres was increased by close-arterial injection of chylous lymph; devazepide (100 microg, i.a.) abolished the afferent response to chylous lymph in 83% of these units. These data suggest that in the intestinal mucosa, chylomicrons or their products release endogenous CCK which activates CCK A receptors on vagal afferent
This article deals with the classification, assessment, and management of painful nerves of the distal upper limb. The author's preferred surgical and rehabilitation techniques in managing these conditions are discussed in detail and include (1) relocation of end-neuromas to specific sites, (2) division and relocation of painful nerves in continuity (neuromas-in-continuity and scar-tethered nerves) involving small nerves to the same sites, and (3) fascial wrapping of painful nerves in continuity involving larger nerves such as the median and ulnar nerves. The results of these treatments are presented as justification for current use of these techniques.
Chávez, H; Vega, R; Valli, P; Mira, E; Benvenuti, C; Guth, P S; Soto, E
Betahistine has been used to treat several vestibular disorders of both central and peripheral origin. The objective of this work was to study the betahistine action mechanism at the vestibular end organs. Experiments were carried out in wild larval axolotl (Ambystoma tigrinum). Multiunit extracellular recordings were obtained from the semicircular canal nerve using a suction electrode. Betahistine (10 microM to 10 mM, n = 32) inhibited the basal spike discharge of the vestibular afferent neurons with an IC50 of 600 microM. To define the site of action of betahistine, its interactions with antagonists of nitric oxide sintethizing enzyme, cholinergic drugs, and excitatory amino acids were studied. Betahistine 1 mM (n = 5) was coadministered with NG-nitro-L-arginine 3 microM. The action of betahistine remained as in control experiments. Betahistine 1 mM reduced the excitatory action of carbachol (200 microM, n = 5) in a 30 +/- 3.4%. Cholinergic antagonists atropine (10 microM, n = 3) and d-tubocurarine (10 microM, n = 3) did not modify betahistine actions. Betahistine 1 mM also reduced kainic acid (10 microM, n = 4) excitatory action in 45.5 +/- 9.8%. These results corroborate that betahistine has a peripheral inhibitory action in the spike discharge of the afferent neurons in the vestibule. This action seems to involve neither NO production nor modifications in the release of acetylcholine from the efferent fibers. The inhibitory action of betahistine seems to be due to a postsynaptic binding site on the afferent neurons.
Peltier, Amanda C; Myers, M Iliza; Artibee, Kay J; Hamilton, Audra D; Yan, Qing; Guo, Jiasong; Shi, Yaping; Wang, Lily; Li, Jun
Skin biopsies have primarily been used to study the non-myelinated nerve fibers of the epidermis in a variety of neuropathies. In this study, we have expanded the skin biopsy technique to glabrous, non-hairy skin to evaluate myelinated nerve fibers in the most highly prevalent peripheral nerve disease, diabetic polyneuropathy (DPN). Twenty patients with DPN (Type I, n = 9; Type II, n = 11) and 16 age-matched healthy controls (age 29-73) underwent skin biopsy of the index finger, nerve conduction studies (NCS), and composite neuropathy scoring. In patients with DPN, we found a statistically significant reduction of both mechanoreceptive Meissner corpuscles (MCs) and their afferent myelinated nerve fibers (p = 0.01). This myelinated nerve fiber loss was correlated with the decreased amplitudes of sensory/motor responses in NCS. This study supports the utilization of skin biopsy to quantitatively evaluate axonal loss of myelinated nerve fibers in patients with DPN.
... Loss of axon tissue Metabolic neuropathies Necrotizing vasculitis Sarcoidosis Risks Allergic reaction to the local anesthetic Discomfort ... Neurosarcoidosis Peripheral neuropathy Primary amyloidosis Radial nerve dysfunction Sarcoidosis Tibial nerve dysfunction Review Date 6/1/2015 ...
Hegarty, Deborah M; Hermes, Sam M; Largent-Milnes, Tally M; Aicher, Sue A
We examined the substrates for ocular nociception in adult male Sprague-Dawley rats. Capsaicin application to the ocular surface in awake rats evoked nocifensive responses and suppressed spontaneous grooming responses. Thus, peripheral capsaicin was able to activate the central pathways encoding ocular nociception. Our capsaicin stimulus evoked c-Fos expression in a select population of neurons within rostral trigeminal nucleus caudalis in anesthetized rats. These activated neurons also received direct contacts from corneal afferent fibers traced with cholera toxin B from the corneal surface. However, the central terminals of the corneal afferents that contacted capsaicin-activated trigeminal neurons did not contain TRPV1. To determine if TRPV1 expression had been altered by capsaicin stimulation, we examined TRPV1 content of corneal afferents in animals that did not receive capsaicin stimulation. These studies confirmed that while TRPV1 was present in 30% of CTb-labeled corneal afferent neurons within the trigeminal ganglion, TRPV1 was only detected in 2% of the central terminals of these corneal afferents within the trigeminal nucleus caudalis. Other TRP channels were also present in low proportions of central corneal afferent terminals in unstimulated animals (TRPM8, 2%; TRPA1, 10%). These findings indicate that a pathway from the cornea to rostral trigeminal nucleus caudalis is involved in corneal nociceptive transmission, but that central TRP channel expression is unrelated to the type of stimulus transduced by the peripheral nociceptive endings.
Peng, Chih-Wei; Chen, Jia-Jin Jason; Cheng, Chen-Li; Grill, Warren M.
Urinary retention is the inability to empty the bladder completely, and may result from bladder hypocontractility, increases in outlet resistance or both. Chronic urinary retention can lead to several urological complications and is often refractory to pharmacologic, behavioral and surgical treatments. We sought to determine whether electrical stimulation of sensory fibers in the pudendal nerve could engage an augmenting reflex and thereby improve bladder emptying in an animal model of urinary retention. We measured the efficiency of bladder emptying with and without concomitant electrical stimulation of pudendal nerve afferents in urethane-anesthetized rats. Voiding efficiency (VE = voided volume/initial volume) was reduced from 72 ± 7% to 29 ± 7% following unilateral transection of the sensory branch of the pudendal nerve (UST) and from 70 ± 5% to 18 ± 4% following bilateral transection (BST). Unilateral electrical stimulation of the proximal transected sensory pudendal nerve during distention-evoked voiding contractions significantly improved VE. Low-intensity stimulation at frequencies of 1-50 Hz increased VE to 40-51% following UST and to 39-49% following BST, while high-intensity stimulation was ineffective at increasing VE. The increase in VE was mediated by increases in the duration of distention-evoked voiding bladder contractions, rather than increases in contraction amplitude. These results are consistent with an essential role for pudendal sensory feedback in efficient bladder emptying, and raise the possibility that electrical activation of pudendal nerve afferents may provide a new approach to restore efficient bladder emptying in persons with urinary retention.
Peng, Chih-Wei; Chen, Jia-Jin Jason; Cheng, Chen-Li; Grill, Warren M.
Urinary retention is the inability to empty the bladder completely, and may result from bladder hypocontractility, increases in outlet resistance, or both. Chronic urinary retention can lead to several urological complications and is often refractory to pharmacologic, behavioral, and surgical treatments. We sought to determine whether electrical stimulation of sensory fibers in the pudendal nerve could engage an augmenting reflex and thereby improve bladder emptying in an animal model of urinary retention. We measured the efficiency of bladder emptying with and without concomitant electrical stimulation of pudendal nerve afferents in urethane anesthetized rats. Voiding efficiency (VE=voided volume/initial volume) was reduced from 72±7% to 29±7% following unilateral transection of the sensory branch of the pudendal nerve (UST) and from 70±5% to 18±4% following bilateral transection (BST). Unilateral electrical stimulation of the proximal transected sensory pudendal nerve during distention-evoked voiding contractions significantly improved VE. Low intensity stimulation at frequencies of 1–50 Hz increased VE to 40–51% following UST and to 39–49% following BST, while high intensity stimulation was ineffective at increasing VE. The increase in VE was mediated by increases in the duration of distention-evoked voiding bladder contractions, rather than increases in contraction amplitude. These results are consistent with an essential role for pudendal sensory feedback in efficient bladder emptying, and raise the possibility that electrical activation of pudendal nerve afferents may provide a new approach to restore efficient bladder emptying in persons with urinary retention. PMID:18430976
Christianson, Julie A.; Bielefeldt, Klaus; Altier, Christophe; Cenac, Nicolas; Davis, Brian M.; Gebhart, Gerald F.; High, Karin W.; Kollarik, Marian; Randich, Alan; Undem, Brad; Vergnolle, Nathalie
Visceral pain is the most common reason for doctor visits in the US. Like somatic pain, virtually all visceral pain sensations begin with the activation of primary sensory neurons innervating the viscera and/or the blood vessels associated with these structures. Visceral afferents also play a central role in tissue homeostasis. Recent studies show that in addition to monitoring the state of the viscera, they perform efferent functions through the release of small molecules (e.g. peptides like CGRP) that can drive inflammation, thereby contributing to the development of visceral pathologies (e.g. diabetes Razavi, R., Chan, Y., Afifiyan, F.N., Liu, X.J., Wan, X., Yantha, J., Tsui, H., Tang, L., Tsai, S., Santamaria, P., Driver, J.P., Serreze, D., Salter, M.W., Dosch, H.M., 2006. TRPV1+ sensory neurons control beta cell stress and islet inflammation in autoimmune diabetes, Cell 127 1123–1135). Visceral afferents are heterogeneous with respect to their anatomy, neurochemistry and function. They are also highly plastic in that their cellular environment continuously influences their response properties. This plasticity makes them susceptible to long-term changes that may contribute significantly to the development of persistent pain states such as those associated with irritable bowel syndrome, pancreatitis, and visceral cancers. This review examines recent insights into visceral afferent anatomy and neurochemistry and how neonatal insults can affect the function of these neurons in the adult. New approaches to the treatment of visceral pain, which focus on primary afferents, will also be discussed. PMID:19150371
Helmich, R C G; Bäumer, T; Siebner, H R; Bloem, B R; Münchau, A
A conditioning electrical stimulus to a digital nerve can inhibit the motor-evoked potentials (MEPs) in adjacent hand muscles elicited by transcranial magnetic stimulation (TMS) to the contralateral primary motor cortex (M1) when given 25-50 ms before the TMS pulse. This is referred to as short-latency afferent inhibition (SAI). We studied inter-hemispheric differences (Experiment 1) and within-limb somatotopy (Experiment 2) of SAI in healthy right-handers. In Experiment 1, conditioning electrical pulses were applied to the right or left index finger (D2) and MEPs were recorded from relaxed first dorsal interosseus (FDI) and abductor digiti minimi (ADM) muscles ipsilateral to the conditioning stimulus. We found that SAI was more pronounced in right hand muscles. In Experiment 2, electrical stimulation was applied to the right D2 and MEPs were recorded from ipsilateral FDI, extensor digitorum communis (EDC) and biceps brachii (BB) muscles. The amount of SAI did not differ between FDI, EDC and BB muscles. These data demonstrate inter-hemispheric differences in the processing of cutaneous input from the hand, with stronger SAI in the dominant left hemisphere. We also found that SAI occurred not only in hand muscles adjacent to electrical digital stimulation, but also in distant hand and forearm and also proximal arm muscles. This suggests that SAI induced by electrical D2 stimulation is not focal and somatotopically specific, but a more widespread inhibitory phenomenon.
Zhong, Yingchun; Wang, Liping; Dong, Jianghui; Zhang, Yi; Luo, Peng; Qi, Jian; Liu, Xiaolin; Xian, Cory J.
Peripheral nerves are important pathways for receiving afferent sensory impulses and sending out efferent motor instructions, as carried out by sensory nerve fibers and motor nerve fibers. It has remained a great challenge to functionally reconnect nerve internal fiber bundles (or fascicles) in nerve repair. One possible solution may be to establish a 3D nerve fascicle visualization system. This study described the key technology of 3D peripheral nerve fascicle reconstruction. Firstly, fixed nerve segments were embedded with position lines, cryostat-sectioned continuously, stained and imaged histologically. Position line cross-sections were identified using a trained support vector machine method, and the coordinates of their central pixels were obtained. Then, nerve section images were registered using the bilinear method, and edges of fascicles were extracted using an improved gradient vector flow snake method. Subsequently, fascicle types were identified automatically using the multi-directional gradient and second-order gradient method. Finally, a 3D virtual model of internal fascicles was obtained after section images were processed. This technique was successfully applied for 3D reconstruction for the median nerve of the hand-wrist and cubital fossa regions and the gastrocnemius nerve. This nerve internal fascicle 3D reconstruction technology would be helpful for aiding peripheral nerve repair and virtual surgery. PMID:26596642
Schelegle, E.S.; Carl, M.L.; Coleridge, H.M.; Coleridge, J.C.; Green, J.F. )
Acute inhalation of ozone induces vagally mediated rapid shallow breathing and bronchoconstriction. In spontaneously breathing anesthetized dogs, we attempted to determine whether afferent vagal C-fibers in the lower airways contributed to these responses. Dogs inhaled 3 ppm ozone for 40-70 min into the lower trachea while cervical vagal temperature was maintained successively at 37, 7, and 0 degrees C. At 37 degrees C, addition of ozone to the inspired air decreased tidal volume and dynamic lung compliance and increased breathing frequency, total lung resistance, and tracheal smooth muscle tension. Ozone still evoked significant effects when conduction in myelinated vagal axons was blocked selectively by cooling the nerves to 7 degrees C. Ozone-induced effects were largely abolished when nonmyelinated vagal axons were blocked by cooling to 0 degree C, breathing during ozone inhalation at 0 degree C being generally similar to that during air breathing at 0 degree C, except that minute volume and inspiratory flow were higher. We conclude that afferent vagal C-fibers in the lower airways make a major contribution to the acute respiratory effects of ozone and that nonvagal afferents contribute to the effects that survive vagal blockade.
Mendez, Arnaldo; Belghith, Abrar; Sawan, Mohamad
In this paper, we present a digital signal processor (DSP) capable of monitoring the urinary bladder volume through afferent neural pathways. The DSP carries out real-time detection and can discriminate extracellular action potentials, also known as on-the-fly spike sorting. Next, the DSP performs a decoding method to estimate either three qualitative levels of fullness or the bladder volume value, depending on the selected output mode. The proposed DSP was tested using both realistic synthetic signals with a known ground-truth, and real signals from bladder afferent nerves recorded during acute experiments with animal models. The spike sorting processing circuit yielded an average accuracy of 92% using signals with highly correlated spike waveforms and low signal-to-noise ratios. The volume estimation circuits, tested with real signals, reproduced accuracies achieved by offline simulations in Matlab, i.e., 94% and 97% for quantitative and qualitative estimations, respectively. To assess feasibility, the DSP was deployed in the Actel FPGA Igloo AGL1000V2, which showed a power consumption of 0.5 mW and a latency of 2.1 ms at a 333 kHz core frequency. These performance results demonstrate that an implantable bladder sensor that perform the detection, discrimination and decoding of afferent neural activity is feasible.
Mifflin, S W
Inspiratory hypoglossal motoneurons (IHMs) mediate contraction of the genioglossus muscle and contribute to the regulation of upper airway patency. Intracellular recordings were obtained from antidromically identified IHMs in anesthetized, vagotomized cats, and IHM responses to electrical activation of superior laryngeal nerve (SLN) afferent fibers at various frequencies and intensities were examined. SLN stimulus frequencies <2 Hz evoked an excitatory-inhibitory postsynaptic potential (EPSP-IPSP) sequence or only an IPSP in most IHMs that did not change in amplitude as the stimulus was maintained. During sustained stimulus frequencies of 5-10 Hz, there was a reduction in the amplitude of SLN-evoked IPSPs with time with variable changes in the EPSP. At stimulus frequencies >25 Hz, the amplitude of EPSPs and IPSPs was reduced over time. At a given stimulus frequency, increasing stimulus intensity enhanced the decay of the SLN-evoked postsynaptic potentials (PSPs). Frequency-dependent attenuation of SLN inputs to IHMs also occurred in newborn kittens. These results suggest that activation of SLN afferents evokes different PSP responses in IHMs depending on the stimulus frequency. At intermediate frequencies, inhibitory inputs are selectively filtered so that excitatory inputs predominate. At higher frequencies there was no discernible SLN-evoked PSP temporally locked to the SLN stimuli. Alterations in SLN-evoked PSPs could play a role in the coordination of genioglossal contraction during respiration, swallowing, and other complex motor acts where laryngeal afferents are activated.
Walters, G E; Mary, D A
In chloralose-anaesthetized dogs, distension of small balloons at the pulmonary vein-atrial junctions to stimulate atrial receptors with myelinated vagal afferent nerves causes an increase in heart rate but does not influence the activity in efferent vagal cardiac nerves. However, distension of these small balloons also stimulates atrial receptors with non-myelinated vagal and sympathetic afferent nerves, which are thought to affect the heart rate and activity in efferent vagal cardiac nerves. In the present investigation, seven dogs anaesthetized with chloralose were studied by distension of small balloons at the pulmonary vein-atrial junctions and in the left atrial appendage, and by graded cooling of the vagal nerves in the neck; cooling to 9 degrees C was used to prevent the increase in activity in myelinated vagal afferent nerves to distension of the small balloons and cooling to 0 degree C was used to prevent responses to the distension in all vagal afferent nerves. Eleven vagal efferent nerve fibers were studied which responded to stimulation of carotid baroreceptors and chemoreceptors. Distension of the small balloons did not affect the activity in these eleven efferent vagal nerve fibres, with the vagi at 37 degrees C or during vagal cooling to 9 degrees C or to 0 degree C. The results indicate that upon distension of the small balloons, none of the three types of atrial receptor influence the activity in efferent vagal cardiac nerves. The results support the conclusion that stimulation of atrial receptors with myelinated vagal afferent nerves, responsible for the reflex increase in heart rate, does not influence the activity in efferent vagal cardiac nerves.
Neuropathy - common peroneal nerve; Peroneal nerve injury; Peroneal nerve palsy ... type of peripheral neuropathy (damage to nerves outside the brain ... nerve injuries. Damage to the nerve disrupts the myelin sheath ...
Uta, Daisuke; Furue, Hidemasa; Pickering, Anthony E; Rashid, Md Harunor; Mizuguchi-Takase, Hiroko; Katafuchi, Toshihiko; Imoto, Keiji; Yoshimura, Megumu
The TRPA1 channel has been proposed to be a molecular transducer of cold and inflammatory nociceptive signals. It is expressed on a subset of small primary afferent neurons both in the peripheral terminals, where it serves as a sensor, and on the central nerve endings in the dorsal horn. The substantia gelatinosa (SG) of the spinal cord is a key site for integration of noxious inputs. The SG neurons are morphologically and functionally heterogeneous and the precise synaptic circuits of the SG are poorly understood. We examined how activation of TRPA1 channels affects synaptic transmission onto SG neurons using whole-cell patch-clamp recordings and morphological analyses in adult rat spinal cord slices. Cinnamaldehyde (TRPA1 agonist) elicited a barrage of excitatory postsynaptic currents (EPSCs) in a subset of the SG neurons that responded to allyl isothiocyanate (less specific TRPA1 agonist) and capsaicin (TRPV1 agonist). Cinnamaldehyde evoked EPSCs in vertical and radial but not islet or central SG cells. Notably, cinnamaldehyde produced no change in inhibitory postsynaptic currents and nor did it produce direct postsynaptic effects. In the presence of tetrodotoxin, cinnamaldehyde increased the frequency but not amplitude of miniature EPSCs. Intriguingly, cinnamaldehyde had a selective inhibitory action on monosynaptic C- (but not Adelta-) fiber-evoked EPSCs. These results indicate that activation of spinal TRPA1 presynaptically facilitates miniature excitatory synaptic transmission from primary afferents onto vertical and radial cells to initiate action potentials. The presence of TRPA1 channels on the central terminals raises the possibility of bidirectional modulatory action in morphologically identified subclasses of SG neurons.
Farmer, Adam D; Albu-Soda, Ahmed; Aziz, Qasim
The diverse array of end organ innervations of the vagus nerve, coupled with increased basic science evidence, has led to vagus nerve stimulation becoming a management option in a number of clinical disorders. This review discusses methods of electrically stimulating the vagus nerve and its current and potential clinical uses.
Man, G C; Man, S F; Kappagoda, C T
This study was undertaken to define the mechanism for the respiratory inhibition observed during high-frequency oscillatory ventilation (HFOV). The effects of HFOV on the activities of single units in the vagus (Vna) and phrenic nerves (Pna) were examined in pentobarbital-anesthetized dogs. The animals were either ventilated by intermittent positive-pressure ventilation (IPPV) with and without positive end-expiratory pressure (PEEP), or by HFOV at a frequency of 25 Hz and pump displacement volume of 3 ml/kg. In 13 vagal units the Vna was much higher during HFOV than during IPPV or airway occlusion at a matched airway pressure. Ten units in the phrenic nerves were examined, and Pna (expressed as bursts/min) was attenuated by HFOV in all of them. In four of them, the effect of cooling the vagi to 8-10 degrees C on Pna was examined, and it was found that HFOV failed to alter the Pna. We conclude that 1) HFOV stimulates the pulmonary vagal afferent fibers continuously and to a degree greater than that due to static lung inflation and increased airway pressure and 2) the increased vagal activity during HFOV probably causes phrenic nerve activity inhibition.
Sanguinetti, C; Tranquilli Leali, P; Grispigni, C
Retrograde axonal flow (R.A.F.) in the sciatic nerve of Sprague Dowley rats was studied by injecting horseradish peroxidase (H.R.P.) peripherally and identifying its appearance in the related segment of the spinal cord. This called for a precise identification of the vertebro-medullary topography, the afferant root levels of the sciatic nerve, and the transport velocity of the H.R.P. Our study revealed a clear difference of neuromuscular end plate permeability as between new-born and adult animals. The vertebral column of the rat consists of 8 cervical metameres, 13 dorsal, 6 lumbar, 4 sacral, and 3 coccygeal. The sciatic nerve is derived principally from the roots L4, L5, L6 and in part from L3 and S1. The injection of H.R.P. in the sural triceps of the new-born rat produced granules in the anterior horn cells as early as 12 hours later. In similar experiments with adult rats H.R.P. in the motorneurons was never detected. In our experimental model the transport velocity of H.R.P. from the point of injection to the anterior horn cells was approximately 68 mm per day. These findings provide a foundation on which to base future studies of retrograde flows in conditions of induced pathology.
Cui, Jian; McQuillan, Patrick M; Blaha, Cheryl; Kunselman, Allen R; Sinoway, Lawrence I
We have recently shown that a saline infusion in the veins of an arterially occluded human forearm evokes a systemic response with increases in muscle sympathetic nerve activity (MSNA) and blood pressure. In this report, we examined whether this response was a reflex that was due to venous distension. Blood pressure (Finometer), heart rate, and MSNA (microneurography) were assessed in 14 young healthy subjects. In the saline trial (n = 14), 5% forearm volume normal saline was infused in an arterially occluded arm. To block afferents in the limb, 90 mg of lidocaine were added to the same volume of saline in six subjects during a separate visit. To examine whether interstitial perfusion of normal saline alone induced the responses, the same volume of albumin solution (5% concentration) was infused in 11 subjects in separate studies. Lidocaine abolished the MSNA and blood pressure responses seen with saline infusion. Moreover, compared with the saline infusion, an albumin infusion induced a larger (MSNA: Δ14.3 ± 2.7 vs. Δ8.5 ± 1.3 bursts/min, P < 0.01) and more sustained MSNA and blood pressure responses. These data suggest that venous distension activates afferent nerves and evokes a powerful systemic sympathoexcitatory reflex. We posit that the venous distension plays an important role in evoking the autonomic adjustments seen with postural stress in human subjects.
De Riu, Pier Luigi; Russo, Antonella; Pellitteri, Rosalia; Stanzani, Stefania; Tringali, Giovanni; Roccazzello, Anna Maria; De Riu, Giacomo; Marongiu, Patrizia; Mameli, Ombretta
Alpha-tyrosinated tubulin is a cytoskeletal protein that is involved in axonal growth and is considered a marker of neuronal plasticity in adult mammals. In adult rats, unilateral ablation of the left facial sensorimotor cortical areas induces degeneration of corticotrigeminal projections and marked denervation of the contralateral sensory trigeminal nuclei. Western blotting and real-time-PCR of homogenates of the contralateral trigeminal ganglion (TG) revealed consistent overexpression of growth proteins 15 days after left decortication in comparison with the ipsilateral side. Immunohistochemical analyses indicated marked overexpression of alpha-tyrosinated tubulin in the cells of the ganglion on the right side. Cytoskeletal changes were primarily observed in the small ganglionic neurons. Application of HRP-CT, WGA-HRP, and HRP to infraorbital nerves on both sides 15 days after left decortication showed a significant degree of terminal sprouting and neosynaptogenesis from right primary afferents at the level of the right caudalis and interpolaris trigeminal subnuclei. These observations suggest that the adaptive response of TG neurons to central deafferentation, leading to overcrowding and rearrangement of the trigeminal primary afferent terminals on V spinal subnuclei neurons, could represent the anatomical basis for distortion of facial modalities, perceived as allodynia and hyperalgesia, despite nerve integrity.
Uncini, A; Pullman, S L; Lovelace, R E; Gambi, D
The sympathetic skin response (SSR), recorded at the hand and foot, was elicited using different classes of stimuli in 20 normal controls and 10 patients with peripheral neuropathy. We found that SSR latencies changed significantly with different recording sites, but not with different stimulation sites. Additionally, after ischemic conduction block of the arm in 3 normal controls, the previously obtainable SSR recorded at the hand became unobtainable with median nerve stimulation. Also, in one patient with subacute ganglionitis and 3 patients with demyelinating neuropathies, the SSR could not be elicited by electrical stimulation, but it could with deep inspiration. These results suggest that large diameter myelinated fibers may serve as afferents for the SSR. Furthermore, these findings imply that an unobtainable SSR by electrical stimulation may be due not only to dysfunction of the autonomic efferent nerve fibers, but also to abnormalities of the sensory afferents of the reflex. Therefore, investigations of autonomic dysfunction utilizing the SSR must be interpreted with caution in patients with peripheral neuropathies.
Bottjer, Sarah W; To, Michelle
Learned behaviors require coordination of diverse sensory inputs with motivational and motor systems. Although mechanisms underlying vocal learning in songbirds have focused primarily on auditory inputs, it is likely that sensory inputs from vocal effectors also provide essential feedback. We investigated the role of somatosensory and respiratory inputs from vocal effectors of juvenile zebra finches (Taeniopygia guttata) during the stage of sensorimotor integration when they are learning to imitate a previously memorized tutor song. We report that song production induced expression of the immediate early gene product Fos in trigeminal regions that receive hypoglossal afferents from the tongue and syrinx (the main vocal organ). Furthermore, unilateral lesion of hypoglossal afferents greatly diminished singing-induced Fos expression on the side ipsilateral to the lesion, but not on the intact control side. In addition, unilateral lesion of the vagus reduced Fos expression in the ipsilateral nucleus of the solitary tract in singing birds. Lesion of the hypoglossal nerve to the syrinx greatly disrupted vocal behavior, whereas lesion of the hypoglossal nerve to the tongue exerted no obvious disruption and lesions of the vagus caused some alterations to song behavior. These results provide the first functional evidence that somatosensory and respiratory feedback from peripheral effectors is activated during vocal production and conveyed to brainstem regions. Such feedback is likely to play an important role in vocal learning during sensorimotor integration in juvenile birds and in maintaining stereotyped vocal behavior in adults.
Habara, Hiromi; Hayashi, Yujiro; Inomata, Norio; Niijima, Akira; Kangawa, Kenji
Ghrelin plays multiple physiological roles such as growth hormone secretion and exerting orexigenic actions; however, its physiological roles in the electrical activity of autonomic nerves remain unclear. Here, we investigated the effects of human ghrelin on several autonomic nerve activities in urethane-anesthetized rats using an electrophysiological method. Intravenous injection of ghrelin at 3 μg/kg significantly and transiently potentiated the efferent activity of the gastric vagus nerve; however, it did not affect the efferent activity of the hepatic vagus nerve. The activated response to ghrelin in the gastric efferent vagus nerve was not affected by the gastric afferent vagotomy, suggesting that this effect was not induced via the gastric afferent vagus nerve. Ghrelin did not affect the efferent activity of the brown adipose tissue, adrenal gland sympathetic nerve, and the renal sympathetic nerve. In addition, rectal temperature and the plasma concentrations of norepinephrine, corticosterone, and renin were also not changed by ghrelin. These findings demonstrate that ghrelin stimulates the gastric efferent vagus nerve in an organ-specific manner without affecting the gastric afferent vagus nerve and that ghrelin does not acutely affect the efferent basal activity of the sympathetic nerve in rats.
Rabbitt, R. D.; Boyle, R.; Holstein, G. R.; Highstein, S. M.
The time course and extent of adaptation in semicircular canal hair cells was compared to adaptation in primary afferent neurons for physiological stimuli in vivo to study the origins of the neural code transmitted to the brain. The oyster toadfish, Opsanus tau, was used as the experimental model. Afferent firing-rate adaptation followed a double-exponential time course in response to step cupula displacements. The dominant adaptation time constant varied considerably among afferent fibers and spanned six orders of magnitude for the population (~1 ms to >1,000 s). For sinusoidal stimuli (0.1–20 Hz), the rapidly adapting afferents exhibited a 90° phase lead and frequency-dependent gain, whereas slowly adapting afferents exhibited a flat gain and no phase lead. Hair-cell voltage and current modulations were similar to the slowly adapting afferents and exhibited a relatively flat gain with very little phase lead over the physiological bandwidth and dynamic range tested. Semicircular canal microphonics also showed responses consistent with the slowly adapting subset of afferents and with hair cells. The relatively broad diversity of afferent adaptation time constants and frequency-dependent discharge modulations relative to hair-cell voltage implicate a subsequent site of adaptation that plays a major role in further shaping the temporal characteristics of semicircular canal afferent neural signals. PMID:15306633
Zakir, M.; Huss, D.; Dickman, J. D.
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.
Gervasio, Sabata; Voigt, Michael; Kersting, Uwe G.; Farina, Dario; Sinkjær, Thomas
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. PMID:28060839
Defourny, Jean; Poirrier, Anne-Lise; Lallemend, François; Mateo Sánchez, Susana; Neef, Jakob; Vanderhaeghen, Pierre; Soriano, Eduardo; Peuckert, Christiane; Kullander, Klas; Fritzsch, Bernd; Nguyen, Laurent; Moonen, Gustave; Moser, Tobias; Malgrange, Brigitte
Hearing requires an optimal afferent innervation of sensory hair cells by spiral ganglion neurons in the cochlea. Here we report that complementary expression of ephrin-A5 in hair cells and EphA4 receptor among spiral ganglion neuron populations controls the targeting of type I and type II afferent fibres to inner and outer hair cells, respectively. In the absence of ephrin-A5 or EphA4 forward signalling, a subset of type I projections aberrantly overshoot the inner hair cell layer and invade the outer hair cell area. Lack of type I afferent synapses impairs neurotransmission from inner hair cells to the auditory nerve. By contrast, radial shift of type I projections coincides with a gain of presynaptic ribbons that could enhance the afferent signalling from outer hair cells. Ephexin-1, cofilin and myosin light chain kinase act downstream of EphA4 to induce type I spiral ganglion neuron growth cone collapse. Our findings constitute the first identification of an Eph/ephrin-mediated mutual repulsion mechanism responsible for specific sorting of auditory projections in the cochlea.
Elinos-Calderón, Diana; Robledo-Arratia, Yolanda; Pérez-De La Cruz, Verónica; Pedraza-Chaverrí, José; Ali, Syed F; Santamaría, Abel
Cell rescue is a primary need during acute and chronic insults to the central nervous system. Functional preservation during the early stages of toxicity in a given degenerative event may represent a significant amelioration of detrimental processes linked to neuronal cell loss. Excitotoxicity and depleted cellular energy are toxic events leading to cell death in several neurodegenerative disorders. In this work, the effects of the well-known antioxidant and energy precursor, L: -carnitine (L: -CAR), were tested as a post-treatment in two neurotoxic models under in vitro and in vivo conditions. The experimental models tested included: (1) a typical excitotoxic and pro-oxidant inducer, quinolinic acid (QUIN); and (2) a mitochondrial energy inhibitor, 3-nitropropionic acid (3-NP). For in vitro studies, increasing concentrations of L: -CAR (10-1,000 microM) were added to the isolated brain synaptosomes at different times (1, 3 and 6 h) after the incubation with toxins (100 microM QUIN and 1 mM 3-NP), and 30 min later, lipid peroxidation (LP) and mitochondrial dysfunction (MD) were evaluated. For in vivo purposes, L: -CAR (100 mg/kg, i.p.) was given to rats either as a single administration 120 min after the intrastriatal infusion of QUIN (240 nmol/microl) or 3-NP (500 nmol/microl), or for 7 consecutive days (starting 120 min post-lesion). LP and MD were evaluated 4 h and 7 days post-lesions in isolated striatal synaptosomes. Our results show that, despite some variations depending on the toxic model tested, the time of exposure, or the biomarker evaluated, nerve ending protection can be mostly achieved by L: -CAR within the first hours after the toxic insults started, suggesting that targeting the ongoing oxidative damage and/or energy depletion during the first stages of neurotoxic events is essential to rescue nerve endings.
Dissecting the Influence of Two Structural Substituents on the Differential Neurotoxic Effects of Acute Methamphetamine and Mephedrone Treatment on Dopamine Nerve Endings with the Use of 4-Methylmethamphetamine and Methcathinone.
Anneken, John H; Angoa-Pérez, Mariana; Sati, Girish C; Crich, David; Kuhn, Donald M
Mephedrone (MEPH) is a β-ketoamphetamine stimulant drug of abuse that is often a constituent of illicit bath salts formulations. Although MEPH bears remarkable similarities to methamphetamine (METH) in terms of chemical structure, as well as its neurochemical and behavioral effects, it has been shown to have a reduced neurotoxic profile compared with METH. The addition of a β-keto moiety and a 4-methyl ring substituent to METH yields MEPH, and a loss of direct neurotoxic potential. In the present study, two analogs of METH, methcathinone (MeCa) and 4-methylmethamphetamine (4MM), were assessed for their effects on mouse dopamine (DA) nerve endings to determine the relative contribution of each individual moiety to the loss of direct neurotoxicity in MEPH. Both MeCa and 4MM caused significant alterations in core body temperature as well as locomotor activity and stereotypy, but 4MM was found to elicit minimal dopaminergic toxicity only at the highest dose. By contrast, MeCa caused significant reductions in all markers of DA nerve-ending damage over a range of doses. These results lead to the conclusion that ring substitution at the 4-position profoundly reduces the neurotoxicity of METH, whereas the β-keto group has much less influence on this property. Although the mechanism(s) by which the 4-methyl substituent reduces METH-induced neurotoxicity remains unclear, it is speculated that this effect is mediated by a loss of DA-releasing action in MEPH and 4MM at the synaptic vesicle monoamine transporter, an effect that is thought to be critical for METH-induced neurotoxicity.
Palmer, Gwen; Hibberd, Timothy J; Roose, Tiina; Brookes, Simon J H; Taylor, Mark
Mechanosensory neurons detect physical events in the local environments of the tissues that they innervate. Studies of mechanosensitivity of neurons or nerve endings in the gut have related their firing to strain, wall tension, or pressure. Digital image correlation (DIC) is a technique from materials engineering that can be adapted to measure the local physical environments of afferent neurons at high resolution. Flat-sheet preparations of guinea pig distal colon were set up with arrays of tissue markers in vitro. Firing of single viscerofugal neurons was identified in extracellular colonic nerve recordings. The locations of viscerofugal nerve cell bodies were inferred by mapping firing responses to focal application of the nicotinic receptor agonist 1,1-dimethyl-4-phenylpiperazinium iodide. Mechanosensory firing was recorded during load-evoked uniaxial or biaxial distensions. Distension caused movement of surface markers which was captured by video imaging. DIC tracked the markers, interpolating the mechanical state of the gut at the location of the viscerofugal nerve cell body. This technique revealed heterogeneous load-evoked strain within preparations. Local strains at viscerofugal nerve cell bodies were usually smaller than global strain measurements and correlated more closely with mechanosensitive firing. Both circumferential and longitudinal strain activated viscerofugal neurons. Simultaneous loading in circumferential and longitudinal axes caused the highest levels of viscerofugal neuron firing. Multiaxial strains, reflecting tissue shearing and changing area, linearly correlated with mechanosensory firing of viscerofugal neurons. Viscerofugal neurons were mechanically sensitive to both local circumferential and local longitudinal gut strain, and appear to lack directionality in their stretch sensitivity.
Liu, Quan; Chen, Dongmei; Wang, Yonggang; Zhao, Xin; Zheng, Yang
OBJECTIVE: To analyze the distribution characteristics of cardiac autonomic nerves and to explore the correlation between cardiac autonomic nerve distribution and arrhythmia. DATA RETRIEVAL: A computer-based retrieval was performed for papers examining the distribution of cardiac autonomic nerves, using heart, autonomic nerve, sympathetic nerve, vagus nerve, nerve distribution, rhythm and atrial fibrillation as the key words. SELECTION CRITERIA: A total of 165 studies examining the distribution of cardiac autonomic nerve were screened, and 46 of them were eventually included. MAIN OUTCOME MEASURES: The distribution and characteristics of cardiac autonomic nerves were observed, and immunohistochemical staining was applied to determine the levels of tyrosine hydroxylase and acetylcholine transferase (main markers of cardiac autonomic nerve distribution). In addition, the correlation between cardiac autonomic nerve distribution and cardiac arrhythmia was investigated. RESULTS: Cardiac autonomic nerves were reported to exhibit a disordered distribution in different sites, mainly at the surface of the cardiac atrium and pulmonary vein, forming a ganglia plexus. The distribution of the pulmonary vein autonomic nerve was prominent at the proximal end rather than the distal end, at the upper left rather than the lower right, at the epicardial membrane rather than the endocardial membrane, at the left atrium rather than the right atrium, and at the posterior wall rather than the anterior wall. The main markers used for cardiac autonomic nerves were tyrosine hydroxylase and acetylcholine transferase. Protein gene product 9.5 was used to label the immunoreactive nerve distribution, and the distribution density of autonomic nerves was determined using a computer-aided morphometric analysis system. CONCLUSION: The uneven distribution of the cardiac autonomic nerves is the leading cause of the occurrence of arrhythmia, and the cardiac autonomic nerves play an important role in
Chen, Wenling; McRoberts, James A.; Marvizón, Juan Carlos G.
Opiate analgesia in the spinal cord is impaired during neuropathic pain. We hypothesized that this is caused by a decrease in μ-opioid receptor inhibition of neurotransmitter release from primary afferents. To investigate this possibility, we measured substance P release in the spinal dorsal horn as neurokinin 1 receptor (NK1R) internalization in rats with chronic constriction injury (CCI) of the sciatic nerve. Noxious stimulation of the paw with CCI produced inconsistent NK1R internalization, suggesting that transmission of nociceptive signals by the injured nerve was variably impaired after CCI. This idea was supported by the fact that CCI produced only small changes in the ability of exogenous substance P to induce NK1R internalization or in the release of substance P evoked centrally from site of nerve injury. In subsequent experiments, NK1R internalization was induced in spinal cord slices by stimulating the dorsal root ipsilateral to CCI. We observed a complete loss of the inhibition of substance P release by the μ-opioid receptor agonist [D-Ala2, NMe-Phe4, Gly-ol5]-enkephalin (DAMGO) in CCI rats but not in sham-operated rats. In contrast, DAMGO still inhibited substance P release after inflammation of the hind paw with complete Freund’s adjuvant and in naïve rats. This loss of inhibition was not due to μ-opioid receptor downregulation in primary afferents, because their colocalization with substance P was unchanged, both in dorsal root ganglion neurons and primary afferent fibers in the dorsal horn. In conclusion, nerve injury eliminates the inhibition of substance P release by μ-opioid receptors, probably by hindering their signaling mechanisms. PMID:24583035
Oszlács, O; Jancsó, G; Kis, G; Dux, M; Sántha, P
The distribution of spinal primary afferent terminals labeled transganglionically with the choleratoxin B subunit (CTB) or its conjugates changes profoundly after perineural treatment with capsaicin. Injection of CTB conjugated with horseradish peroxidase (HRP) into an intact nerve labels somatotopically related areas in the ipsilateral dorsal horn with the exceptions of the marginal zone and the substantia gelatinosa, whereas injection of this tracer into a capsaicin-pretreated nerve also results in massive labeling of these most superficial layers of the dorsal horn. The present study was initiated to clarify the role of C-fiber primary afferent neurons in this phenomenon. In L5 dorsal root ganglia, analysis of the size frequency distribution of neurons labeled after injection of CTB-HRP into the ipsilateral sciatic nerve treated previously with capsaicin or resiniferatoxin revealed a significant increase in the proportion of small neurons. In the spinal dorsal horn, capsaicin or resiniferatoxin pretreatment resulted in intense CTB-HRP labeling of the marginal zone and the substantia gelatinosa. Electron microscopic histochemistry disclosed a dramatic, ∼10-fold increase in the proportion of CTB-HRP-labeled unmyelinated dorsal root axons following perineural capsaicin or resiniferatoxin. The present results indicate that CTB-HRP labeling of C-fiber dorsal root ganglion neurons and their central terminals after perineural treatment with vanilloid compounds may be explained by their phenotypic switch rather than a sprouting response of thick myelinated spinal afferents which, in an intact nerve, can be labeled selectively with CTB-HRP. The findings also suggest a role for GM1 ganglioside in the modulation of nociceptor function and pain.
Martelli, D; Yao, S T; McKinley, M J; McAllen, R M
We investigated a neural reflex that controls the strength of inflammatory responses to immune challenge - the inflammatory reflex. In anaesthetized rats challenged with intravenous lipopolysaccharide (LPS, 60 μg kg(-1)), we found strong increases in plasma levels of the key inflammatory mediator tumour necrosis factor α (TNFα) 90 min later. Those levels were unaffected by previous bilateral cervical vagotomy, but were enhanced approximately 5-fold if the greater splanchnic sympathetic nerves had been cut. Sham surgery had no effect, and plasma corticosterone levels were unaffected by nerve sections, so could not explain this result. Electrophysiological recordings demonstrated that efferent neural activity in the splanchnic nerve and its splenic branch was strongly increased by LPS treatment. Splenic nerve activity was dependent on inputs from the splanchnic nerves: vagotomy had no effect on the activity in either nerve. Together, these data demonstrate that immune challenge with this dose of LPS activates a neural reflex that is powerful enough to cause an 80% suppression of the acute systemic inflammatory response. The efferent arm of this reflex is in the splanchnic sympathetic nerves, not the vagi as previously proposed. As with other physiological responses to immune challenge, the afferent pathway is presumptively humoral: the present data show that vagal afferents play no measurable part. Because inflammation sits at the gateway to immune responses, this reflex could play an important role in immune function as well as inflammatory diseases.
Barbour, John R; Yee, Andrew; Moore, Amy M; Trulock, Elbert P; Buchowski, Jacob M; Mackinnon, Susan E
When relief from neuralgia cannot be achieved with traditional methods, neurectomy may be considered to abate the stimulus, and primary opposition of the terminal nerve ending is recommended to prevent neuroma. Nerve repair with autograft is limited by autologous nerves available for large nerve defects. Cadaveric allografts provide an unlimited graft source without donor-site morbidities, but are rapidly rejected unless appropriate immunosuppression is achieved. An optimal treatment method for nerve allograft transplantation would minimize rejection while simultaneously permitting nerve regeneration. This report details a novel experience of nerve allograft transplantation using cadaveric nerve grafts to desensitize persistent postoperative thoracic neuralgia.
Khan, Serajul I; Burne, John A
Electrical stimulation of the Achilles tendon produced strong reflex inhibition of the ongoing voluntary EMG activity in the two heads of the gastrocnemius (GA) muscle in all tested subjects. The inhibition was seen clearly in both averaged and single sweep surface EMG records. The inhibitory response was produced without electrical (M wave) or mechanical, (muscle twitch) signs of direct muscle stimulation. The onset latency and duration for the first period of inhibition (I(1)) were 47-49 ms and 67 ms, respectively. A second inhibition (I(2)) had an onset latency of 187-193 ms and duration under 40 ms. Non-noxious stimuli in the range of 2.6-7.6 x mean perceptual threshold, when delivered to four locations over the GA tendon, all produced clear inhibition of the voluntary muscle activity. The inhibition was maximal when the cathode was a large metal plate located near the musculotendinous junction and decreased approximately linearly with distances more distal to that site. The effect of passive muscle stretch on the electrically induced tendon reflex inhibition (TRE) was tested at ankle joint angles incremented in steps of 20 degrees. It was found that TRE is strongly dependent on joint angle, being maximal in the fully stretched muscle. TRE was lost completely after partial tibial nerve block. In comparison, GA inhibition produced by cutaneous (sural) nerve stimulation was of a higher threshold, longer latency and persisted after partial tibial nerve block. We thus demonstrated a powerful autogenic inhibition in the lower limb arising from tendon afferents in conscious subjects that is increased by passive muscle stretch and likely to originate from group I tendon afferents.
Canning, B J; Undem, B J
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
Si, X.; Angelaki, D. E.; Dickman, J. D.
In the present study, the sensitivity to sinusoidal linear accelerations in the plane of the utricular macula was tested in afferents. The head orientation relative to the translation axis was varied in order to determine the head position that elicited the maximal and minimal responses for each afferent. The response gain and phase values obtained to 0.5-Hz and 2-Hz linear acceleration stimuli were then plotted as a function of head orientation and a modified cosine function was fit to the data. From the best-fit cosine function, the predicted head orientations that would produce the maximal and minimal response gains were estimated. The estimated maximum response gains to linear acceleration in the utricular plane for the afferents varied between 75 and 1420 spikes s-1 g-1. The mean maximal gains for all afferents to 0.5-Hz and 2-Hz sinusoidal linear acceleration stimuli were 282 and 367 spikes s-1 g-1, respectively. The minimal response gains were essentially zero for most units. The response phases always led linear acceleration and remained constant for each afferent, regardless of head orientation. These response characteristics indicate that otolith afferents are cosine tuned and behave as one-dimensional linear accelerometers. The directions of maximal sensitivity to linear acceleration for the afferents varied throughout the plane of the utricle; however, most vectors were directed out of the opposite ear near the interaural axis. The response dynamics of the afferents were tested using stimulus frequencies ranging between 0.25 Hz and 10 Hz (0.1 g peak acceleration). Across stimulus frequencies, most afferents had increasing gains and constant phase values. These dynamic properties for individual afferents were fit with a simple transfer function that included three parameters: a mechanical time constant, a gain constant, and a fractional order distributed adaptation operator.
He, Qian-ru; Cong, Meng; Chen, Qing-zhong; Sheng, Ya-feng; Li, Jian; Zhang, Qi; Ding, Fei; Gong, Yan-pei
The expression of nerve cell adhesion molecule L1 in the neuronal growth cone of the central nervous system is strongly associated with the direction of growth of the axon, but its role in the regeneration of the peripheral nerve is still unknown. This study explored the problem in a femoral nerve section model in rats. L1 and semaphorin 3A mRNA and protein expressions were measured over the 4-week recovery period. Quantitative polymerase chain reaction showed that nerve cell adhesion molecule L1 expression was higher in the sensory nerves than in motor nerves at 2 weeks after injury, but vice versa for the expression of semaphorin 3A. Western blot assay results demonstrated that nerve cell adhesion molecule L1 expression was higher in motor nerves than in the sensory nerves at the proximal end after injury, but its expression was greater in the sensory nerves at 2 weeks. Semaphorin 3A expression was higher in the motor nerves than in the sensory nerves at 3 days and 1 week after injury. Nerve cell adhesion molecule L1 and semaphorin 3A expressions at the distal end were higher in the motor nerves than in the sensory nerves at 3 days, 1 and 2 weeks. Immunohistochemical staining results showed that nerve cell adhesion molecule L1 expression at the proximal end was greater in the sensory nerves than in the motor nerves; semaphorin 3A expression was higher in the motor nerves than in the sensory nerves at 2 weeks after injury. Taken together, these results indicated that nerve cell adhesion molecules L1 and semaphorin 3A exhibited different expression patterns at the proximal and distal ends of sensory and motor nerves, and play a coordinating role in neural chemotaxis regeneration. PMID:28197202
Rudomin, P; Hernández, E
The present series of experiments was designed to examine, in the anesthetized cat, the extent to which the synaptic efficacy of knee joint afferents is modified during the state of central sensitization produced by the injection of capsaicin into the hindlimb plantar cushion. We found that the intradermic injection of capsaicin increased the N2 and N3 components of the focal potentials produced by stimulation of intermediate and high threshold myelinated fibers in the posterior articular nerve (PAN), respectively. This facilitation lasted several hours, had about the same time course as the paw inflammation and was more evident for the N2 and N3 potentials recorded within the intermediate zone in the L6 than in the L7 spinal segments. The capsaicin-induced facilitation of the N2 focal potentials, which are assumed to be generated by activation of fibers signaling joint position, suggests that nociception may affect the processing of proprioceptive and somato-sensory information and, probably also, movement. In addition, the increased effectiveness of these afferents could activate, besides neurons in the intermediate region, neurons located in the more superficial layers of the dorsal horn. As a consequence, normal joint movements could produce pain representing a secondary hyperalgesia. The capsaicin-induced increased efficacy of the PAN afferents producing the N3 focal potentials, together with the reduced post-activation depression that follows high frequency autogenetic stimulation of these afferents, could further contribute to the pain sensation from non-inflamed joints during skin inflammation in humans. The persistence, after capsaicin, of the inhibitory effects produced by stimulation of cutaneous nerves innervating non-inflamed skin regions may account for the reported reduction of the articular pain sensations produced by trans-cutaneous stimulation.
Yi, Eunyoung; Roux, Isabelle; Glowatzki, Elisabeth
Synaptic transmission at the inner hair cell (IHC) afferent synapse, the first synapse in the auditory pathway, is specialized for rapid and reliable signaling. Here we investigated the properties of a hyperpolarization-activated current (I(h)), expressed in the afferent dendrite of auditory nerve fibers, and its role in shaping postsynaptic activity. We used whole cell patch-clamp recordings from afferent dendrites directly where they contact the IHC in excised postnatal rat cochlear turns. Excitatory postsynaptic potentials (EPSPs) of variable amplitude (1-35 mV) were found with 10-90% rise times of about 1 ms and time constants of decay of about 5 ms at room temperature. Current-voltage relations recorded in afferent dendrites revealed I(h). The pharmacological profile and reversal potential (-45 mV) indicated that I(h) is mediated by hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channels. The HCN channel subunits HCN1, HCN2, and HCN4 were found to be expressed in afferent dendrites using immunolabeling. Raising intracellular cAMP levels sped up the activation kinetics, increased the magnitude of I(h) and shifted the half activation voltage (V(half)) to more positive values (-104 +/- 3 to -91 +/- 2 mV). Blocking I(h) with 50 microM ZD7288 resulted in hyperpolarization of the resting membrane potential (approximately 4 mV) and slowing the decay of the EPSP by 47%, suggesting that I(h) is active at rest and shortens EPSPs, thereby potentially improving rapid and reliable signaling at this first synapse in the auditory pathway.
Hudson, Kathryn M; Condon, Melia; Ackerley, Rochelle; McGlone, Francis; Olausson, Håkan; Macefield, Vaughan G; Birznieks, Ingvars
It is not known how changes in skin mechanics affect the responses of cutaneous mechanoreceptors in the finger pads to compression forces. We used venous occlusion to change the stiffness of the fingers and investigated whether this influenced the firing of low-threshold mechanoreceptors to surfaces of differing stiffness. Unitary recordings were made from 10 slowly adapting type I (SAI), 10 fast adapting type I (FAI) and 9 slowly adapting type II (SAII) units via tungsten microelectrodes inserted into the median nerve at the wrist. A servo-controlled stimulator applied ramp-and-hold forces (1, 2, and 4 N) at a constant loading and unloading rate (2 N/s) via a flat 2.5-cm-diameter silicone disk over the center of the finger pad. Nine silicone disks (objects), varying in compliance, were used. Venous occlusion, produced by inflating a sphygmomanometer cuff around the upper arm to 40 ± 5 mmHg, was used to induce swelling of the fingers and increase the compliance of the finger pulp. Venous occlusion had no effect on the firing rates of the SAI afferents, nor on the slopes of the relationship between mean firing rate and object compliance at each amplitude, but did significantly reduce the slopes for the FAI afferents. Although the SAII afferents possess a poor capacity to encode changes in object compliance, mean firing rates were significantly lower during venous occlusion. The finding that venous occlusion had no effect on the firing properties of SAI afferents indicates that these afferents preserve their capacity to encode changes in object compliance, despite changes in skin mechanics.
Hudson, Kathryn M.; Condon, Melia; Ackerley, Rochelle; McGlone, Francis; Olausson, Håkan; Birznieks, Ingvars
It is not known how changes in skin mechanics affect the responses of cutaneous mechanoreceptors in the finger pads to compression forces. We used venous occlusion to change the stiffness of the fingers and investigated whether this influenced the firing of low-threshold mechanoreceptors to surfaces of differing stiffness. Unitary recordings were made from 10 slowly adapting type I (SAI), 10 fast adapting type I (FAI) and 9 slowly adapting type II (SAII) units via tungsten microelectrodes inserted into the median nerve at the wrist. A servo-controlled stimulator applied ramp-and-hold forces (1, 2, and 4 N) at a constant loading and unloading rate (2 N/s) via a flat 2.5-cm-diameter silicone disk over the center of the finger pad. Nine silicone disks (objects), varying in compliance, were used. Venous occlusion, produced by inflating a sphygmomanometer cuff around the upper arm to 40 ± 5 mmHg, was used to induce swelling of the fingers and increase the compliance of the finger pulp. Venous occlusion had no effect on the firing rates of the SAI afferents, nor on the slopes of the relationship between mean firing rate and object compliance at each amplitude, but did significantly reduce the slopes for the FAI afferents. Although the SAII afferents possess a poor capacity to encode changes in object compliance, mean firing rates were significantly lower during venous occlusion. The finding that venous occlusion had no effect on the firing properties of SAI afferents indicates that these afferents preserve their capacity to encode changes in object compliance, despite changes in skin mechanics. PMID:26269550
Fox, A J; Barnes, P J; Dray, A
1. Inhalation of low-chloride or non-isosmotic solutions evokes cough or reflex bronchoconstriction in humans that is inhibited by frusemide (furosemide), whilst capsaicin-evoked cough is unaffected. Here we have examined the responses of single vagal afferent fibres innervating the isolated guinea-pig trachea to these stimuli, and tested the effect of frusemide on fibre responses. 2. Both distilled water and hypertonic saline applied for 30 s onto identified receptive fields produced marked excitation of all A delta and C fibres tested. Isotonic glucose, a low-chloride solution, was a less potent stimulant and caused excitation in 37% of A delta fibres and 69% of C fibres. There was no difference in the distribution of low-chloride sensitive and insensitive receptive fields. 3. In the presence of frusemide, responses of A delta fibres to isotonic glucose were significantly inhibited to 34.2 +/- 6.2% of the pre-drug control level. However, frusemide was without effect either on responses of A delta fibres to distilled water or hypertonic saline, or on responses of C fibres to capsaicin. 4. These data support a role for tracheo-bronchial A delta and C fibres in airway reflexes evoked by hypotonic, hypertonic and low-chloride stimuli. The protective effect of frusemide against airway responses to low-chloride but not to non-isosmotic solutions may reflect an action on sensory nerve endings.
... Sometimes the needle has to be inserted fairly deep to reach the nerve causing your problem. This ... understanding of the possible charges you will incur. Web page review process: This Web page is reviewed ...
Fernandez, C.; Lysakowski, A.; Goldberg, J. M.
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
Colado, M I; O'Shea, E; Granados, R; Esteban, B; Martín, A B; Green, A R
We investigated whether dopamine plays a role in the neurodegeneration of 5-hydroxytryptamine (5-HT) nerve endings occurring in Dark Agouti rat brain after 3,4-methylenedioxymethamphetamine (MDMA or ‘ecstasy') administration. Haloperidol (2 mg kg−1 i.p.) injected 5 min prior and 55 min post MDMA (15 mg kg−1 i.p.) abolished the acute MDMA-induced hyperthermia and attenuated the neurotoxic loss of 5-HT 7 days later. When the rectal temperature of MDMA+haloperidol treated rats was kept elevated, this protective effect was marginal. MDMA (15 mg kg−1) increased the dopamine concentration in the dialysate from a striatal microdialysis probe by 800%. L-DOPA (25 mg kg−1 i.p., plus benserazide, 6.25 mg kg−1 i.p.) injected 2 h after MDMA (15 mg kg−1) enhanced the increase in dopamine in the dialysate, but subsequent neurodegeneration was unaltered. L-DOPA (25 mg kg−1) injected before a sub-toxic dose of MDMA (5 mg kg−1) failed to induce neurodegeneration. The MDMA-induced increase in free radical formation in the hippocampus (indicated by increased 2,3- and 2,5-dihydroxybenzoic acid in a microdialysis probe perfused with salicylic acid) was unaltered by L-DOPA. The neuroprotective drug clomethiazole (50 mg kg−1 i.p.) did not influence the MDMA-induced increase in extracellular dopamine. These data suggest that previous observations on the protective effect of haloperidol and potentiating effect of L-DOPA on MDMA-induced neurodegeneration may have resulted from effects on MDMA-induced hyperthermia. The increased extracellular dopamine concentration following MDMA may result from effects of MDMA on dopamine re-uptake, monoamine oxidase and 5-HT release rather than an ‘amphetamine-like' action on dopamine release, thus explaining why the drug does not induce degeneration of dopamine nerve endings. PMID:10193771
Sata, Yusuke; Schlaich, Markus P
Sympathetic activation is a hallmark of chronic and end-stage renal disease and adversely affects cardiovascular prognosis. Hypertension is present in the vast majority of these patients and plays a key role in the progressive deterioration of renal function and the high rate of cardiovascular events in this patient cohort. Augmentation of renin release, tubular sodium reabsorption, and renal vascular resistance are direct consequences of efferent renal sympathetic nerve stimulation and the major components of neural regulation of renal function. Renal afferent nerve activity directly influences sympathetic outflow to the kidneys and other highly innervated organs involved in blood pressure control via hypothalamic integration. Renal denervation of the kidney has been shown to reduce blood pressure in many experimental models of hypertension. Targeting the renal nerves directly may therefore be specifically useful in patients with chronic and end-stage renal disease. In this review, we will discuss the potential role of catheter-based renal denervation in patients with impaired kidney function and also reflect on the potential impact on other cardiovascular conditions commonly associated with chronic kidney disease such as heart failure and arrhythmias.
Cochran, S. L.
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
Lewis, Edwin R.
The long-range goal of this research was to refine our understanding of the sensitivity of the vestibular components of the ear to very-low-amplitude motion, especially, the role of gravity in this sensitivity. We focused on the American bullfrog--a common animal subject for vestibular sensory research. Our principal experimental method was to apply precise, sinusoidal microrotational stimuli to an anesthetized animal subject, to record the resulting responses in an individual vestibular nerve fiber from the intact ear, and to use intracellular dye to trace the fiber and thus identify the vestibular sensor that gave rise to it. In this way, we were able to identify specific micromotional sensitivities and to associate those sensitivities definitely with specific sensors. Furthermore, by recording from nerve fibers after they leave the intact inner-ear cavity, we were able to achieve these identifications without interrupting the delicate micromechanics of the inner ear. We were especially concerned with the relative roles of the utricle and the anterior semicircular canal in the sensing of microrotational motion of the head about horizontal axes, and with the role of gravity in mediating that sensing process in the utricle. The functional characterization of individual nerve fibers was accomplished with a conventional analytical tool, the cycle histogram, in which the nerve impulse rate was plotted against the phase of the sinusoidal stimulus.
The anatomy of the intratemporal part of the vestibular nerve in man, and the possible age related degenerative changes in the nerve were studied. The form and structure of the vestibular ganglion was studied with the light microscope. A numerical analysis of the vestibular nerve, and caliber spectra of the myelinated fibers in the vestibular nerve branches were studied in individuals of varying ages. It was found that the peripheral endings of the vestibular nerve form a complicated pattern inside the vestibular sensory epithelia. A detailed description of the sensory cells and their surface organelles is included.
around the nerve ends performed following application of 0.1% Rose Bengal dye in saline to wrap and epineurium with illumination at 532 nm. The HAM...results obtained with the three fixation methods under study (a) epineurial suture, (b) fibrin glue and (c) photochemical tissue bonding (PTB) with a...wrap material. All methods induced bonding between the nerve segments with bond strength in the order of suture>PTB> fibrin glue. Conventional
harvested from donor rats immediately post-euthanasia (Task 1g) and bonding of the wrap around the nerve ends performed following application of 0.1...a) epineurial suture, (b) fibrin glue and (c) photochemical tissue bonding (PTB) with a wrap material. All methods induced bonding between the nerve...segments with bond strength in the order of suture>PTB> fibrin glue. Conventional epineurial suturing using six 10.0 nylon sutures resulted in the
Woodland, Philip; Aktar, Rubina; Mthunzi, Engelbert; Lee, Chung; Peiris, Madusha; Preston, Sean L; Blackshaw, L Ashley; Sifrim, Daniel
Little is known about the mucosal phenotype of the proximal human esophagus. There is evidence to suggest that the proximal esophagus is more sensitive to chemical and mechanical stimulation compared with the distal. This may have physiological relevance (e.g., in prevention of aspiration of gastroesophageal refluxate), but also pathological relevance (e.g., in reflux perception or dysphagia). Reasons for this increased sensitivity are unclear but may include impairment in mucosal barrier integrity or changes in sensory innervation. We assessed mucosal barrier integrity and afferent nerve distribution in the proximal and distal esophagus of healthy human volunteers. In 10 healthy volunteers baseline proximal and distal esophageal impedance was measured in vivo. Esophageal mucosal biopsies from the distal and proximal esophagus were taken, and baseline transepithelial electrical resistance (TER) was measured in Ussing chambers. Biopsies were examined immunohistochemically for presence and location of calcitonin gene-related peptide (CGRP)-immunoreactive nerve fibers. In a further four healthy volunteers we investigated for colocalization of CGRP and protein gene product (PGP) 9.5 immunoreactivity in nerve fibers. Baseline impedance was higher in the proximal than in the distal esophagus [2,936 Ω (SD578) vs. 2,229 Ω (SD821); P = 0.03], however, baseline TER was not significantly different between them. Mucosal CGRP-immunoreactive nerves were found in the epithelium of both proximal and distal esophagus, but were located more superficially in the proximal mucosa compared with the distal [11.5 (SD7) vs. 21.7 (SD5) cell layers from lumen, P = 0.002] 19% of proximal, and 10% of distal mucosal PGP-immunoreactive fibers colocalized with CGRP. PGP-immunoreactive fibers were also significantly closer to the luminal surface in the proximal compared with the distal esophagus (P < 0.001). We conclude that mucosal barrier integrity is similar in proximal and distal esophagus
Simonetta-Moreau, M; Marque, P; Marchand-Pauvert, V; Pierrot-Deseilligny, E
Heteronymous group II effects were investigated in the human lower limb. Changes in firing probability of single motor units in quadriceps (Q), biceps (Bi), semitendinosus (ST), gastrocnemius medialis (GM) and tibialis anterior (TA) were studied after electrical stimuli between 1 and 3 times motor threshold (MT) applied to common peroneal (CP), superficial (SP) and deep (DP) peroneal, Bi and GM nerves in those nerve-muscle combinations without recurrent inhibition. Stimulation of the CP and Bi nerves evoked in almost all of the explored Q motor units a biphasic excitation with a low-threshold early peak, attributable to non-monosynaptic group I excitation, and a higher threshold late peak. When the CP nerve was cooled (or the stimulation applied to a distal branch, DP), the increase in latency was greater for the late than for the early peak, indicating that the late excitation is due to stimulation of afferents with a slower conduction velocity than group I fibres, presumably in the group II range. In ST motor units the group II excitation elicited by stimulation of the GM and SP nerves was particularly large and frequent, and the non-monosynaptic group I excitation was often replaced by an inhibition. A late group II-induced excitation from CP to Q motoneurones and from GM and SP to ST motoneurones was also observed when using the H reflex as a test. The electrical threshold and conduction velocity of the largest diameter fibres evoking the group II excitation were estimated to be 2·1 and 0·65 times those of the fastest Ia afferents, respectively. In the combinations tested in the present investigation the group II input seemed to be primarily of muscle origin. The potent heteronymous group II excitation of motoneurones of both flexors and extensors of the knee contrasted with the absence of a group II effect from DP to GM and from GM to TA. In none of the combinations explored was there any evidence for group II inhibition of motoneurones. The possible
Lin, Yu-Jung; Lin, Ruei-Lung; Ruan, Ting; Khosravi, Mehdi; Lee, Lu-Yuan
Transient receptor potential ankyrin type 1 (TRPA1) and vanilloid type 1 (TRPV1) receptors are coexpressed in vagal pulmonary C-fiber sensory nerves. Because both these receptors are sensitive to a number of endogenous inflammatory mediators, it is conceivable that they can be activated simultaneously during airway inflammation. This study aimed to determine whether there is an interaction between these two polymodal transducers upon simultaneous activation, and how it modulates the activity of vagal pulmonary C-fiber sensory nerves. In anesthetized, spontaneously breathing rats, the reflex-mediated apneic response to intravenous injection of a combined dose of allyl isothiocyanate (AITC, a TRPA1 activator) and capsaicin (Cap, a TRPV1 activator) was ∼202% greater than the mathematical sum of the responses to AITC and Cap when they were administered individually. Similar results were also observed in anesthetized mice. In addition, the synergistic effect was clearly demonstrated when the afferent activity of single vagal pulmonary C-fiber afferents were recorded in anesthetized, artificially ventilated rats; C-fiber responses to AITC, Cap and AITC + Cap (in combination) were 0.6 ± 0.1, 0.8 ± 0.1, and 4.8 ± 0.6 impulses/s (n = 24), respectively. This synergism was absent when either AITC or Cap was replaced by other chemical activators of pulmonary C-fiber afferents. The pronounced potentiating effect was further demonstrated in isolated vagal pulmonary sensory neurons using the Ca(2+) imaging technique. In summary, this study showed a distinct positive interaction between TRPA1 and TRPV1 when they were activated simultaneously in pulmonary C-fiber sensory nerves.
LaBella, L A; McCrea, D A
1. We previously reported that excitatory postsynaptic potentials (EPSPs) produced by low-threshold electrical stimulation of the caudal cutaneous sural nerve (CCS) occur preferentially and with the shortest central latencies in the medial gastrocnemius (MG) portion of the triceps surae motor nuclei. The present study employs the spatial facilitation technique to assess interneuronal convergence on the short-latency excitatory pathway from CCS to MG by several other ipsilateral hindlimb afferents [the lateral cutaneous sural (LCS), caudal cutaneous femoral (CCF), saphenous (SAPH), superficial peroneal (SP), posterior tibial (TIB), and posterior articular (Joint) nerves]. 2. Spatial facilitation of CCF EPSPs in MG motoneurons was demonstrated with conditioning stimulation of the LCS, CCF, SAPH, SP, and TIB nerves, but was most readily and consistently observed with CCF conditioning. Facilitation of CCS and CCF EPSPs was obtained in individual MG motoneurons with a wide range of condition-test intervals. 3. CCF EPSPs in MG motoneurons produced by twice threshold (2T) afferent stimulation had a mean latency of 4.8 ms and often appeared as slowly rising, asynchronous potentials. On the other hand, 2T CCS EPSPs had a mean latency of 2.8 ms and appeared as sharper rising, less variable depolarizations. The optimum condition-test interval for facilitation of CCS and CCF EPSPs was found to be 5.2 ms on average, with CCS stimulation delayed from that of CCF. The longer latency of CCF EPSPs and the finding that the minimum condition-test interval was on the order of 3.9 ms suggests that convergence occurs late in the excitatory CCF pathway to MG motoneurons. 4. Convergence between excitatory pathways to MG from CCF and CCS afferents is discussed with regard to the original observations of Hagbarth on the location of cutaneous receptive fields and excitation of ankle extensors. In addition, evidence for the segregation of these specialized reflex pathways from those involved
Zhu, Guo-Qing; Gao, Xing-Ya; Zhang, Feng; Wang, Wei
The purpose of this study was to determine the effect of nitric oxide (NO) in the rostral ventrolateral medulla (RVLM) on the central integration of the cardiac sympathetic afferent reflex (CSAR) in normal rats and in rats with coronary ligation-induced chronic heart failure (CHF). Under alpha-chloralose and urethane anesthesia, mean arterial pressure, heart rate and renal sympathetic nerve activity (RSNA) were recorded at baseline and during elicitation of the CSAR evoked by electrical stimulation of the cardiac afferent sympathetic nerves in sino-aortic denervated and cervical vagotomized rats. A cannula was inserted into the left RVLM for microinjection of NO synthase inhibitor, S-methyl-L-thiocitruline (MeTC) or NO donor, S-nitroso-N-acetyl-penicillamine (SNAP). The CSAR was tested by electrical stimulation (5, 10, 20 and 30 Hz at 10 V for 1 ms) of the afferent cardiac sympathetic nerves. It was observed that (1) the responses of RSNA to stimulation were enhanced in rats with CHF; (2) MeTC (80 nmol) potentiated the responses of RSNA to stimulation in sham rats but not in rats with CHF; (3) SNAP (50 nmol) depressed the enhanced RSNA response to stimulation in CHF rats but had no effect in sham rats; and (4) MeTC increased the baseline RSNA and MAP only in sham rats, but SNAP inhibited the baseline RSNA and MAP in both sham and CHF rats. These results indicate that reductance of NO in the RVLM is involved in the augmentation of CSAR in CHF rats.
Bensmaïa, S J; Craig, J C; Yoshioka, T; Johnson, K O
SA1 and RA afferent fibers differ both in their ability to convey information about the fine spatial structure of tactile stimuli and in their frequency sensitivity profiles. In the present study, we investigated the extent to which the spatial resolution of the signal conveyed by SA1 and RA fibers depends on the temporal properties of the stimulus. To that end, we recorded the responses evoked in SA1 and RA fibers of macaques by static and vibrating gratings that varied in spatial period, vibratory frequency, and amplitude. Gratings were oriented either parallel to the long axis of the finger (vertical) or perpendicular to it (horizontal). We examined the degree to which afferent responses were dependent on the spatial period, vibratory frequency, amplitude, and orientation of the gratings. We found that the spatial modulation of the afferent responses increased as the spatial period of the gratings increased; the spatial modulation was the same for static and vibrating gratings, despite large differences in evoked spike rates; the spatial modulation in SA1 responses was independent of stimulus amplitude over the range of amplitudes tested, whereas RA modulation decreased slightly as the stimulus amplitude increased; vertical gratings evoked stronger and more highly modulated responses than horizontal gratings; the modulation in SA1 responses was higher than that in RA responses at all frequencies and amplitudes. The behavioral consequences of these neurophysiological findings are examined in a companion paper.
Nielsen, J; Petersen, N; Fedirchuk, B
1. Stimulation of the superficial peroneal or the sural nerve (3 shocks, 3 ms interval, 1 ms duration, 2.5 x perception threshold) evoked a reflex activation of the tibialis anterior muscle at a latency of approximately 70-95 ms in all of nine healthy human subjects. Stimulation of the medial plantar nerve only rarely produced similar effects. The possibility that a transcortical pathway contributes to these late reflex responses was investigated by combining the cutaneous stimulations and a transcranial magnetic stimulation of the contralateral motor cortex. 2. A significant facilitation of short-latency peaks in the post-stimulus time histogram of single tibialis anterior motor units evoked by the transcortical magnetic stimulation was observed in eight out of nine subjects following stimulation of the superficial peroneal or sural nerves at the latency of the long-latency reflex. In contrast such a facilitation was only rarely seen when the medial plantar nerve was stimulated. 3. With the same timing for the stimuli, the superficial peroneal and sural nerve stimulations also produced a significant increase in the short-latency, presumed monosynaptic, facilitation of the tibialis anterior H reflex produced by the brain stimulation. 4. Similar facilitatory effects of the cutaneous stimuli could not be demonstrated when the magnetic stimulation of the cortex was replaced with electrical stimulation, implying that cortical excitability is affected by a conditioning cutaneous stimulation. 5. It is suggested that the long-latency reflexes in the tibialis anterior muscle evoked by activation of cutaneous afferents from the human foot are, at least partly, mediated by a transcortical pathway. PMID:9192318
... Nerve Decompression Dacryocystorhinostomy (DCR) Disclosure Statement Printer Friendly Optic Nerve Decompression John Lee, MD Introduction Optic nerve decompression is a surgical procedure aimed at ...
Neuropathy - ulnar nerve; Ulnar nerve palsy; Mononeuropathy; Cubital tunnel syndrome ... compressed in the elbow, a problem called cubital tunnel syndrome may result. When damage destroys the nerve ...
Shi, J G; Xu, X M; Sun, J C; Wang, Y; Guo, Y F; Yang, H S; Kong, Q J; Yang, Y; Shi, G D; Yuan, W; Jia, L S
Objective: To define a novel disease-lumbosacral nerve bowstring disease, and propose the diagnostic criteria, while capsule surgery was performed and evaluated in the preliminary study. Methods: From June 2016 to December 2016, a total of 30 patients (22 male and 8 female; mean age of 55.1±9.7 years) with lumbosacral nerve bowstring disease were included in Department of Spine Surgery, Changzheng Hospital, the Second Military Medical University.Lumbosacral nerve bowstring disease was defined as axial hypertension of nerve root and spinal cord caused by congenital anomalies, which could be accompanied by other lesions as lumbar disc herniation, spinal cord stenosis or spondylolisthesis, or aggravated by iatrogenic lesions, resulting in neurological symptoms.This phenomenon is similar to a stretched string, the higher tension on each end the louder sound.Meanwhile, the shape of lumbosacral spine looks like a bow, thus, the disease is nominated as lumbosacral nerve bowstring disease.All the patients underwent capsule surgery and filled out Owestry disability index (ODI) and Tempa scale for kinesiophobia (TSK) before and after surgery. Results: The mean surgery time was (155±36) min, (4.3±0.4) segments were performed surgery.The pre-operative VAS, TSK and ODI scores were (7.6±0.8), (52.0±10.3) and (68.4±12.7), respectively.The post-operative VAS, TSK and ODI scores were (3.3±0.4), ( 24.6±5.2) and (32.1±7.4)(P<0.05, respectively), respectively. Conclusion: The definition and diagnostic criteria of lumbosacral nerve bowstring disease was proposed.Capsule surgery was an effective strategy with most patients acquired excellent outcomes as symptoms relieved and quality of life improved.
Xing, Nian-Zeng; Kang, Ning; Song, Li-Mming; Niu, Yi-Nong; Wang, Ming-Shuai; Zhang, Jun-Hui
ABSTRACT Purpose To introduce a new method of constructing an orthotopic ileal neobladder with bilateral isoperistaltic afferent limbs, and to describe its clinical outcomes. Materials and Methods From January 2012 to December 2013, 16 patients underwent a new method of orthotopic ileal neobladder after laparoscopic radical cystectomy for bladder cancer. To construct the neobladder, an ileal segment 60cm long was isolated approximately 25cm proximally to the ileocecum. The proximal 20cm of the ileal segment was divided into two parts for bilateral isoperistaltic afferent limbs. The proximal 10cm of the ileal segment was moved to the distal end of the ileal segment for the right isoperistaltic afferent limb, and the remaining proximal 10cm ileal segment was reserved for the left isoperistaltic afferent limb. The remaining length of the 40cm ileal segment was detubularized along its antimesenteric border to form a reservoir. The neobladder was sutured to achieve a spherical configuration. Results All procedures were carried out successfully. The mean operative time was 330 min, mean blood loss was 328mL, and mean hospital stay was 12.5 days. The mean neobladder capacity 6 and 12 months after surgery was 300mL and 401mL, respectively. With a mean follow-up of 22.8 months, all patients achieved daytime continence and 15 achieved nighttime continence. The mean peak urinary flow rate was 11.9mL/s and 12.8mL/s at 6 and 12 months postoperatively, respectively. Conclusions This novel procedure is feasible, safe, simple to perform, and provides encouraging functional outcomes. However, comparative studies with long-term follow-up are required to prove its superiority. PMID:28124527
Jiménez, I; Rudomín, P; Solodkin, M; Vyklický, L
In the spinal cord of the anesthetized cat, we measured the changes in extracellular concentration of potassium ions [K+]e and the negative DC shifts produced by stimulation of muscle, cutaneous and mixed afferent nerves, together with alterations in the threshold of single group Ia fibers that were tested at the same site as the potassium measurements. This approach provided information on the extent to which the excitability changes of single Ia-fibers can be correlated with the changes in [K+]e occurring at the same site. Stimulation of the tibial (TIB) nerve and of the cutaneous sural (SU), and superficial peroneous (SP) nerve (100-Hz trains lasting 30-60 s) with stimulus strengths of 10-15 times threshold increased the concentration of [K+]e in the dorsal horn by 2-5 mmol/l above the resting value of 3 mmol/l. This was in clear contrast with the very small [K+]e increases produced at the same site during stimulation of muscle nerves, such as the posterior biceps and semitendinosus (PBSt), gastrocnemius soleus (GS), and deep peroneus (DP), which were generally smaller than 0.25 mmol/l. Stimulation of the PBSt and GS muscle nerves did produce small, but clear, increases of [K+]e (up to 0.3 mmol/l) in the region of the intermediate nucleus, where these fibers synapse with second order cells. These changes were nevertheless smaller than those produced at the same site by stimulation of the TIB, SU, and SP nerves. The peak amplitudes of the [K+]e transients produced by long-lasting 100-Hz trains applied to cutaneous and/or to muscle nerves showed a linear relationship with the amplitudes of the slow negative DC shifts, which were simultaneously recorded from the NaCl barrel of the potassium electrode assembly. Stimulus trains (100 Hz) applied to group I muscle afferents (PBSt and DP) very effectively reduced the threshold for intraspinal activation of individual group I GS fibers but produced negligible negative DC shifts at the same site. On the other hand, 100-Hz
Woodbury, C J; Ritter, A M; Koerber, H R
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
Mercier, Catherine; Gagné, Martin; Reilly, Karen T.; Bouyer, Laurent J.
Sensorimotor integration is altered in people with chronic pain. While there is substantial evidence that pain interferes with neural activity in primary sensory and motor cortices, much less is known about its impact on integrative sensorimotor processes. Here, the short latency afferent inhibition (SAI) paradigm was used to assess sensorimotor integration in the presence and absence of experimental cutaneous heat pain applied to the hand. Ulnar nerve stimulation was combined with transcranial magnetic stimulation to condition motor evoked potentials (MEPs) in the first dorsal interosseous muscle. Four interstimulus intervals (ISI) were tested, based on the latency of the N20 component of the afferent sensory volley (N20−5 ms, N20+2 ms, N20+4 ms, N20+10 ms). In the PAIN condition, MEPs were smaller compared to the NEUTRAL condition (p = 0.005), and were modulated as a function of the ISI (p = 0.012). Post-hoc planned comparisons revealed that MEPs at N20+2 and N20+4 were inhibited compared to unconditioned MEPs. However, the level of inhibition (SAI) was similar in the PAIN and NEUTRAL conditions. This suggests that the interplay between pain and sensorimotor integration is not mediated through direct and rapid pathways as assessed by SAI, but rather might involve higher-order integrative areas. PMID:27690117
Dideriksen, Jakob L; Muceli, Silvia; Dosen, Strahinja; Laine, Christopher M; Farina, Dario
Neuromuscular electrical stimulation (NMES) is commonly used in rehabilitation, but electrically evoked muscle activation is in several ways different from voluntary muscle contractions. These differences lead to challenges in the use of NMES for restoring muscle function. We investigated the use of low-current, high-frequency nerve stimulation to activate the muscle via the spinal motoneuron (MN) pool to achieve more natural activation patterns. Using a novel stimulation protocol, the H-reflex responses to individual stimuli in a train of stimulation pulses at 100 Hz were reliably estimated with surface EMG during low-level contractions. Furthermore, single motor unit recruitment by afferent stimulation was analyzed with intramuscular EMG. The results showed that substantially elevated H-reflex responses were obtained during 100-Hz stimulation with respect to a lower stimulation frequency. Furthermore, motor unit recruitment using 100-Hz stimulation was not fully synchronized, as it occurs in classic NMES, and the discharge rates differed among motor units because each unit was activated only after a specific number of stimuli. The most likely mechanism behind these observations is the temporal summation of subthreshold excitatory postsynaptic potentials from Ia fibers to the MNs. These findings and their interpretation were also verified by a realistic simulation model of afferent stimulation of a MN population. These results suggest that the proposed stimulation strategy may allow generation of considerable levels of muscle activation by motor unit recruitment that resembles the physiological conditions.
Patel, Minal; Vandevord, Pamela J; Matthew, Howard W; Desilva, Stephen; Wu, Bin; Wooley, Paul H
The objective of this work was to use a functional gait analysis technique to evaluate sciatic nerve repair through tissue-engineered nerve guides in a rodent animal model. The nerve guides were fabricated by blending collagen with chitosan material and evaluated over a 12-week period for motor and sensory nerve recovery assessed by gait analysis and behavioral testing. Gastrocnemius muscle weight measurements were obtained at the end of each experimental time point and correlated to motor nerve recovery. Functional gait analysis studied both the stance and swing phase angle formations during a normal gait cycle. During the stance phase, functional results revealed that blended nerve guides promoted increased motor nerve recovery than unblended chitosan nerve guides. Similar results were obtained from behavioral tests, indicating that blended nerve guides created increased sensitivity to applied stimulus compared to unblended nerve guides. Muscle strength also correlated with functional recovery and was significantly higher when compared to the unblended nerve guides. From this study, we conclude that collagen-blended chitosan nerve guides enhanced motor and sensory nerve recovery assayed through gait and behavioral testing compared to unblended nerve guides.
Boulton, Daniel; Taylor, Chloe E.; Macefield, Vaughan G.; Green, Simon
During voluntary contractions, muscle sympathetic nerve activity (MSNA) to contracting muscles increases in proportion to force but the underlying mechanisms are not clear. To shed light on these mechanisms, particularly the influences of central command and muscle afferent feedback, the present study tested the hypothesis that MSNA is greater during voluntary compared with electrically-evoked contractions. Seven male subjects performed a series of 1-min isometric dorsiflexion contractions (left leg) separated by 2-min rest periods, alternating between voluntary and electrically-evoked contractions at similar forces (5–10% of maximum). MSNA was recorded continuously (microneurography) from the left peroneal nerve and quantified from cardiac-synchronized, negative-going spikes in the neurogram. Compared with pre-contraction values, MSNA increased by 51 ± 34% (P < 0.01) during voluntary contractions but did not change significantly during electrically-evoked contractions (−8 ± 12%, P > 0.05). MSNA analyzed at 15-s intervals revealed that this effect of voluntary contraction appeared 15–30 s after contraction onset (P < 0.01), remained elevated until the end of contraction, and disappeared within 15 s after contraction. These findings suggest that central command, and not feedback from contracting muscle, is the primary mechanism responsible for the increase in MSNA to contracting muscle. The time-course of MSNA suggests that there is a longer delay in the onset of this effect compared with its cessation after contraction. PMID:27242537
Potisk, K P; Gregoric, M; Vodovnik, L
The effect of afferent cutaneous electrical stimulation on the spasticity of leg muscles was studied in 20 patients with chronic hemiplegia after stroke. Stimulation electrodes were placed over the sural nerve of the affected limb. The standard method of cutaneous stimulation, TENS with impulse frequency of 100 Hz, was applied. The tonus of the leg muscles was measured by means of an electrohydraulic measuring brace. The EMG stretch reflex activity of the tibialis anterior and triceps surae muscles was detected by surface electrodes and recorded simultaneously with the measured biomechanical parameters. In 18 out of 20 patients, a mild but statistically significant decrease in resistive torques at all frequencies of passive ankle movements was recorded following 20 min of TENS application. The decrease in resistive torque was often (but not always) accompanied by a decrease in reflex EMG activity. This effect of TENS persisted up to 45 min after the end of TENS. The results of the study support the hypothesis that TENS applied to the sural nerve may induce short-term post-stimulation inhibitory effects on the abnormally enhanced stretch reflex activity in spasticity of cerebral origin.
Raybould, H E
The possible mechanisms that may be involved in nutrient detection in the wall of the gastrointestinal tract are reviewed. There is strong functional and electrophysiological evidence that both intrinsic and extrinsic primary afferent neurones mediate mechano- and chemosensitive responses in the gastrointestinal tract. This review focuses on the extrinsic afferent pathways as these are the ones that convey information to the central nervous system which is clearly necessary for perception to occur.
Capra, Norman F; Hisley, Calvin K; Masri, Radi M
Muscle spindles provide proprioceptive feedback supporting normal patterns of motor activity and kinesthetic sensibility. During mastication, jaw muscle spindles play an important role in monitoring and regulating the chewing cycle and the bite forces generated during mastication. Both acute and chronic orofacial pain disorders are associated with changes in proprioceptive feedback and motor function. Experimental jaw muscle pain also alters the normal response of masseter spindle afferents to ramp and hold jaw movements. It has been proposed that altered motor function and proprioceptive input results from group III muscle afferent modulation of the fusimotor system which alters spindle afferent sensitivity in limb muscles. The response to nociceptive stimuli may enhance or reduce the response of spindle afferents to proprioceptive stimuli. Several experimental observations suggesting the possibility that a similar mechanism also functions in jaw muscles are presented in this report. First, evidence is provided to show that nociceptive stimulation of the masseter muscle primarily influences the amplitude sensitivity of spindle afferents with relatively little effect on the dynamic sensitivity. Second, reversible inactivation of the caudal trigeminal nuclei attenuates the nociceptive modulation of spindle afferents. Finally, functionally identified gamma-motoneurons in the trigeminal motor nucleus are modulated by intramuscular injection with algesic substances. Taken together, these results suggest that pain-induced modulation of spindle afferent responses are mediated by small diameter muscle afferents and that this modulation is dependent, in part, on the relay of muscle nociceptive information from trigeminal subnucleus caudalis onto trigeminal gamma-motoneurons. The implication of these results will be considered in light of current theories on the relationship between jaw muscle pain and oral motor function.
Vyas, Pankhuri; Wu, Jingjing Sherry; Zimmerman, Amanda; Fuchs, Paul; Glowatzki, Elisabeth
Acoustic information propagates from the ear to the brain via spiral ganglion neurons that innervate hair cells in the cochlea. These afferents include unmyelinated type II fibers that constitute 5 % of the total, the majority being myelinated type I neurons. Lack of specific genetic markers of type II afferents in the cochlea has been a roadblock in studying their functional role. Unexpectedly, type II afferents were visualized by reporter proteins induced by tyrosine hydroxylase (TH)-driven Cre recombinase. The present study was designed to determine whether TH-driven Cre recombinase (TH-2A-CreER) provides a selective and reliable tool for identification and genetic manipulation of type II rather than type I cochlear afferents. The "TH-2A-CreER neurons" radiated from the spiral lamina, crossed the tunnel of Corti, turned towards the base of the cochlea, and traveled beneath the rows of outer hair cells. Neither the processes nor the somata of TH-2A-CreER neurons were labeled by antibodies that specifically labeled type I afferents and medial efferents. TH-2A-CreER-positive processes partially co-labeled with antibodies to peripherin, a known marker of type II afferents. Individual TH-2A-CreER neurons gave off short branches contacting 7-25 outer hair cells (OHCs). Only a fraction of TH-2A-CreER boutons were associated with CtBP2-immunopositive ribbons. These results show that TH-2A-CreER provides a selective marker for type II versus type I afferents and can be used to describe the morphology and arborization pattern of type II cochlear afferents in the mouse cochlea.
Vagus nerve stimulation Overview By Mayo Clinic Staff Vagus nerve stimulation is a procedure that involves implantation of a device that stimulates the vagus nerve with electrical impulses. There's one vagus nerve on ...
Nerve biopsy is the removal of a small piece of nerve for examination. Through a small incision, a sample ... is removed and examined under a microscope. Nerve biopsy may be performed to identify nerve degeneration, identify ...
Olsen, Anne C.K.; Triblehorn, Jeffrey D.
The wind-sensitive insect cercal system is involved in many important behaviors, such as initiating terrestrial escape responses and providing sensory feedback during flight. The occurrence of these behaviors vary in cockroach species Periplaneta americana (strong terrestrial response and flight), Blaberus craniifer (weak terrestrial response and flight), and Gromphodorhina portentosa (no terrestrial response and no flight). A previous study focusing on wind-sensitive interneuron (WSI) responses demonstrated that variations in sensory processing of wind information accompany these behavioral differences. In this study, we recorded extracellurlarly from the cercal nerve to characterize filiform afferent population responses to different wind velocities to investigate how sensory processing differs across these species at the initial encoding of wind. We compared these results and responses from the WSI population to examine information transfer at the first synapse. Our main results were: 1) G portentosa had the weakest responses of the three species over the stimulus duration and possessed the smallest cerci with the least filiform hair receptors of the three species; 2) B. craniifer filiform responses were similar to or greater than P. americana responses even though B. craniifer possessed smaller cerci with less filiform hair receptors than P. americana; 3) the greater filiform afferent responses in B. craniifer, including a larger amplitude second positive peak compared to the other two species, suggest more synchronous activity between filiform afferents in this species; 4) the transfer of information at the first synapse appears to be similar in both P. americana and G. portentosa, but different in B. craniifer. PMID:25046275
Soto, E; Chávez, H; Valli, P; Benvenuti, C; Vega, R
Betahistine has been used to treat several vestibular disorders of both central and peripheral origin. The objective of this work was to study the action of betahistine in the vestibular endorgans. Experiments were done in wild larval axolotl (Ambystoma tigrinum). Multiunit extracellular recordings were obtained from the semicircular canal nerve using a suction electrode. Betahistine (10 microM to 10 mM; n = 32) inhibited the basal spike discharge of the vestibular afferent neurons with an IC50 of 600 microM. To define the site of action of betahistine, its interactions with the nitric oxide synthase inhibitor NG-nitro-L-arginine (3 microM) and with the cholinergic antagonists atropine (10 microM; n = 3) and d-tubocurarine (10 microM; n = 3) were studied. The action of betahistine when co-administered with these drugs was the same as that in control experiments, indicating that its effects did not include nitric oxide production or the activation of cholinergic receptors. In contrast, 0.01-1 mM betahistine reduced the excitatory action of kainic acid (10 microM; n = 6) and quiscualic acid (1 microM; n = 13). These results indicate that the action of betahistine on the spike discharge of afferent neurons seems to be due to a post-synaptic inhibitory action on the primary afferent neuron response to the hair cell neurotransmitter.
Taylor, J L; Burke, D; Heywood, J
1. The depression in axonal excitability that follows short trains of impulses (H1) may lead to spike frequency adaptation to a sustained stimulus, and has been attributed to a slow K+ conductance. The present experiments sought indirect evidence for slow K+ channels at the node of Ranvier of human cutaneous afferents based on the demonstration of post-tetanic changes in excitability typical of H1. 2. The excitability changes in low-threshold cutaneous afferents in the digital nerves of the index finger were explored using a submaximal test pulse conditioned by trains of supramaximal stimuli, containing up to 100 impulses. Changes in the amplitude of the compound sensory action potential set up by a constant test stimulus were used as a measure of the changes in excitability. These changes in amplitude were paralleled by inverse changes in latency. 3. When the conditioning stimulus was a single supramaximal pulse, excitability was enhanced at conditioning-test intervals of 4-40 ms, with a peak at 6-8 ms. When the conditioning stimulus consisted of a train of ten pulses delivered at 200 Hz, the recovery cycle was dominated by subnormality that was maximal at 20 ms and subsided gradually over 50 ms. 4. The post-train depression in excitability increased as the number of pulses in the conditioning train increased to ten but changed little with further increases in train duration. The degree of depression increased with the pulse frequency within the train. Cooling the hand from a skin temperature of 35 to 25 degrees C slowed the recovery processes but did not alter the magnitude of the post-train depression. 5. These characteristics are typical of the H1 phase of post-tetanic depression in axonal excitability. The extent of the depression in excitability suggests, first, that there may be a significant K+ conductance at the nodes of human cutaneous afferents and, secondly, that H1 may play a significant role in limiting repetitive discharge in normal and pathological
Hämäläinen, Minna M; Gebhart, G F; Brennan, Timothy J
The purpose of this study was to examine which primary afferent fibers are sensitized to mechanical stimuli after an experimental surgical incision to the glabrous skin of the rat hindpaw. Afferent fibers teased from the L(5) dorsal root or the tibial nerve were recorded in anesthetized rats. The mechanical response properties of each fiber were characterized before and 45 min after an incision (or sham procedure) within the mechanical receptive field. Sensitization is characterized by an expansion of the mechanical receptive field, an increase in background activity, an increase in response magnitude, or a decrease in response threshold. After incision, the background activity and response properties of Abeta-fibers (n = 9) to mechanical stimuli were unchanged. Four of 13 mechanosensitive Adelta-fibers exhibited sensitization after the incision; response threshold decreased, response magnitude increased, or receptive field size increased. Background activity of Adelta-fibers was not increased by the incision. Sensitization was observed in 4 of 18 mechanosensitive C-fibers 45 min after the incision. Background activity of C-fibers was not increased by the incision. In a group of mechanically insensitive afferent fibers (MIAs), 3 of 7 Adelta-fibers and 4 of 10 C-fibers sensitized 45 min after incision. Response threshold was decreased in only 2 of 17 MIAs; receptive field size increased in 7 of 17 MIAs. Abeta-fibers did not sensitize after the incision, and only 8 of 31 (26%) mechanosensitive Adelta- and C-fibers gave evidence of sensitization. In a group of MIA Adelta- and C-fibers, a greater percentage of 17 fibers studied (41%) were sensitized after incision. In this model, the principal effect of an incision, when examined 45 min after the insult, is an increase in receptive field size of the afferents, particularly those characterized as MIAs. To the extent that the mechanical hyperalgesia characterized in the same model is initiated in the periphery, it would
Lysakowski, A.; Minor, L. B.; Fernandez, C.; Goldberg, J. M.
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
Jankowski, Michael P; Baumbauer, Kyle M; Wang, Ting; Albers, Kathryn M; Davis, Brian M; Koerber, H Richard
Neurotrophic factors play an important role in the regulation of functional properties of sensory neurons under normal and pathological conditions. The GDNF family member neurturin is one such factor that has been linked to modulating responsiveness to peripheral stimuli. Neurturin binds to the GFRα2 receptor, a receptor found primarily in isolectin B4-expressing polymodal cutaneous nociceptors. Previous work has shown that knockout of GFRα2 alters heat, but not mechanical, responses in dissociated sensory neurons and reduces pain-related behaviors during the second phase of the formalin test. Research has also shown that overexpression of neurturin in basal keratinocytes increases behavioral responsiveness to mechanical stimulation and innocuous cooling of the skin without affecting noxious heat responses. Here we directly examined the impact of neurturin overexpression on cutaneous afferent function. We compared physiological responses of individual sensory neurons to mechanical and thermal stimulation of the skin, using an ex vivo skin-nerve-dorsal root ganglion-spinal cord preparation produced from neurturin-overexpressing (NRTN/OE) mice and wild-type littermate controls. We found that neurturin overexpression increases responsiveness to innocuous mechanical stimuli in A-fiber nociceptors, alters thermal responses in the polymodal subpopulation of C-fiber sensory neurons, and changes the relative numbers of mechanically sensitive but thermally insensitive C-fiber afferents. These results demonstrate the potential roles of different functional groups of sensory neurons in the behavioral changes observed in mice overexpressing cutaneous neurturin and highlight the importance of neurturin in regulating cutaneous afferent response properties.NEW & NOTEWORTHY GDNF family neurotrophic factors regulate the development and function of primary sensory neurons. Of these, neurturin has been shown to modulate mechanical and cooling sensitivity behaviorally. Here we show
Hoffman, Larry F.; Honrubia, Vicente
A morphometric study of the chinchilla's ampullary nerves was conducted to produce an unbiased accounting of the diameter distribution of their constituent fibers. Diameter analyses were determined from 1 microm plastic-embedded nerve sections taken at a plane immediately proximal to the sensory epithelium. We found these nerves to be composed of 2094+/-573 fibers, having diameters that ranged from 0.5 to 8 microm. The distributions of diameters were positively skewed, where approximately 75% of the fibers were found to have diameters less than 3.5 microm. An analysis of the spatial distribution of diameters within the nerve section revealed that the lateralmost areas of the nerve contained larger fractions of fibers within the smallest diameter quintiles, and the central area harbored greater proportions of the larger diameter quintiles. However, significant fractions of all quintiles were found in all areas. These data were integrated with available data of Fernandez et al. (1998) to produce diameter estimates of calyx, dimorphic, and bouton morphology subpopulations. In view of a general relationship between diameter, innervation locus, and an afferent's physiologic characteristics, these data provide the basis for developing a perspective for the in situ distribution of afferent response dynamics.
Si, Xiaohong; Zakir, Mridha Md; Dickman, J. David
Biotinylated dextran amine (BDA) was used to retrogradely label afferents innervating the utricular macula in adult pigeons. The pigeon utriclar macula consists of a large rectangular-shaped neuroepithelium with a dorsally curved anterior edge and an extended medioposterior tail. The macula could be demarcated into several regions based on cytoarchitectural differences. The striola occupied 30% of the macula and contained a large density of type I hair cells with fewer type II hair cells. Medial and lateral extrastriola zones were located outside the striola and contained only type II hair cells. A six- to eight-cell-wide band of type II hair cells existed near the center of the striola. The reversal line marked by the morphological polarization of hair cells coursed throughout the epithelium, near the peripheral margin, and through the center of the type II band. Calyx afferents innervated type I hair cells with calyceal terminals that contained between 2 and 15 receptor cells. Calyx afferents were located only in the striola region, exclusive of the type II band, had small total fiber innervation areas and low innervation densities. Dimorph afferents innervated both type I and type II hair cells with calyceal and bouton terminals and were primarily located in the striola region. Dimorph afferents had smaller calyceal terminals with few type I hair cells, extended fiber branches with bouton terminals and larger innervation areas. Bouton afferents innervated only type II hair cells in the extrastriola and type II band regions. Bouton afferents innervating the type II band had smaller terminal fields with fewer bouton terminals and smaller innervation areas than fibers located in the extrastriolar zones. Bouton afferents had the most bouton terminals on the longest fibers, the largest innervation areas with the highest innervation densities of all afferents. Among all afferents, smaller terminal innervation fields were observed in the striola and large fields were
Fisher, Lee E.; Ayers, Christopher A.; Ciollaro, Mattia; Ventura, Valérie; Weber, Douglas J.; Gaunt, Robert A.
Objective. This study describes results of primary afferent neural microstimulation experiments using microelectrode arrays implanted chronically in the lumbar dorsal root ganglia (DRG) of four cats. The goal was to test the stability and selectivity of these microelectrode arrays as a potential interface for restoration of somatosensory feedback after damage to the nervous system such as amputation. Approach. A five-contact nerve-cuff electrode implanted on the sciatic nerve was used to record the antidromic compound action potential response to DRG microstimulation (2-15 µA biphasic pulses, 200 µs cathodal pulse width), and the threshold for eliciting a response was tracked over time. Recorded responses were segregated based on conduction velocity to determine thresholds for recruiting Group I and Group II/Aβ primary afferent fibers. Main results. Thresholds were initially low (5.1 ± 2.3 µA for Group I and 6.3 ± 2.0 µA for Group II/Aβ) and increased over time. Additionally the number of electrodes with thresholds less than or equal to 15 µA decreased over time. Approximately 12% of tested electrodes continued to elicit responses at 15 µA up to 26 weeks after implantation. Higher stimulation intensities (up to 30 µA) were tested in one cat at 23 weeks post-implantation yielding responses on over 20 additional electrodes. Within the first six weeks after implantation, approximately equal numbers of electrodes elicited only Group I or Group II/Aβ responses at threshold, but the relative proportion of Group II/Aβ responses decreased over time. Significance. These results suggest that it is possible to activate Group I or Group II/Aβ primary afferent fibers in isolation with penetrating microelectrode arrays implanted in the DRG, and that those responses can be elicited up to 26 weeks after implantation, although it may be difficult to achieve a consistent response day-to-day with currently available electrode technology. The DRG are compelling targets
Zhang, Yi; Liu, Hao; Liu, En-Zhong; Lin, You-Zhi; Zhao, Shi-Guang; Jing, Guo-Hua
This study was designed to provide anatomic data to help surgeons avoid damage to the ocular motor nerves during intraorbital operations. The microsurgical anatomy of the ocular motor nerves was studied in 50 adult cadaveric heads (100 orbits). Dissections were performed with a microscope. The nerves were exposed and the neural and muscular relationships of each portion of the nerve were examined and measured. The superior division of the oculomotor nerve coursed between the optic nerve and the superior rectus muscle after it left the annular tendon, and its branches entered into the superior rectus muscle and levator muscle. A mean of five fibers (range 3-7) innervated the superior rectus muscle, and a mean of one fiber (range 1-2) followed a medial direction (84%) or went straight through the superior rectus muscle (16%). The inferior division of the oculomotor nerve branched into the medial rectus, inferior rectus and inferior oblique muscles. The trochlear nerve ended on the orbital side of the posterior one-third of the superior oblique muscle in 76 specimens. The abducens nerve ended on the posterior one-third of the lateral rectus muscle in 86 specimens. If the belly of the lateral rectus muscle was divided into three superior-inferior parts, the nerve commonly entered into the middle one-third in 74 specimens. Based on the observed data, microanatomical relationships of the orbital contents were revised.
Martín-Oliva, X; Elgueta-Grillo, J; Veliz-Ayta, P; Orosco-Villaseñor, S; Elgueta-Grillo, M; Viladot-Perice, R
The tarsal tunnel is composed of the posterior border of the medial malleoulus, the posterior aspect of the talus and the medial aspect of the calcaneus. The medial calcaneal nerve emerges from the posterior aspect of the posterior tibial nerve in 75% of cases and from the lateral plantar nerve in the remaining 25%. Finally, the medial calcaneal nerve ends as a single terminal branch in 79% of cases and in numerous terminal branches in the remaining 21%. To describe the anatomical variants of the posterior tibial nerve and its terminal branches. To describe the steps for tarsal tunnel release. To describe Baxter nerve release. The anatomical variants of the posterior tibial nerve and its terminal branches within the tarsal tunnel were studied. Then the Lam technique was performed; it consists of: 1) opening of the laciniate ligament, 2) opening of the fascia over the abductor hallucis muscle, 3) exoneurolysis of the posterior tibial nerve and its terminal branches, identifying the emergence and pathway of the medial calcaneal branch, the lateral plantar nerve and its Baxter nerve branch and the medial plantar nerve. Baxter nerve was found in 100% of cases. In 100% of cases in our series the nerve going to the abductor digiti minimi muscle of the foot was found; 87.5% of cases had two terminal branches. The dissections proved that a crucial step was the release of the distal tarsal tunnel.
Gordon, Lynn K
Optic nerve diseases arise from many different etiologies including inflammatory, neoplastic, genetic, infectious, ischemic, and idiopathic. Understanding some of the characteristics of the most common optic neuropathies along with therapeutic approaches to these diseases is helpful in designing recommendations for individual patients. Although many optic neuropathies have no specific treatment, some do, and it is those potentially treatable or preventable conditions which need to be recognized in order to help patients regain their sight or develop a better understanding of their own prognosis. In this chapter several diseases are discussed including idiopathic intracranial hypertension, optic neuritis, ischemic optic neuropathies, hereditary optic neuropathies, trauma, and primary tumors of the optic nerve. For each condition there is a presentation of the signs and symptoms of the disease, in some conditions the evaluation and diagnostic criteria are highlighted, and where possible, current therapy or past trials are discussed.
Klarer, Melanie; Arnold, Myrtha; Günther, Lydia; Winter, Christine; Langhans, Wolfgang; Meyer, Urs
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.
Guth, P.; Norris, C.; Fermin, C. D.; Pantoja, M.
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.
de Lartigue, Guillaume
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.
Abbruzzese, M; Rubino, V; Schieppati, M
The effect of low intensity electrical stimulation of the posterior tibial nerve (PTN) at the ankle on the active triceps surae (TS) muscles was studied in normal subjects, both in a prone position and while standing. PTN stimulation regularly evoked the H-reflex in the flexor digitorum brevis and, in the prone position, a short-latency facilitatory effect in the soleus muscle. During standing, the facilitatory effect was preceded by a clear-cut reduction in electromyograph (EMG) activity. The inhibition-facilitation sequence was evoked in the gastrocnemii under both conditions, on average, though individual differences were present. An EMG modulation similar to that observed under standing conditions was present also in the prone position when subjects pressed the sole of the foot against the wall. Stimulation of sural or digital nerves did not evoke similar effects. It is concluded that foot muscle afferents establish oligosynaptic connections transmitting mixed effects to the TS motoneuronal pool, and that contact with the sole of the foot plays an enabling role for the inhibitory pathway directed to the soleus muscle.
Koralek, K A; Killackey, H P
During the first postnatal week, the distribution of callosal projection neurons in the rat somatosensory cortex changes from a uniform to a discontinuous pattern. To determine if this change is influenced by afferent inputs to the somatosensory cortex, the effect of both early unilateral infraorbital nerve section and unilateral removal of the dorsal thalamus on the distribution of callosal projections in rat somatosensory cortex was examined. One month after either of the above manipulations at birth, the tangential distribution of callosal projections in the somatosensory cortex was examined using the combined retrograde and anterograde transport of horseradish peroxidase. Both manipulations alter the distribution of callosal projection neurons and terminations in the somatosensory cortex. After infraorbital nerve section, the distribution of callosal projections is altered in the contralateral primary somatosensory cortex. The abnormalities observed are consistent with the altered distribution of thalamocortical projections. In addition, consistent abnormalities were observed in the pattern of callosal projections of the second somatosensory area of both hemispheres. Most notably, they are absent in a portion of the region that contains the representation of the mystacial vibrissae and sinus hairs in this area. Thalamic ablation resulted in highly aberrant patterns of callosal projections in the somatosensory cortex on the operated side, where abnormal bands and clusters of callosal projections were observed in apparently random locations. These results are interpreted as evidence that both peripheral and central inputs influence the maturational changes in the distribution of callosal projection neurons. Images PMID:2304906
Andrade, Marcus V M; Souza, Danielle G; de A Castro, Maria Salete; Cunha-Melo, José R; Teixeira, Mauro M
In the most severe cases of human envenoming by Tityus serrulatus, pulmonary oedema is a frequent finding and can be the cause of death. We have previously demonstrated a role for neuropeptides acting on tachykinin NK(1) receptors in the development of lung oedema following i.v. injection of T. serrulatus venom (TsV) in experimental animals. The present work was designed to investigate whether capsaicin-sensitive primary afferent neurons were a potential source of NK(1)-acting neuropeptides. To this end, sensory nerves were depleted of neuropeptides by neonatal treatment of rats with capsaicin. The effectiveness of this strategy at depleting sensory nerves was demonstrated by the inhibition of the neuropeptide-dependent response to intraplantar injection of formalin. Pulmonary oedema, as assessed by the levels of extravasation of Evans blue dye in the bronchoalveolar lavage and in the left lung, was markedly inhibited in capsaicin-treated animals. In contrast, capsaicin treatment failed to alter the increase in arterial blood pressure or the lethality following i.v. injection of TsV. Our results demonstrate an important role for capsaicin-sensitive sensory nerves in the cascade of events leading to lung injury following the i.v. administration of TsV.
Zhilyaev, S Yu; Moskvin, A N; Platonova, T F; Demchenko, I T
The activation of autonomic afferents (achieved through the vagus nerve (VN) electrical stimulation) on CNS O2 toxicity and cardiovascular function was investigated. In conscious rabbits at 5 ATA 02, prodromal signs of CNS O2 toxicity and convulsion latency were determined with and without vagus nerve (VN) stimulation. EEG, ECG and respiration were also recorded. In rabbits at 5 ATA, sympathetic overdrive and specific patterns on the EEG (synchronization of slow-waves), ECG (tachycardia) and respiration (respiratory minute volume increase) preceded motor convulsions. Vagus nerve stimulation increased parasympathetic component of autonomic drive and significantly delayed prodromal signs of oxygen toxicity and convulsion latency. Autonomic afferent input to the brain is a novel target for preventing CNS toxicity in HBO2.
Kuzdas-Wood, Daniela; Irschick, Regina; Theurl, Markus; Malsch, Philipp; Mair, Norbert; Mantinger, Christine; Wanschitz, Julia; Klimaschewski, Lars; Poewe, Werner; Stefanova, Nadia; Wenning, Gregor K.
Multiple system atrophy (MSA) is a fatal, rapidly progressive neurodegenerative disease with (oligodendro-)glial cytoplasmic α-synuclein (α-syn) inclusions (GCIs). Peripheral neuropathies have been reported in up to 40% of MSA patients, the cause remaining unclear. In a transgenic MSA mouse model featuring GCI-like inclusion pathology based on PLP-promoter driven overexpression of human α-syn in oligodendroglia motor and non-motor deficits are associated with MSA-like neurodegeneration. Since α-syn is also expressed in Schwann cells we aimed to investigate whether peripheral nerves are anatomically and functionally affected in the PLP-α-syn MSA mouse model. Results To this end, heat/cold as well as mechanical sensitivity tests were performed. Furthermore, in vivo and ex vivo nerve conduction and the G-ratios of the sciatic nerve were analyzed, and thermosensitive ion channel mRNA expression in dorsal root ganglia (DRG) was assessed. The presence of human α-syn in Schwann cells was associated with subtle behavioral impairments. The G-ratio of the sciatic nerve, the conduction velocity of myelinated and unmyelinated primary afferents and the expression of thermosensitive ion channels in the sensory neurons, however, were similar to wildtype mice. Conclusion Our results suggest that the PNS appears to be affected by Schwann cell α-syn deposits in the PLP-α-syn MSA mouse model. However, there was no consistent evidence for functional PNS perturbations resulting from such α-syn aggregates suggesting a more central cause of the observed behavioral abnormalities. Nonetheless, our results do not exclude a causal role of α-syn in the pathogenesis of MSA associated peripheral neuropathy. PMID:26496712
Garcia-Nicas, E; Laird, J M; Cervero, F
In areas of secondary hyperalgesia, innocuous mechanical stimuli evoke pain (allodynia). We have proposed that this is produced by a central pre-synaptic interaction whereby A beta-fibers evoke spike activity (dorsal root reflexes) in nociceptive afferents (Pain, 68 (1996) 13). This activity should conduct centrally, evoking allodynia, and peripherally, evoking neurogenic vasodilatation. Here we tested this hypothesis by examining the effects of electrical stimulation of A beta-fibers on cutaneous blood flow before and after producing secondary hyperalgesia in anesthetized rats. Cutaneous blood flow was recorded in the hind paw skin innervated by the sural nerve using a laser Doppler flowmeter. The sural nerve was prepared for electrical stimulation, and the evoked activity was recorded from the sciatic nerve in continuity. Electrical stimulation (1 Hz, 4 x 0.2 ms pulses, 20 s) was applied to the sural nerve at 2T (A beta-fibers only) and 4T and 6T (A beta + A delta-fibers). Flux was recorded at baseline and after capsaicin or mustard oil application outside the sural nerve territory. The effects of intravenous administration of the calcitonin gene-related peptide (CGRP) receptor antagonist, alpha-CGRP(8-37), or of section of the sciatic nerve or of the L4-L6 dorsal roots were examined. Selective activation of the sural nerve A beta-fibers reliably evoked increases in cutaneous blood flow close to areas of chemical irritation or skin damage. A beta-fiber-evoked vasodilatation was abolished by sciatic nerve or dorsal root section and had a spatial arrangement and optimal stimulation pattern suggesting a central synaptic interaction similar to that responsible for dorsal root reflexes. The flux increases were dose-dependently and reversibly inhibited by alpha-CGRP(8-37), indicating that the A beta-fiber-evoked vasodilatation resulted from the antidromic activation of nociceptive cutaneous afferent fibers. These results support our hypothesis by showing activation of
Donner, T R; Kline, D G
Eighty-three consecutive patients with extracranial accessory nerve injury seen over a 12-year period are reviewed. The most common etiology was iatrogenic injury to the nerve at the time of previous surgery. Such operations were usually minor in nature and often related to lymph node or benign tumor removal. Examination usually distinguished winging due to trapezius weakness from that of serratus anterior palsy. Trapezius weakness was seen in all cases. Sternocleidomastoid weakness was unusual. Patients with accessory palsy were evaluated by both clinical and electromyographic studies. Patients who exhibited no clinical or electrical evidence of regeneration were operated on (44 cases). Based on intraoperative nerve action potential studies, 8 lesions in continuity had neurolysis alone. Resection with repair either by end-to-end suture or by grafts was necessary in 31 cases. One case had suture removed from nerve, two had nerve placed into target muscle, and two had more proximal neurotization. Function was usually improved in both operative and nonoperative patients. Related anatomy is discussed.
Nerve growth factor (NGF) plays a critical role in the maintenance and survival of both sympathetic and sensory nerves. Also, NGF can regulate receptor expression and neuronal activity in the sympathetic and sensory neurons. Abnormalities in NGF regulation are observed in patients and animals with heart failure (HF). Nevertheless, the effects of chronic HF on the levels of NGF within the sympathetic and sensory nerves are not known. Thus, the ELISA method was used to assess the levels of NGF in the stellate ganglion (SG) and dorsal root ganglion (DRG) neurons of control rats and rats with chronic HF induced by myocardial infarction. Our data show for the first time that the levels of NGF were significantly decreased (P < 0.05) in the SG and DRG neurons 6–20 weeks after ligation of the coronary artery. In addition, a close relation was observed between the NGF levels and the left ventricular function. In conclusion, chronic HF impairs the expression of NGF in the sympathetic and sensory nerves. Given that sensory afferent nerves are engaged in the sympathetic nervous responses to somatic stimulation (i.e. muscle activity during exercise) via a reflex mechanism, our data indicate that NGF is likely responsible for the development of muscle reflex-mediated abnormal sympathetic responsiveness observed in chronic HF. PMID:24913185
Carlton, Susan M
Nociceptive primary afferents have three surprising properties: they are highly complex in their expression of neurotransmitters and receptors and most probably participate in autocrine and paracrine interactions; they are capable of exerting tonic and activity-dependent inhibitory control over incoming nociceptive input; they can generate signals in the form of dorsal root reflexes that are transmitted antidromically out to the periphery and these signals can result in neurogenic inflammation in the innervated tissue. Thus, nociceptive primary afferents are highly complicated structures, capable of modifying input before it is ever transmitted to the central nervous system and capable of altering the tissue they innervate. PMID:24879874
Pascual-Font, A; Maranillo, E; Merchán, A; Vázquez, T; Sañudo, J R; Valderrama-Canales, F J
Laryngeal nerves contain the fibres that control the laryngeal function. The studies carried out on the rat with the purpose of having a better knowledge of the functional components and the real origin of the fibres conveyed by the recurrent laryngeal nerve (RLN) are few and in disagreement. No one of such papers were developed using biotinylated dextrane amines (BDA), a powerful tool for tracing neural pathways. The aim of our study was to identify in the rat using BDA, the nuclei of real origin of the fibres of the RLN, knowing in this way the functional components of this nerve. The study has been developed in 31 adult male Sprague-Dawley rats, applying the BDA into the lesioned RLN. The results obtained in all the animals show that the rat's RLN does not contain afferent fibres, whereas the efferent fibres were originated within the ipsilateral nucleus ambiguus (NA). So, in the rat, the RLN seems to contain exclusively efferent fibres, probably been the superior laryngeal nerve who conveyed the afferent fibres.
Ross, M. D.; Linton, S. W.; Parnas, B. R.
A quasi-three-dimensional finite-volume numerical simulator was developed to study passive voltage spread in vestibular macular afferents. The method, borrowed from computational fluid dynamics, discretizes events transpiring in small volumes over time. The afferent simulated had three calyces with processes. The number of processes and synapses, and direction and timing of synapse activation, were varied. Simultaneous synapse activation resulted in shortest latency, while directional activation (proximal to distal and distal to proximal) yielded most regular discharges. Color-coded visualizations showed that the simulator discretized events and demonstrated that discharge produced a distal spread of voltage from the spike initiator into the ending. The simulations indicate that directional input, morphology, and timing of synapse activation can affect discharge properties, as must also distal spread of voltage from the spike initiator. The finite volume method has generality and can be applied to more complex neurons to explore discrete synaptic effects in four dimensions.
Tanbouzi Husseini, Sami; Kumar, David Victor; De Donato, Giuseppe; Almutair, Tamama; Sanna, Mario
To evaluate the results of facial nerve reanimation after facial nerve injury by means of hypoglossal to facial nerve anastomosis. Retrospective case review. Private neuro-otologic and cranial base quaternary referral center. Sixty patients underwent hypoglossal to facial nerve anastomosis for facial nerve reanimation between April 1987 and December 2010. Only forty patients completed a minimal follow up of 24 months at the time of evaluation and were included in the study population. Facial nerve paralysis was present for a mean duration of 11.3 months (range 2-42 months) and all the patients had a HB grade VI prior their surgery. Final facial nerve motor function. The most common cause of facial paralysis was vestibular Schwannoma surgery. All the patients achieved a postoperative HB grade III or IV after a mean follow-up time of 20 months. The facial movements were detected after a period that ranged from ranged from 5 to 9 months. Only 4 patients suffered from difficulties during eating and drinking and three of them had associated lower cranial nerve deficit. Despite the various techniques in facial reanimation following total facial nerve paralysis, the end to end of hypoglossal to facial nerve anastomosis remains one of the best treatments in cases of viable distal facial stump and nonatrophic musculature.
Nilsson Remahl, A Ingela M; Masterman, Thomas; Risling, Mårten
Ventral roots in all mammalian species, including humans, contain significant numbers of unmyelinated axons, many of them afferents transmitting nociceptive signals from receptive fields in skin, viscera, muscles and joints. Observations in cats indicate that these afferents do not enter the spinal cord via the ventral root, but rather turn distally and enter the dorsal root. Some unmyelinated axons are postganglionic autonomic efferents that innervate blood vessels of the root and the pia mater. In the feline L7 segment, a substantial proportion of unmyelinated axons are not detectable until late in perinatal development. The mechanisms inducing this late ingrowth, and the recruitment of Schwann cells (indispensable, at this stage, for axonal survival and sustenance), are unknown. We have counted axons and Schwann cells in both ends of the L7 ventral root in young kittens and made the following observations. (1) The total number of axons detectable in the root increased throughout the range of investigated ages. (2) The number of myelinated axons was similar in the root's proximal and distal ends. The increased number of unmyelinated axons with age is thus due to increased numbers of small unmyelinated axons. (3) The number of separated large probably promyelin axons was about the same in the proximal and distal ends of the root. (4) Schwann cells appeared to undergo redistribution, from myelinated to unmyelinated axons. (5) During redistribution of Schwann cells they first appear as aberrant Schwann cells and then become endoneurial X-cells temporarily free of axonal contact. We hypothesize that unmyelinated axons invade the ventral root from its distal end, that this ingrowth is particularly intense during the first postnatal month and that disengaged Schwann cells, eliminated from myelinated motoneuron axons, provide the ingrowing axons with structural and trophic support.
Leong, S K; Tan, C K
The central projection of afferent fibres in the rat sciatic nerve has been studied by means of the suicide transport of a lectin, Ricinus communis agglutinin 60 (RCA 60), and the transganglionic transport of horseradish peroxidase (HRP). The results obtained from these two methods are similar; however, the RCA method gave a more consistent and better localisation of the primary afferent terminals than the HRP method. The present study has shown that primary afferents from the sciatic nerve project predominantly to the ipsilateral gracile nucleus. In addition, they also project to several other brainstem nuclei; these include the contralateral nucleus gracilis, the ipsilateral main cuneate nucleus, the external cuneate nucleus and the presumptive nucleus z.
... polyneuropathy Tibial nerve dysfunction Ulnar nerve dysfunction Any peripheral neuropathy can cause abnormal results. Damage to the spinal ... Herniated disk Lambert-Eaton syndrome Mononeuropathy Multiple ... azotemia Primary amyloidosis Radial nerve dysfunction Sciatica ...
Calvillo, O; Madrid, J; Rudomín, P
Low intensity (1-20 micro A) intraspinal stimulation produces in the sural nerve of the anesthetized cat short latency responses (3-4 ms) due to antidromic activation of fibers conducting in the A range (43-65 m/s). With higher stimulus intensities (up to 400 micro A) late responses (120-250 ms latency) may also be recorded. Simultaneous recording from two sites in the sural nerve shows that the peripheral processes of the fibers generating the late responses have a conduction velocity between 0.8-1.3 m/s. Collision between antidromic and orthodromic responses further indicates that these fibers have a peripheral threshold 20-25 times that of the A fibers. The late responses were largest when the intraspinal stimulating electrode was located in the dorsal horn, in the region corresponding to Laminae II and III of Rexed. The above observations suggest that the late responses are due to population responses of C fibers which are antidromically activated in the dorsal horn. The excitability of the C fiber terminals is increased by conditioning stimuli applied to other cutaneous afferents with a time course resembling that of the excitability increase of the A fibers on the same nerve. It is suggested that the effectiveness of synaptic transmission from C fibers to second order cells may be modulated presynaptically. In the decerebrate cat the antidromic responses of C fibers are reduced, but not abolished, by reversible spinalization produced by cooling or by sectioning the thoracic spinal cord. This suggests in addition that in the decerebrate preparation the presynaptic effectiveness of the C fiber (presumably nociceptive) input may be tonically decreased by supraspinal influences.
Scheff, Nicole N.
Persistent inflammation results in an increase in the amplitude and duration of depolarization-evoked Ca2+ transients in putative nociceptive afferents. Previous data indicated that these changes were the result of neither increased neuronal excitability nor an increase in the amplitude of depolarization. Subsequent data also ruled out an increase in voltage-gated Ca2+ currents and recruitment of Ca2+-induced Ca2+ release. Parametric studies indicated that the inflammation-induced increase in the duration of the evoked Ca2+ transient required a relatively large and long-lasting increase in the concentration of intracellular Ca2+ implicating the Na+/Ca2+ exchanger (NCX), a major Ca2+ extrusion mechanism activated with high intracellular Ca2+ loads. The contribution of NCX to the inflammation-induced increase in the evoked Ca2+ transient in rat sensory neurons was tested using fura-2 AM imaging and electrophysiological recordings. Changes in NCX expression and protein were assessed with real-time PCR and Western blot analysis, respectively. An inflammation-induced decrease in NCX activity was observed in a subpopulation of putative nociceptive neurons innervating the site of inflammation. The time course of the decrease in NCX activity paralleled that of the inflammation-induced changes in nociceptive behavior. The change in NCX3 in the cell body was associated with a decrease in NCX3 protein in the ganglia, an increase in the peripheral nerve (sciatic) yet no change in the central root. This single response to inflammation is associated with changes in at least three different segments of the primary afferent, all of which are likely to contribute to the dynamic response to persistent inflammation. PMID:26041911
Scheff, Nicole N; Gold, Michael S
Persistent inflammation results in an increase in the amplitude and duration of depolarization-evoked Ca(2+) transients in putative nociceptive afferents. Previous data indicated that these changes were the result of neither increased neuronal excitability nor an increase in the amplitude of depolarization. Subsequent data also ruled out an increase in voltage-gated Ca(2+) currents and recruitment of Ca(2+)-induced Ca(2+) release. Parametric studies indicated that the inflammation-induced increase in the duration of the evoked Ca(2+) transient required a relatively large and long-lasting increase in the concentration of intracellular Ca(2+) implicating the Na(+)/Ca(2+) exchanger (NCX), a major Ca(2+) extrusion mechanism activated with high intracellular Ca(2+) loads. The contribution of NCX to the inflammation-induced increase in the evoked Ca(2+) transient in rat sensory neurons was tested using fura-2 AM imaging and electrophysiological recordings. Changes in NCX expression and protein were assessed with real-time PCR and Western blot analysis, respectively. An inflammation-induced decrease in NCX activity was observed in a subpopulation of putative nociceptive neurons innervating the site of inflammation. The time course of the decrease in NCX activity paralleled that of the inflammation-induced changes in nociceptive behavior. The change in NCX3 in the cell body was associated with a decrease in NCX3 protein in the ganglia, an increase in the peripheral nerve (sciatic) yet no change in the central root. This single response to inflammation is associated with changes in at least three different segments of the primary afferent, all of which are likely to contribute to the dynamic response to persistent inflammation.
Onishi, H; Yamada, T; Saito, T; Emori, T; Fuchigami, T; Hasegawa, A; Nagaoka, T; Ross, M
We examined the effect of stimulus rate on somatosensory evoked potentials (SEPs) following stimulation of the common peroneal nerve (CPN) at the knee, and the posterior tibial nerve (PTN) and sural nerve (SN) at the ankle. We measured the amplitude of P40-N50 and N50-P60 in the PTN-SEP and corresponding amplitude of CPN-SEP and SN-SEP at the rate of 2.3, 3.4, 4.1, and 5.1 Hz. When the stimulation rate was increased from 2.3 to 5.1 Hz, the P40-N50 amplitude decreased by 50% for the CPN-SEP and 20% for the PTN-SEP. Also, the N50-P60 amplitude was reduced by 30% in the CPN-SEP and 20% in the PTN-SEP. In contrast, this change in stimulus rate produced no significant amplitude decline in the SN-SEP. Blocking the peroneal nerve with lidocaine just distal to the stimulating electrodes eliminated the descending peroneal nerve volley and abolished the amplitude attenuation observed with the faster stimulus rate. The findings suggest that at higher rates of stimulation, the afferent volleys induced by the movements that follow mixed nerve stimulation interfere with the SEP produced by electrical activation of the sensory afferents. The interference is greater when the more proximal site of the mixed nerve is stimulated.
Grinnell, Alan D.
depolarization can increase transmitter release at terminals and increase coupling at electrical junctions. 7. Possible morphological correlates for the two electrical interactions are discussed. It is speculated that the motoneurone interaction arises at numerous areas of close apposition between dendrites in dendritic `thickets', and that the early VR-DRP is mediated by fewer, lower-resistance, electrical junctions between dendrites and afferent nerve terminals. PMID:5500776
Blatt, F. J.
Summarizes research done on the resting and action potential of nerve impulses, electrical excitation of nerve cells, electrical properties of Nitella, and temperature effects on action potential. (GS)
Khamis, Heba A; Redmond, Stephen J; Macefield, Vaughan G; Birznieks, Ingvars
Adjustments to frictional forces are crucial to maintain a safe grip during precision object handling in both humans and robotic manipulators. The aim of this work was to investigate whether a population of human tactile afferents can provide information about the current tangential/normal force ratio expressed as the percentage of the critical load capacity - the tangential/normal force ratio at which the object would slip. A smooth stimulation surface was tested on the fingertip under three frictional conditions, with a 4 N normal force and a tangential force generated by motion in the ulnar or distal direction at a fixed speed. During stimulation, the responses of 29 afferents (12 SA-I, 2 SA-II, 12 FA-I, 3 FA-II) were recorded. A multiple regression model was trained and tested using cross-validation to estimate the percentage of the critical load capacity in real-time as the tangential force increased. The features for the model were the number of spikes from each afferent in windows of fixed length (50, 100 or 200 ms) around points spanning the range from 50% to 100% of the critical load capacity, in 5% increments. The mean regression estimate error was less than 1% of the critical load capacity with a standard deviation between 5% and 10%. A larger number of afferents is expected to improve the estimate error. This work is important for understanding human dexterous manipulation and inspiring improvements in robotic grippers and prostheses.
Raybould, Helen E
Chemosensing in the gastrointestinal tract is less well understood than many aspects of gut mechanosensitivity; however, it is important in the overall function of the GI tract and indeed the organism as a whole. Chemosensing in the gut represents a complex interplay between the function of enteroendocrine (EEC) cells and visceral (primarily vagal) afferent neurons. In this brief review, I will concentrate on a new data on endocrine cells in chemosensing in the GI tract, in particular on new findings on glucose-sensing by gut EEC cells and the importance of incretin peptides and vagal afferents in glucose homeostasis, on the role of G protein coupled receptors in gut chemosensing, and on the possibility that gut endocrine cells may be involved in the detection of a luminal constituent other than nutrients, the microbiota. The role of vagal afferent pathways as a downstream target of EEC cell products will be considered and, in particular, exciting new data on the plasticity of the vagal afferent pathway with respect to expression of receptors for GI hormones and how this may play a role in energy homeostasis will also be discussed.
Oliva, Idaira; Wanat, Matthew J.
Drug-related behaviors in both humans and rodents are commonly thought to arise from aberrant learning processes. Preclinical studies demonstrate that the acquisition and expression of many drug-dependent behaviors involves the ventral tegmental area (VTA), a midbrain structure comprised of dopamine, GABA, and glutamate neurons. Drug experience alters the excitatory and inhibitory synaptic input onto VTA dopamine neurons, suggesting a critical role for VTA afferents in mediating the effects of drugs. In this review, we present evidence implicating the VTA in drug-related behaviors, highlight the diversity of neuronal populations in the VTA, and discuss the behavioral effects of selectively manipulating VTA afferents. Future experiments are needed to determine which VTA afferents and what neuronal populations in the VTA mediate specific drug-dependent behaviors. Further studies are also necessary for identifying the afferent-specific synaptic alterations onto dopamine and non-dopamine neurons in the VTA following drug administration. The identification of neural circuits and adaptations involved with drug-dependent behaviors can highlight potential neural targets for pharmacological and deep brain stimulation interventions to treat substance abuse disorders. PMID:27014097
Elitt, Christopher M; Malin, Sacha A; Koerber, H Richard; Davis, Brian M; Albers, Kathryn M
Artemin, a member of the glial cell line-derived neurotrophic factor (GDNF) family, supports a subpopulation of trigeminal sensory neurons through activation of the Ret/GFRalpha3 receptor tyrosine kinase complex. In a previous study we showed that artemin is increased in inflamed skin of wildtype mice and that transgenic overexpression of artemin in skin increases TRPV1 and TRPA1 expression in dorsal root ganglia neurons. In this study we examined how transgenic overexpression of artemin in tongue epithelium affects the anatomy, gene expression and calcium handling properties of trigeminal sensory afferents. At the RNA level, trigeminal ganglia of artemin overexpresser mice (ART-OEs) had an 81% increase in GFRalpha3, a 190% increase in TRPV1 and a 403% increase in TRPA1 compared to wildtype (WT) controls. Myelinated and unmyelinated fibers of the lingual nerve were increased in diameter, as was the density of GFRalpha3 and TRPV1-positive innervation to the dorsal anterior tongue and fungiform papilla. Retrograde labeling of trigeminal afferents by WGA injection into the tip of the tongue showed an increased percentage of GFRalpha3, TRPV1 and isolectin B4 afferents in ART-OE mice. ART-OE afferents had larger calcium transients in response to ligands of TRPV1 (capsaicin) and TRPA1 (mustard oil). Behavioral sensitivity was also exhibited by ART-OE mice to capsaicin and mustard oil, measured using a two-choice drinking test. These results suggest a potential role for artemin-responsive GFRalpha3/TRPV1/TRPA1 sensory afferents in mediating sensitivity associated with tissue injury, chemical sensitivity or disease states such as burning mouth syndrome.
Alvarez, Francisco J; Titus-Mitchell, Haley E; Bullinger, Katie L; Kraszpulski, Michal; Nardelli, Paul; Cope, Timothy C
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.
Cattaert, Daniel; Bévengut, Michelle
Contrary to orthodromic spikes that are generated in sensory organs and conveyed to CNS, antidromic spikes are generated in the axon terminals of the sensory neurons within the CNS and are conveyed to the peripheral sensory organ. Antidromic discharges are observed in primary afferent neurons of both vertebrates and invertebrates and seem to be related to the rhythmic activity of central neural networks. In this study, we analyzed the effect of antidromic discharges on the sensory activity of a leg proprioceptor in in vitro preparations of the crayfish CNS. Intracellular microelectrodes were used both to record the orthodromic spikes and to elicit antidromic spikes by injecting squares pulses of depolarizing current at various frequencies. Experiments were performed on the three types of identified sensory afferents (tonic, phasotonic, and phasic). The main results showed a reduction of the firing frequency of the orthodromic activity in 82% of the tested afferents. In tonic afferents, during their occurrences and according to their frequency, antidromic spikes or bursts reduced or suppressed the orthodromic activity. Following their terminations, they also induced a silent period and a gradual recovery of the orthodromic activity, both of which increased as the duration and the frequency of the antidromic bursts increased. In phasotonic and phasic afferents, antidromic bursts reduced or suppressed the phasic responses as their frequency and durations increased. In phasotonic afferents, if elicited prior to the movements, long-duration bursts with increasing frequency reduced more rapidly the tonic background activity than the phasic one whereas short-duration bursts at high frequency produced strong decreases of both. The effect of antidromic bursts accumulated when they are repetitively elicited. Antidromic bursts induced a much larger decrease of the sensory activity than adaptation alone. The occurrences of antidromic spikes or bursts may have a functional role
Kargo, W J; Giszter, S F
and its degree of change after loss of proprioception depended on the degree of joint staggering used by the frog (i.e., the relative phasing between knee and hip motion) and on the degree of motor-pattern change. We examined these variations in 31 frogs. Twenty percent (6/31) of frogs showed largely synchronous joint coordination and little effect of deafferentation on joint coordination, end-point path, or the underlying synchronous motor pattern. Eighty percent of frogs (25/31) showed some degree of staggered joint coordination and also strong effects of loss of afferents. Loss of afferents caused two major joint level changes in these frogs: collapse of joint phasing into synchronous joint motion and increased hip velocity. Fifty percent of frogs (16/31) showed joint-coordination changes of type (1) without type (2). This change was associated with reduction, loss, or collapse of phasing of the sartorius, semitendinosus and biceps (iliofibularis) in the initial EMG burst in the motor pattern. The remaining 30% (9/31) of frogs showed both joint-coordination changes 1 and 2. These changes were associated with both the knee flexor EMG changes seen in the other frogs and with additional increased activity of rectus internus and semimembranosus muscles. Our data show that multiple ipsilateral modalities all play some role in regulating muscle activity patterns in the wiping limb. Our data support a strong role of ipsilateral proprioception in the process of trajectory formation and specifically in the control of limb segment interactions during wiping by way of the regulation and coordination of muscle groups based on initial limb configuration.
Watkins, Roger H; Wessberg, Johan; Backlund Wasling, Helena; Dunham, James P; Olausson, Håkan; Johnson, Richard D; Ackerley, Rochelle
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
Tseng, Ming-Tsung; Kong, Yazhuo; Chiang, Ming-Chang; Chao, Chi-Chao; Tseng, Wen-Yih I; Hsieh, Sung-Tsang
Although the small-diameter primary afferent fibers in the skin promptly respond to nociceptive stimuli and convey sensory inputs to the central nervous system, the neural signatures that underpin the relationship between cutaneous afferent fibers and pain perception remain elusive. We combined skin biopsy at the lateral aspect of the distal leg, which is used to quantify cutaneous afferent fibers, with fMRI, which is used to assess brain responses and functional connectivity, to investigate the relationship between cutaneous sensory nerves and the corresponding pain perception in the brain after applying heat pain stimulation to the dorsum of the right foot in healthy subjects. During painful stimulation, the degree of cutaneous innervation, as measured by epidermal nerve fiber density, was correlated with individual blood oxygen level-dependent (BOLD) signals of the posterior insular cortex and of the thalamus, periaqueductal gray, and rostral ventromedial medulla. Pain perception was associated with the activation of the anterior insular cortex and with the functional connectivity from the anterior insular cortex to the primary somatosensory cortex during painful stimulation. Most importantly, both epidermal nerve fiber density and activity in the posterior insular cortex showed a positive correlation with the strength of coupling under pain between the anterior insular cortex and the primary somatosensory cortex. Thus, our findings support the notion that the neural circuitry subserving pain perception interacts with the cerebral correlates of peripheral nociceptive fibers, which implicates an indirect role for skin nerves in human pain perception.
Saito, Kei; Yamaguchi, Tomofumi; Yoshida, Naoshin; Tanabe, Shigeo; Kondo, Kunitsugu; Sugawara, Kenichi
Although motor imagery enhances the excitability of the corticospinal tract, there are no peripheral afferent inputs during motor imagery. In contrast, peripheral nerve electrical stimulation (ES) can induce peripheral afferent inputs; thus, a combination of motor imagery and ES may enhance the excitability of the corticospinal tract compared with motor imagery alone. Moreover, the level of stimulation intensity may also be related to the modulation of the excitability of the corticospinal tract during motor imagery. Here, we evaluated whether a combination of motor imagery and peripheral nerve ES influences the excitability of the corticospinal tract and measured the effect of ES intensity on the excitability induced during motor imagery. The imagined task was a movement that involved touching the thumb to the little finger, whereas ES involved simultaneous stimulation of the ulnar and median nerves at the wrist. Two different ES intensities were used, one above the motor threshold and another above the sensory threshold. Further, we evaluated whether actual movement with afferent input induced by ES modulates the excitability of the corticospinal tract as well as motor imagery. We found that a combination of motor imagery and ES enhanced the excitability of the motor cortex in the thenar muscle compared with the other condition. Furthermore, we established that the modulation of the corticospinal tract was related to ES intensity. However, we found that the excitability of the corticospinal tract induced by actual movement was enhanced by peripheral nerve ES above the sensory threshold.
Cash, Robin F H; Isayama, Reina; Gunraj, Carolyn A; Ni, Zhen; Chen, Robert
Key points In the human, sensorimotor integration can be investigated using combined sensory and transcranial magnetic stimulation (TMS). Short latency afferent inhibition (SAI) refers to motor cortical inhibition 20–25ms after median nerve stimulation. We investigated the influence of SAI on a local excitatory interneuronal motor cortical circuit known as short-interval intracortical facilitation (SICF) and found that, contrary to expectations, SICF was facilitated in the presence of SAI (SICFSAI); this effect is specific to SICF since there was no effect in control conditions in which SICF was not elicited, and the facilitatory SICFSAI interaction increased with increasing strength of SICF or SAI. The influence of sensory input on excitatory motor cortical circuitry was similar across different bodily regions, different circuits within motor cortex and across functional states, suggesting that this interaction may have general applicability in sensorimotor integration and motor control. SAI and SICF were found to correlate between individuals in that those with high SAI were found to have high SICF, and this relationship was maintained when SICF was delivered in the presence of SAI, suggesting an intrinsic relationship between SAI and SICF; these findings are compatible with brain-slice studies of sensorimotor circuitry and add to our understanding of sensorimotor integration. Abstract In human, sensorimotor integration can be investigated by combining sensory input and transcran