Mechanisms of Transient Signaling via Short and Long Prolactin Receptor Isoforms in Female and Male Sensory Neurons*

PubMed Central

Belugin, Sergei; Diogenes, Anibal R.; Patil, Mayur J.; Ginsburg, Erika; Henry, Michael A.; Akopian, Armen N.

2013-01-01

Prolactin (PRL) regulates activity of nociceptors and causes hyperalgesia in pain conditions. PRL enhances nociceptive responses by rapidly modulating channels in nociceptors. The molecular mechanisms underlying PRL-induced transient signaling in neurons are not well understood. Here we use a variety of cell biology and pharmacological approaches to show that PRL transiently enhanced capsaicin-evoked responses involve protein kinase C ϵ (PKCϵ) or phosphatidylinositol 3-kinase (PI3K) pathways in female rat trigeminal (TG) neurons. We next reconstituted PRL-induced signaling in a heterologous expression system and TG neurons from PRL receptor (PRLR)-null mutant mice by expressing rat PRLR-long isoform (PRLR-L), PRLR-short isoform (PRLR-S), or a mix of both. Results show that PRLR-S, but not PRLR-L, is capable of mediating PRL-induced transient enhancement of capsaicin responses in both male and female TG neurons. However, co-expression of PRLR-L with PRLR-S (1:1 ratio) leads to the inhibition of the transient PRL actions. Co-expression of PRLR-L deletion mutants with PRLR-S indicated that the cytoplasmic site adjacent to the trans-membrane domain of PRLR-L was responsible for inhibitory effects of PRLR-L. Furthermore, in situ hybridization and immunohistochemistry data indicate that in normal conditions, PRLR-L is expressed mainly in glia with little expression in rat sensory neurons (3–5%) and human nerves. The predominant PRLR form in TG neurons/nerves from rats and humans is PRLR-S. Altogether, PRL-induced transient signaling in sensory neurons is governed by PI3K or PKCϵ, mediated via the PRLR-S isoform, and transient effects mediated by PRLR-S are inhibited by presence of PRLR-L in these cells. PMID:24142695

Mechanisms of transient signaling via short and long prolactin receptor isoforms in female and male sensory neurons.

PubMed

Belugin, Sergei; Diogenes, Anibal R; Patil, Mayur J; Ginsburg, Erika; Henry, Michael A; Akopian, Armen N

2013-11-29

Prolactin (PRL) regulates activity of nociceptors and causes hyperalgesia in pain conditions. PRL enhances nociceptive responses by rapidly modulating channels in nociceptors. The molecular mechanisms underlying PRL-induced transient signaling in neurons are not well understood. Here we use a variety of cell biology and pharmacological approaches to show that PRL transiently enhanced capsaicin-evoked responses involve protein kinase C ε (PKCε) or phosphatidylinositol 3-kinase (PI3K) pathways in female rat trigeminal (TG) neurons. We next reconstituted PRL-induced signaling in a heterologous expression system and TG neurons from PRL receptor (PRLR)-null mutant mice by expressing rat PRLR-long isoform (PRLR-L), PRLR-short isoform (PRLR-S), or a mix of both. Results show that PRLR-S, but not PRLR-L, is capable of mediating PRL-induced transient enhancement of capsaicin responses in both male and female TG neurons. However, co-expression of PRLR-L with PRLR-S (1:1 ratio) leads to the inhibition of the transient PRL actions. Co-expression of PRLR-L deletion mutants with PRLR-S indicated that the cytoplasmic site adjacent to the trans-membrane domain of PRLR-L was responsible for inhibitory effects of PRLR-L. Furthermore, in situ hybridization and immunohistochemistry data indicate that in normal conditions, PRLR-L is expressed mainly in glia with little expression in rat sensory neurons (3-5%) and human nerves. The predominant PRLR form in TG neurons/nerves from rats and humans is PRLR-S. Altogether, PRL-induced transient signaling in sensory neurons is governed by PI3K or PKCε, mediated via the PRLR-S isoform, and transient effects mediated by PRLR-S are inhibited by presence of PRLR-L in these cells.

Proteasome inhibition induces DNA damage and reorganizes nuclear architecture and protein synthesis machinery in sensory ganglion neurons.

PubMed

Palanca, Ana; Casafont, Iñigo; Berciano, María T; Lafarga, Miguel

2014-05-01

Bortezomib is a reversible proteasome inhibitor used as an anticancer drug. However, its clinical use is limited since it causes peripheral neurotoxicity. We have used Sprague-Dawley rats as an animal model to investigate the cellular mechanisms affected by both short-term and chronic bortezomib treatments in sensory ganglia neurons. Proteasome inhibition induces dose-dependent alterations in the architecture, positioning, shape and polarity of the neuronal nucleus. It also produces DNA damage without affecting neuronal survival, and severe disruption of the protein synthesis machinery at the central cytoplasm accompanied by decreased expression of the brain-derived neurotrophic factor. As a compensatory or adaptive survival response against proteotoxic stress caused by bortezomib treatment, sensory neurons preserve basal levels of transcriptional activity, up-regulate the expression of proteasome subunit genes, and generate a new cytoplasmic perinuclear domain for protein synthesis. We propose that proteasome activity is crucial for controlling nuclear architecture, DNA repair and the organization of the protein synthesis machinery in sensory neurons. These neurons are primary targets of bortezomib neurotoxicity, for which reason their dysfunction may contribute to the pathogenesis of the bortezomib-induced peripheral neuropathy in treated patients.

Enhanced excitability of small dorsal root ganglion neurons in rats with bone cancer pain

PubMed Central

2012-01-01

Background Primary and metastatic cancers that affect bone are frequently associated with severe and intractable pain. The mechanisms underlying the development of bone cancer pain are largely unknown. The aim of this study was to determine whether enhanced excitability of primary sensory neurons contributed to peripheral sensitization and tumor-induced hyperalgesia during cancer condition. In this study, using techniques of whole-cell patch-clamp recording associated with immunofluorescent staining, single-cell reverse-transcriptase PCR and behavioral test, we investigated whether the intrinsic membrane properties and the excitability of small-sized dorsal root ganglion (DRG) neurons altered in a rat model of bone cancer pain, and whether suppression of DRG neurons activity inhibited the bone cancer-induced pain. Results Our present study showed that implantation of MRMT-1 tumor cells into the tibial canal in rats produced significant mechanical and thermal hyperalgesia in the ipsilateral hind paw. Moreover, implantation of tumor cells provoked spontaneous discharges and tonic excitatory discharges evoked by a depolarizing current pulse in small-sized DRG neurons. In line with these findings, alterations in intrinsic membrane properties that reflect the enhanced neuronal excitability were observed in small DRG neurons in bone cancer rats, of which including: 1) depolarized resting membrane potential (RMP); 2) decreased input resistance (Rin); 3) a marked reduction in current threshold (CT) and voltage threshold (TP) of action potential (AP); 4) a dramatic decrease in amplitude, overshot, and duration of evoked action potentials as well as in amplitude and duration of afterhyperpolarization (AHP); and 5) a significant increase in the firing frequency of evoked action potentials. Here, the decreased AP threshold and increased firing frequency of evoked action potentials implicate the occurrence of hyperexcitability in small-sized DRG neurons in bone cancer rats. In

Sensory neurons do not induce motor neuron loss in a human stem cell model of spinal muscular atrophy.

PubMed

Schwab, Andrew J; Ebert, Allison D

2014-01-01

Spinal muscular atrophy (SMA) is an autosomal recessive disorder leading to paralysis and early death due to reduced SMN protein. It is unclear why there is such a profound motor neuron loss, but recent evidence from fly and mouse studies indicate that cells comprising the whole sensory-motor circuit may contribute to motor neuron dysfunction and loss. Here, we used induced pluripotent stem cells derived from SMA patients to test whether sensory neurons directly contribute to motor neuron loss. We generated sensory neurons from SMA induced pluripotent stem cells and found no difference in neuron generation or survival, although there was a reduced calcium response to depolarizing stimuli. Using co-culture of SMA induced pluripotent stem cell derived sensory neurons with control induced pluripotent stem cell derived motor neurons, we found no significant reduction in motor neuron number or glutamate transporter boutons on motor neuron cell bodies or neurites. We conclude that SMA sensory neurons do not overtly contribute to motor neuron loss in this human stem cell system.

Endogenous angiotensinergic system in neurons of rat and human trigeminal ganglia

PubMed Central

Imboden, Hans; Patil, Jaspal; Nussberger, Juerg; Nicoud, Françoise; Hess, Benno; Ahmed, Nermin; Schaffner, Thomas; Wellner, Maren; Müller, Dominik; Inagami, Tadashi; Senbonmatsu, Takaaki; Pavel, Jaroslav; Saavedra, Juan M.

2009-01-01

To clarify the role of Angiotensin II (Ang II) in the sensory system and especially in the trigeminal ganglia, we studied the expression of angiotensinogen (Ang-N)-, renin-, angiotensin converting enzyme (ACE)- and cathepsin D-mRNA, and the presence of Ang II and substance P in the rat and human trigeminal ganglia. The rat trigeminal ganglia expressed substantial amounts of Ang-N- and ACE mRNA as determined by quantitative real time PCR. Renin mRNA was untraceable in rat samples. Cathepsin D was detected in the rat trigeminal ganglia indicating the possibility of existence of pathways alternative to renin for Ang I formation. In situ hybridization in rat trigeminal ganglia revealed expression of Ang-N mRNA in the cytoplasm of numerous neurons. By using immunocytochemistry, a number of neurons and their processes in both the rat and human trigeminal ganglia were stained for Ang II. Post in situ hybridization immunocytochemistry reveals that in the rat trigeminal ganglia some, but not all Ang-N mRNA-positive neurons marked for Ang II. In some neurons Substance P was found colocalized with Ang II. Angiotensins from rat trigeminal ganglia were quantitated by radioimmunoassay with and without prior separation by high performance liquid chromatography. Immunoreactive angiotensin II (ir-Ang II) was consistently present and the sum of true Ang II (1-8) octapeptide and its specifically measured metabolites were found to account for it. Radioimmunological and immunocytochemical evidence of ir-Ang II in neuronal tissue is compatible with Ang II as a neurotransmitter. In conclusion, these results suggest that Ang II could be produced locally in the neurons of rat trigeminal ganglia. The localization and colocalization of neuronal Ang II with Substance P in the trigeminal ganglia neurons may be the basis for a participation and function of Ang II in the regulation of nociception and migraine pathology. PMID:19323983

Gastrodin Inhibits Allodynia and Hyperalgesia in Painful Diabetic Neuropathy Rats by Decreasing Excitability of Nociceptive Primary Sensory Neurons

PubMed Central

Ye, Xin; Han, Wen-Juan; Wang, Wen-Ting; Luo, Ceng; Hu, San-Jue

2012-01-01

Painful diabetic neuropathy (PDN) is a common complication of diabetes mellitus and adversely affects the patients’ quality of life. Evidence has accumulated that PDN is associated with hyperexcitability of peripheral nociceptive primary sensory neurons. However, the precise cellular mechanism underlying PDN remains elusive. This may result in the lacking of effective therapies for the treatment of PDN. The phenolic glucoside, gastrodin, which is a main constituent of the Chinese herbal medicine Gastrodia elata Blume, has been widely used as an anticonvulsant, sedative, and analgesic since ancient times. However, the cellular mechanisms underlying its analgesic actions are not well understood. By utilizing a combination of behavioral surveys and electrophysiological recordings, the present study investigated the role of gastrodin in an experimental rat model of STZ-induced PDN and to further explore the underlying cellular mechanisms. Intraperitoneal administration of gastrodin effectively attenuated both the mechanical allodynia and thermal hyperalgesia induced by STZ injection. Whole-cell patch clamp recordings were obtained from nociceptive, capsaicin-sensitive small diameter neurons of the intact dorsal root ganglion (DRG). Recordings from diabetic rats revealed that the abnormal hyperexcitability of neurons was greatly abolished by application of GAS. To determine which currents were involved in the antinociceptive action of gastrodin, we examined the effects of gastrodin on transient sodium currents (I NaT) and potassium currents in diabetic small DRG neurons. Diabetes caused a prominent enhancement of I NaT and a decrease of potassium currents, especially slowly inactivating potassium currents (I AS); these effects were completely reversed by GAS in a dose-dependent manner. Furthermore, changes in activation and inactivation kinetics of I NaT and total potassium current as well as I AS currents induced by STZ were normalized by GAS. This study provides a

Selective block of late Na+ current by local anaesthetics in rat large sensory neurones

PubMed Central

Baker, Mark D

2000-01-01

The actions of lignocaine and benzocaine on transient and late Na+ current generated by large diameter (⩾50 μm) adult rat dorsal root ganglion neurones, were studied using patch-clamp techniques.Both drugs blocked whole-cell late Na+ current in a concentration-dependent manner. At 200 ms following the onset of a clamp step from −110 to −40 mV, the apparent K for block of late Na+ current by lignocaine was 57.8±15 μM (mean±s.e.mean, n=4). The value for benzocaine was 24.9±3.3 μM, (mean±s.e.mean, n=3).The effect of lignocaine on transient current, in randomly selected neurones, appeared variable (n=8, half-block from ∼50 to 400 μM). Half-block by benzocaine was not attained, but both whole-cell (n=11) and patch data suggested a high apparent K,>250 μM. Transient current always remained after late current was blocked.The voltage-dependence of residual late current steady-state inactivation was not shifted by 20 μM benzocaine (n=3), whereas 200 μM benzocaine shifted the voltage-dependence of transient current steady-state inactivation by −18.7±5.9 mV (mean±s.e.mean, n=4).In current-clamp, benzocaine (250 μM) could block subthreshold, voltage-dependent inward current, increasing the threshold for eliciting action potentials, without preventing their generation (n=2).Block of late Na+ current by systemic local anaesthetic may play a part in preventing ectopic impulse generation in sensory neurones. PMID:10780966

P2X receptors, sensory neurons and pain.

PubMed

Bele, Tanja; Fabbretti, Elsa

2015-01-01

Pain represents a very large social and clinical problem since the current treatment provides insufficient pain relief. Plasticity of pain receptors together with sensitisation of sensory neurons, and the role of soluble mediators released from non-neuronal cells render difficult to understand the spatial and temporal scale of pain development, neuronal responses and disease progression. In pathological conditions, ATP is one of the most powerful mediators that activates P2X receptors that behave as sensitive ATP-detectors, such as neuronal P2X3 receptor subtypes and P2X4 and P2X7 receptors expressed on non-neuronal cells. Dissecting the molecular mechanisms occurring in sensory neurons and in accessory cells allows to design appropriate tissue- and cell- targeted approaches to treat chronic pain.

Orbital cortex neuronal responses during an odor-based conditioned associative task in rats.

PubMed

Yonemori, M; Nishijo, H; Uwano, T; Tamura, R; Furuta, I; Kawasaki, M; Takashima, Y; Ono, T

2000-01-01

Neuronal activity in the rat orbital cortex during discrimination of various odors [five volatile organic compounds (acetophenone, isoamyl acetate, cyclohexanone, p-cymene and 1,8-cineole), and food- and cosmetic-related odorants (black pepper, cheese, rose and perfume)] and other conditioned sensory stimuli (tones, light and air puff) was recorded and compared with behavioral responses to the same odors (black pepper, cheese, rose and perfume). In a neurophysiological study, the rats were trained to lick a spout that protruded close to its mouth to obtain sucrose or intracranial self-stimulation reward after presentation of conditioned stimuli. Of 150 orbital cortex neurons recorded during the task, 65 responded to one or more types of sensory stimuli. Of these, 73.8% (48/65) responded during presentation of an odor. Although the mean breadth of responsiveness (entropy) of the olfactory neurons based on the responses to five volatile organic compounds and air (control) was rather high (0.795), these stimuli were well discriminated in an odor space resulting from multidimensional scaling using Pearson's correlation coefficients between the stimuli. In a behavioral study, a rat was housed in an equilateral octagonal cage, with free access to food and choice among eight levers, four of which elicited only water (no odor, controls), and four of which elicited both water and one of four odors (black pepper, cheese, rose or perfume). Lever presses for each odor and control were counted. Distributions of these five stimuli (four odors and air) in an odor space derived from the multidimensional scaling using Pearson's correlation coefficients based on behavioral responses were very similar to those based on neuronal responses to the same five stimuli. Furthermore, Pearson's correlation coefficients between the same five stimuli based on the neuronal responses and those based on behavioral responses were significantly correlated. The results demonstrated a pivotal role of

Adrenergic signaling mediates mechanical hyperalgesia through activation of P2X3 receptors in primary sensory neurons of rats with chronic pancreatitis.

PubMed

Wang, Shusheng; Zhu, Hong-Yan; Jin, Yi; Zhou, Youlang; Hu, Shufen; Liu, Tong; Jiang, Xinghong; Xu, Guang-Yin

2015-04-15

The mechanism of pain in chronic pancreatitis (CP) is poorly understood. The aim of this study was designed to investigate roles of norepinephrine (NE) and P2X receptor (P2XR) signaling pathway in the pathogenesis of hyperalgesia in a rat model of CP. CP was induced in male adult rats by intraductal injection of trinitrobenzene sulfonic acid (TNBS). Mechanical hyperalgesia was assessed by referred somatic behaviors to mechanical stimulation of rat abdomen. P2XR-mediated responses of pancreatic dorsal root ganglion (DRG) neurons were measured utilizing calcium imaging and whole cell patch-clamp-recording techniques. Western blot analysis and immunofluorescence were performed to examine protein expression. TNBS injection produced a significant upregulation of P2X3R expression and an increase in ATP-evoked responses of pancreatic DRG neurons. The sensitization of P2X3Rs was reversed by administration of β-adrenergic receptor antagonist propranolol. Incubation of DRG neurons with NE significantly enhanced ATP-induced intracellular calcium signals, which were abolished by propranolol, and partially blocked by protein kinase A inhibitor H-89. Interestingly, TNBS injection led to a significant elevation of NE concentration in DRGs and the pancreas, an upregulation of β2-adrenergic receptor expression in DRGs, and amplification of the NE-induced potentiation of ATP responses. Importantly, pancreatic hyperalgesia was markedly attenuated by administration of purinergic receptor antagonist suramin or A317491 or β2-adrenergic receptor antagonist butoxamine. Sensitization of P2X3Rs, which was likely mediated by adrenergic signaling in primary sensory neurons, contributes to pancreatic pain, thus identifying a potential target for treating pancreatic pain caused by inflammation. Copyright © 2015 the American Physiological Society.

Odor-evoked inhibition of olfactory sensory neurons drives olfactory perception in Drosophila.

PubMed

Cao, Li-Hui; Yang, Dong; Wu, Wei; Zeng, Xiankun; Jing, Bi-Yang; Li, Meng-Tong; Qin, Shanshan; Tang, Chao; Tu, Yuhai; Luo, Dong-Gen

2017-11-07

Inhibitory response occurs throughout the nervous system, including the peripheral olfactory system. While odor-evoked excitation in peripheral olfactory cells is known to encode odor information, the molecular mechanism and functional roles of odor-evoked inhibition remain largely unknown. Here, we examined Drosophila olfactory sensory neurons and found that inhibitory odors triggered outward receptor currents by reducing the constitutive activities of odorant receptors, inhibiting the basal spike firing in olfactory sensory neurons. Remarkably, this odor-evoked inhibition of olfactory sensory neurons elicited by itself a full range of olfactory behaviors from attraction to avoidance, as did odor-evoked olfactory sensory neuron excitation. These results indicated that peripheral inhibition is comparable to excitation in encoding sensory signals rather than merely regulating excitation. Furthermore, we demonstrated that a bidirectional code with both odor-evoked inhibition and excitation in single olfactory sensory neurons increases the odor-coding capacity, providing a means of efficient sensory encoding.

TRPA1 Is Functionally Expressed Primarily by IB4-Binding, Non-Peptidergic Mouse and Rat Sensory Neurons

PubMed Central

Stucky, Cheryl L.

2012-01-01

Subpopulations of somatosensory neurons are characterized by functional properties and expression of receptor proteins and surface markers. CGRP expression and IB4-binding are commonly used to define peptidergic and non-peptidergic subpopulations. TRPA1 is a polymodal, plasma membrane ion channel that contributes to mechanical and cold hypersensitivity during tissue injury, making it a key target for pain therapeutics. Some studies have shown that TRPA1 is predominantly expressed by peptidergic sensory neurons, but others indicate that TRPA1 is expressed extensively within non-peptidergic, IB4-binding neurons. We used FURA-2 calcium imaging to define the functional distribution of TRPA1 among peptidergic and non-peptidergic adult mouse (C57BL/6J) DRG neurons. Approximately 80% of all small-diameter (<27 µm) neurons from lumbar 1–6 DRGs that responded to TRPA1 agonists allyl isothiocyanate (AITC; 79%) or cinnamaldehyde (84%) were IB4-positive. Retrograde labeling via plantar hind paw injection of WGA-Alexafluor594 showed similarly that most (81%) cutaneous neurons responding to TRPA1 agonists were IB4-positive. Additionally, we cultured DRG neurons from a novel CGRP-GFP mouse where GFP expression is driven by the CGRPα promoter, enabling identification of CGRP-expressing live neurons. Interestingly, 78% of TRPA1-responsive neurons were CGRP-negative. Co-labeling with IB4 revealed that the majority (66%) of TRPA1 agonist responders were IB4-positive but CGRP-negative. Among TRPA1-null DRGs, few small neurons (2–4%) responded to either TRPA1 agonist, indicating that both cinnamaldehyde and AITC specifically target TRPA1. Additionally, few large neurons (≥27 µm diameter) responded to AITC (6%) or cinnamaldehyde (4%), confirming that most large-diameter somata lack functional TRPA1. Comparison of mouse and rat DRGs showed that the majority of TRPA1-responsive neurons in both species were IB4-positive. Together, these data demonstrate that TRPA1 is functionally

A role for Runx transcription factor signaling in dorsal root ganglion sensory neuron diversification.

PubMed

Kramer, Ina; Sigrist, Markus; de Nooij, Joriene C; Taniuchi, Ichiro; Jessell, Thomas M; Arber, Silvia

2006-02-02

Subpopulations of sensory neurons in the dorsal root ganglion (DRG) can be characterized on the basis of sensory modalities that convey distinct peripheral stimuli, but the molecular mechanisms that underlie sensory neuronal diversification remain unclear. Here, we have used genetic manipulations in the mouse embryo to examine how Runx transcription factor signaling controls the acquisition of distinct DRG neuronal subtype identities. Runx3 acts to diversify an Ngn1-independent neuronal cohort by promoting the differentiation of proprioceptive sensory neurons through erosion of TrkB expression in prospective TrkC+ sensory neurons. In contrast, Runx1 controls neuronal diversification within Ngn1-dependent TrkA+ neurons by repression of neuropeptide CGRP expression and controlling the fine pattern of laminar termination in the dorsal spinal cord. Together, our findings suggest that Runx transcription factor signaling plays a key role in sensory neuron diversification.

Visualization of Sensory Neurons and Their Projections in an Upper Motor Neuron Reporter Line.

PubMed

Genç, Barış; Lagrimas, Amiko Krisa Bunag; Kuru, Pınar; Hess, Robert; Tu, Michael William; Menichella, Daniela Maria; Miller, Richard J; Paller, Amy S; Özdinler, P Hande

2015-01-01

Visualization of peripheral nervous system axons and cell bodies is important to understand their development, target recognition, and integration into complex circuitries. Numerous studies have used protein gene product (PGP) 9.5 [a.k.a. ubiquitin carboxy-terminal hydrolase L1 (UCHL1)] expression as a marker to label sensory neurons and their axons. Enhanced green fluorescent protein (eGFP) expression, under the control of UCHL1 promoter, is stable and long lasting in the UCHL1-eGFP reporter line. In addition to the genetic labeling of corticospinal motor neurons in the motor cortex and degeneration-resistant spinal motor neurons in the spinal cord, here we report that neurons of the peripheral nervous system are also fluorescently labeled in the UCHL1-eGFP reporter line. eGFP expression is turned on at embryonic ages and lasts through adulthood, allowing detailed studies of cell bodies, axons and target innervation patterns of all sensory neurons in vivo. In addition, visualization of both the sensory and the motor neurons in the same animal offers many advantages. In this report, we used UCHL1-eGFP reporter line in two different disease paradigms: diabetes and motor neuron disease. eGFP expression in sensory axons helped determine changes in epidermal nerve fiber density in a high-fat diet induced diabetes model. Our findings corroborate previous studies, and suggest that more than five months is required for significant skin denervation. Crossing UCHL1-eGFP with hSOD1G93A mice generated hSOD1G93A-UeGFP reporter line of amyotrophic lateral sclerosis, and revealed sensory nervous system defects, especially towards disease end-stage. Our studies not only emphasize the complexity of the disease in ALS, but also reveal that UCHL1-eGFP reporter line would be a valuable tool to visualize and study various aspects of sensory nervous system development and degeneration in the context of numerous diseases.

Transient Receptor Potential Channels Encode Volatile Chemicals Sensed by Rat Trigeminal Ganglion Neurons

PubMed Central

Schöbel, Nicole; Beltrán, Leopoldo; Wetzel, Christian Horst; Hatt, Hanns

2013-01-01

Primary sensory afferents of the dorsal root and trigeminal ganglia constantly transmit sensory information depicting the individual’s physical and chemical environment to higher brain regions. Beyond the typical trigeminal stimuli (e.g. irritants), environmental stimuli comprise a plethora of volatile chemicals with olfactory components (odorants). In spite of a complete loss of their sense of smell, anosmic patients may retain the ability to roughly discriminate between different volatile compounds. While the detailed mechanisms remain elusive, sensory structures belonging to the trigeminal system seem to be responsible for this phenomenon. In order to gain a better understanding of the mechanisms underlying the activation of the trigeminal system by volatile chemicals, we investigated odorant-induced membrane potential changes in cultured rat trigeminal neurons induced by the odorants vanillin, heliotropyl acetone, helional, and geraniol. We observed the dose-dependent depolarization of trigeminal neurons upon application of these substances occurring in a stimulus-specific manner and could show that distinct neuronal populations respond to different odorants. Using specific antagonists, we found evidence that TRPA1, TRPM8, and/or TRPV1 contribute to the activation. In order to further test this hypothesis, we used recombinantly expressed rat and human variants of these channels to investigate whether they are indeed activated by the odorants tested. We additionally found that the odorants dose-dependently inhibit two-pore potassium channels TASK1 and TASK3 heterologously expressed In Xenopus laevis oocytes. We suggest that the capability of various odorants to activate different TRP channels and to inhibit potassium channels causes neuronal depolarization and activation of distinct subpopulations of trigeminal sensory neurons, forming the basis for a specific representation of volatile chemicals in the trigeminal ganglia. PMID:24205061

Neuronal Entropy-Rate Feature of Entopeduncular Nucleus in Rat Model of Parkinson's Disease.

PubMed

Darbin, Olivier; Jin, Xingxing; Von Wrangel, Christof; Schwabe, Kerstin; Nambu, Atsushi; Naritoku, Dean K; Krauss, Joachim K; Alam, Mesbah

2016-03-01

The function of the nigro-striatal pathway on neuronal entropy in the basal ganglia (BG) output nucleus, i.e. the entopeduncular nucleus (EPN) was investigated in the unilaterally 6-hyroxydopamine (6-OHDA)-lesioned rat model of Parkinson's disease (PD). In both control subjects and subjects with 6-OHDA lesion of dopamine (DA) the nigro-striatal pathway, a histological hallmark for parkinsonism, neuronal entropy in EPN was maximal in neurons with firing rates ranging between 15 and 25 Hz. In 6-OHDA lesioned rats, neuronal entropy in the EPN was specifically higher in neurons with firing rates above 25 Hz. Our data establishes that the nigro-striatal pathway controls neuronal entropy in motor circuitry and that the parkinsonian condition is associated with abnormal relationship between firing rate and neuronal entropy in BG output nuclei. The neuronal firing rates and entropy relationship provide putative relevant electrophysiological information to investigate the sensory-motor processing in normal condition and conditions such as movement disorders.

Distribution of binding sites for the plant lectin Ulex europaeus agglutinin I on primary sensory neurones in seven different mammalian species.

PubMed

Gerke, Michelle B; Plenderleith, Mark B

2002-01-01

There is an increasing body of evidence to suggest that different functional classes of neurones express characteristic cell-surface carbohydrates. Previous studies have shown that the plant lectin Ulex europaeus agglutinin-I (UEA) binds to a population of small to medium diameter primary sensory neurones in rabbits and humans. This suggests that a fucose-containing glycoconjugate may be expressed by nociceptive primary sensory neurones. In order to determine the extent to which this glycoconjugate is expressed by other species, in the current study, we have examined the distribution of UEA-binding sites on primary sensory neurones in seven different mammals. Binding sites for UEA were associated with the plasma membrane and cytoplasmic granules of small to medium dorsal root ganglion cells and their axon terminals in laminae I-III of the grey matter of the spinal cord, in the rabbit, cat and marmoset monkey. However, no binding was observed in either the dorsal root ganglia or spinal cord in the mouse, rat, guinea pig or flying fox. These results indicate an inter-species variation in the expression of cell-surface glycoconjugates on mammalian primary sensory neurones.

Differential motor and sensory functional recovery in male but not female adult rats is associated with remyelination rather than axon regeneration after sciatic nerve crush.

PubMed

Tong, Ling-Ling; Ding, You-Quan; Jing, Hong-Bo; Li, Xuan-Yang; Qi, Jian-Guo

2015-05-06

Peripheral nerve functional recovery after injuries relies on both axon regeneration and remyelination. Both axon regeneration and remyelination require intimate interactions between regenerating neurons and their accompanying Schwann cells. Previous studies have shown that motor and sensory neurons are intrinsically different in their regeneration potentials. Moreover, denervated Schwann cells accompanying myelinated motor and sensory axons have distinct gene expression profiles for regeneration-associated growth factors. However, it is unknown whether differential motor and sensory functional recovery exists. If so, the particular one among axon regeneration and remyelination responsible for this difference remains unclear. Here, we aimed to establish an adult rat sciatic nerve crush model with the nonserrated microneedle holders and measured rat motor and sensory functions during regeneration. Furthermore, axon regeneration and remyelination was evaluated by morphometric analysis of electron microscopic images on the basis of nerve fiber classification. Our results showed that Aα fiber-mediated motor function was successfully recovered in both male and female rats. Aδ fiber-mediated sensory function was partially restored in male rats, but completely recovered in female littermates. For both male and female rats, the numbers of regenerated motor and sensory axons were quite comparable. However, remyelination was diverse among myelinated motor and sensory nerve fibers. In detail, Aβ and Aδ fibers incompletely remyelinated in male, but not female rats, whereas Aα fibers fully remyelinated in both sexes. Our result indicated that differential motor and sensory functional recovery in male but not female adult rats is associated with remyelination rather than axon regeneration after sciatic nerve crush.

Kv7.2 regulates the function of peripheral sensory neurons.

PubMed

King, Chih H; Lancaster, Eric; Salomon, Daniela; Peles, Elior; Scherer, Steven S

2014-10-01

The Kv7 (KCNQ) family of voltage-gated K(+) channels regulates cellular excitability. The functional role of Kv7.2 has been hampered by the lack of a viable Kcnq2-null animal model. In this study, we generated homozygous Kcnq2-null sensory neurons using the Cre-Lox system; in these mice, Kv7.2 expression is absent in the peripheral sensory neurons, whereas the expression of other molecular components of nodes (including Kv7.3), paranodes, and juxtaparanodes is not altered. The conditional Kcnq2-null animals exhibit normal motor performance but have increased thermal hyperalgesia and mechanical allodynia. Whole-cell patch recording technique demonstrates that Kcnq2-null sensory neurons have increased excitability and reduced spike frequency adaptation. Taken together, our results suggest that the loss of Kv7.2 activity increases the excitability of primary sensory neurons. © 2014 Wiley Periodicals, Inc.

Systemic Chemical Desensitization of Peptidergic Sensory Neurons with Resiniferatoxin Inhibits Experimental Periodontitis

PubMed Central

Breivik, Torbjørn; Gundersen, Yngvar; Gjermo, Per; Fristad, Inge; Opstad, Per Kristian

2011-01-01

Background and objective: The immune system is an important player in the pathophysiology of periodontitis. The brain controls immune responses via neural and hormonal pathways, and brain-neuro-endocrine dysregulation may be a central determinant for pathogenesis. Our current knowledge also emphasizes the central role of sensory nerves. In line with this, we wanted to investigate how desensitization of peptidergic sensory neurons influences the progression of ligature-induced periodontitis, and, furthermore, how selected cytokine and stress hormone responses to Gram-negative bacterial lipopolysaccharide (LPS) stimulation are affected. Material and methods: Resiniferatoxin (RTX; 50 μg/kg) or vehicle was injected subcutaneously on days 1, 2, and 3 in stress high responding and periodontitis-susceptible Fischer 344 rats. Periodontitis was induced 2 days thereafter. Progression of the disease was assessed after the ligatures had been in place for 20 days. Two h before decapitation all rats received LPS (150 μg/kg i.p.) to induce a robust immune and stress response. Results: Desensitization with RTX significantly reduced bone loss as measured by digital X-rays. LPS provoked a significantly higher increase in serum levels of the pro-inflammatory cytokine tumour necrosis factor (TNF)-α, but lower serum levels of the anti-inflammatory cytokine interleukin (IL)-10 and the stress hormone corticosterone. Conclusions: In this model RTX-induced chemical desensitization of sensory peptidergic neurons attenuated ligature-induced periodontitis and promoted a shift towards stronger pro-inflammatory cytokine and weaker stress hormone responses to LPS. The results may partly be explained by the attenuated transmission of immuno-inflammatory signals to the brain. In turn, this may weaken the anti-inflammatory brain-derived pathways. PMID:21339860

[The mirror neuron system in motor and sensory rehabilitation].

PubMed

Oouchida, Yutaka; Izumi, Shinichi

2014-06-01

The discovery of the mirror neuron system has dramatically changed the study of motor control in neuroscience. The mirror neuron system provides a conceptual framework covering the aspects of motor as well as sensory functions in motor control. Previous studies of motor control can be classified as studies of motor or sensory functions, and these two classes of studies appear to have advanced independently. In rehabilitation requiring motor learning, such as relearning movement after limb paresis, however, sensory information of feedback for motor output as well as motor command are essential. During rehabilitation from chronic pain, motor exercise is one of the most effective treatments for pain caused by dysfunction in the sensory system. In rehabilitation where total intervention unifying the motor and sensory aspects of motor control is important, learning through imitation, which is associated with the mirror neuron system can be effective and suitable. In this paper, we introduce the clinical applications of imitated movement in rehabilitation from motor impairment after brain damage and phantom limb pain after limb amputation.

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

PubMed

Ikeda, Ryo; Gu, Jianguo

2016-01-01

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

Sensory Neurons Arouse C. elegans Locomotion via Both Glutamate and Neuropeptide Release

PubMed Central

Chatzigeorgiou, Marios; Hu, Zhitao; Schafer, William R.; Kaplan, Joshua M.

2015-01-01

C. elegans undergoes periods of behavioral quiescence during larval molts (termed lethargus) and as adults. Little is known about the circuit mechanisms that establish these quiescent states. Lethargus and adult locomotion quiescence is dramatically reduced in mutants lacking the neuropeptide receptor NPR-1. Here, we show that the aroused locomotion of npr-1 mutants results from the exaggerated activity in multiple classes of sensory neurons, including nociceptive (ASH), touch sensitive (ALM and PLM), and stretch sensing (DVA) neurons. These sensory neurons accelerate locomotion via both neuropeptide and glutamate release. The relative contribution of these sensory neurons to arousal differs between larval molts and adults. Our results suggest that a broad network of sensory neurons dictates transitions between aroused and quiescent behavioral states. PMID:26154367

O-GlcNAc Transferase Is Essential for Sensory Neuron Survival and Maintenance

PubMed Central

Su, Cathy

2017-01-01

O-GlcNAc transferase (OGT) regulates a wide range of cellular processes through the addition of the O-GlcNAc sugar moiety to thousands of protein substrates. Because nutrient availability affects the activity of OGT, its role has been broadly studied in metabolic tissues. OGT is enriched in the nervous system, but little is known about its importance in basic neuronal processes in vivo. Here, we show that OGT is essential for sensory neuron survival and maintenance in mice. Sensory neuron-specific knock-out of OGT results in behavioral hyposensitivity to thermal and mechanical stimuli accompanied by decreased epidermal innervation and cell-body loss in the dorsal root ganglia. These effects are observed early in postnatal development and progress as animals age. Cultured sensory neurons lacking OGT also exhibit decreased axonal outgrowth. The effects on neuronal health in vivo are not solely due to disruption of developmental processes, because inducing OGT knock-out in the sensory neurons of adult mice results in a similar decrease in nerve fiber endings and cell bodies. Significant nerve-ending loss occurs before a decrease in cell bodies; this phenotype is indicative of axonal dieback that progresses to neuronal death. Our findings demonstrate that OGT is important in regulating axonal maintenance in the periphery and the overall health and survival of sensory neurons. SIGNIFICANCE STATEMENT We show the importance of O-GlcNAc transferase (OGT) for sensory neuron health and survival in vivo. This study is the first to find that loss of OGT results in neuronal cell death. Moreover, it suggests that aberrant O-GlcNAc signaling can contribute to the development of neuropathy. The sensory neurons lie outside of the blood–brain barrier and therefore, compared to central neurons, may have a greater need for mechanisms of metabolic sensing and compensation. Peripheral sensory neurons in particular are subject to degeneration in diabetes. Our findings provide a

Unimodal primary sensory cortices are directly connected by long-range horizontal projections in the rat sensory cortex

PubMed Central

Stehberg, Jimmy; Dang, Phat T.; Frostig, Ron D.

2014-01-01

Research based on functional imaging and neuronal recordings in the barrel cortex subdivision of primary somatosensory cortex (SI) of the adult rat has revealed novel aspects of structure-function relationships in this cortex. Specifically, it has demonstrated that single whisker stimulation evokes subthreshold neuronal activity that spreads symmetrically within gray matter from the appropriate barrel area, crosses cytoarchitectural borders of SI and reaches deeply into other unimodal primary cortices such as primary auditory (AI) and primary visual (VI). It was further demonstrated that this spread is supported by a spatially matching underlying diffuse network of border-crossing, long-range projections that could also reach deeply into AI and VI. Here we seek to determine whether such a network of border-crossing, long-range projections is unique to barrel cortex or characterizes also other primary, unimodal sensory cortices and therefore could directly connect them. Using anterograde (BDA) and retrograde (CTb) tract-tracing techniques, we demonstrate that such diffuse horizontal networks directly and mutually connect VI, AI and SI. These findings suggest that diffuse, border-crossing axonal projections connecting directly primary cortices are an important organizational motif common to all major primary sensory cortices in the rat. Potential implications of these findings for topics including cortical structure-function relationships, multisensory integration, functional imaging, and cortical parcellation are discussed. PMID:25309339

Unimodal primary sensory cortices are directly connected by long-range horizontal projections in the rat sensory cortex.

PubMed

Stehberg, Jimmy; Dang, Phat T; Frostig, Ron D

2014-01-01

Research based on functional imaging and neuronal recordings in the barrel cortex subdivision of primary somatosensory cortex (SI) of the adult rat has revealed novel aspects of structure-function relationships in this cortex. Specifically, it has demonstrated that single whisker stimulation evokes subthreshold neuronal activity that spreads symmetrically within gray matter from the appropriate barrel area, crosses cytoarchitectural borders of SI and reaches deeply into other unimodal primary cortices such as primary auditory (AI) and primary visual (VI). It was further demonstrated that this spread is supported by a spatially matching underlying diffuse network of border-crossing, long-range projections that could also reach deeply into AI and VI. Here we seek to determine whether such a network of border-crossing, long-range projections is unique to barrel cortex or characterizes also other primary, unimodal sensory cortices and therefore could directly connect them. Using anterograde (BDA) and retrograde (CTb) tract-tracing techniques, we demonstrate that such diffuse horizontal networks directly and mutually connect VI, AI and SI. These findings suggest that diffuse, border-crossing axonal projections connecting directly primary cortices are an important organizational motif common to all major primary sensory cortices in the rat. Potential implications of these findings for topics including cortical structure-function relationships, multisensory integration, functional imaging, and cortical parcellation are discussed.

Block of voltage-gated potassium channels by Pacific ciguatoxin-1 contributes to increased neuronal excitability in rat sensory neurons

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

Birinyi-Strachan, Liesl C.; Gunning, Simon J.; Lewis, Richard J.

2005-04-15

The present study investigated the actions of the polyether marine toxin Pacific ciguatoxin-1 (P-CTX-1) on neuronal excitability in rat dorsal root ganglion (DRG) neurons using patch-clamp recording techniques. Under current-clamp conditions, bath application of 2-20 nM P-CTX-1 caused a rapid, concentration-dependent depolarization of the resting membrane potential in neurons expressing tetrodotoxin (TTX)-sensitive voltage-gated sodium (Na{sub v}) channels. This action was completely suppressed by the addition of 200 nM TTX to the external solution, indicating that this effect was mediated through TTX-sensitive Na{sub v} channels. In addition, P-CTX-1 also prolonged action potential and afterhyperpolarization (AHP) duration. In a subpopulation of neurons,more » P-CTX-1 also produced tonic action potential firing, an effect that was not accompanied by significant oscillation of the resting membrane potential. Conversely, in neurons expressing TTX-resistant Na{sub v} currents, P-CTX-1 failed to alter any parameter of neuronal excitability examined in this study. Under voltage-clamp conditions in rat DRG neurons, P-CTX-1 inhibited both delayed-rectifier and 'A-type' potassium currents in a dose-dependent manner, actions that occurred in the absence of alterations to the voltage dependence of activation. These actions appear to underlie the prolongation of the action potential and AHP, and contribute to repetitive firing. These data indicate that a block of potassium channels contributes to the increase in neuronal excitability, associated with a modulation of Na{sub v} channel gating, observed clinically in response to ciguatera poisoning.« less

Traumatic Brain Injury and Neuronal Functionality Changes in Sensory Cortex

PubMed Central

Carron, Simone F.; Alwis, Dasuni S.; Rajan, Ramesh

2016-01-01

Traumatic brain injury (TBI), caused by direct blows to the head or inertial forces during relative head-brain movement, can result in long-lasting cognitive and motor deficits which can be particularly consequential when they occur in young people with a long life ahead. Much is known of the molecular and anatomical changes produced in TBI but much less is known of the consequences of these changes to neuronal functionality, especially in the cortex. Given that much of our interior and exterior lives are dependent on responsiveness to information from and about the world around us, we have hypothesized that a significant contributor to the cognitive and motor deficits seen after TBI could be changes in sensory processing. To explore this hypothesis, and to develop a model test system of the changes in neuronal functionality caused by TBI, we have examined neuronal encoding of simple and complex sensory input in the rat’s exploratory and discriminative tactile system, the large face macrovibrissae, which feeds to the so-called “barrel cortex” of somatosensory cortex. In this review we describe the short-term and long-term changes in the barrel cortex encoding of whisker motion modeling naturalistic whisker movement undertaken by rats engaged in a variety of tasks. We demonstrate that the most common form of TBI results in persistent neuronal hyperexcitation specifically in the upper cortical layers, likely due to changes in inhibition. We describe the types of cortical inhibitory neurons and their roles and how selective effects on some of these could produce the particular forms of neuronal encoding changes described in TBI, and then generalize to compare the effects on inhibition seen in other forms of brain injury. From these findings we make specific predictions as to how non-invasive extra-cranial electrophysiology can be used to provide the high-precision information needed to monitor and understand the temporal evolution of changes in neuronal

Secretagogin is expressed in sensory CGRP neurons and in spinal cord of mouse and complements other calcium-binding proteins, with a note on rat and human

PubMed Central

2012-01-01

Background Secretagogin (Scgn), a member of the EF-hand calcium-binding protein (CaBP) superfamily, has recently been found in subsets of developing and adult neurons. Here, we have analyzed the expression of Scgn in dorsal root ganglia (DRGs) and trigeminal ganglia (TGs), and in spinal cord of mouse at the mRNA and protein levels, and in comparison to the well-known CaBPs, calbindin D-28k, parvalbumin and calretinin. Rat DRGs, TGs and spinal cord, as well as human DRGs and spinal cord were used to reveal phylogenetic variations. Results We found Scgn mRNA expressed in mouse and human DRGs and in mouse ventral spinal cord. Our immunohistochemical data showed a complementary distribution of Scgn and the three CaBPs in mouse DRG neurons and spinal cord. Scgn was expressed in ~7% of all mouse DRG neuron profiles, mainly small ones and almost exclusively co-localized with calcitonin gene-related peptide (CGRP). This co-localization was also seen in human, but not in rat DRGs. Scgn could be detected in the mouse sciatic nerve and accumulated proximal to its constriction. In mouse spinal cord, Scgn-positive neuronal cell bodies and fibers were found in gray matter, especially in the dorsal horn, with particularly high concentrations of fibers in the superficial laminae, as well as in cell bodies in inner lamina II and in some other laminae. A dense Scgn-positive fiber network and some small cell bodies were also found in the superficial dorsal horn of humans. In the ventral horn, a small number of neurons were Scgn-positive in mouse but not rat, confirming mRNA distribution. Both in mouse and rat, a subset of TG neurons contained Scgn. Dorsal rhizotomy strongly reduced Scgn fiber staining in the dorsal horn. Peripheral axotomy did not clearly affect Scgn expression in DRGs, dorsal horn or ventral horn neurons in mouse. Conclusions Scgn is a CaBP expressed in a subpopulation of nociceptive DRG neurons and their processes in the dorsal horn of mouse, human and rat, the

Anti-Hu antibodies activate enteric and sensory neurons

PubMed Central

Li, Qin; Michel, Klaus; Annahazi, Anita; Demir, Ihsan E.; Ceyhan, Güralp O.; Zeller, Florian; Komorowski, Lars; Stöcker, Winfried; Beyak, Michael J.; Grundy, David; Farrugia, Gianrico; De Giorgio, Roberto; Schemann, Michael

2016-01-01

IgG of type 1 anti-neuronal nuclear antibody (ANNA-1, anti-Hu) specificity is a serological marker of paraneoplastic neurological autoimmunity (including enteric/autonomic) usually related to small-cell lung carcinoma. We show here that IgG isolated from such sera and also affinity-purified anti-HuD label enteric neurons and cause an immediate spike discharge in enteric and visceral sensory neurons. Both labelling and activation of enteric neurons was prevented by preincubation with the HuD antigen. Activation of enteric neurons was inhibited by the nicotinic receptor antagonists hexamethonium and dihydro-β-erythroidine and reduced by the P2X antagonist pyridoxal phosphate-6-azo (benzene-2,4-disulfonic acid (PPADS) but not by the 5-HT3 antagonist tropisetron or the N-type Ca-channel blocker ω-Conotoxin GVIA. Ca++ imaging experiments confirmed activation of enteric neurons but not enteric glia. These findings demonstrate a direct excitatory action of ANNA-1, in particular anti-HuD, on visceral sensory and enteric neurons, which involves nicotinic and P2X receptors. The results provide evidence for a novel link between nerve activation and symptom generation in patients with antibody-mediated gut dysfunction. PMID:27905561

Physiological characterization, localization and synaptic inputs of bursting and nonbursting neurons in the trigeminal principal sensory nucleus of the rat.

PubMed

Athanassiadis, T; Westberg, K-G; Olsson, K A; Kolta, A

2005-12-01

A population of neurons in the trigeminal principal sensory nucleus (NVsnpr) fire rhythmically during fictive mastication induced in the in vivo rabbit. To elucidate whether these neurons form part of the central pattern generator (CPG) for mastication, we performed intracellular recordings in brainstem slices taken from young rats. Two cell types were defined, nonbursting (63%) and bursting (37%). In response to membrane depolarization, bursting cells, which dominated in the dorsal part of the NVsnpr, fired an initial burst followed by single spikes or recurring bursts. Non-bursting neurons, scattered throughout the nucleus, fired single action potentials. Microstimulation applied to the trigeminal motor nucleus (NVmt), the reticular border zone surrounding the NVmt, the parvocellular reticular formation or the nucleus reticularis pontis caudalis (NPontc) elicited a postsynaptic potential in 81% of the neurons tested for synaptic inputs. Responses obtained were predominately excitatory and sensitive to glutamatergic antagonists DNQX and/or APV. Some inhibitory and biphasic responses were also evoked. Bicuculline methiodide or strychnine blocked the IPSPs indicating that they were mediated by GABA(A) or glycinergic receptors. About one-third of the stimulations activated both types of neurons antidromically, mostly from the masseteric motoneuron pool of NVmt and dorsal part of NPontc. In conclusion, our new findings show that some neurons in the dorsal NVsnpr display both firing properties and axonal connections which support the hypothesis that they may participate in masticatory pattern generation. Thus, the present data provide an extended basis for further studies on the organization of the masticatory CPG network.

Slack channels expressed in sensory neurons control neuropathic pain in mice.

PubMed

Lu, Ruirui; Bausch, Anne E; Kallenborn-Gerhardt, Wiebke; Stoetzer, Carsten; Debruin, Natasja; Ruth, Peter; Geisslinger, Gerd; Leffler, Andreas; Lukowski, Robert; Schmidtko, Achim

2015-01-21

Slack (Slo2.2) is a sodium-activated potassium channel that regulates neuronal firing activities and patterns. Previous studies identified Slack in sensory neurons, but its contribution to acute and chronic pain in vivo remains elusive. Here we generated global and sensory neuron-specific Slack mutant mice and analyzed their behavior in various animal models of pain. Global ablation of Slack led to increased hypersensitivity in models of neuropathic pain, whereas the behavior in models of inflammatory and acute nociceptive pain was normal. Neuropathic pain behaviors were also exaggerated after ablation of Slack selectively in sensory neurons. Notably, the Slack opener loxapine ameliorated persisting neuropathic pain behaviors. In conclusion, Slack selectively controls the sensory input in neuropathic pain states, suggesting that modulating its activity might represent a novel strategy for management of neuropathic pain. Copyright © 2015 the authors 0270-6474/15/351125-11$15.00/0.

Primary sensory neuron-specific interference of TRPV1 signaling by adeno-associated virus-encoded TRPV1 peptide aptamer attenuates neuropathic pain

PubMed Central

Xiang, Hongfei; Liu, Zhen; Wang, Fei; Xu, Hao; Roberts, Christopher; Fischer, Gregory; Stucky, Cheryl L; Dean, Caron; Pan, Bin; Hogan, Quinn H; Yu, Hongwei

2017-01-01

Background TRPV1 (transient receptor potential vanilloid subfamily member 1) is a pain signaling channel highly expressed in primary sensory neurons. Attempts for analgesia by systemic TRPV1 blockade produce undesirable side effects, such as hyperthermia and impaired heat pain sensation. One approach for TRPV1 analgesia is to target TRPV1 along the peripheral sensory pathway. Results For functional blockade of TRPV1 signaling, we constructed an adeno-associated virus (AAV) vector expressing a recombinant TRPV1 interfering peptide aptamer, derived from a 38mer tetrameric assembly domain (TAD), encompassing residues 735 to 772 of rat TRPV1, fused to the C-terminus of enhanced green fluorescent protein (EGFP). AAV-targeted sensory neurons expressing EGFP-TAD after vector injection into the dorsal root ganglia (DRG) revealed decreased inward calcium current and diminished intracellular calcium accumulation in response to capsaicin, compared to neurons of naïve or expressing EGFP alone. To examine the potential for treating neuropathic pain, AAV-EGFP-TAD was injected into fourth and fifth lumbar (L) DRGs of rats subjected to neuropathic pain by tibial nerve injury (TNI). Results showed that AAV-directed selective expression of EGFP-TAD in L4/L5 DRG neuron somata, and their peripheral and central axonal projections can limit TNI-induced neuropathic pain behavior, including hypersensitivity to heat and, to a less extent, mechanical stimulation. Conclusion Selective inhibition of TRPV1 activity in primary sensory neurons by DRG delivery of AAV-encoded analgesic interfering peptide aptamers is efficacious in attenuation of neuropathic pain. With further improvements of vector constructs and in vivo application, this approach might have the potential to develop as an alternative gene therapy strategy to treat chronic pain, especially heat hypersensitivity, without complications due to systemic TRPV1 blockade. PMID:28604222

Immunization Elicits Antigen-Specific Antibody Sequestration in Dorsal Root Ganglia Sensory Neurons

PubMed Central

Gunasekaran, Manojkumar; Chatterjee, Prodyot K.; Shih, Andrew; Imperato, Gavin H.; Addorisio, Meghan; Kumar, Gopal; Lee, Annette; Graf, John F.; Meyer, Dan; Marino, Michael; Puleo, Christopher; Ashe, Jeffrey; Cox, Maureen A.; Mak, Tak W.; Bouton, Chad; Sherry, Barbara; Diamond, Betty; Andersson, Ulf; Coleman, Thomas R.; Metz, Christine N.; Tracey, Kevin J.; Chavan, Sangeeta S.

2018-01-01

The immune and nervous systems are two major organ systems responsible for host defense and memory. Both systems achieve memory and learning that can be retained, retrieved, and utilized for decades. Here, we report the surprising discovery that peripheral sensory neurons of the dorsal root ganglia (DRGs) of immunized mice contain antigen-specific antibodies. Using a combination of rigorous molecular genetic analyses, transgenic mice, and adoptive transfer experiments, we demonstrate that DRGs do not synthesize these antigen-specific antibodies, but rather sequester primarily IgG1 subtype antibodies. As revealed by RNA-seq and targeted quantitative PCR (qPCR), dorsal root ganglion (DRG) sensory neurons harvested from either naïve or immunized mice lack enzymes (i.e., RAG1, RAG2, AID, or UNG) required for generating antibody diversity and, therefore, cannot make antibodies. Additionally, transgenic mice that express a reporter fluorescent protein under the control of Igγ1 constant region fail to express Ighg1 transcripts in DRG sensory neurons. Furthermore, neural sequestration of antibodies occurs in mice rendered deficient in neuronal Rag2, but antibody sequestration is not observed in DRG sensory neurons isolated from mice that lack mature B cells [e.g., Rag1 knock out (KO) or μMT mice]. Finally, adoptive transfer of Rag1-deficient bone marrow (BM) into wild-type (WT) mice or WT BM into Rag1 KO mice revealed that antibody sequestration was observed in DRG sensory neurons of chimeric mice with WT BM but not with Rag1-deficient BM. Together, these results indicate that DRG sensory neurons sequester and retain antigen-specific antibodies released by antibody-secreting plasma cells. Coupling this work with previous studies implicating DRG sensory neurons in regulating antigen trafficking during immunization raises the interesting possibility that the nervous system collaborates with the immune system to regulate antigen-mediated responses. PMID:29755449

Modulatory role of sensory innervation on hair follicle stem cell progeny during wound healing of the rat skin.

PubMed

Martínez-Martínez, Eduardo; Galván-Hernández, Claudio I; Toscano-Márquez, Brenda; Gutiérrez-Ospina, Gabriel

2012-01-01

The bulge region of the hair follicle contains resident epithelial stem cells (SCs) that are activated and mobilized during hair growth and after epidermal wounding. However, little is known about the signals that modulate these processes. Clinical and experimental observations show that a reduced supply of sensory innervation is associated with delayed wound healing. Since axon terminals of sensory neurons are among the components of the bulge SC niche, we investigated whether these neurons are involved in the activation and mobilization of the hair stem cells during wound healing. We used neonatal capsaicin treatment to reduce sensory terminals in the rat skin and performed morphometric analyses using design-based stereological methods. Epithelial proliferation was analyzed by quantifying the number of bromodeoxyuridine-labeled (BrdU(+)) nuclei in the epidermis and hair follicles. After wounding, the epidermis of capsaicin-treated rats presented fewer BrdU(+) nuclei than in control rats. To assess SC progeny migration, we employed a double labeling protocol with iododeoxyuridine and chlorodeoxyuridine (IdU(+)/CldU(+)). The proportion of double-labeled cells was similar in the hair follicles of both groups at 32 h postwounding. IdU(+)/CldU(+) cell proportion increased in the epidermis of control rats and decreased in treated rats at 61 h postwounding. The epidermal volume immunostained for keratin 6 was greater in treated rats at 61 h. Confocal microscopy analysis revealed that substance P (SP) and calcitonin gene-related peptide (CGRP) receptor immunoreactivity were both present in CD34(+) and BrdU-retaining cells of the hair follicles. Our results suggest that capsaicin denervation impairs SC progeny egress from the hair follicles, a circumstance associated with a greater epidermal activation. Altogether, these phenomena would explain the longer times for healing in denervated skin. Thus, sensory innervation may play a functional role in the modulation of hair

Sensory integration: neuronal filters for polarized light patterns.

PubMed

Krapp, Holger G

2014-09-22

Animal and human behaviour relies on local sensory signals that are often ambiguous. A new study shows how tuning neuronal responses to celestial cues helps locust navigation, demonstrating a common principle of sensory information processing: the use of matched filters. Copyright © 2014 Elsevier Ltd. All rights reserved.

Supralinear and Supramodal Integration of Visual and Tactile Signals in Rats: Psychophysics and Neuronal Mechanisms.

PubMed

Nikbakht, Nader; Tafreshiha, Azadeh; Zoccolan, Davide; Diamond, Mathew E

2018-02-07

To better understand how object recognition can be triggered independently of the sensory channel through which information is acquired, we devised a task in which rats judged the orientation of a raised, black and white grating. They learned to recognize two categories of orientation: 0° ± 45° ("horizontal") and 90° ± 45° ("vertical"). Each trial required a visual (V), a tactile (T), or a visual-tactile (VT) discrimination; VT performance was better than that predicted by optimal linear combination of V and T signals, indicating synergy between sensory channels. We examined posterior parietal cortex (PPC) and uncovered key neuronal correlates of the behavioral findings: PPC carried both graded information about object orientation and categorical information about the rat's upcoming choice; single neurons exhibited identical responses under the three modality conditions. Finally, a linear classifier of neuronal population firing replicated the behavioral findings. Taken together, these findings suggest that PPC is involved in the supramodal processing of shape. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Regulation of Drosophila hematopoietic sites by Activin-β from active sensory neurons

PubMed Central

Makhijani, Kalpana; Alexander, Brandy; Rao, Deepti; Petraki, Sophia; Herboso, Leire; Kukar, Katelyn; Batool, Itrat; Wachner, Stephanie; Gold, Katrina S.; Wong, Corinna; O’Connor, Michael B.; Brückner, Katja

2017-01-01

An outstanding question in animal development, tissue homeostasis and disease is how cell populations adapt to sensory inputs. During Drosophila larval development, hematopoietic sites are in direct contact with sensory neuron clusters of the peripheral nervous system (PNS), and blood cells (hemocytes) require the PNS for their survival and recruitment to these microenvironments, known as Hematopoietic Pockets. Here we report that Activin-β, a TGF-β family ligand, is expressed by sensory neurons of the PNS and regulates the proliferation and adhesion of hemocytes. These hemocyte responses depend on PNS activity, as shown by agonist treatment and transient silencing of sensory neurons. Activin-β has a key role in this regulation, which is apparent from reporter expression and mutant analyses. This mechanism of local sensory neurons controlling blood cell adaptation invites evolutionary parallels with vertebrate hematopoietic progenitors and the independent myeloid system of tissue macrophages, whose regulation by local microenvironments remain undefined. PMID:28748922

Co-cultures provide a new tool to probe communication between adult sensory neurons and urothelium.

PubMed

O'Mullane, Lauren M; Keast, Janet R; Osborne, Peregrine B

2013-08-01

Recent evidence suggests that the urothelium functions as a sensory transducer of chemical, mechanical or thermal stimuli and signals to nerve terminals and other cells in the bladder wall. The cellular and molecular basis of neuro-urothelial communication is not easily studied in the intact bladder. This led us to establish a method of co-culturing dorsal root ganglion sensory neurons and bladder urothelial cells. Sensory neurons and urothelial cells obtained from dorsal root ganglia and bladders dissected from adult female Sprague-Dawley® rats were isolated by enzyme treatment and mechanical dissociation. They were plated together or separately on collagen coated substrate and cultured in keratinocyte medium for 48 to 72 hours. Retrograde tracer labeling was performed to identify bladder afferents used for functional testing. Neurite growth and complexity in neurons co-cultured with urothelial cells was increased relative to that in neuronal monocultures. The growth promoting effect of urothelial cells was reduced by the tyrosine kinase inhibitor K252a but upstream inhibition of nerve growth factor signaling with TrkA-Fc had no effect. Fura-2 calcium imaging of urothelial cells showed responses to adenosine triphosphate (100 μM) and activation of TRPV4 (4α-PDD, 10 μM) but not TRPV1 (capsaicin, 1 μM), TRPV3 (farnesyl pyrophosphate, 1 μM) or TRPA1 (mustard oil, 100 μM). In contrast, co-cultured neurons were activated by all agonists except farnesyl pyrophosphate. Co-culturing provides a new methodology for investigating neuro-urothelial interactions in animal models of urological conditions. Results suggest that neuronal properties are maintained in the presence of urothelium and neurite growth is potentiated by a nerve growth factor independent mechanism. Copyright © 2013 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Targeting dorsal root ganglia and primary sensory neurons for the treatment of chronic pain

PubMed Central

Berta, Temugin; Qadri, Yawar; Tan, Ping-Heng; Ji, Ru-Rong

2018-01-01

Introduction Currently the treatment of chronic pain is inadequate and compromised by debilitating central nervous system side effects. Here we discuss new therapeutic strategies that target dorsal root ganglia (DRGs) in the peripheral nervous system for a better and safer treatment of chronic pain. Areas covered The DRGs contain the cell bodies of primary sensory neurons including nociceptive neurons. After painful injuries, primary sensory neurons demonstrate maladaptive molecular changes in DRG cell bodies and in their axons. These changes result in hypersensitivity and hyperexcitability of sensory neurons (peripheral sensitization) and are crucial for the onset and maintenance of chronic pain. We discuss the following new strategies to target DRGs and primary sensory neurons as a means of alleviating chronic pain and minimizing side effects: inhibition of sensory neuron-expressing ion channels such as TRPA1, TRPV1, and Nav1.7, selective blockade of C- and Aβ-afferent fibers, gene therapy, and implantation of bone marrow stem cells. Expert opinion These peripheral pharmacological treatments, as well as gene and cell therapies, aimed at DRG tissues and primary sensory neurons can offer better and safer treatments for inflammatory, neuropathic, cancer, and other chronic pain states. PMID:28480765

Morphology and Nanomechanics of Sensory Neurons Growth Cones following Peripheral Nerve Injury

PubMed Central

Szabo, Vivien; Végh, Attila-Gergely; Lucas, Olivier; Cloitre, Thierry; Scamps, Frédérique; Gergely, Csilla

2013-01-01

A prior peripheral nerve injury in vivo, promotes a rapid elongated mode of sensory neurons neurite regrowth in vitro. This in vitro model of conditioned axotomy allows analysis of the cellular and molecular mechanisms leading to an improved neurite re-growth. Our differential interference contrast microscopy and immunocytochemistry results show that conditioned axotomy, induced by sciatic nerve injury, did not increase somatic size of adult lumbar sensory neurons from mice dorsal root ganglia sensory neurons but promoted the appearance of larger neurites and growth cones. Using atomic force microscopy on live neurons, we investigated whether membrane mechanical properties of growth cones of axotomized neurons were modified following sciatic nerve injury. Our data revealed that neurons having a regenerative growth were characterized by softer growth cones, compared to control neurons. The increase of the growth cone membrane elasticity suggests a modification in the ratio and the inner framework of the main structural proteins. PMID:23418549

Robo2 determines subtype-specific axonal projections of trigeminal sensory neurons

PubMed Central

Pan, Y. Albert; Choy, Margaret; Prober, David A.; Schier, Alexander F.

2012-01-01

How neurons connect to form functional circuits is central to the understanding of the development and function of the nervous system. In the somatosensory system, perception of sensory stimuli to the head requires specific connections between trigeminal sensory neurons and their many target areas in the central nervous system. Different trigeminal subtypes have specialized functions and downstream circuits, but it has remained unclear how subtype-specific axonal projection patterns are formed. Using zebrafish as a model system, we followed the development of two trigeminal sensory neuron subtypes: one that expresses trpa1b, a nociceptive channel important for sensing environmental chemicals; and a distinct subtype labeled by an islet1 reporter (Isl1SS). We found that Trpa1b and Isl1SS neurons have overall similar axon trajectories but different branching morphologies and distributions of presynaptic sites. Compared with Trpa1b neurons, Isl1SS neurons display reduced branch growth and synaptogenesis at the hindbrain-spinal cord junction. The subtype-specific morphogenesis of Isl1SS neurons depends on the guidance receptor Robo2. robo2 is preferentially expressed in the Isl1SS subset and inhibits branch growth and synaptogenesis. In the absence of Robo2, Isl1SS afferents acquire many of the characteristics of Trpa1b afferents. These results reveal that subtype-specific activity of Robo2 regulates subcircuit morphogenesis in the trigeminal sensory system. PMID:22190641

Impact of the Sensory Neurons on Melanoma Growth In Vivo

PubMed Central

Tapias, Victor; Watkins, Simon C.; Ma, Yang; Shurin, Michael R.; Shurin, Galina V.

2016-01-01

Nerve endings are often identified within solid tumors, but their impact on the tumor growth and progression remains poorly understood. Emerging data suggests that the central nervous system may affect cancer development and spreading via the hypothalamic-pituitary-adrenal axis and autonomous nervous system. However, the role of the afferent sensory neurons in tumor growth is unclear, except some reports on perineural invasion in prostate and pancreatic cancer and cancer-related pain syndrome. Here, we provide the results of primary testing of the concept that the interaction between melanoma cells and sensory neurons may induce the formation of tumor-supporting microenvironment via attraction of immune regulatory cells by the tumor-activated dorsal root ganglion (DRG) neurons. We report that despite DRG cells not directly up-regulating proliferation of melanoma cells in vitro, presence of DRG neurons allows tumors to grow significantly faster in vivo. This effect has been associated with increased production of chemokines by tumor-activated DRG neurons and attraction of myeloid-derived suppressor cells both in vitro and in vivo. These initial proof-of-concept results justify further investigations of the sensory (afferent) nervous system in the context of tumorigenesis and the local protumorigenic immunoenvironment. PMID:27227315

Dicer maintains the identity and function of proprioceptive sensory neurons

PubMed Central

O’Toole, Sean M.; Ferrer, Monica M.; Mekonnen, Jennifer; Zhang, Haihan; Shima, Yasuyuki; Ladle, David R.

2017-01-01

Neuronal cell identity is established during development and must be maintained throughout an animal’s life (Fishell G, Heintz N. Neuron 80: 602–612, 2013). Transcription factors critical for establishing neuronal identity can be required for maintaining it (Deneris ES, Hobert O. Nat Neurosci 17: 899–907, 2014). Posttranscriptional regulation also plays an important role in neuronal differentiation (Bian S, Sun T. Mol Neurobiol 44: 359–373, 2011), but its role in maintaining cell identity is less established. To better understand how posttranscriptional regulation might contribute to cell identity, we examined the proprioceptive neurons in the dorsal root ganglion (DRG), a highly specialized sensory neuron class, with well-established properties that distinguish them from other neurons in the ganglion. By conditionally ablating Dicer in mice, using parvalbumin (Pvalb)-driven Cre recombinase, we impaired posttranscriptional regulation in the proprioceptive sensory neuron population. Knockout (KO) animals display a progressive form of ataxia at the beginning of the fourth postnatal week that is accompanied by a cell death within the DRG. Before cell loss, expression profiling shows a reduction of proprioceptor specific genes and an increased expression of nonproprioceptive genes normally enriched in other ganglion neurons. Furthermore, although central connections of these neurons are intact, the peripheral connections to the muscle are functionally impaired. Posttranscriptional regulation is therefore necessary to retain the transcriptional identity and support functional specialization of the proprioceptive sensory neurons. NEW & NOTEWORTHY We have demonstrated that selectively impairing Dicer in parvalbumin-positive neurons, which include the proprioceptors, triggers behavioral changes, a lack of muscle connectivity, and a loss of transcriptional identity as observed through RNA sequencing. These results suggest that Dicer and, most likely by extension

Dicer maintains the identity and function of proprioceptive sensory neurons.

PubMed

O'Toole, Sean M; Ferrer, Monica M; Mekonnen, Jennifer; Zhang, Haihan; Shima, Yasuyuki; Ladle, David R; Nelson, Sacha B

2017-03-01

Neuronal cell identity is established during development and must be maintained throughout an animal's life (Fishell G, Heintz N. Neuron 80: 602-612, 2013). Transcription factors critical for establishing neuronal identity can be required for maintaining it (Deneris ES, Hobert O. Nat Neurosci 17: 899-907, 2014). Posttranscriptional regulation also plays an important role in neuronal differentiation (Bian S, Sun T. Mol Neurobiol 44: 359-373, 2011), but its role in maintaining cell identity is less established. To better understand how posttranscriptional regulation might contribute to cell identity, we examined the proprioceptive neurons in the dorsal root ganglion (DRG), a highly specialized sensory neuron class, with well-established properties that distinguish them from other neurons in the ganglion. By conditionally ablating Dicer in mice, using parvalbumin (Pvalb)-driven Cre recombinase, we impaired posttranscriptional regulation in the proprioceptive sensory neuron population. Knockout (KO) animals display a progressive form of ataxia at the beginning of the fourth postnatal week that is accompanied by a cell death within the DRG. Before cell loss, expression profiling shows a reduction of proprioceptor specific genes and an increased expression of nonproprioceptive genes normally enriched in other ganglion neurons. Furthermore, although central connections of these neurons are intact, the peripheral connections to the muscle are functionally impaired. Posttranscriptional regulation is therefore necessary to retain the transcriptional identity and support functional specialization of the proprioceptive sensory neurons. NEW & NOTEWORTHY We have demonstrated that selectively impairing Dicer in parvalbumin-positive neurons, which include the proprioceptors, triggers behavioral changes, a lack of muscle connectivity, and a loss of transcriptional identity as observed through RNA sequencing. These results suggest that Dicer and, most likely by extension, micro

Postnatal Experience Modulates Functional Properties of Mouse Olfactory Sensory Neurons

PubMed Central

He, Jiwei; Tian, Huikai; Lee, Anderson C.; Ma, Minghong

2012-01-01

Early experience considerably modulates the organization and function of all sensory systems. In the mammalian olfactory system, deprivation of the sensory inputs via neonatal, unilateral naris closure has been shown to induce structural, molecular, and functional changes from the olfactory epithelium to the olfactory bulb and cortex. However, it remains unknown how early experience shapes functional properties of individual olfactory sensory neurons (OSNs), the primary odor detectors in the nose. To address this question, we examined odorant response properties of mouse OSNs in both the closed and open nostril after four weeks of unilateral naris closure with age-matched untreated animals as control. Using patch-clamp technique on genetically-tagged OSNs with defined odorant receptors (ORs), we found that sensory deprivation increased the sensitivity of MOR23 neurons in the closed side while overexposure caused the opposite effect in the open side. We next analyzed the response properties including rise time, decay time, and adaptation induced by repeated stimulation in MOR23 and M71 neurons. Even though these two types of neurons showed distinct properties in dynamic range and response kinetics, sensory deprivation significantly slowed down the decay phase of odorant-induced transduction events in both types. Using western blotting and antibody staining, we confirmed upregulation of several signaling proteins in the closed side as compared with the open side. This study suggests that early experience modulates functional properties of OSNs, probably via modifying the signal transduction cascade. PMID:22703547

Molecular Correlates of Cortical Network Modulation by Long-Term Sensory Experience in the Adult Rat Barrel Cortex

ERIC Educational Resources Information Center

Vallès, Astrid; Granic, Ivica; De Weerd, Peter; Martens, Gerard J. M.

2014-01-01

Modulation of cortical network connectivity is crucial for an adaptive response to experience. In the rat barrel cortex, long-term sensory stimulation induces cortical network modifications and neuronal response changes of which the molecular basis is unknown. Here, we show that long-term somatosensory stimulation by enriched environment…

Knockout of glial channel ACD-1 exacerbates sensory deficits in a C. elegans mutant by regulating calcium levels of sensory neurons

PubMed Central

Wang, Ying; D'Urso, Giulia

2012-01-01

Degenerin/epithelial Na+ channels (DEG/ENaCs) are voltage-independent Na+ or Na+/Ca2+ channels expressed in many tissues and are needed for a wide range of physiological functions, including sensory perception and transepithelial Na+ transport. In the nervous system, DEG/ENaCs are expressed in both neurons and glia. However, the role of glial vs. neuronal DEG/ENaCs remains unclear. We recently reported the characterization of a novel DEG/ENaC in Caenorhabditis elegans that we named ACD-1. ACD-1 is expressed in glial amphid sheath cells. The glial ACD-1, together with the neuronal DEG/ENaC DEG-1, is necessary for acid avoidance and attraction to lysine. We report presently that knockout of acd-1 in glia exacerbates sensory deficits caused by another mutant: the hypomorphic allele of the cGMP-gated channel subunit tax-2. Furthermore, sensory deficits caused by mutations in Gi protein odr-3 and guanylate cyclase daf-11, which regulate the activity of TAX-2/TAX-4 channels, are worsened by knockout of acd-1. We also show that sensory neurons of acd-1 tax-2(p694) double mutants fail to undergo changes in intracellular Ca2+ when animals are exposed to low concentrations of attractant. Finally, we show that exogenous expression of TRPV1 in sensory neurons and exposure to capsaicin rescue sensory deficits of acd-1 tax-2(p694) mutants, suggesting that sensory deficits of these mutants are bypassed by increasing neuronal excitability. Our data suggest a role of glial DEG/ENaC channel ACD-1 in supporting neuronal activity. PMID:21994266

Knockout of glial channel ACD-1 exacerbates sensory deficits in a C. elegans mutant by regulating calcium levels of sensory neurons.

PubMed

Wang, Ying; D'Urso, Giulia; Bianchi, Laura

2012-01-01

Degenerin/epithelial Na(+) channels (DEG/ENaCs) are voltage-independent Na(+) or Na(+)/Ca(2+) channels expressed in many tissues and are needed for a wide range of physiological functions, including sensory perception and transepithelial Na(+) transport. In the nervous system, DEG/ENaCs are expressed in both neurons and glia. However, the role of glial vs. neuronal DEG/ENaCs remains unclear. We recently reported the characterization of a novel DEG/ENaC in Caenorhabditis elegans that we named ACD-1. ACD-1 is expressed in glial amphid sheath cells. The glial ACD-1, together with the neuronal DEG/ENaC DEG-1, is necessary for acid avoidance and attraction to lysine. We report presently that knockout of acd-1 in glia exacerbates sensory deficits caused by another mutant: the hypomorphic allele of the cGMP-gated channel subunit tax-2. Furthermore, sensory deficits caused by mutations in G(i) protein odr-3 and guanylate cyclase daf-11, which regulate the activity of TAX-2/TAX-4 channels, are worsened by knockout of acd-1. We also show that sensory neurons of acd-1 tax-2(p694) double mutants fail to undergo changes in intracellular Ca(2+) when animals are exposed to low concentrations of attractant. Finally, we show that exogenous expression of TRPV1 in sensory neurons and exposure to capsaicin rescue sensory deficits of acd-1 tax-2(p694) mutants, suggesting that sensory deficits of these mutants are bypassed by increasing neuronal excitability. Our data suggest a role of glial DEG/ENaC channel ACD-1 in supporting neuronal activity.

Reduction in voltage-gated K+ channel activity in primary sensory neurons in painful diabetic neuropathy: role of brain-derived neurotrophic factor.

PubMed

Cao, Xue-Hong; Byun, Hee-Sun; Chen, Shao-Rui; Cai, You-Qing; Pan, Hui-Lin

2010-09-01

Abnormal hyperexcitability of primary sensory neurons plays an important role in neuropathic pain. Voltage-gated potassium (Kv) channels regulate neuronal excitability by affecting the resting membrane potential and influencing the repolarization and frequency of the action potential. In this study, we determined changes in Kv channels in dorsal root ganglion (DRG) neurons in a rat model of diabetic neuropathic pain. The densities of total Kv, A-type (IA) and sustained delayed (IK) currents were markedly reduced in medium- and large-, but not in small-, diameter DRG neurons in diabetic rats. Quantitative RT-PCR analysis revealed that the mRNA levels of IA subunits, including Kv1.4, Kv3.4, Kv4.2, and Kv4.3, in the DRG were reduced approximately 50% in diabetic rats compared with those in control rats. However, there were no significant differences in the mRNA levels of IK subunits (Kv1.1, Kv1.2, Kv2.1, and Kv2.2) in the DRG between the two groups. Incubation with brain-derived neurotrophic factor (BDNF) caused a large reduction in Kv currents, especially IA currents, in medium and large DRG neurons from control rats. Furthermore, the reductions in Kv currents and mRNA levels of IA subunits in diabetic rats were normalized by pre-treatment with anti-BDNF antibody or K252a, a TrkB tyrosine kinase inhibitor. In addition, the number of medium and large DRG neurons with BDNF immunoreactivity was greater in diabetic than control rats. Collectively, our findings suggest that diabetes primarily reduces Kv channel activity in medium and large DRG neurons. Increased BDNF activity in these neurons likely contributes to the reduction in Kv channel function through TrkB receptor stimulation in painful diabetic neuropathy.

Informational basis of sensory adaptation: entropy and single-spike efficiency in rat barrel cortex.

PubMed

Adibi, Mehdi; Clifford, Colin W G; Arabzadeh, Ehsan

2013-09-11

We showed recently that exposure to whisker vibrations enhances coding efficiency in rat barrel cortex despite increasing correlations in variability (Adibi et al., 2013). Here, to understand how adaptation achieves this improvement in sensory representation, we decomposed the stimulus information carried in neuronal population activity into its fundamental components in the framework of information theory. In the context of sensory coding, these components are the entropy of the responses across the entire stimulus set (response entropy) and the entropy of the responses conditional on the stimulus (conditional response entropy). We found that adaptation decreased response entropy and conditional response entropy at both the level of single neurons and the pooled activity of neuronal populations. However, the net effect of adaptation was to increase the mutual information because the drop in the conditional entropy outweighed the drop in the response entropy. The information transmitted by a single spike also increased under adaptation. As population size increased, the information content of individual spikes declined but the relative improvement attributable to adaptation was maintained.

Feedforward motor information enhances somatosensory responses and sharpens angular tuning of rat S1 barrel cortex neurons.

PubMed

Khateb, Mohamed; Schiller, Jackie; Schiller, Yitzhak

2017-01-06

The primary vibrissae motor cortex (vM1) is responsible for generating whisking movements. In parallel, vM1 also sends information directly to the sensory barrel cortex (vS1). In this study, we investigated the effects of vM1 activation on processing of vibrissae sensory information in vS1 of the rat. To dissociate the vibrissae sensory-motor loop, we optogenetically activated vM1 and independently passively stimulated principal vibrissae. Optogenetic activation of vM1 supra-linearly amplified the response of vS1 neurons to passive vibrissa stimulation in all cortical layers measured. Maximal amplification occurred when onset of vM1 optogenetic activation preceded vibrissa stimulation by 20 ms. In addition to amplification, vM1 activation also sharpened angular tuning of vS1 neurons in all cortical layers measured. Our findings indicated that in addition to output motor signals, vM1 also sends preparatory signals to vS1 that serve to amplify and sharpen the response of neurons in the barrel cortex to incoming sensory input signals.

Modulatory Role of Sensory Innervation on Hair Follicle Stem Cell Progeny during Wound Healing of the Rat Skin

PubMed Central

Martínez-Martínez, Eduardo; Galván-Hernández, Claudio I.; Toscano-Márquez, Brenda; Gutiérrez-Ospina, Gabriel

2012-01-01

Background The bulge region of the hair follicle contains resident epithelial stem cells (SCs) that are activated and mobilized during hair growth and after epidermal wounding. However, little is known about the signals that modulate these processes. Clinical and experimental observations show that a reduced supply of sensory innervation is associated with delayed wound healing. Since axon terminals of sensory neurons are among the components of the bulge SC niche, we investigated whether these neurons are involved in the activation and mobilization of the hair stem cells during wound healing. Methodology/Principal Findings We used neonatal capsaicin treatment to reduce sensory terminals in the rat skin and performed morphometric analyses using design-based stereological methods. Epithelial proliferation was analyzed by quantifying the number of bromodeoxyuridine-labeled (BrdU+) nuclei in the epidermis and hair follicles. After wounding, the epidermis of capsaicin-treated rats presented fewer BrdU+ nuclei than in control rats. To assess SC progeny migration, we employed a double labeling protocol with iododeoxyuridine and chlorodeoxyuridine (IdU+/CldU+). The proportion of double-labeled cells was similar in the hair follicles of both groups at 32 h postwounding. IdU+/CldU+ cell proportion increased in the epidermis of control rats and decreased in treated rats at 61 h postwounding. The epidermal volume immunostained for keratin 6 was greater in treated rats at 61 h. Confocal microscopy analysis revealed that substance P (SP) and calcitonin gene-related peptide (CGRP) receptor immunoreactivity were both present in CD34+ and BrdU-retaining cells of the hair follicles. Conclusions/Significance Our results suggest that capsaicin denervation impairs SC progeny egress from the hair follicles, a circumstance associated with a greater epidermal activation. Altogether, these phenomena would explain the longer times for healing in denervated skin. Thus, sensory innervation

Capsaicin-sensitive sensory neurons are involved in the plasma catecholamine response of rats to selective stressors.

PubMed Central

Zhou, X F; Livett, B G

1991-01-01

1. The effect of capsaicin pre-treatment on adrenal catecholamine (CA) secretion in response to stress is controversial. In earlier experiments performed under pentobarbitone anaesthesia, the release of CA in response to stress was complicated by the effects of the barbiturate anaesthesia. 2. In the present study we have used conscious freely moving rats with indwelling cannulae to study the effect of neonatal capsaicin pre-treatment on the plasma CA response to different types of stressors (swimming stress, hypovolaemic stress, immobilization stress and cold stress). 3. After swimming for 20 min, plasma noradrenaline (NA) levels increased by 8-fold and adrenaline by 2-fold in control rats. The increase in plasma NA levels in the capsaicin group was attenuated at 10 min of swimming compared with the vehicle group (P < 0.05). 4. With hypovolaemic stress, there were no differences in plasma CA levels, blood pressure and heart rate between the capsaicin group and the vehicle group. There were also no differences in plasma CA levels after immobilization stress between the two groups. 5. With cold stress, plasma NA levels increased 5-fold and adrenaline levels by 3-fold over basal at 45 min in the vehicle pre-treated rats. This increase was not observed in the capsaicin group. 6. Immunoreactive substance P was depleted by only 68% in the splanchnic nerve following capsaicin pre-treatment. If the remaining 32% was biologically active substance P then it could account for the maintenance of the response to hypovolaemic and immobilization stress. However, it might be possible that the responses to hypovolaemic and immobilization stresses could be attenuated if a more complete depletion were achieved. 7. These results in conscious rats indicate that capsaicin-sensitive sensory neurons are required for plasma CA response to selective stressors. They are required for CA output in response to cold stress and to the early phase of swimming stress, but not to hypovolaemic stress

Bortezomib alters microtubule polymerization and axonal transport in rat dorsal root ganglion neurons

PubMed Central

Staff, Nathan P.; Podratz, Jewel L.; Grassner, Lukas; Bader, Miranda; Paz, Justin; Knight, Andrew M.; Loprinzi, Charles L.; Trushina, Eugenia; Windebank, Anthony J.

2013-01-01

Bortezomib is part of a newer class of chemotherapeutic agents whose mechanism of action is inhibition of the proteasome-ubiquitination system. Primarily used in multiple myeloma, bortezomib causes a sensory-predominant axonal peripheral neuropathy in approximately 30% of patients. There are no established useful preventative agents for bortezomib-induced peripheral neuropathy (BIPN), and the molecular mechanisms of BIPN are unknown. We have developed an in vitro model of BIPN using rat dorsal root ganglia neuronal cultures. At clinically–relevant dosages, bortezomib produces a sensory axonopathy as evidenced by whole explant outgrowth and cell survival assays. This sensory axonopathy is associated with alterations in tubulin and results in accumulation of somatic tubulin without changes in microtubule ultrastructure. Furthermore, we observed an increased proportion of polymerized tubulin, but not total or acetylated tubulin, in bortezomib-treated DRG neurons. Similar findings are observed with lactacystin, an unrelated proteasome-inhibitor, which argues for a class effect of proteasome inhibition on dorsal root ganglion neurons. Finally, there is a change in axonal transport of mitochondria induced by bortezomib in a time-dependent fashion. In summary, we have developed an in vitro model of BIPN that recapitulates the clinical sensory axonopathy; this model demonstrates that bortezomib induces an alteration in microtubules and axonal transport. This robust model will be used in future mechanistic studies of BIPN and its prevention. PMID:24035926

The evolutionarily conserved transcription factor PRDM12 controls sensory neuron development and pain perception.

PubMed

Nagy, Vanja; Cole, Tiffany; Van Campenhout, Claude; Khoung, Thang M; Leung, Calvin; Vermeiren, Simon; Novatchkova, Maria; Wenzel, Daniel; Cikes, Domagoj; Polyansky, Anton A; Kozieradzki, Ivona; Meixner, Arabella; Bellefroid, Eric J; Neely, G Gregory; Penninger, Josef M

2015-01-01

PR homology domain-containing member 12 (PRDM12) belongs to a family of conserved transcription factors implicated in cell fate decisions. Here we show that PRDM12 is a key regulator of sensory neuronal specification in Xenopus. Modeling of human PRDM12 mutations that cause hereditary sensory and autonomic neuropathy (HSAN) revealed remarkable conservation of the mutated residues in evolution. Expression of wild-type human PRDM12 in Xenopus induced the expression of sensory neuronal markers, which was reduced using various human PRDM12 mutants. In Drosophila, we identified Hamlet as the functional PRDM12 homolog that controls nociceptive behavior in sensory neurons. Furthermore, expression analysis of human patient fibroblasts with PRDM12 mutations uncovered possible downstream target genes. Knockdown of several of these target genes including thyrotropin-releasing hormone degrading enzyme (TRHDE) in Drosophila sensory neurons resulted in altered cellular morphology and impaired nociception. These data show that PRDM12 and its functional fly homolog Hamlet are evolutionary conserved master regulators of sensory neuronal specification and play a critical role in pain perception. Our data also uncover novel pathways in multiple species that regulate evolutionary conserved nociception.

Peptidergic CGRPα primary sensory neurons encode heat and itch and tonically suppress sensitivity to cold

PubMed Central

McCoy, Eric S.; Taylor-Blake, Bonnie; Street, Sarah E.; Pribisko, Alaine L.; Zheng, Jihong; Zylka, Mark J.

2013-01-01

SUMMARY Calcitonin gene-related peptide (CGRP) is a classic molecular marker of peptidergic primary somatosensory neurons. Despite years of research, it is unknown if these neurons are required to sense pain or other sensory stimuli. Here, we found that genetic ablation of CGRPα-expressing sensory neurons reduced sensitivity to noxious heat, capsaicin and itch (histamine and chloroquine) and impaired thermoregulation but did not impair mechanosensation or β-alanine itch—stimuli associated with nonpeptidergic sensory neurons. Unexpectedly, ablation enhanced behavioral responses to cold stimuli and cold mimetics without altering peripheral nerve responses to cooling. Mechanistically, ablation reduced tonic and evoked activity in postsynaptic spinal neurons associated with TRPV1/heat, while profoundly increasing tonic and evoked activity in spinal neurons associated with TRPM8/cold. Our data reveal that CGRPα sensory neurons encode heat and itch and tonically cross-inhibit cold-responsive spinal neurons. Disruption of this crosstalk unmasks cold hypersensitivity, with mechanistic implications for neuropathic pain and temperature perception. PMID:23523592

Voltage-gated Na+ currents in human dorsal root ganglion neurons

PubMed Central

Zhang, Xiulin; Priest, Birgit T; Belfer, Inna; Gold, Michael S

2017-01-01

Available evidence indicates voltage-gated Na+ channels (VGSCs) in peripheral sensory neurons are essential for the pain and hypersensitivity associated with tissue injury. However, our understanding of the biophysical and pharmacological properties of the channels in sensory neurons is largely based on the study of heterologous systems or rodent tissue, despite evidence that both expression systems and species differences influence these properties. Therefore, we sought to determine the extent to which the biophysical and pharmacological properties of VGSCs were comparable in rat and human sensory neurons. Whole cell patch clamp techniques were used to study Na+ currents in acutely dissociated neurons from human and rat. Our results indicate that while the two major current types, generally referred to as tetrodotoxin (TTX)-sensitive and TTX-resistant were qualitatively similar in neurons from rats and humans, there were several differences that have important implications for drug development as well as our understanding of pain mechanisms. DOI: http://dx.doi.org/10.7554/eLife.23235.001 PMID:28508747

Inflammation and nerve injury induce expression of pancreatitis-associated protein-II in primary sensory neurons.

PubMed

He, Shao-Qiu; Yao, Jun-Ru; Zhang, Fang-Xiong; Wang, Qiong; Bao, Lan; Zhang, Xu

2010-04-26

Pancreatitis-associated protein (PAP)-I and -II, lectin-related secretory proteins, are members of the regenerating gene (Reg) family. Although expression of PAP-I was found in the dorsal root ganglion (DRG) neurons following peripheral nerve injury and cystitis, whether PAP-II could be expressed in DRG neurons in chronic pain models remains unclear. The present study shows an inflammation- and nerve injury-triggered expression of PAP-II in rat DRG neurons. In situ hybridization showed that only a few DRG neurons normally contained PAP-I and -II mRNAs. After peripheral inflammation, PAP-I and -II mRNAs were present in over half of small DRG neurons. Such an elevated expression of PAP-I and -II reached the peak level on the second day. Immunostaining showed that the expression of PAP-II was mostly increased in the isolectin B4-positive subset of small DRG neurons after inflammation. Furthermore, the expression of PAP-II was also induced in DRG neurons after peripheral nerve injury. Interestingly, PAP-II expression was shifted from small neurons on day 2 to large DRG neurons that expressed neuropeptide Y during the later post-injury days. These results suggest that PAP-II may play potential roles in the modulation of spinal sensory pathways in pathological pain states.

Neto2 Assembles with Kainate Receptors in DRG Neurons during Development and Modulates Neurite Outgrowth in Adult Sensory Neurons

PubMed Central

Vernon, Claire G.

2017-01-01

Peripheral sensory neurons in the dorsal root ganglia (DRG) are the initial transducers of sensory stimuli, including painful stimuli, from the periphery to central sensory and pain-processing centers. Small- to medium-diameter non-peptidergic neurons in the neonatal DRG express functional kainate receptors (KARs), one of three subfamilies of ionotropic glutamate receptors, as well as the putative KAR auxiliary subunit Neuropilin- and tolloid-like 2 (Neto2). Neto2 alters recombinant KAR function markedly but has yet to be confirmed as an auxiliary subunit that assembles with and alters the function of endogenous KARs. KARs in neonatal DRG require the GluK1 subunit as a necessary constituent, but it is unclear to what extent other KAR subunits contribute to the function and proposed roles of KARs in sensory ganglia, which include promotion of neurite outgrowth and modulation of glutamate release at the DRG–dorsal horn synapse. In addition, KARs containing the GluK1 subunit are implicated in modes of persistent but not acute pain signaling. We show here that the Neto2 protein is highly expressed in neonatal DRG and modifies KAR gating in DRG neurons in a developmentally regulated fashion in mice. Although normally at very low levels in adult DRG neurons, Neto2 protein expression can be upregulated via MEK/ERK signaling and after sciatic nerve crush and Neto2−/− neurons from adult mice have stunted neurite outgrowth. These data confirm that Neto2 is a bona fide KAR auxiliary subunit that is an important constituent of KARs early in sensory neuron development and suggest that Neto2 assembly is critical to KAR modulation of DRG neuron process outgrowth. SIGNIFICANCE STATEMENT Pain-transducing peripheral sensory neurons of the dorsal root ganglia (DRG) express kainate receptors (KARs), a subfamily of glutamate receptors that modulate neurite outgrowth and regulate glutamate release at the DRG–dorsal horn synapse. The putative KAR auxiliary subunit Neuropilin- and

T-type calcium channels cause bursts of spikes in motor but not sensory thalamic neurons during mimicry of natural patterns of synaptic input.

PubMed

Kim, Haram R; Hong, Su Z; Fiorillo, Christopher D

2015-01-01

Although neurons within intact nervous systems can be classified as 'sensory' or 'motor,' it is not known whether there is any general distinction between sensory and motor neurons at the cellular or molecular levels. Here, we extend and test a theory according to which activation of certain subtypes of voltage-gated ion channel (VGC) generate patterns of spikes in neurons of motor systems, whereas VGC are proposed to counteract patterns in sensory neurons. We previously reported experimental evidence for the theory from visual thalamus, where we found that T-type calcium channels (TtCCs) did not cause bursts of spikes but instead served the function of 'predictive homeostasis' to maximize the causal and informational link between retinogeniculate excitation and spike output. Here, we have recorded neurons in brain slices from eight sensory and motor regions of rat thalamus while mimicking key features of natural excitatory and inhibitory post-synaptic potentials. As predicted by theory, TtCC did cause bursts of spikes in motor thalamus. TtCC-mediated responses in motor thalamus were activated at more hyperpolarized potentials and caused larger depolarizations with more spikes than in visual and auditory thalamus. Somatosensory thalamus is known to be more closely connected to motor regions relative to auditory and visual thalamus, and likewise the strength of its TtCC responses was intermediate between these regions and motor thalamus. We also observed lower input resistance, as well as limited evidence of stronger hyperpolarization-induced ('H-type') depolarization, in nuclei closer to motor output. These findings support our theory of a specific difference between sensory and motor neurons at the cellular level.

Behavioral aging is associated with reduced sensory neuron excitability in Aplysia californica.

PubMed

Kempsell, Andrew T; Fieber, Lynne A

2014-01-01

Invertebrate models have advantages for understanding the basis of behavioral aging due to their simple nervous systems and short lifespans. The potential usefulness of Aplysia californica in aging research is apparent from its long history of neurobiological research, but it has been underexploited in this model use. Aging of simple reflexes at both single sensory neuron and neural circuit levels was studied to connect behavioral aging to neurophysiological aging. The tail withdrawal reflex (TWR), righting reflex, and biting response were measured throughout sexual maturity in 3 cohorts of hatchery-reared animals of known age. Reflex times increased and reflex amplitudes decreased significantly during aging. Aging in sensory neurons of animals with deficits in measures of the TWR and biting response resulted in significantly reduced excitability in old animals compared to their younger siblings. The threshold for firing increased while the number of action potentials in response to depolarizing current injection decreased during aging in sensory neurons, but not in tail motoneurons. Glutamate receptor-activated responses in sensory neurons also decreased with aging. In old tail motoneurons, the amplitude of evoked EPSPs following tail shock decreased, presumably due to reduced sensory neuron excitability during aging. The results were used to develop stages of aging relevant to both hatchery-reared and wild-caught Aplysia. Aplysia is a viable aging model in which the contributions of differential aging of components of neural circuits may be assessed.

Behavioral aging is associated with reduced sensory neuron excitability in Aplysia californica

PubMed Central

Kempsell, Andrew T.; Fieber, Lynne A.

2014-01-01

Invertebrate models have advantages for understanding the basis of behavioral aging due to their simple nervous systems and short lifespans. The potential usefulness of Aplysia californica in aging research is apparent from its long history of neurobiological research, but it has been underexploited in this model use. Aging of simple reflexes at both single sensory neuron and neural circuit levels was studied to connect behavioral aging to neurophysiological aging. The tail withdrawal reflex (TWR), righting reflex, and biting response were measured throughout sexual maturity in 3 cohorts of hatchery-reared animals of known age. Reflex times increased and reflex amplitudes decreased significantly during aging. Aging in sensory neurons of animals with deficits in measures of the TWR and biting response resulted in significantly reduced excitability in old animals compared to their younger siblings. The threshold for firing increased while the number of action potentials in response to depolarizing current injection decreased during aging in sensory neurons, but not in tail motoneurons. Glutamate receptor-activated responses in sensory neurons also decreased with aging. In old tail motoneurons, the amplitude of evoked EPSPs following tail shock decreased, presumably due to reduced sensory neuron excitability during aging. The results were used to develop stages of aging relevant to both hatchery-reared and wild-caught Aplysia. Aplysia is a viable aging model in which the contributions of differential aging of components of neural circuits may be assessed. PMID:24847260

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

PubMed Central

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

2010-01-01

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

C. elegans multi-dendritic sensory neurons: morphology and function

PubMed Central

Albeg, Adi; Smith, Cody; Chatzigeorgiou, Marios; Feitelson, Dror G.; Hall, David H.; Schafer, William R.; Miller, David M.; Treinin, Millet

2010-01-01

PVD and FLP sensory neurons envelope the body of the C. elegans adult with a highly branched network of thin sensory processes. Both PVD and FLP neurons are mechanosensors. PVD is known to mediate the response to high threshold mechanical stimuli. Thus PVD and FLP neurons are similar in both morphology and function to mammalian nociceptors. To better understand the function of these neurons we generated strains lacking them. Behavioral analysis shows that PVD and FLP regulate movement under normal growth conditions, as animals lacking these neurons demonstrate higher dwelling behavior. In addition, PVD—whose thin branches project across the body-wall muscles—may have a role in proprioception, as ablation of PVD leads to defective posture. Moreover, movement-dependent calcium transients are seen in PVD, a response that requires MEC-10, a subunit of the mechanosensory DEG/ENaC channel that is also required for maintaining wild-type posture. Hence, PVD senses both noxious and innocuous signals to regulate C. elegans behavior, and thus combines the functions of multiple mammalian somatosensory neurons. Finally, strong mechanical stimulation leads to inhibition of egg-laying, and this response also depends on PVD and FLP neurons. Based on all these results we suggest that noxious signals perceived by PVD and FLP promote an escape behavior consisting of increased speed, reduced pauses and reversals, and inhibition of egg-laying. PMID:20971193

Modality distribution of sensory neurons in the feline caudate nucleus and the substantia nigra.

PubMed

Márkus, Zita; Eördegh, Gabriella; Paróczy, Zsuzsanna; Benedek, G; Nagy, A

2008-09-01

Despite extensive analysis of the motor functions of the basal ganglia and the fact that multisensory information processing appears critical for the execution of their behavioral action, little is known concerning the sensory functions of the caudate nucleus (CN) and the substantia nigra (SN). In the present study, we set out to describe the sensory modality distribution and to determine the proportions of multisensory units within the CN and the SN. The separate single sensory modality tests demonstrated that a majority of the neurons responded to only one modality, so that they seemed to be unimodal. In contrast with these findings, a large proportion of these neurons exhibited significant multisensory cross-modal interactions. Thus, these neurons should also be classified as multisensory. Our results suggest that a surprisingly high proportion of sensory neurons in the basal ganglia are multisensory, and demonstrate that an analysis without a consideration of multisensory cross-modal interactions may strongly underrepresent the number of multisensory units. We conclude that a majority of the sensory neurons in the CN and SN process multisensory information and only a minority of these units are clearly unimodal.

Decoupling kinematics and mechanics reveals coding properties of trigeminal ganglion neurons in the rat vibrissal system

PubMed Central

Bush, Nicholas E; Schroeder, Christopher L; Hobbs, Jennifer A; Yang, Anne ET; Huet, Lucie A; Solla, Sara A; Hartmann, Mitra JZ

2016-01-01

Tactile information available to the rat vibrissal system begins as external forces that cause whisker deformations, which in turn excite mechanoreceptors in the follicle. Despite the fundamental mechanical origin of tactile information, primary sensory neurons in the trigeminal ganglion (Vg) have often been described as encoding the kinematics (geometry) of object contact. Here we aimed to determine the extent to which Vg neurons encode the kinematics vs. mechanics of contact. We used models of whisker bending to quantify mechanical signals (forces and moments) at the whisker base while simultaneously monitoring whisker kinematics and recording single Vg units in both anesthetized rats and awake, body restrained rats. We employed a novel manual stimulation technique to deflect whiskers in a way that decouples kinematics from mechanics, and used Generalized Linear Models (GLMs) to show that Vg neurons more directly encode mechanical signals when the whisker is deflected in this decoupled stimulus space. DOI: http://dx.doi.org/10.7554/eLife.13969.001 PMID:27348221

TRPA1 is a major oxidant sensor in murine airway sensory neurons

PubMed Central

Bessac, Bret F.; Sivula, Michael; von Hehn, Christian A.; Escalera, Jasmine; Cohn, Lauren; Jordt, Sven-Eric

2008-01-01

Sensory neurons in the airways are finely tuned to respond to reactive chemicals threatening airway function and integrity. Nasal trigeminal nerve endings are particularly sensitive to oxidants formed in polluted air and during oxidative stress as well as to chlorine, which is frequently released in industrial and domestic accidents. Oxidant activation of airway neurons induces respiratory depression, nasal obstruction, sneezing, cough, and pain. While normally protective, chemosensory airway reflexes can provoke severe complications in patients affected by inflammatory airway conditions like rhinitis and asthma. Here, we showed that both hypochlorite, the oxidizing mediator of chlorine, and hydrogen peroxide, a reactive oxygen species, activated Ca2+ influx and membrane currents in an oxidant-sensitive subpopulation of chemosensory neurons. These responses were absent in neurons from mice lacking TRPA1, an ion channel of the transient receptor potential (TRP) gene family. TRPA1 channels were strongly activated by hypochlorite and hydrogen peroxide in primary sensory neurons and heterologous cells. In tests of respiratory function, Trpa1–/– mice displayed profound deficiencies in hypochlorite- and hydrogen peroxide–induced respiratory depression as well as decreased oxidant-induced pain behavior. Our results indicate that TRPA1 is an oxidant sensor in sensory neurons, initiating neuronal excitation and subsequent physiological responses in vitro and in vivo. PMID:18398506

Sensory neurons that detect stretch and nutrients in the digestive system

PubMed Central

Williams, Erika K.; Chang, Rui B.; Strochlic, David E.; Umans, Benjamin D.; Lowell, Bradford B.; Liberles, Stephen D.

2016-01-01

SUMMARY Neural inputs from internal organs are essential for normal autonomic function. The vagus nerve is a key body-brain connection that monitors the digestive, cardiovascular, and respiratory systems. Within the gastrointestinal tract, vagal sensory neurons detect gut hormones and organ distension. Here, we investigate the molecular diversity of vagal sensory neurons and their roles in sensing gastrointestinal inputs. Genetic approaches allowed targeted investigation of gut-to-brain afferents involved in homeostatic responses to ingested nutrients (GPR65 neurons) and mechanical distension of the stomach and intestine (GLP1R neurons). Optogenetics, in vivo ganglion imaging, and genetically guided anatomical mapping provide direct links between neuron identity, peripheral anatomy, central anatomy, conduction velocity, response properties in vitro and in vivo, and physiological function. These studies clarify the roles of vagal afferents in mediating particular gut hormone responses. Moreover, genetic control over gut-to-brain neurons provides a molecular framework for understanding neural control of gastrointestinal physiology. PMID:27238020

Sound sensitivity of neurons in rat hippocampus during performance of a sound-guided task

PubMed Central

Vinnik, Ekaterina; Honey, Christian; Schnupp, Jan; Diamond, Mathew E.

2012-01-01

To investigate how hippocampal neurons encode sound stimuli, and the conjunction of sound stimuli with the animal's position in space, we recorded from neurons in the CA1 region of hippocampus in rats while they performed a sound discrimination task. Four different sounds were used, two associated with water reward on the right side of the animal and the other two with water reward on the left side. This allowed us to separate neuronal activity related to sound identity from activity related to response direction. To test the effect of spatial context on sound coding, we trained rats to carry out the task on two identical testing platforms at different locations in the same room. Twenty-one percent of the recorded neurons exhibited sensitivity to sound identity, as quantified by the difference in firing rate for the two sounds associated with the same response direction. Sensitivity to sound identity was often observed on only one of the two testing platforms, indicating an effect of spatial context on sensory responses. Forty-three percent of the neurons were sensitive to response direction, and the probability that any one neuron was sensitive to response direction was statistically independent from its sensitivity to sound identity. There was no significant coding for sound identity when the rats heard the same sounds outside the behavioral task. These results suggest that CA1 neurons encode sound stimuli, but only when those sounds are associated with actions. PMID:22219030

Regulation of voltage-gated Ca(2+) currents by Ca(2+)/calmodulin-dependent protein kinase II in resting sensory neurons.

PubMed

Kostic, Sandra; Pan, Bin; Guo, Yuan; Yu, Hongwei; Sapunar, Damir; Kwok, Wai-Meng; Hudmon, Andy; Wu, Hsiang-En; Hogan, Quinn H

2014-09-01

Calcium/calmodulin-dependent protein kinase II (CaMKII) is recognized as a key element in encoding depolarization activity of excitable cells into facilitated voltage-gated Ca(2+) channel (VGCC) function. Less is known about the participation of CaMKII in regulating VGCCs in resting cells. We examined constitutive CaMKII control of Ca(2+) currents in peripheral sensory neurons acutely isolated from dorsal root ganglia (DRGs) of adult rats. The small molecule CaMKII inhibitor KN-93 (1.0μM) reduced depolarization-induced ICa by 16-30% in excess of the effects produced by the inactive homolog KN-92. The specificity of CaMKII inhibition on VGCC function was shown by the efficacy of the selective CaMKII blocking peptide autocamtide-2-related inhibitory peptide in a membrane-permeable myristoylated form, which also reduced VGCC current in resting neurons. Loss of VGCC currents is primarily due to reduced N-type current, as application of mAIP selectively reduced N-type current by approximately 30%, and prior N-type current inhibition eliminated the effect of mAIP on VGCCs, while prior block of L-type channels did not reduce the effect of mAIP on total ICa. T-type currents were not affected by mAIP in resting DRG neurons. Transduction of sensory neurons in vivo by DRG injection of an adeno-associated virus expressing AIP also resulted in a loss of N-type currents. Together, these findings reveal a novel molecular adaptation whereby sensory neurons retain CaMKII support of VGCCs despite remaining quiescent. Published by Elsevier Inc.

Met receptor signaling is required for sensory nerve development and HGF promotes axonal growth and survival of sensory neurons

PubMed Central

Maina, Flavio; Hilton, Mark C.; Ponzetto, Carola; Davies, Alun M.; Klein, Rüdiger

1997-01-01

The development of the nervous system is a dynamic process during which factors act in an instructive fashion to direct the differentiation and survival of neurons, and to induce axonal outgrowth, guidance to, and terminal branching within the target tissue. Here we report that mice expressing signaling mutants of the hepatocyte growth factor (HGF) receptor, the Met tyrosine kinase, show a striking reduction of sensory nerves innervating the skin of the limbs and thorax, implicating the HGF/Met system in sensory neuron development. Using in vitro assays, we find that HGF cooperates with nerve growth factor (NGF) to enhance axonal outgrowth from cultured dorsal root ganglion (DRG) neurons. HGF also enhances the neurotrophic activities of NGF in vitro, and Met receptor signaling is required for the survival of a proportion of DRG neurons in vivo. This synergism is specific for NGF but not for the related neurotrophins BDNF and NT3. By using a mild signaling mutant of Met, we have demonstrated previously that Met requires signaling via the adapter molecule Grb2 to induce proliferation of myoblasts. In contrast, the actions of HGF on sensory neurons are mediated by Met effectors distinct from Grb2. Our findings demonstrate a requirement for Met signaling in neurons during development. PMID:9407027

Neto2 Assembles with Kainate Receptors in DRG Neurons during Development and Modulates Neurite Outgrowth in Adult Sensory Neurons.

PubMed

Vernon, Claire G; Swanson, Geoffrey T

2017-03-22

Peripheral sensory neurons in the dorsal root ganglia (DRG) are the initial transducers of sensory stimuli, including painful stimuli, from the periphery to central sensory and pain-processing centers. Small- to medium-diameter non-peptidergic neurons in the neonatal DRG express functional kainate receptors (KARs), one of three subfamilies of ionotropic glutamate receptors, as well as the putative KAR auxiliary subunit Neuropilin- and tolloid-like 2 (Neto2). Neto2 alters recombinant KAR function markedly but has yet to be confirmed as an auxiliary subunit that assembles with and alters the function of endogenous KARs. KARs in neonatal DRG require the GluK1 subunit as a necessary constituent, but it is unclear to what extent other KAR subunits contribute to the function and proposed roles of KARs in sensory ganglia, which include promotion of neurite outgrowth and modulation of glutamate release at the DRG-dorsal horn synapse. In addition, KARs containing the GluK1 subunit are implicated in modes of persistent but not acute pain signaling. We show here that the Neto2 protein is highly expressed in neonatal DRG and modifies KAR gating in DRG neurons in a developmentally regulated fashion in mice. Although normally at very low levels in adult DRG neurons, Neto2 protein expression can be upregulated via MEK/ERK signaling and after sciatic nerve crush and Neto2 -/- neurons from adult mice have stunted neurite outgrowth. These data confirm that Neto2 is a bona fide KAR auxiliary subunit that is an important constituent of KARs early in sensory neuron development and suggest that Neto2 assembly is critical to KAR modulation of DRG neuron process outgrowth. SIGNIFICANCE STATEMENT Pain-transducing peripheral sensory neurons of the dorsal root ganglia (DRG) express kainate receptors (KARs), a subfamily of glutamate receptors that modulate neurite outgrowth and regulate glutamate release at the DRG-dorsal horn synapse. The putative KAR auxiliary subunit Neuropilin- and

Redox and Nitric Oxide-Mediated Regulation of Sensory Neuron Ion Channel Function

PubMed Central

2015-01-01

Abstract Significance: Reactive oxygen and nitrogen species (ROS and RNS, respectively) can intimately control neuronal excitability and synaptic strength by regulating the function of many ion channels. In peripheral sensory neurons, such regulation contributes towards the control of somatosensory processing; therefore, understanding the mechanisms of such regulation is necessary for the development of new therapeutic strategies and for the treatment of sensory dysfunctions, such as chronic pain. Recent Advances: Tremendous progress in deciphering nitric oxide (NO) and ROS signaling in the nervous system has been made in recent decades. This includes the recognition of these molecules as important second messengers and the elucidation of their metabolic pathways and cellular targets. Mounting evidence suggests that these targets include many ion channels which can be directly or indirectly modulated by ROS and NO. However, the mechanisms specific to sensory neurons are still poorly understood. This review will therefore summarize recent findings that highlight the complex nature of the signaling pathways involved in redox/NO regulation of sensory neuron ion channels and excitability; references to redox mechanisms described in other neuron types will be made where necessary. Critical Issues: The complexity and interplay within the redox, NO, and other gasotransmitter modulation of protein function are still largely unresolved. Issues of specificity and intracellular localization of these signaling cascades will also be addressed. Future Directions: Since our understanding of ROS and RNS signaling in sensory neurons is limited, there is a multitude of future directions; one of the most important issues for further study is the establishment of the exact roles that these signaling pathways play in pain processing and the translation of this understanding into new therapeutics. Antioxid. Redox Signal. 22, 486–504. PMID:24735331

The expression of hyperpolarization-activated cyclic nucleotide-gated channel 1 (HCN1) and HCN2 in the rat trigeminal ganglion, sensory root, and dental pulp.

PubMed

Cho, Y S; Kim, Y S; Moozhayil, S J; Yang, E S; Bae, Y C

2015-04-16

Hyperpolarization-activated cyclic nucleotide-gated channel 1 (HCN1) and 2 (HCN2) are abundantly expressed in primary sensory neurons and contribute to neuronal excitability and pathological pain. We studied the expression of HCN1 and HCN2 in the rat trigeminal ganglion (TG) neurons and axons in the dental pulp, and the changes in their expression following inflammation, using light- and electron-microscopic immunocytochemistry and quantitative analysis. HCN1 and HCN2 were expressed predominantly in large-sized, neurofilament 200-immunopositive (+) or parvalbumin+ soma in the TG whereas they were expressed mostly in unmyelinated and small myelinated axons in the sensory root. The expression was particularly strong along the plasma membrane in the soma. In the dental pulp, majority of HCN1+ and HCN2+ axons coexpressed calcitonin gene-related peptide. They were expressed mainly in the peripheral pulp and pulp horn where the axons branch extensively in the dental pulp. The expression of HCN1 and HCN2 in TG neurons increased significantly in rats with experimentally induced inflammation of the dental pulp. Our findings support the notion that HCN1 and HCN2 are expressed mainly by both the soma of mechanosensitive neurons in the TG and peripheral axons of nociceptive neurons in the sensory root, and may play a role in the mechanisms of inflammatory pain from the dental pulp. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

The dusp1 Immediate Early Gene is Regulated by Natural Stimuli Predominantly in Sensory Input Neurons

PubMed Central

Horita, Haruhito; Wada, Kazuhiro; Rivas, Miriam V.; Hara, Erina; Jarvis, Erich D.

2010-01-01

Many immediate early genes (IEGs) have activity-dependent induction in a subset of brain subdivisions or neuron types. However, none have been reported yet with regulation specific to thalamic-recipient sensory neurons of the telencephalon or in the thalamic sensory input neurons themselves. Here, we report the first such gene, dual specificity phosphatase 1 (dusp1). Dusp1 is an inactivator of mitogen-activated protein kinase (MAPK), and MAPK activates expression of egr1, one of the most commonly studied IEGs, as determined in cultured cells. We found that in the brain of naturally behaving songbirds and other avian species, hearing song, seeing visual stimuli, or performing motor behavior caused high dusp1 upregulation, respectively, in auditory, visual, and somatosensory input cell populations of the thalamus and thalamic-recipient sensory neurons of the telencephalic pallium, whereas high egr1 upregulation occurred only in subsequently connected secondary and tertiary sensory neuronal populations of these same pathways. Motor behavior did not induce high levels of dusp1 expression in the motor-associated areas adjacent to song nuclei, where egr1 is upregulated in response to movement. Our analysis of dusp1 expression in mouse brain suggests similar regulation in the sensory input neurons of the thalamus and thalamic-recipient layer IV and VI neurons of the cortex. These findings suggest that dusp1 has specialized regulation to sensory input neurons of the thalamus and telencephalon; they further suggest that this regulation may serve to attenuate stimulus-induced expression of egr1 and other IEGs, leading to unique molecular properties of forebrain sensory input neurons. PMID:20506480

Excitatory interneurons dominate sensory processing in the spinal substantia gelatinosa of rat

PubMed Central

Santos, Sónia F A; Rebelo, Sandra; Derkach, Victor A; Safronov, Boris V

2007-01-01

Substantia gelatinosa (SG, lamina II) is a spinal cord region where most unmyelinated primary afferents terminate and the central nociceptive processing begins. It is formed by several distinct groups of interneurons whose functional properties and synaptic connections are poorly understood, in part, because recordings from synaptically coupled pairs of SG neurons are quite challenging due to a very low probability of finding connected cells. Here, we describe an efficient method for identifying synaptically coupled interneurons in rat spinal cord slices and characterizing their excitatory or inhibitory function. Using tight-seal whole-cell recordings and a cell-attached stimulation technique, we routinely tested about 1500 SG interneurons, classifying 102 of them as monosynaptically connected to neurons in lamina I–III. Surprisingly, the vast majority of SG interneurons (n = 87) were excitatory and glutamatergic, while only 15 neurons were inhibitory. According to their intrinsic firing properties, these 102 SG neurons were also classified as tonic (n = 49), adapting (n = 17) or delayed-firing neurons (n = 36). All but two tonic neurons and all adapting neurons were excitatory interneurons. Of 36 delayed-firing neurons, 23 were excitatory and 13 were inhibitory. We conclude that sensory integration in the intrinsic SG neuronal network is dominated by excitatory interneurons. Such organization of neuronal circuitries in the spinal SG can be important for nociceptive encoding. PMID:17331995

Dose-Dependent Differential Effect of Neurotrophic Factors on In Vitro and In Vivo Regeneration of Motor and Sensory Neurons

PubMed Central

Santos, Daniel; Gonzalez-Perez, Francisco; Navarro, Xavier

2016-01-01

Although peripheral axons can regenerate after nerve transection and repair, functional recovery is usually poor due to inaccurate reinnervation. Neurotrophic factors promote directional guidance to regenerating axons and their selective application may help to improve functional recovery. Hence, we have characterized in organotypic cultures of spinal cord and dorsal root ganglia the effect of GDNF, FGF-2, NGF, NT-3, and BDNF at different concentrations on motor and sensory neurite outgrowth. In vitro results show that GDNF and FGF-2 enhanced both motor and sensory neurite outgrowth, NGF and NT-3 were the most selective to enhance sensory neurite outgrowth, and high doses of BDNF selectively enhanced motor neurite outgrowth. Then, NGF, NT-3, and BDNF (as the most selective factors) were delivered in a collagen matrix within a silicone tube to repair the severed sciatic nerve of rats. Quantification of Fluorogold retrolabeled neurons showed that NGF and NT-3 did not show preferential effect on sensory regeneration whereas BDNF preferentially promoted motor axons regeneration. Therefore, the selective effects of NGF and NT-3 shown in vitro are lost when they are applied in vivo, but a high dose of BDNF is able to selectively enhance motor neuron regeneration both in vitro and in vivo. PMID:27867665

Role of motoneuron-derived neurotrophin 3 in survival and axonal projection of sensory neurons during neural circuit formation.

PubMed

Usui, Noriyoshi; Watanabe, Keisuke; Ono, Katsuhiko; Tomita, Koichi; Tamamaki, Nobuaki; Ikenaka, Kazuhiro; Takebayashi, Hirohide

2012-03-01

Sensory neurons possess the central and peripheral branches and they form unique spinal neural circuits with motoneurons during development. Peripheral branches of sensory axons fasciculate with the motor axons that extend toward the peripheral muscles from the central nervous system (CNS), whereas the central branches of proprioceptive sensory neurons directly innervate motoneurons. Although anatomically well documented, the molecular mechanism underlying sensory-motor interaction during neural circuit formation is not fully understood. To investigate the role of motoneuron on sensory neuron development, we analyzed sensory neuron phenotypes in the dorsal root ganglia (DRG) of Olig2 knockout (KO) mouse embryos, which lack motoneurons. We found an increased number of apoptotic cells in the DRG of Olig2 KO embryos at embryonic day (E) 10.5. Furthermore, abnormal axonal projections of sensory neurons were observed in both the peripheral branches at E10.5 and central branches at E15.5. To understand the motoneuron-derived factor that regulates sensory neuron development, we focused on neurotrophin 3 (Ntf3; NT-3), because Ntf3 and its receptors (Trk) are strongly expressed in motoneurons and sensory neurons, respectively. The significance of motoneuron-derived Ntf3 was analyzed using Ntf3 conditional knockout (cKO) embryos, in which we observed increased apoptosis and abnormal projection of the central branch innervating motoneuron, the phenotypes being apparently comparable with that of Olig2 KO embryos. Taken together, we show that the motoneuron is a functional source of Ntf3 and motoneuron-derived Ntf3 is an essential pre-target neurotrophin for survival and axonal projection of sensory neurons.

Intraflagellar transport genes are essential for differentiation and survival of vertebrate sensory neurons.

PubMed

Tsujikawa, Motokazu; Malicki, Jarema

2004-06-10

Cilia play diverse roles in vertebrate and invertebrate sensory neurons. We show that a mutation of the zebrafish oval (ovl) locus affects a component of the ciliary transport (IFT) mechanism, the IFT88 polypeptide. In mutant retina, cilia are generated but not maintained, producing the absence of photoreceptor outer segments. A loss of cilia also occurs in auditory hair cells and olfactory sensory neurons. In all three sense organs, cilia defects are followed by degeneration of sensory cells. Similar phenotypes are induced by the absence of the IFT complex B polypeptides, ift52 and ift57, but not by the loss of complex A protein, ift140. The degeneration of mutant photoreceptor cells is caused, at least partially, by the ectopic accumulation of opsins. These studies reveal an essential role for IFT genes in vertebrate sensory neurons and implicate the molecular components of intraflagellar transport in degenerative disorders of these cells.

Zebrafish narrowminded suggests a genetic link between formation of neural crest and primary sensory neurons

PubMed Central

Bruk Artinger, Kristin; Chitnis, Ajay B.; Mercola, Mark; Driever, Wolfgang

2014-01-01

SUMMARY In the developing vertebrate nervous system, both neural crest and sensory neurons form at the boundary between non-neural ectoderm and the neural plate. From an in situ hybridization based expression analysis screen, we have identified a novel zebrafish mutation, narrowminded (nrd), which reduces the number of early neural crest cells and eliminates Rohon-Beard (RB) sensory neurons. Mosaic analysis has shown that the mutation acts cell autonomously suggesting that nrd is involved in either the reception or interpretation of signals at the lateral neural plate boundary. Characterization of the mutant phenotype indicates that nrd is required for a primary wave of neural crest cell formation during which progenitors generate both RB sensory neurons and neural crest cells. Moreover, the early deficit in neural crest cells in nrd homozygotes is compensated later in development. Thus, we propose that a later wave can compensate for the loss of early neural crest cells but, interestingly, not the RB sensory neurons. We discuss the implications of these findings for the possibility that RB sensory neurons and neural crest cells share a common evolutionary origin. PMID:10457007

Mathematical Relationships between Neuron Morphology and Neurite Growth Dynamics in Drosophila melanogaster Larva Class IV Sensory Neurons

NASA Astrophysics Data System (ADS)

Ganguly, Sujoy; Liang, Xin; Grace, Michael; Lee, Daniel; Howard, Jonathon

The morphology of neurons is diverse and reflects the diversity of neuronal functions, yet the principles that govern neuronal morphogenesis are unclear. In an effort to better understand neuronal morphogenesis we will be focusing on the development of the dendrites of class IV sensory neuron in Drosophila melanogaster. In particular we attempt to determine how the the total length, and the number of branches of dendrites are mathematically related to the dynamics of neurite growth and branching. By imaging class IV neurons during early embryogenesis we are able to measure the change in neurite length l (t) as a function of time v (t) = dl / dt . We found that the distribution of v (t) is well characterized by a hyperbolic secant distribution, and that the addition of new branches per unit time is well described by a Poisson process. Combining these measurements with the assumption that branching occurs with equal probability anywhere along the dendrite we were able to construct a mathematical model that provides reasonable agreement with the observed number of branches, and total length of the dendrites of the class IV sensory neuron.

The Upregulation of α2δ-1 Subunit Modulates Activity-Dependent Ca2+ Signals in Sensory Neurons

PubMed Central

Margas, Wojciech; Cassidy, John S.

2015-01-01

As auxiliary subunits of voltage-gated Ca2+ channels, the α2δ proteins modulate membrane trafficking of the channels and their localization to specific presynaptic sites. Following nerve injury, upregulation of the α2δ-1 subunit in sensory dorsal root ganglion neurons contributes to the generation of chronic pain states; however, very little is known about the underlying molecular mechanisms. Here we show that the increased expression of α2δ-1 in rat sensory neurons leads to prolonged Ca2+ responses evoked by membrane depolarization. This mechanism is coupled to CaV2.2 channel-mediated responses, as it is blocked by a ω-conotoxin GVIA application. Once initiated, the prolonged Ca2+ transients are not dependent on extracellular Ca2+ and do not require Ca2+ release from the endoplasmic reticulum. The selective inhibition of mitochondrial Ca2+ uptake demonstrates that α2δ-1-mediated prolonged Ca2+ signals are buffered by mitochondria, preferentially activated by Ca2+ influx through CaV2.2 channels. Thus, by controlling channel abundance at the plasma membrane, the α2δ-1 subunit has a major impact on the organization of depolarization-induced intracellular Ca2+ signaling in dorsal root ganglion neurons. PMID:25878262

Temporal-pattern recognition by single neurons in a sensory pathway devoted to social communication behavior

PubMed Central

Carlson, Bruce A.

2010-01-01

Sensory systems often encode stimulus information into the temporal pattern of action potential activity. However, little is known about how the information contained within these patterns is extracted by postsynaptic neurons. Similar to temporal coding by sensory neurons, social information in mormyrid fish is encoded into the temporal patterning of an electric organ discharge (EOD). In the current study, sensitivity to temporal patterns of electrosensory stimuli was found to arise within the midbrain posterior exterolateral nucleus (ELp). Whole-cell patch recordings from ELp neurons in vivo revealed three patterns of interpulse interval (IPI) tuning: low-pass neurons tuned to long intervals, high-pass neurons tuned to short intervals and band-pass neurons tuned to intermediate intervals. Many neurons within each class also responded preferentially to either increasing or decreasing IPIs. Playback of electric signaling patterns recorded from freely behaving fish revealed that the IPI and direction tuning of ELp neurons resulted in selective responses to particular social communication displays characterized by distinct IPI patterns. The postsynaptic potential responses of many neurons indicated a combination of excitatory and inhibitory synaptic input, and the IPI tuning of ELp neurons was directly related to rate-dependent changes in the direction and amplitude of postsynaptic potentials. These results suggest that differences in the dynamics of short-term synaptic plasticity in excitatory and inhibitory pathways may tune central sensory neurons to particular temporal patterns of presynaptic activity. This may represent a general mechanism for the processing of behaviorally-relevant stimulus information encoded into temporal patterns of activity by sensory neurons. PMID:19641105

Temporal-pattern recognition by single neurons in a sensory pathway devoted to social communication behavior.

PubMed

Carlson, Bruce A

2009-07-29

Sensory systems often encode stimulus information into the temporal pattern of action potential activity. However, little is known about how the information contained within these patterns is extracted by postsynaptic neurons. Similar to temporal coding by sensory neurons, social information in mormyrid fish is encoded into the temporal patterning of an electric organ discharge. In the current study, sensitivity to temporal patterns of electrosensory stimuli was found to arise within the midbrain posterior exterolateral nucleus (ELp). Whole-cell patch recordings from ELp neurons in vivo revealed three patterns of interpulse interval (IPI) tuning: low-pass neurons tuned to long intervals, high-pass neurons tuned to short intervals, and bandpass neurons tuned to intermediate intervals. Many neurons within each class also responded preferentially to either increasing or decreasing IPIs. Playback of electric signaling patterns recorded from freely behaving fish revealed that the IPI and direction tuning of ELp neurons resulted in selective responses to particular social communication displays characterized by distinct IPI patterns. The postsynaptic potential responses of many neurons indicated a combination of excitatory and inhibitory synaptic input, and the IPI tuning of ELp neurons was directly related to rate-dependent changes in the direction and amplitude of postsynaptic potentials. These results suggest that differences in the dynamics of short-term synaptic plasticity in excitatory and inhibitory pathways may tune central sensory neurons to particular temporal patterns of presynaptic activity. This may represent a general mechanism for the processing of behaviorally relevant stimulus information encoded into temporal patterns of activity by sensory neurons.

The Sensory Neurons of Touch

PubMed Central

Abraira, Victoria E.; Ginty, David D.

2013-01-01

The somatosensory system decodes a wide range of tactile stimuli and thus endows us with a remarkable capacity for object recognition, texture discrimination, sensory-motor feedback and social exchange. The first step leading to perception of innocuous touch is activation of cutaneous sensory neurons called low-threshold mechanoreceptors (LTMRs). Here, we review the properties and functions of LTMRs, emphasizing the unique tuning properties of LTMR subtypes and the organizational logic of their peripheral and central axonal projections. We discuss the spinal cord neurophysiological representation of complex mechanical forces acting upon the skin and current views of how tactile information is processed and conveyed from the spinal cord to the brain. An integrative model in which ensembles of impulses arising from physiologically distinct LTMRs are integrated and processed in somatotopically aligned mechanosensory columns of the spinal cord dorsal horn underlies the nervous system’s enormous capacity for perceiving the richness of the tactile world. PMID:23972592

Differential neural representation of oral ethanol by central taste-sensitive neurons in ethanol-preferring and genetically heterogeneous rats

PubMed Central

Wilson, David M.; Brasser, Susan M.

2011-01-01

In randomly bred rats, orally applied ethanol stimulates neural substrates for appetitive sweet taste. To study associations between ethanol's oral sensory characteristics and genetically mediated ethanol preference, we made electrophysiological recordings of oral responses (spike density) by taste-sensitive nucleus tractus solitarii neurons in anesthetized selectively bred ethanol-preferring (P) rats and their genetically heterogeneous Wistar (W) control strain. Stimuli (25 total) included ethanol [3%, 5%, 10%, 15%, 25%, and 40% (vol/vol)], a sucrose series (0.01, 0.03, 0.1, 0.3, 0.5, and 1 M), and other sweet, salt, acidic, and bitter stimuli; 50 P and 39 W neurons were sampled. k-means clustering applied to the sucrose response series identified cells showing high (S1) or relatively low (S0) sensitivity to sucrose. A three-way factorial analysis revealed that activity to ethanol was influenced by a neuron's sensitivity to sucrose, ethanol concentration, and rat line (P = 0.01). Ethanol produced concentration-dependent responses in S1 neurons that were larger than those in S0 cells. Although responses to ethanol by S1 cells did not differ between lines, neuronal firing rates to ethanol in S0 cells increased across concentration only in P rats. Correlation and multivariate analyses revealed that ethanol evoked responses in W neurons that were strongly and selectively associated with activity to sweet stimuli, whereas responses to ethanol by P neurons were not easily associated with activity to representative sweet, sodium salt, acidic, or bitter stimuli. These findings show differential central neural representation of oral ethanol between genetically heterogeneous rats and P rats genetically selected to prefer alcohol. PMID:21918002

Differential neural representation of oral ethanol by central taste-sensitive neurons in ethanol-preferring and genetically heterogeneous rats.

PubMed

Lemon, Christian H; Wilson, David M; Brasser, Susan M

2011-12-01

In randomly bred rats, orally applied ethanol stimulates neural substrates for appetitive sweet taste. To study associations between ethanol's oral sensory characteristics and genetically mediated ethanol preference, we made electrophysiological recordings of oral responses (spike density) by taste-sensitive nucleus tractus solitarii neurons in anesthetized selectively bred ethanol-preferring (P) rats and their genetically heterogeneous Wistar (W) control strain. Stimuli (25 total) included ethanol [3%, 5%, 10%, 15%, 25%, and 40% (vol/vol)], a sucrose series (0.01, 0.03, 0.1, 0.3, 0.5, and 1 M), and other sweet, salt, acidic, and bitter stimuli; 50 P and 39 W neurons were sampled. k-means clustering applied to the sucrose response series identified cells showing high (S(1)) or relatively low (S(0)) sensitivity to sucrose. A three-way factorial analysis revealed that activity to ethanol was influenced by a neuron's sensitivity to sucrose, ethanol concentration, and rat line (P = 0.01). Ethanol produced concentration-dependent responses in S(1) neurons that were larger than those in S(0) cells. Although responses to ethanol by S(1) cells did not differ between lines, neuronal firing rates to ethanol in S(0) cells increased across concentration only in P rats. Correlation and multivariate analyses revealed that ethanol evoked responses in W neurons that were strongly and selectively associated with activity to sweet stimuli, whereas responses to ethanol by P neurons were not easily associated with activity to representative sweet, sodium salt, acidic, or bitter stimuli. These findings show differential central neural representation of oral ethanol between genetically heterogeneous rats and P rats genetically selected to prefer alcohol.

RAGE-dependent potentiation of TRPV1 currents in sensory neurons exposed to high glucose.

PubMed

Lam, Doris; Momeni, Zeinab; Theaker, Michael; Jagadeeshan, Santosh; Yamamoto, Yasuhiko; Ianowski, Juan P; Campanucci, Verónica A

2018-01-01

Diabetes mellitus is associated with sensory abnormalities, including exacerbated responses to painful (hyperalgesia) or non-painful (allodynia) stimuli. These abnormalities are symptoms of diabetic peripheral neuropathy (DPN), which is the most common complication that affects approximately 50% of diabetic patients. Yet, the underlying mechanisms linking hyperglycemia and symptoms of DPN remain poorly understood. The transient receptor potential vanilloid 1 (TRPV1) channel plays a central role in such sensory abnormalities and shows elevated expression levels in animal models of diabetes. Here, we investigated the function of TRPV1 channels in sensory neurons cultured from the dorsal root ganglion (DRG) of neonatal mice, under control (5mM) and high glucose (25mM) conditions. After maintaining DRG neurons in high glucose for 1 week, we observed a significant increase in capsaicin (CAP)-evoked currents and CAP-evoked depolarizations, independent of TRPV1 channel expression. These functional changes were largely dependent on the expression of the receptor for Advanced Glycation End-products (RAGE), calcium influx, cytoplasmic ROS accumulation, PKC, and Src kinase activity. Like cultured neurons from neonates, mature neurons from adult mice also displayed a similar potentiation of CAP-evoked currents in the high glucose condition. Taken together, our data demonstrate that under the diabetic condition, DRG neurons are directly affected by elevated levels of glucose, independent of vascular or glial signals, and dependent on RAGE expression. These early cellular and molecular changes to sensory neurons in vitro are potential mechanisms that might contribute to sensory abnormalities that can occur in the very early stages of diabetes.

RAGE-dependent potentiation of TRPV1 currents in sensory neurons exposed to high glucose

PubMed Central

Lam, Doris; Momeni, Zeinab; Theaker, Michael; Jagadeeshan, Santosh; Yamamoto, Yasuhiko; Ianowski, Juan P.

2018-01-01

Diabetes mellitus is associated with sensory abnormalities, including exacerbated responses to painful (hyperalgesia) or non-painful (allodynia) stimuli. These abnormalities are symptoms of diabetic peripheral neuropathy (DPN), which is the most common complication that affects approximately 50% of diabetic patients. Yet, the underlying mechanisms linking hyperglycemia and symptoms of DPN remain poorly understood. The transient receptor potential vanilloid 1 (TRPV1) channel plays a central role in such sensory abnormalities and shows elevated expression levels in animal models of diabetes. Here, we investigated the function of TRPV1 channels in sensory neurons cultured from the dorsal root ganglion (DRG) of neonatal mice, under control (5mM) and high glucose (25mM) conditions. After maintaining DRG neurons in high glucose for 1 week, we observed a significant increase in capsaicin (CAP)-evoked currents and CAP-evoked depolarizations, independent of TRPV1 channel expression. These functional changes were largely dependent on the expression of the receptor for Advanced Glycation End-products (RAGE), calcium influx, cytoplasmic ROS accumulation, PKC, and Src kinase activity. Like cultured neurons from neonates, mature neurons from adult mice also displayed a similar potentiation of CAP-evoked currents in the high glucose condition. Taken together, our data demonstrate that under the diabetic condition, DRG neurons are directly affected by elevated levels of glucose, independent of vascular or glial signals, and dependent on RAGE expression. These early cellular and molecular changes to sensory neurons in vitro are potential mechanisms that might contribute to sensory abnormalities that can occur in the very early stages of diabetes. PMID:29474476

H2S-induced HCO3- secretion in the rat stomach--involvement of nitric oxide, prostaglandins, and capsaicin-sensitive sensory neurons.

PubMed

Takeuchi, Koji; Ise, Fumitaka; Takahashi, Kento; Aihara, Eitaro; Hayashi, Shusaku

2015-04-30

Hydrogen sulfide (H2S) is known to be an important gaseous mediator that affects various functions under physiological and pathological conditions. We examined the effects of NaHS, a H2S donor, on HCO3(-) secretion in rat stomachs and investigated the mechanism involved in this response. Under urethane anesthesia, rat stomachs were mounted on an ex vivo chamber and perfused with saline. Acid secretion had been inhibited by omeprazole. The secretion of HCO3(-) was measured at pH 7.0 using a pH-stat method and by the addition of 10 mM HCl. NaHS (0.5-10 mM) was perfused in the stomach for 5 min. Indomethacin or L-NAME was administered s.c. before NaHS treatment, while glibenclamide (a KATP channel blocker), ONO-8711 (an EP1 antagonist), or propargylglycine (a cystathionine γ-lyase inhibitor) was given i.p. before. The mucosal perfusion of NaHS dose-dependently increased the secretion of HCO3(-), and this effect was significantly attenuated by indomethacin, L-NAME, and sensory deafferentation, but not by glibenclamide or ONO-8711. The luminal output of nitric oxide, but not the mucosal production of prostaglandin E2, was increased by the perfusion of NaHS. Mucosal acidification stimulated HCO3(-) secretion, and this response was inhibited by sensory deafferentation, indomethacin, L-NAME, and ONO-8711, but not by propargylglycine. These results suggested that H2S increased HCO3(-) secretion in the stomach, and this effect was mediated by capsaicin-sensitive afferent neurons and dependent on nitric oxide and prostaglandins, but not ATP-sensitive K(+) channels. Further study is needed to define the role of endogenous H2S in the mechanism underlying acid-induced gastric HCO3(-) secretion. Copyright © 2014 Elsevier Inc. All rights reserved.

Immunohistochemical localization of serotonin and choline acetyltransferase in sensory neurones of the locust.

PubMed

Lutz, E M; Tyrer, N M

1988-01-15

Sensory neuronal cell bodies in the leg of locust, Schistocerca gregaria, were visualized with antibodies to locust choline acetyltransferase and with antibodies to serotonin by the avidin-biotin peroxidase technique. Two groups of sensory cells react with the antibody to choline acetyltransferase: One group is associated with external mechanoreceptors (i.e., hair-plate hairs and campaniform sensilla) and the other with internal proprioceptors (i.e., chordotonal organs and multiterminal receptors). Sensory cells which react with the antibody to serotonin are associated only with internal proprioceptors being found in both chordotonal organs and multiterminal receptors. In the metathoracic femoral chordotonal organ indirect evidence suggests that some sensory cells are reactive to both antibodies. Some multiterminal receptors react with anti-choline-acetyltransferase, while others react with antiserotonin. These results support the conclusion that most insect sensory neurones are cholinergic but some are serotoninergic.

Identification of motor neurons and a mechanosensitive sensory neuron in the defecation circuitry of Drosophila larvae

PubMed Central

Zhang, Wei; Yan, Zhiqiang; Li, Bingxue; Jan, Lily Yeh; Jan, Yuh Nung

2014-01-01

Defecation allows the body to eliminate waste, an essential step in food processing for animal survival. In contrast to the extensive studies of feeding, its obligate counterpart, defecation, has received much less attention until recently. In this study, we report our characterizations of the defecation behavior of Drosophila larvae and its neural basis. Drosophila larvae display defecation cycles of stereotypic frequency, involving sequential contraction of hindgut and anal sphincter. The defecation behavior requires two groups of motor neurons that innervate hindgut and anal sphincter, respectively, and can excite gut muscles directly. These two groups of motor neurons fire sequentially with the same periodicity as the defecation behavior, as revealed by in vivo Ca2+ imaging. Moreover, we identified a single mechanosensitive sensory neuron that innervates the anal slit and senses the opening of the intestine terminus. This anus sensory neuron relies on the TRP channel NOMPC but not on INACTIVE, NANCHUNG, or PIEZO for mechanotransduction. DOI: http://dx.doi.org/10.7554/eLife.03293.001 PMID:25358089

Role of female sex hormones in neuronal nitric oxide release and metabolism in rat mesenteric arteries.

PubMed

Minoves, Nuria; Balfagón, Gloria; Ferrer, Mercedes

2002-09-01

This study examines the effects of female sex hormones on the vasoconstrictor response to electrical field stimulation (EFS), as well as the modulation of this response by neuronal NO. For this purpose, segments of denuded superior mesenteric artery from ovariectomized (OvX) female Sprague-Dawley rats and from control rats (in oestrus phase) were used. EFS induced frequency-dependent contractions, which were greater in segments from OvX rats than in those from control rats. The NO synthase inhibitor N(G)-nitro-l-arginine methyl ester strengthened EFS-elicited contractions to a greater extent in arteries from OvX rats than in those from control rats. Similar results were observed with the preferential neuronal NO synthase inhibitor 7-nitroindazole. The sensorial neurotoxin capsaicin did not modify EFS-induced contractions in segments from either group. In noradrenaline-precontracted segments, sodium nitroprusside (SNP) induced concentration-dependent relaxation, which was greater in segments from control rats than in those from OvX rats. 8-Bromo-cGMP induced similar concentration-dependent relaxation in noradrenaline-precontracted segments from both OvX and control rats. Diethyldithiocarbamate, a superoxide dismutase (SOD) inhibitor, reduced the relaxation induced by SNP in segments from both groups of rats. SOD, a superoxide anion scavenger, enhanced the relaxation induced by SNP in segments from OvX rats, but did not modify it in segments from control rats. EFS induced NO(-)(2) formation, which was greater in segments from OvX than in those from control rats, and pretreatment with tetrodotoxin, a blocker of nerve impulse propagation, abolished release in both cases. These results suggest that EFS induces greater neuronal NO release in mesenteric segments from OvX rats than in those from control rats and, although NO metabolism is also higher, the contribution of net neuronal NO in the vasomotor response to EFS is greater in segments from OvX rats than in those

Intraganglionic AAV6 results in efficient and long-term gene transfer to peripheral sensory nervous system in adult rats.

PubMed

Yu, Hongwei; Fischer, Gregory; Ferhatovic, Lejla; Fan, Fan; Light, Alan R; Weihrauch, Dorothee; Sapunar, Damir; Nakai, Hiroyuki; Park, Frank; Hogan, Quinn H

2013-01-01

We previously demonstrated safe and reliable gene transfer to the dorsal root ganglion (DRG) using a direct microinjection procedure to deliver recombinant adeno-associated virus (AAV) vector. In this study, we proceed to compare the in vivo transduction patterns of self-complementary (sc) AAV6 and AAV8 in the peripheral sensory pathway. A single, direct microinjection of either AAV6 or AAV8 expressing EGFP, at the adjusted titer of 2×10(9) viral particle per DRG, into the lumbar (L) 4 and L5 DRGs of adult rats resulted in efficient EGFP expression (48±20% for AAV6 and 25±4% for AAV8, mean ± SD) selectively in sensory neurons and their axonal projections 3 weeks after injection, which remained stable for up to 3 months. AAV6 efficiently transfers EGFP to all neuronal size groups without differential neurotropism, while AAV8 predominantly targets large-sized neurons. Neurons transduced with AAV6 penetrate into the spinal dorsal horn (DH) and terminate predominantly in superficial DH laminae, as well as in the dorsal columns and deeper laminae III-V. Only few AAV8-transduced afferents were evident in the superficial laminae, and spinal EGFP was mostly present in the deeper dorsal horn (lamina III-V) and dorsal columns, with substantial projections to the ventral horn. AAV6-mediated EGFP-positive nerve fibers were widely observed in the medial plantar skin of ipsilateral hindpaws. No apparent inflammation, tissue damage, or major pain behaviors were observed for either AAV serotype. Taken together, both AAV6 and AAV8 are efficient and safe vectors for transgene delivery to primary sensory neurons, but they exhibit distinct functional features. Intraganglionic delivery of AAV6 is more uniform and efficient compared to AAV8 in gene transfer to peripheral sensory neurons and their axonal processes.

Piezo Is Essential for Amiloride-Sensitive Stretch-Activated Mechanotransduction in Larval Drosophila Dorsal Bipolar Dendritic Sensory Neurons

PubMed Central

Suslak, Thomas J.; Watson, Sonia; Thompson, Karen J.; Shenton, Fiona C.; Bewick, Guy S.; Armstrong, J. Douglas; Jarman, Andrew P.

2015-01-01

Stretch-activated afferent neurons, such as those of mammalian muscle spindles, are essential for proprioception and motor co-ordination, but the underlying mechanisms of mechanotransduction are poorly understood. The dorsal bipolar dendritic (dbd) sensory neurons are putative stretch receptors in the Drosophila larval body wall. We have developed an in vivo protocol to obtain receptor potential recordings from intact dbd neurons in response to stretch. Receptor potential changes in dbd neurons in response to stretch showed a complex, dynamic profile with similar characteristics to those previously observed for mammalian muscle spindles. These profiles were reproduced by a general in silico model of stretch-activated neurons. This in silico model predicts an essential role for a mechanosensory cation channel (MSC) in all aspects of receptor potential generation. Using pharmacological and genetic techniques, we identified the mechanosensory channel, DmPiezo, in this functional role in dbd neurons, with TRPA1 playing a subsidiary role. We also show that rat muscle spindles exhibit a ruthenium red-sensitive current, but found no expression evidence to suggest that this corresponds to Piezo activity. In summary, we show that the dbd neuron is a stretch receptor and demonstrate that this neuron is a tractable model for investigating mechanisms of mechanotransduction. PMID:26186008

Piezo Is Essential for Amiloride-Sensitive Stretch-Activated Mechanotransduction in Larval Drosophila Dorsal Bipolar Dendritic Sensory Neurons.

PubMed

Suslak, Thomas J; Watson, Sonia; Thompson, Karen J; Shenton, Fiona C; Bewick, Guy S; Armstrong, J Douglas; Jarman, Andrew P

2015-01-01

Stretch-activated afferent neurons, such as those of mammalian muscle spindles, are essential for proprioception and motor co-ordination, but the underlying mechanisms of mechanotransduction are poorly understood. The dorsal bipolar dendritic (dbd) sensory neurons are putative stretch receptors in the Drosophila larval body wall. We have developed an in vivo protocol to obtain receptor potential recordings from intact dbd neurons in response to stretch. Receptor potential changes in dbd neurons in response to stretch showed a complex, dynamic profile with similar characteristics to those previously observed for mammalian muscle spindles. These profiles were reproduced by a general in silico model of stretch-activated neurons. This in silico model predicts an essential role for a mechanosensory cation channel (MSC) in all aspects of receptor potential generation. Using pharmacological and genetic techniques, we identified the mechanosensory channel, DmPiezo, in this functional role in dbd neurons, with TRPA1 playing a subsidiary role. We also show that rat muscle spindles exhibit a ruthenium red-sensitive current, but found no expression evidence to suggest that this corresponds to Piezo activity. In summary, we show that the dbd neuron is a stretch receptor and demonstrate that this neuron is a tractable model for investigating mechanisms of mechanotransduction.

Recovery of function, peripheral sensitization and sensory neurone activation by novel pathways following axonal injury in Aplysia californica.

PubMed

Dulin, M F; Steffensen, I; Morris, C E; Walters, E T

1995-10-01

Recovery of behavioural and sensory function was examined following unilateral pedal nerve crush in Aplysia californica. Nerve crush that transected all axons connecting the tail to the central nervous system (CNS) eliminated the ipsilateral tail-evoked siphon reflex, whose sensory input travels in the crushed tail nerve (p9). The first reliable signs of recovery of this reflex were observed within 1 week, and most animals displayed tail-evoked siphon responses within 2 weeks. Wide-dynamic-range mechanosensory neurons with somata in the ventrocaudal (VC) cluster of the ipsilateral pleural ganglion exhibited a few receptive fields (RFs) on the tail 3 weeks after unilateral pedal nerve crush, indicating that the RFs had either regenerated or been reconnected to the central somata. These RFs were smaller and sensitized compared with corresponding RFs on the contralateral, uncrushed side. Centrally conducted axon responses of VC sensory neurones to electrical stimulation distal to the nerve crush site did not reappear until at least 10 days after the crush. Because the crush site was much closer to the CNS than to the tail, the failure of axon responses to be restored earlier than the behavioural responses indicates that early stages of reflex recovery are not due to regeneration of VC sensory neurone axons into the tail. Following nerve crush, VC sensory neurones often could be activated by stimulating central connectives or peripheral nerves that do not normally contain the sensory neurone's axons. These results suggest that recovery of behavioral function after nerve injury involves complex mechanisms, including regenerative growth of axotomized VC sensory neurones, sensitization of regenerating RFs and sprouting of VC sensory neurone fibres within the CNS. Furthermore, the rapidity of behavioural recovery indicates that its initial phases are mediated by additional mechanisms, perhaps centripetal regeneration of unidentified sensory neurones having peripheral

Identification of Linear and Nonlinear Sensory Processing Circuits from Spiking Neuron Data.

PubMed

Florescu, Dorian; Coca, Daniel

2018-03-01

Inferring mathematical models of sensory processing systems directly from input-output observations, while making the fewest assumptions about the model equations and the types of measurements available, is still a major issue in computational neuroscience. This letter introduces two new approaches for identifying sensory circuit models consisting of linear and nonlinear filters in series with spiking neuron models, based only on the sampled analog input to the filter and the recorded spike train output of the spiking neuron. For an ideal integrate-and-fire neuron model, the first algorithm can identify the spiking neuron parameters as well as the structure and parameters of an arbitrary nonlinear filter connected to it. The second algorithm can identify the parameters of the more general leaky integrate-and-fire spiking neuron model, as well as the parameters of an arbitrary linear filter connected to it. Numerical studies involving simulated and real experimental recordings are used to demonstrate the applicability and evaluate the performance of the proposed algorithms.

Quantitation of Contacts Among Sensory, Motor, and Serotonergic Neurons in the Pedal Ganglion of Aplysia

PubMed Central

Zhang, Han; Wainwright, Marcy; Byrne, John H.; Cleary, Leonard J.

2003-01-01

Present models of long-term sensitization in Aplysia californica indicate that the enhanced behavioral response is due, at least in part, to outgrowth of sensory neurons mediating defensive withdrawal reflexes. Presumably, this outgrowth strengthens pre-existing connections by formation of newsynapses with follower neurons. However, the relationship between the number of sensorimotor contacts and the physiological strength of the connection has never been examined in intact ganglia. As a first step in addressing this issue, we used confocal microscopy to examine sites of contact between sensory and motor neurons in naive animals. Our results revealed relatively fewcontacts between physiologically connected cells. In addition, the number of contact sites was proportional to the amplitude of the EPSP elicited in the follower motor neuron by direct stimulation of the sensory neuron. This is the first time such a correlation has been observed in the central nervous system. Serotonin is the neurotransmitter most closely examined for its role in modulating synaptic strength at the sensorimotor synapse. However, the structural relationship of serotonergic processes and sensorimotor synapses has never been examined. Surprisingly, serotonergic processes usually made contact with sensory and motor neurons at sites located relatively distant from the sensorimotor synapse. This result implies that heterosynaptic regulation is due to nondirected release of serotonin into the neuropil. PMID:14557611

Development of inner ear afferent connections: forming primary neurons and connecting them to the developing sensory epithelia

NASA Technical Reports Server (NTRS)

Fritzsch, Bernd

2003-01-01

The molecular and cellular origin of the primary neurons of the inner ear, the vestibular and spiral neurons, is reviewed including how they connect to the specific sensory epithelia and what the molecular nature of their survival is. Primary neurons of the ear depend on a single basic Helix-Loop-Helix (bHLH) protein for their formation, neurogenin 1 (ngn1). An immediate downstream gene is the bHLH gene neuronal differentiation (NeuroD). Targeted null mutations of ngn1 results in absence of primary neuron formation; targeted null mutation of NeuroD results in loss of almost all spiral and many vestibular neurons. NeuroD and a later expressed gene, Brn3a, play a role in pathfinding to and within sensory epithelia. The molecular nature of this pathfinding property is unknown. Reduction of hair cells in ngn1 null mutations suggests a clonal relationship with primary neurons. This relationship may play some role in specifying the identity of hair cells and the primary neurons that connect with them. Primary neuron neurites growth to sensory epithelia is initially independent of trophic factors released from developing sensory epithelia, but becomes rapidly dependent on those factors. Null mutations of specific neurotrophic factors lose distinct primary neuron populations which undergo rapid embryonic cell death.

Coupled Activation of Primary Sensory Neurons Contributes to Chronic Pain.

PubMed

Kim, Yu Shin; Anderson, Michael; Park, Kyoungsook; Zheng, Qin; Agarwal, Amit; Gong, Catherine; Saijilafu; Young, LeAnne; He, Shaoqiu; LaVinka, Pamela Colleen; Zhou, Fengquan; Bergles, Dwight; Hanani, Menachem; Guan, Yun; Spray, David C; Dong, Xinzhong

2016-09-07

Primary sensory neurons in the DRG play an essential role in initiating pain by detecting painful stimuli in the periphery. Tissue injury can sensitize DRG neurons, causing heightened pain sensitivity, often leading to chronic pain. Despite the functional importance, how DRG neurons function at a population level is unclear due to the lack of suitable tools. Here we developed an imaging technique that allowed us to simultaneously monitor the activities of >1,600 neurons/DRG in live mice and discovered a striking neuronal coupling phenomenon that adjacent neurons tend to activate together following tissue injury. This coupled activation occurs among various neurons and is mediated by an injury-induced upregulation of gap junctions in glial cells surrounding DRG neurons. Blocking gap junctions attenuated neuronal coupling and mechanical hyperalgesia. Therefore, neuronal coupling represents a new form of neuronal plasticity in the DRG and contributes to pain hypersensitivity by "hijacking" neighboring neurons through gap junctions. Copyright © 2016 Elsevier Inc. All rights reserved.

RELATIONSHIP BETWEEN ENTROPY OF SPIKE TIMING AND FIRING RATE IN ENTOPEDUNCULAR NUCLEUS NEURONS IN ANESTHETIZED RATS: FUNCTION OF THE NIGRO-STRIATAL PATHWAY

PubMed Central

Darbin, Olivier; Jin, Xingxing; von Wrangel, Christof; Schwabe, Kerstin; Nambu, Atsushi; Naritoku, Dean K; Krauss, Joachim K.; Alam, Mesbah

2016-01-01

The function of the nigro-striatal pathway on neuronal entropy in the basal ganglia (BG) output nucleus (entopeduncular nucleus, EPN) was investigated in the unilaterally 6-hyroxydopamine (6-OHDA)-lesioned rat model of Parkinson’s disease (PD). In both control subjects and subjects with 6-OHDA lesion of the nigro-striatal pathway, a histological hallmark for parkinsonism, neuronal entropy in EPN was maximal in neurons with firing rates ranging between 15Hz and 25 Hz. In 6-OHDA lesioned rats, neuronal entropy in the EPN was specifically higher in neurons with firing rates above 25Hz. Our data establishes that nigro-striatal pathway controls neuronal entropy in motor circuitry and that the parkinsonian condition is associated with abnormal relationship between firing rate and neuronal entropy in BG output nuclei. The neuronal firing rates and entropy relationship provide putative relevant electrophysiological information to investigate the sensory-motor processing in normal condition and conditions with movement disorders. PMID:26711712

Trafficking regulates the subcellular distribution of voltage-gated sodium channels in primary sensory neurons.

PubMed

Bao, Lan

2015-09-30

Voltage-gated sodium channels (Navs) comprise at least nine pore-forming α subunits. Of these, Nav1.6, Nav1.7, Nav1.8 and Nav1.9 are the most frequently studied in primary sensory neurons located in the dorsal root ganglion and are mainly localized to the cytoplasm. A large pool of intracellular Navs raises the possibility that changes in Nav trafficking could alter channel function. The molecular mediators of Nav trafficking mainly consist of signals within the Navs themselves, interacting proteins and extracellular factors. The surface expression of Navs is achieved by escape from the endoplasmic reticulum and proteasome degradation, forward trafficking and plasma membrane anchoring, and it is also regulated by channel phosphorylation and ubiquitination in primary sensory neurons. Axonal transport and localization of Navs in afferent fibers involves the motor protein KIF5B and scaffold proteins, including contactin and PDZ domain containing 2. Localization of Nav1.6 to the nodes of Ranvier in myelinated fibers of primary sensory neurons requires node formation and the submembrane cytoskeletal protein complex. These findings inform our understanding of the molecular and cellular mechanisms underlying Nav trafficking in primary sensory neurons.

Modulation of Specific Sensory Cortical Areas by Segregated Basal Forebrain Cholinergic Neurons Demonstrated by Neuronal Tracing and Optogenetic Stimulation in Mice.

PubMed

Chaves-Coira, Irene; Barros-Zulaica, Natali; Rodrigo-Angulo, Margarita; Núñez, Ángel

2016-01-01

Neocortical cholinergic activity plays a fundamental role in sensory processing and cognitive functions. Previous results have suggested a refined anatomical and functional topographical organization of basal forebrain (BF) projections that may control cortical sensory processing in a specific manner. We have used retrograde anatomical procedures to demonstrate the existence of specific neuronal groups in the BF involved in the control of specific sensory cortices. Fluoro-Gold (FlGo) and Fast Blue (FB) fluorescent retrograde tracers were deposited into the primary somatosensory (S1) and primary auditory (A1) cortices in mice. Our results revealed that the BF is a heterogeneous area in which neurons projecting to different cortical areas are segregated into different neuronal groups. Most of the neurons located in the horizontal limb of the diagonal band of Broca (HDB) projected to the S1 cortex, indicating that this area is specialized in the sensory processing of tactile stimuli. However, the nucleus basalis magnocellularis (B) nucleus shows a similar number of cells projecting to the S1 as to the A1 cortices. In addition, we analyzed the cholinergic effects on the S1 and A1 cortical sensory responses by optogenetic stimulation of the BF neurons in urethane-anesthetized transgenic mice. We used transgenic mice expressing the light-activated cation channel, channelrhodopsin-2, tagged with a fluorescent protein (ChR2-YFP) under the control of the choline-acetyl transferase promoter (ChAT). Cortical evoked potentials were induced by whisker deflections or by auditory clicks. According to the anatomical results, optogenetic HDB stimulation induced more extensive facilitation of tactile evoked potentials in S1 than auditory evoked potentials in A1, while optogenetic stimulation of the B nucleus facilitated either tactile or auditory evoked potentials equally. Consequently, our results suggest that cholinergic projections to the cortex are organized into segregated

Impact of Aging on Proprioceptive Sensory Neurons and Intrafusal Muscle Fibers in Mice.

PubMed

Vaughan, Sydney K; Stanley, Olivia L; Valdez, Gregorio

2017-06-01

The impact of aging on proprioceptive sensory neurons and intrafusal muscle fibers (IMFs) remains largely unexplored despite the central function these cells play in modulating voluntary movements. Here, we show that proprioceptive sensory neurons undergo deleterious morphological changes in middle age (11- to 13-month-old) and old (15- to 21-month-old) mice. In the extensor digitorum longus and soleus muscles of middle age and old mice, there is a significant increase in the number of Ia afferents with large swellings that fail to properly wrap around IMFs compared with young adult (2- to 4-month-old) mice. Fewer II afferents were also found in the same muscles of middle age and old mice. Although these age-related changes in peripheral nerve endings were accompanied by degeneration of proprioceptive sensory neuron cell bodies in dorsal root ganglia (DRG), the morphology and number of IMFs remained unchanged. Our analysis also revealed normal levels of neurotrophin 3 (NT3) but dysregulated expression of the tyrosine kinase receptor C (TrkC) in aged muscles and DRGs, respectively. These results show that proprioceptive sensory neurons degenerate prior to atrophy of IMFs during aging, and in the presence of the NT3/TrkC signaling axis. © The Author 2016. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

A high-threshold heat-activated channel in cultured rat dorsal root ganglion neurons resembles TRPV2 and is blocked by gadolinium.

PubMed

Leffler, Andreas; Linte, Ramona Madalina; Nau, Carla; Reeh, Peter; Babes, Alexandru

2007-07-01

Heat-activated ion channels from the vanilloid-type TRP group (TRPV1-4) seem to be central for heat-sensitivity of nociceptive sensory neurons. Displaying a high-threshold (> 52 degrees C) for activation, TRPV2 was proposed to act as a sensor for intense noxious heat in mammalian sensory neurons. However, although TRPV2 is expressed in a distinct population of thinly myelinated primary afferents, a widespread expression in a variety of neuronal and non-neuronal tissues suggests a more diverse physiological role of TRPV2. In its role as a heat-sensor, TRPV2 has not been thoroughly characterized in terms of biophysical and pharmacological properties. In the present study, we demonstrate that the features of heterologously expressed rat TRPV2 closely resemble those of high-threshold heat-evoked currents in medium- and large-sized capsaicin-insensitive rat dorsal root ganglion (DRG) neurons. Both in TRPV2-expressing human embryonic kidney (HEK)293t cells and in DRGs, high-threshold heat-currents were sensitized by repeated activation and by the TRPV1-3 agonist, 2-aminoethoxydiphenyl borate (2-APB). In addition to a previously described block by ruthenium red, we identified the trivalent cations, lanthanum (La(3+)) and gadolinium (Gd(3+)) as potent blockers of TRPV2. Thus, we present a new pharmacological tool to distinguish between heat responses of TRPV2 and the closely related capsaicin-receptor, TRPV1, which is strongly sensitized by trivalent cations. We demonstrate that self-sensitization of heat-evoked currents through TRPV2 does not require extracellular calcium and that TRPV2 can be activated in cell-free membrane patches in the outside-out configuration. Taken together our results provide new evidence for a role of TRPV2 in mediating high-threshold heat responses in a subpopulation of mammalian sensory neurons.

Polysensory response characteristics of dorsal root ganglion neurones that may serve sensory functions during myocardial ischaemia.

PubMed

Huang, M H; Horackova, M; Negoescu, R M; Wolf, S; Armour, J A

1996-09-01

To determine the response characteristics of dorsal root ganglion neurones that may serve sensory functions during myocardial ischaemia. Extracellular recordings were made from 54 spontaneously active and 5 normally quiescent dorsal root ganglion neurones (T2-T5) in 22 anaesthetized open-chest dogs under control conditions and during epicardial mechanical or chemical stimulation and myocardial ischaemia. The activity of 78% of spontaneously active and all quiescent neurones with left ventricular sensory fields was modified by left ventricular ischaemia. Forty-six spontaneously active neurones (85%) were polysensory with respect to mechanical and chemical stimuli. The 5 quiescent neurones responded only to chemical stimuli. Spontaneously active neurones associated with left ventricular mechanosensory endings (37 neurones) generated four different activity patterns in response to similar mechanical stimuli (high or low pressure active, high-low pressure active, high-low pressure inactive). A fifth group generated activity which was not related to chamber dynamics. Adenosine, adenosine 5'-triphosphate, substance P and bradykinin modified 72, 61, 65 and 63% of the spontaneously active neurones, respectively. Maximum local mechanical or chemical stimuli enhanced activity to similar degrees, as did ischaemia. Each ischaemia-sensitive neurone displayed unique activity patterns in response to similar mechanical or chemical stimuli. Most myocardial ischemia-sensitive dorsal root ganglion neurones associated with epicardial neurites sense mechanical and multiple chemical stimuli, a small population sensing only mechanical or chemical stimuli. Activity patterns generated by these neurones depend on their primary sensory characteristics or those of other neurones that may converge on them, as well as the type and magnitude of the stimuli that impinge upon their sensory fields, both normally and during ischaemia.

A single-neuron tracing study of arkypallidal and prototypic neurons in healthy rats.

PubMed

Fujiyama, Fumino; Nakano, Takashi; Matsuda, Wakoto; Furuta, Takahiro; Udagawa, Jun; Kaneko, Takeshi

2016-12-01

The external globus pallidus (GP) is known as a relay nucleus of the indirect pathway of the basal ganglia. Recent studies in dopamine-depleted and healthy rats indicate that the GP comprises two main types of pallidofugal neurons: the so-called "prototypic" and "arkypallidal" neurons. However, the reconstruction of complete arkypallidal neurons in healthy rats has not been reported. Here we visualized the entire axonal arborization of four single arkypallidal neurons and six single prototypic neurons in rat brain using labeling with a viral vector expressing membrane-targeted green fluorescent protein and examined the distribution of axon boutons in the target nuclei. Results revealed that not only the arkypallidal neurons but nearly all of the prototypic neurons projected to the striatum with numerous axon varicosities. Thus, the striatum is a major target nucleus for pallidal neurons. Arkypallidal and prototypic GP neurons located in the calbindin-positive and calbindin-negative regions mainly projected to the corresponding positive and negative regions in the striatum. Because the GP and striatum calbindin staining patterns reflect the topographic organization of the striatopallidal projection, the striatal neurons in the sensorimotor and associative regions constitute the reciprocal connection with the GP neurons in the corresponding regions.

Synaptic activation of putative sensory neurons by hexamethonium-sensitive nerve pathways in mouse colon.

PubMed

Hibberd, Timothy J; Travis, Lee; Wiklendt, Lukasz; Costa, Marcello; Brookes, Simon J H; Hu, Hongzhen; Keating, Damien J; Spencer, Nick J

2018-01-01

The gastrointestinal tract contains its own independent population of sensory neurons within the gut wall. These sensory neurons have been referred to as intrinsic primary afferent neurons (IPANs) and can be identified by immunoreactivity to calcitonin gene-related peptide (CGRP) in mice. A common feature of IPANs is a paucity of fast synaptic inputs observed during sharp microelectrode recordings. Whether this is observed using different recording techniques is of particular interest for understanding the physiology of these neurons and neural circuit modeling. Here, we imaged spontaneous and evoked activation of myenteric neurons in isolated whole preparations of mouse colon and correlated recordings with CGRP and nitric oxide synthase (NOS) immunoreactivity, post hoc. Calcium indicator fluo 4 was used for this purpose. Calcium responses were recorded in nerve cell bodies located 5-10 mm oral to transmural electrical nerve stimuli. A total of 618 recorded neurons were classified for CGRP or NOS immunoreactivity. Aboral electrical stimulation evoked short-latency calcium transients in the majority of myenteric neurons, including ~90% of CGRP-immunoreactive Dogiel type II neurons. Activation of Dogiel type II neurons had a time course consistent with fast synaptic transmission and was always abolished by hexamethonium (300 μM) and by low-calcium Krebs solution. The nicotinic receptor agonist 1,1-dimethyl-4-phenylpiperazinium iodide (during synaptic blockade) directly activated Dogiel type II neurons. The present study suggests that murine colonic Dogiel type II neurons receive prominent fast excitatory synaptic inputs from hexamethonium-sensitive neural pathways. NEW & NOTEWORTHY Myenteric neurons in isolated mouse colon were recorded using calcium imaging and then neurochemically defined. Short-latency calcium transients were detected in >90% of calcitonin gene-related peptide-immunoreactive neurons to electrical stimulation of hexamethonium-sensitive pathways

Central Projections of Antennal and Labial Palp Sensory Neurons in the Migratory Armyworm Mythimna separata

PubMed Central

Ma, Bai-Wei; Zhao, Xin-Cheng; Berg, Bente G.; Xie, Gui-Ying; Tang, Qing-Bo; Wang, Gui-Rong

2017-01-01

The oriental armyworm, Mythimna separata (Walker), is a polyphagous, migratory pest relying on olfactory cues to find mates, locate nectar, and guide long-distance flight behavior. In the present study, a combination of neuroanatomical techniques were utilized on this species, including backfills, confocal microscopy, and three-dimensional reconstructions, to trace the central projections of sensory neurons from the antenna and the labial pit organ, respectively. As previously shown, the axons of the labial sensory neurons project via the ipsilateral labial nerve and terminate in three main areas of the central nervous system: (1) the labial-palp pit organ glomerulus of each antennal lobe, (2) the gnathal ganglion, and (3) the prothoracic ganglion of the ventral nerve cord. Similarly, the antennal sensory axons project to multiple areas of the central nervous system. The ipsilateral antennal nerve targets mainly the antennal lobe, the antennal mechanosensory and motor center, and the prothoracic and mesothoracic ganglia. Specific staining experiments including dye application to each of the three antennal segments indicate that the antennal lobe receives input from flagellar olfactory neurons exclusively, while the antennal mechanosensory and motor center is innervated by mechanosensory neurons from the whole antenna, comprising the flagellum, pedicle, and scape. The terminals in the mechanosensory and motor center are organized in segregated zones relating to the origin of neurons. The flagellar mechanosensory axons target anterior zones, while the pedicular and scapal axons terminate in posterior zones. In the ventral nerve cord, the processes from the antennal sensory neurons terminate in the motor area of the thoracic ganglia, suggesting a close connection with motor neurons. Taken together, the numerous neuropils innervated by axons both from the antenna and labial palp indicate the multiple roles these sensory organs serve in insect behavior. PMID:29209176

Activity-dependent sensitivity of proprioceptive sensory neurons in the stick insect femoral chordotonal organ.

PubMed

DiCaprio, Ralph A; Wolf, Harald; Büschges, Ansgar

2002-11-01

Mechanosensory neurons exhibit a wide range of dynamic changes in response, including rapid and slow adaptation. In addition to mechanical factors, electrical processes may also contribute to sensory adaptation. We have investigated adaptation of afferent neurons in the stick insect femoral chordotonal organ (fCO). The fCO contains sensory neurons that respond to position, velocity, and acceleration of the tibia. We describe the influence of random mechanical stimulation of the fCO on the response of fCO afferent neurons. The activity of individual sensory neurons was recorded intracellularly from their axons in the main leg nerve. Most fCO afferents (93%) exhibited a marked decrease in response to trapezoidal stimuli following sustained white noise stimulation (bandwidth = 60 Hz, amplitudes from +/-5 to +/-30 degrees ). Concurrent decreases in the synaptic drive to leg motoneurons and interneurons were also observed. Electrical stimulation of spike activity in individual fCO afferents in the absence of mechanical stimulation also led to a dramatic decrease in response in 15 of 19 afferents tested. This indicated that electrical processes are involved in the regulation of the generator potential or encoding of action potentials and partially responsible for the decreased response of the afferents. Replacing Ca(2+) with Ba(2+) in the saline surrounding the fCO greatly reduced or blocked the decrease in response elicited by electrically induced activity or mechanical stimulation when compared with control responses. Our results indicate that activity of fCO sensory neurons strongly affects their sensitivity, most likely via Ca(2+)-dependent processes.

Dose-response characteristics of methylphenidate on locomotor behavior and on sensory evoked potentials recorded from the VTA, NAc, and PFC in freely behaving rats.

PubMed

Yang, Pamela B; Swann, Alan C; Dafny, Nachum

2006-01-17

Methylphenidate (MPD) is a psychostimulant commonly prescribed for attention deficit/hyperactivity disorder. The mode of action of the brain circuitry responsible for initiating the animals' behavior in response to psychostimulants is not well understood. There is some evidence that psychostimulants activate the ventral tegmental area (VTA), nucleus accumbens (NAc), and prefrontal cortex (PFC). The present study was designed to investigate the acute dose-response of MPD (0.6, 2.5, and 10.0 mg/kg) on locomotor behavior and sensory evoked potentials recorded from the VTA, NAc, and PFC in freely behaving rats previously implanted with permanent electrodes. For locomotor behavior, adult male Wistar-Kyoto (WKY; n = 39) rats were given saline on experimental day 1 and either saline or an acute injection of MPD (0.6, 2.5, or 10.0 mg/kg, i.p.) on experimental day 2. Locomotor activity was recorded for 2-h post injection on both days using an automated, computerized activity monitoring system. Electrophysiological recordings were also performed in the adult male WKY rats (n = 10). Five to seven days after the rats had recovered from the implantation of electrodes, each rat was placed in a sound-insulated, electrophysiological test chamber where its sensory evoked field potentials were recorded before and after saline and 0.6, 2.5, and 10.0 mg/kg MPD injection. Time interval between injections was 90 min. Results showed an increase in locomotion with dose-response characteristics, while a dose-response decrease in amplitude of the components of sensory evoked field responses of the VTA, NAc, and PFC neurons. For example, the P3 component of the sensory evoked field response of the VTA decreased by 19.8% +/- 7.4% from baseline after treatment of 0.6 mg/kg MPD, 37.8% +/- 5.9% after 2.5 mg/kg MPD, and 56.5% +/- 3.9% after 10 mg/kg MPD. Greater attenuation from baseline was observed in the NAc and PFC. Differences in the intensity of MPD-induced attenuation were also found among

Mycolactone-mediated neurite degeneration and functional effects in cultured human and rat DRG neurons

PubMed Central

Sinisi, M; Fox, M; MacQuillan, A; Quick, T; Korchev, Y; Bountra, C; McCarthy, T; Anand, P

2016-01-01

Background Mycolactone is a polyketide toxin secreted by the mycobacterium Mycobacterium ulcerans, responsible for the extensive hypoalgesic skin lesions characteristic of patients with Buruli ulcer. A recent pre-clinical study proposed that mycolactone may produce analgesia via activation of the angiotensin II type 2 receptor (AT2R). In contrast, AT2R antagonist EMA401 has shown analgesic efficacy in animal models and clinical trials for neuropathic pain. We therefore investigated the morphological and functional effects of mycolactone in cultured human and rat dorsal root ganglia (DRG) neurons and the role of AT2R using EMA401. Primary sensory neurons were prepared from avulsed cervical human DRG and rat DRG; 24 h after plating, neurons were incubated for 24 to 96 h with synthetic mycolactone A/B, followed by immunostaining with antibodies to PGP9.5, Gap43, β tubulin, or Mitotracker dye staining. Acute functional effects were examined by measuring capsaicin responses with calcium imaging in DRG neuronal cultures treated with mycolactone. Results Morphological effects: Mycolactone-treated cultures showed dramatically reduced numbers of surviving neurons and non-neuronal cells, reduced Gap43 and β tubulin expression, degenerating neurites and reduced cell body diameter, compared with controls. Dose-related reduction of neurite length was observed in mycolactone-treated cultures. Mitochondria were distributed throughout the length of neurites and soma of control neurons, but clustered in the neurites and soma of mycolactone-treated neurons. Functional effects: Mycolactone-treated human and rat DRG neurons showed dose-related inhibition of capsaicin responses, which were reversed by calcineurin inhibitor cyclosporine and phosphodiesterase inhibitor 3-isobutyl-1-Methylxanthine, indicating involvement of cAMP/ATP reduction. The morphological and functional effects of mycolactone were not altered by Angiotensin II or AT2R antagonist EMA401. Conclusion Mycolactone

Repeated whisker stimulation evokes invariant neuronal responses in the dorsolateral striatum of anesthetized rats: a potential correlate of sensorimotor habits

PubMed Central

Mowery, Todd M.; Harrold, Jon B.

2011-01-01

The dorsolateral striatum (DLS) receives extensive projections from primary somatosensory cortex (SI), but very few studies have used somesthetic stimulation to characterize the sensory coding properties of DLS neurons. In this study, we used computer-controlled whisker deflections to characterize the extracellular responses of DLS neurons in rats lightly anesthetized with isoflurane. When multiple whiskers were synchronously deflected by rapid back-and-forth movements, whisker-sensitive neurons in the DLS responded to both directions of movement. The latency and magnitude of these neuronal responses displayed very little variation with changes in the rate (2, 5, or 8 Hz) of whisker stimulation. Simultaneous recordings in SI barrel cortex and the DLS revealed important distinctions in the neuronal responses of these serially connected brain regions. In contrast to DLS neurons, SI neurons were activated by the initial deflection of the whiskers but did not respond when the whiskers moved back to their original position. As the rate of whisker stimulation increased, SI responsiveness declined, and the latencies of the responses increased. In fact, when whiskers were deflected at 5 or 8 Hz, many neurons in the DLS responded before the SI neurons. These results and earlier anatomic findings suggest that a component of the sensory-induced response in the DLS is mediated by inputs from the thalamus. Furthermore, the lack of sensory adaptation in the DLS may represent a critical part of the neural mechanism by which the DLS encodes stimulus-response associations that trigger motor habits and other stimulus-evoked behaviors that are not contingent on rewarded outcomes. PMID:21389309

Repeated whisker stimulation evokes invariant neuronal responses in the dorsolateral striatum of anesthetized rats: a potential correlate of sensorimotor habits.

PubMed

Mowery, Todd M; Harrold, Jon B; Alloway, Kevin D

2011-05-01

The dorsolateral striatum (DLS) receives extensive projections from primary somatosensory cortex (SI), but very few studies have used somesthetic stimulation to characterize the sensory coding properties of DLS neurons. In this study, we used computer-controlled whisker deflections to characterize the extracellular responses of DLS neurons in rats lightly anesthetized with isoflurane. When multiple whiskers were synchronously deflected by rapid back-and-forth movements, whisker-sensitive neurons in the DLS responded to both directions of movement. The latency and magnitude of these neuronal responses displayed very little variation with changes in the rate (2, 5, or 8 Hz) of whisker stimulation. Simultaneous recordings in SI barrel cortex and the DLS revealed important distinctions in the neuronal responses of these serially connected brain regions. In contrast to DLS neurons, SI neurons were activated by the initial deflection of the whiskers but did not respond when the whiskers moved back to their original position. As the rate of whisker stimulation increased, SI responsiveness declined, and the latencies of the responses increased. In fact, when whiskers were deflected at 5 or 8 Hz, many neurons in the DLS responded before the SI neurons. These results and earlier anatomic findings suggest that a component of the sensory-induced response in the DLS is mediated by inputs from the thalamus. Furthermore, the lack of sensory adaptation in the DLS may represent a critical part of the neural mechanism by which the DLS encodes stimulus-response associations that trigger motor habits and other stimulus-evoked behaviors that are not contingent on rewarded outcomes.

Whisker row deprivation affects the flow of sensory information through rat barrel cortex.

PubMed

Jacob, Vincent; Mitani, Akinori; Toyoizumi, Taro; Fox, Kevin

2017-01-01

Whisker trimming causes substantial reorganization of neuronal response properties in barrel cortex. However, little is known about experience-dependent rerouting of sensory processing following sensory deprivation. To address this, we performed in vivo intracellular recordings from layers 2/3 (L2/3), layer 4 (L4), layer 5 regular-spiking (L5RS), and L5 intrinsically bursting (L5IB) neurons and measured their multiwhisker receptive field at the level of spiking activity, membrane potential, and synaptic conductance before and after sensory deprivation. We used Chernoff information to quantify the "sensory information" contained in the firing patterns of cells in response to spared and deprived whisker stimulation. In the control condition, information for flanking-row and same-row whiskers decreased in the order L4, L2/3, L5IB, L5RS. However, after whisker-row deprivation, spared flanking-row whisker information was reordered to L4, L5RS, L5IB, L2/3. Sensory information from the trimmed whiskers was reduced and delayed in L2/3 and L5IB neurons, whereas sensory information from spared whiskers was increased and advanced in L4 and L5RS neurons. Sensory information from spared whiskers was increased in L5IB neurons without a latency change. L5RS cells exhibited the largest changes in sensory information content through an atypical plasticity combining a significant decrease in spontaneous activity and an increase in a short-latency excitatory conductance. Sensory cortical plasticity is usually quantified by changes in evoked firing rate. In this study we quantified plasticity by changes in sensory detection performance using Chernoff information and receiver operating characteristic analysis. We found that whisker deprivation causes a change in information flow within the cortical layers and that layer 5 regular-spiking cells, despite showing only a small potentiation of short-latency input, show the greatest increase in information content for the spared input partly

Rearing in enriched environment increases parvalbumin-positive small neurons in the amygdala and decreases anxiety-like behavior of male rats.

PubMed

Urakawa, Susumu; Takamoto, Kouich; Hori, Etsuro; Sakai, Natsuko; Ono, Taketoshi; Nishijo, Hisao

2013-01-25

Early life experiences including physical exercise, sensory stimulation, and social interaction can modulate development of the inhibitory neuronal network and modify various behaviors. In particular, alteration of parvalbumin-expressing neurons, a gamma-aminobutyric acid (GABA)ergic neuronal subpopulation, has been suggested to be associated with psychiatric disorders. Here we investigated whether rearing in enriched environment could modify the expression of parvalbumin-positive neurons in the basolateral amygdala and anxiety-like behavior. Three-week-old male rats were divided into two groups: those reared in an enriched environment (EE rats) and those reared in standard cages (SE rats). After 5 weeks of rearing, the EE rats showed decreased anxiety-like behavior in an open field than the SE rats. Under another anxiogenic situation, in a beam walking test, the EE rats more quickly traversed an elevated narrow beam. Anxiety-like behavior in the open field was significantly and negatively correlated with walking time in the beam-walking test. Immunohistochemical tests revealed that the number of parvalbumin-positive neurons significantly increased in the basolateral amygdala of the EE rats than that of the SE rats, while the number of calbindin-D28k-positive neurons did not change. These parvalbumin-positive neurons had small, rounded soma and co-expressed the glutamate decarboxylase (GAD67). Furthermore, the number of parvalbumin-positive small cells in the basolateral amygdala tended to positively correlate with emergence in the center arena of the open field and negatively correlated with walking time in the beam walking test. Rearing in the enriched environment augmented the number of parvalbumin-containing specific inhibitory neuron in the basolateral amygdala, but not that of calbindin-containing neuronal phenotype. Furthermore, the number of parvalbumin-positive small neurons in the basolateral amygdala was negatively correlated with walking time in the

Rearing in enriched environment increases parvalbumin-positive small neurons in the amygdala and decreases anxiety-like behavior of male rats

PubMed Central

2013-01-01

Background Early life experiences including physical exercise, sensory stimulation, and social interaction can modulate development of the inhibitory neuronal network and modify various behaviors. In particular, alteration of parvalbumin-expressing neurons, a gamma-aminobutyric acid (GABA)ergic neuronal subpopulation, has been suggested to be associated with psychiatric disorders. Here we investigated whether rearing in enriched environment could modify the expression of parvalbumin-positive neurons in the basolateral amygdala and anxiety-like behavior. Results Three-week-old male rats were divided into two groups: those reared in an enriched environment (EE rats) and those reared in standard cages (SE rats). After 5 weeks of rearing, the EE rats showed decreased anxiety-like behavior in an open field than the SE rats. Under another anxiogenic situation, in a beam walking test, the EE rats more quickly traversed an elevated narrow beam. Anxiety-like behavior in the open field was significantly and negatively correlated with walking time in the beam-walking test. Immunohistochemical tests revealed that the number of parvalbumin-positive neurons significantly increased in the basolateral amygdala of the EE rats than that of the SE rats, while the number of calbindin-D28k-positive neurons did not change. These parvalbumin-positive neurons had small, rounded soma and co-expressed the glutamate decarboxylase (GAD67). Furthermore, the number of parvalbumin-positive small cells in the basolateral amygdala tended to positively correlate with emergence in the center arena of the open field and negatively correlated with walking time in the beam walking test. Conclusion Rearing in the enriched environment augmented the number of parvalbumin-containing specific inhibitory neuron in the basolateral amygdala, but not that of calbindin-containing neuronal phenotype. Furthermore, the number of parvalbumin-positive small neurons in the basolateral amygdala was negatively

Phenotypic alterations of neuropeptide Y and calcitonin gene-related peptide-containing neurons innervating the rat temporomandibular joint during carrageenan-induced arthritis

PubMed Central

Damico, J.P.; Ervolino, E.; Torres, K.R.; Batagello, D.S.; Cruz-Rizzolo, R.J.; Casatti, C.A.; Bauer, J.A.

2012-01-01

The aim of this study was to identify immunoreactive neuropeptide Y (NPY) and calcitonin gene-related peptide (CGRP) neurons in the autonomic and sensory ganglia, specifically neurons that innervate the rat temporomandibular joint (TMJ). A possible variation between the percentages of these neurons in acute and chronic phases of carrageenan-induced arthritis was examined. Retrograde neuronal tracing was combined with indirect immunofluorescence to identify NPY-immunoreactive (NPY-IR) and CGRP- immunoreactive (CGRP-IR) neurons that send nerve fibers to the normal and arthritic temporomandibular joint. In normal joints, NPY-IR neurons constitute 78±3%, 77±6% and 10±4% of double-labeled nucleated neuronal profile originated from the superior cervical, stellate and otic ganglia, respectively. These percentages in the sympathetic ganglia were significantly decreased in acute (58±2% for superior cervical ganglion and 58±8% for stellate ganglion) and chronic (60±2% for superior cervical ganglion and 59±15% for stellate ganglion) phases of arthritis, while in the otic ganglion these percentages were significantly increased to 19±5% and 13±3%, respectively. In the trigeminal ganglion, CGRP-IR neurons innervating the joint significantly increased from 31±3% in normal animals to 54±2% and 49±3% in the acute and chronic phases of arthritis, respectively. It can be concluded that NPY neurons that send nerve fibers to the rat temporomandibular joint are located mainly in the superior cervical, stellate and otic ganglia. Acute and chronic phases of carrageenan-induced arthritis lead to an increase in the percentage of NPY-IR parasympathetic and CGRP-IR sensory neurons and to a decrease in the percentage of NPY-IR sympathetic neurons related to TMJ innervation. PMID:23027347

Nociceptive neuronal Fc-gamma receptor I is involved in IgG immune complex induced pain in the rat.

PubMed

Jiang, Haowu; Shen, Xinhua; Chen, Zhiyong; Liu, Fan; Wang, Tao; Xie, Yikuan; Ma, Chao

2017-05-01

Antigen-specific immune diseases such as rheumatoid arthritis are often accompanied by pain and hyperalgesia. Our previous studies have demonstrated that Fc-gamma-receptor type I (FcγRI) is expressed in a subpopulation of rat dorsal root ganglion (DRG) neurons and can be directly activated by IgG immune complex (IgG-IC). In this study we investigated whether neuronal FcγRI contributes to antigen-specific pain in the naïve and rheumatoid arthritis model rats. In vitro calcium imaging and whole-cell patch clamp recordings in dissociated DRG neurons revealed that only the small-, but not medium- or large-sized DRG neurons responded to IgG-IC. Accordingly, in vivo electrophysiological recordings showed that intradermal injection of IgG-IC into the peripheral receptive field could sensitize only the C- (but not A-) type sensory neurons and evoke action potential discharges. Pain-related behavioral tests showed that intradermal injection of IgG-IC dose-dependently produced mechanical and thermal hyperalgesia in the hindpaw of rats. These behavioral effects could be alleviated by localized administration of non-specific IgG or an FcγRI antibody, but not by mast cell stabilizer or histamine antagonist. In a rat model of antigen-induced arthritis (AIA) produced by methylated bovine serum albumin, FcγRI were found upregulated exclusively in the small-sized DRG neurons. In vitro calcium imaging revealed that significantly more small-sized DRG neurons responded to IgG-IC in the AIA rats, although there was no significant difference between the AIA and control rats in the magnitude of calcium changes in the DRG neurons. Moreover, in vivo electrophysiological recordings showed that C-nociceptive neurons in the AIA rats exhibited a greater incidence of action potential discharges and stronger responses to mechanical stimuli after IgG-IC was injected to the receptive fields. These results suggest that FcγRI expressed in the peripheral nociceptors might be directly activated

Morphological analysis of Drosophila larval peripheral sensory neuron dendrites and axons using genetic mosaics.

PubMed

Karim, M Rezaul; Moore, Adrian W

2011-11-07

Nervous system development requires the correct specification of neuron position and identity, followed by accurate neuron class-specific dendritic development and axonal wiring. Recently the dendritic arborization (DA) sensory neurons of the Drosophila larval peripheral nervous system (PNS) have become powerful genetic models in which to elucidate both general and class-specific mechanisms of neuron differentiation. There are four main DA neuron classes (I-IV)(1). They are named in order of increasing dendrite arbor complexity, and have class-specific differences in the genetic control of their differentiation(2-10). The DA sensory system is a practical model to investigate the molecular mechanisms behind the control of dendritic morphology(11-13) because: 1) it can take advantage of the powerful genetic tools available in the fruit fly, 2) the DA neuron dendrite arbor spreads out in only 2 dimensions beneath an optically clear larval cuticle making it easy to visualize with high resolution in vivo, 3) the class-specific diversity in dendritic morphology facilitates a comparative analysis to find key elements controlling the formation of simple vs. highly branched dendritic trees, and 4) dendritic arbor stereotypical shapes of different DA neurons facilitate morphometric statistical analyses. DA neuron activity modifies the output of a larval locomotion central pattern generator(14-16). The different DA neuron classes have distinct sensory modalities, and their activation elicits different behavioral responses(14,16-20). Furthermore different classes send axonal projections stereotypically into the Drosophila larval central nervous system in the ventral nerve cord (VNC)(21). These projections terminate with topographic representations of both DA neuron sensory modality and the position in the body wall of the dendritic field(7,22,23). Hence examination of DA axonal projections can be used to elucidate mechanisms underlying topographic mapping(7,22,23), as well as

Modulation of Specific Sensory Cortical Areas by Segregated Basal Forebrain Cholinergic Neurons Demonstrated by Neuronal Tracing and Optogenetic Stimulation in Mice

PubMed Central

Chaves-Coira, Irene; Barros-Zulaica, Natali; Rodrigo-Angulo, Margarita; Núñez, Ángel

2016-01-01

Neocortical cholinergic activity plays a fundamental role in sensory processing and cognitive functions. Previous results have suggested a refined anatomical and functional topographical organization of basal forebrain (BF) projections that may control cortical sensory processing in a specific manner. We have used retrograde anatomical procedures to demonstrate the existence of specific neuronal groups in the BF involved in the control of specific sensory cortices. Fluoro-Gold (FlGo) and Fast Blue (FB) fluorescent retrograde tracers were deposited into the primary somatosensory (S1) and primary auditory (A1) cortices in mice. Our results revealed that the BF is a heterogeneous area in which neurons projecting to different cortical areas are segregated into different neuronal groups. Most of the neurons located in the horizontal limb of the diagonal band of Broca (HDB) projected to the S1 cortex, indicating that this area is specialized in the sensory processing of tactile stimuli. However, the nucleus basalis magnocellularis (B) nucleus shows a similar number of cells projecting to the S1 as to the A1 cortices. In addition, we analyzed the cholinergic effects on the S1 and A1 cortical sensory responses by optogenetic stimulation of the BF neurons in urethane-anesthetized transgenic mice. We used transgenic mice expressing the light-activated cation channel, channelrhodopsin-2, tagged with a fluorescent protein (ChR2-YFP) under the control of the choline-acetyl transferase promoter (ChAT). Cortical evoked potentials were induced by whisker deflections or by auditory clicks. According to the anatomical results, optogenetic HDB stimulation induced more extensive facilitation of tactile evoked potentials in S1 than auditory evoked potentials in A1, while optogenetic stimulation of the B nucleus facilitated either tactile or auditory evoked potentials equally. Consequently, our results suggest that cholinergic projections to the cortex are organized into segregated

N-Acetylcysteine Prevents Retrograde Motor Neuron Death after Neonatal Peripheral Nerve Injury.

PubMed

Catapano, Joseph; Zhang, Jennifer; Scholl, David; Chiang, Cameron; Gordon, Tessa; Borschel, Gregory H

2017-05-01

Neuronal death may be an overlooked and unaddressed component of disability following neonatal nerve injuries, such as obstetric brachial plexus injury. N-acetylcysteine and acetyl-L-carnitine improve survival of neurons after adult nerve injury, but it is unknown whether they improve survival after neonatal injury, when neurons are most susceptible to retrograde neuronal death. The authors' objective was to examine whether N-acetylcysteine or acetyl-L-carnitine treatment improves survival of neonatal motor or sensory neurons in a rat model of neonatal nerve injury. Rat pups received either a sciatic nerve crush or transection injury at postnatal day 3 and were then randomized to receive either intraperitoneal vehicle (5% dextrose), N-acetylcysteine (750 mg/kg), or acetyl-L-carnitine (300 mg/kg) once or twice daily. Four weeks after injury, surviving neurons were retrograde-labeled with 4% Fluoro-Gold. The lumbar spinal cord and L4/L5 dorsal root ganglia were then harvested and sectioned to count surviving motor and sensory neurons. Transection and crush injuries resulted in significant motor and sensory neuron loss, with transection injury resulting in significantly less neuron survival. High-dose N-acetylcysteine (750 mg/kg twice daily) significantly increased motor neuron survival after neonatal sciatic nerve crush and transection injury. Neither N-acetylcysteine nor acetyl-L-carnitine treatment improved sensory neuron survival. Proximal neonatal nerve injuries, such as obstetric brachial plexus injury, produce significant retrograde neuronal death after injury. High-dose N-acetylcysteine significantly increases motor neuron survival, which may improve functional outcomes after obstetrical brachial plexus injury.

Isolation, Purification, and Culture of Primary Murine Sensory Neurons.

PubMed

Katzenell, Sarah; Cabrera, Jorge R; North, Brian J; Leib, David A

2017-01-01

Cultured primary neurons have been of extraordinary value for the study of neuronal anatomy, cell biology, and physiology. While use of neuronal cell lines has ease and utility, there are often caveats that arise due to their mitotic nature. This methods article presents detailed methodology for the preparation, purification, and culture of adult murine sensory neurons for the study of herpes simplex virus lytic and latent infections. While virology is the application for our laboratory, these cultures also have broad utility for neurobiologists and cell biologists. While these primary cultures have been highly informative, the methodology is challenging to many investigators. Through publication of this highly detailed protocol, it is our hope that the use of this culture system can spread in the field to allow more rapid progress in furthering our understanding of neurotropic virus infection.

TRPV1 recapitulates native capsaicin receptor in sensory neurons in association with Fas-associated factor 1.

PubMed

Kim, Sangsung; Kang, Changjoong; Shin, Chan Young; Hwang, Sun Wook; Yang, Young Duk; Shim, Won Sik; Park, Min-Young; Kim, Eunhee; Kim, Misook; Kim, Byung-Moon; Cho, Hawon; Shin, Youngki; Oh, Uhtaek

2006-03-01

TRPV1, a cloned capsaicin receptor, is a molecular sensor for detecting adverse stimuli and a key element for inflammatory nociception and represents biophysical properties of native channel. However, there seems to be a marked difference between TRPV1 and native capsaicin receptors in the pharmacological response profiles to vanilloids or acid. One plausible explanation for this overt discrepancy is the presence of regulatory proteins associated with TRPV1. Here, we identify Fas-associated factor 1 (FAF1) as a regulatory factor, which is coexpressed with and binds to TRPV1 in sensory neurons. When expressed heterologously, FAF1 reduces the responses of TRPV1 to capsaicin, acid, and heat, to the pharmacological level of native capsaicin receptor in sensory neurons. Furthermore, silencing FAF1 by RNA interference augments capsaicin-sensitive current in native sensory neurons. We therefore conclude that FAF1 forms an integral component of the vanilloid receptor complex and that it constitutively modulates the sensitivity of TRPV1 to various noxious stimuli in sensory neurons.

Bidirectional communication between sensory neurons and osteoblasts in an in vitro coculture system.

PubMed

Kodama, Daisuke; Hirai, Takao; Kondo, Hisataka; Hamamura, Kazunori; Togari, Akifumi

2017-02-01

Recent studies have revealed that the sensory nervous system is involved in bone metabolism. However, the mechanism of communication between neurons and osteoblasts is yet to be elucidated. In this study, we investigated the signaling pathways between sensory neurons of the dorsal root ganglion (DRG) and the osteoblast-like MC3T3-E1 cells using an in vitro coculture system. Our findings indicate that signal transduction from DRG-derived neurons to MC3T3-E1 cells is suppressed by antagonists of the AMPA receptor and the NK 1 receptor. Conversely, signal transduction from MC3T3-E1 cells to DRG-derived neurons is suppressed by a P2X 7 receptor antagonist. Our results suggest that these cells communicate with each other by exocytosis of glutamate, substance P in the efferent signal, and ATP in the afferent signal. © 2017 Federation of European Biochemical Societies.

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

PubMed Central

2010-01-01

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

PROS-1/Prospero Is a Major Regulator of the Glia-Specific Secretome Controlling Sensory-Neuron Shape and Function in C. elegans.

PubMed

Wallace, Sean W; Singhvi, Aakanksha; Liang, Yupu; Lu, Yun; Shaham, Shai

2016-04-19

Sensory neurons are an animal's gateway to the world, and their receptive endings, the sites of sensory signal transduction, are often associated with glia. Although glia are known to promote sensory-neuron functions, the molecular bases of these interactions are poorly explored. Here, we describe a post-developmental glial role for the PROS-1/Prospero/PROX1 homeodomain protein in sensory-neuron function in C. elegans. Using glia expression profiling, we demonstrate that, unlike previously characterized cell fate roles, PROS-1 functions post-embryonically to control sense-organ glia-specific secretome expression. PROS-1 functions cell autonomously to regulate glial secretion and membrane structure, and non-cell autonomously to control the shape and function of the receptive endings of sensory neurons. Known glial genes controlling sensory-neuron function are PROS-1 targets, and we identify additional PROS-1-dependent genes required for neuron attributes. Drosophila Prospero and vertebrate PROX1 are expressed in post-mitotic sense-organ glia and astrocytes, suggesting conserved roles for this class of transcription factors. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Functional relationship between brainstem putative pain-facilitating neurons and spinal nociceptfive neurons during development of inflammation in rats.

PubMed

Salas, Rafael; Ramirez, Karla; Tortorici, Victor; Vanegas, Horacio; Vazquez, Enrique

2018-05-01

The so-called on- and off-cells of the rostral ventromedial medulla (RVM) send their axons to the spinal dorsal horn. Activation of on-cells precedes and coincides with a facilitation, and activation of off-cells coincides with an inhibition, of withdrawal reflexes elicited by noxious agents. Considerable evidence supports the notion that on- and off-cells modulate nocifensive reflexes during opioid and non-opioid action and also during normal circumstances and during peripheral neuropathy and inflammation. Yet it is unclear whether on- and off-cells act upon sensory spinal circuits that might lead to ascending projections and the experience of pain. Here, in deeply anesthetized rats we recorded single unit discharges from pairs of one on-like or off-like cell in RVM and a nociceptive neuron in the spinal dorsal horn with input from a hind paw. Both ongoing activity and responses to a calibrated noxious stimulus applied to the paw were documented during basal conditions and during development of paw inflammation. Probably due to the strong barbiturate anesthesia, off-like cells were depressed and did not yield interpretable results. However, we showed for the first time that during the increase in neuronal activity that results from paw inflammation the activity of spinal nociceptive neurons reflects the activity of their partner on-like cells in a highly correlated manner. This implies a tight relationship between spinal sensory and RVM modulatory functions that may underlie inflammation-induced hyperreflexia and clinically relevant hyperalgesia. Copyright © 2018 Elsevier B.V. All rights reserved.

Weak signal amplification and detection by higher-order sensory neurons.

PubMed

Jung, Sarah N; Longtin, Andre; Maler, Leonard

2016-04-01

Sensory systems must extract behaviorally relevant information and therefore often exhibit a very high sensitivity. How the nervous system reaches such high sensitivity levels is an outstanding question in neuroscience. Weakly electric fish (Apteronotus leptorhynchus/albifrons) are an excellent model system to address this question because detailed background knowledge is available regarding their behavioral performance and its underlying neuronal substrate. Apteronotus use their electrosense to detect prey objects. Therefore, they must be able to detect electrical signals as low as 1 μV while using a sensory integration time of <200 ms. How these very weak signals are extracted and amplified by the nervous system is not yet understood. We studied the responses of cells in the early sensory processing areas, namely, the electroreceptor afferents (EAs) and pyramidal cells (PCs) of the electrosensory lobe (ELL), the first-order electrosensory processing area. In agreement with previous work we found that EAs cannot encode very weak signals with a spike count code. However, PCs can encode prey mimic signals by their firing rate, revealing a huge signal amplification between EAs and PCs and also suggesting differences in their stimulus encoding properties. Using a simple leaky integrate-and-fire (LIF) model we predict that the target neurons of PCs in the midbrain torus semicircularis (TS) are able to detect very weak signals. In particular, TS neurons could do so by assuming biologically plausible convergence rates as well as very simple decoding strategies such as temporal integration, threshold crossing, and combining the inputs of PCs. Copyright © 2016 the American Physiological Society.

Weak signal amplification and detection by higher-order sensory neurons

PubMed Central

Longtin, Andre; Maler, Leonard

2016-01-01

Sensory systems must extract behaviorally relevant information and therefore often exhibit a very high sensitivity. How the nervous system reaches such high sensitivity levels is an outstanding question in neuroscience. Weakly electric fish (Apteronotus leptorhynchus/albifrons) are an excellent model system to address this question because detailed background knowledge is available regarding their behavioral performance and its underlying neuronal substrate. Apteronotus use their electrosense to detect prey objects. Therefore, they must be able to detect electrical signals as low as 1 μV while using a sensory integration time of <200 ms. How these very weak signals are extracted and amplified by the nervous system is not yet understood. We studied the responses of cells in the early sensory processing areas, namely, the electroreceptor afferents (EAs) and pyramidal cells (PCs) of the electrosensory lobe (ELL), the first-order electrosensory processing area. In agreement with previous work we found that EAs cannot encode very weak signals with a spike count code. However, PCs can encode prey mimic signals by their firing rate, revealing a huge signal amplification between EAs and PCs and also suggesting differences in their stimulus encoding properties. Using a simple leaky integrate-and-fire (LIF) model we predict that the target neurons of PCs in the midbrain torus semicircularis (TS) are able to detect very weak signals. In particular, TS neurons could do so by assuming biologically plausible convergence rates as well as very simple decoding strategies such as temporal integration, threshold crossing, and combining the inputs of PCs. PMID:26843601

Spiking irregularity and frequency modulate the behavioral report of single-neuron stimulation.

PubMed

Doron, Guy; von Heimendahl, Moritz; Schlattmann, Peter; Houweling, Arthur R; Brecht, Michael

2014-02-05

The action potential activity of single cortical neurons can evoke measurable sensory effects, but it is not known how spiking parameters and neuronal subtypes affect the evoked sensations. Here, we examined the effects of spike train irregularity, spike frequency, and spike number on the detectability of single-neuron stimulation in rat somatosensory cortex. For regular-spiking, putative excitatory neurons, detectability increased with spike train irregularity and decreasing spike frequencies but was not affected by spike number. Stimulation of single, fast-spiking, putative inhibitory neurons led to a larger sensory effect compared to regular-spiking neurons, and the effect size depended only on spike irregularity. An ideal-observer analysis suggests that, under our experimental conditions, rats were using integration windows of a few hundred milliseconds or more. Our data imply that the behaving animal is sensitive to single neurons' spikes and even to their temporal patterning. Copyright © 2014 Elsevier Inc. All rights reserved.

Functional crosstalk in culture between macrophages and trigeminal sensory neurons of a mouse genetic model of migraine.

PubMed

Franceschini, Alessia; Nair, Asha; Bele, Tanja; van den Maagdenberg, Arn Mjm; Nistri, Andrea; Fabbretti, Elsa

2012-11-21

Enhanced activity of trigeminal ganglion neurons is thought to underlie neuronal sensitization facilitating the onset of chronic pain attacks, including migraine. Recurrent headache attacks might establish a chronic neuroinflammatory ganglion profile contributing to the hypersensitive phenotype. Since it is difficult to study this process in vivo, we investigated functional crosstalk between macrophages and sensory neurons in primary cultures from trigeminal sensory ganglia of wild-type (WT) or knock-in (KI) mice expressing the Cacna1a gene mutation (R192Q) found in familial hemiplegic migraine-type 1. After studying the number and morphology of resident macrophages in culture, the consequences of adding host macrophages on macrophage phagocytosis and membrane currents mediated by pain-transducing P2X3 receptors on sensory neurons were examined. KI ganglion cultures constitutively contained a larger number of active macrophages, although no difference in P2X3 receptor expression was found. Co-culturing WT or KI ganglia with host macrophages (active as much as resident cells) strongly stimulated single cell phagocytosis. The same protocol had no effect on P2X3 receptor expression in WT or KI co-cultures, but it largely enhanced WT neuron currents that grew to the high amplitude constitutively seen for KI neurons. No further potentiation of KI neuronal currents was observed. Trigeminal ganglion cultures from a genetic mouse model of migraine showed basal macrophage activation together with enhanced neuronal currents mediated by P2X3 receptors. This phenotype could be replicated in WT cultures by adding host macrophages, indicating an important functional crosstalk between macrophages and sensory neurons.

Neuropathic pain in a Fabry disease rat model

PubMed Central

Miller, James J.; Aoki, Kazuhiro; Murphy, Carly A.; O’Hara, Crystal L.; Tiemeyer, Michael; Stucky, Cheryl L.; Dahms, Nancy M.

2018-01-01

Fabry disease, the most common lysosomal storage disease, affects multiple organs and results in a shortened life span. This disease is caused by a deficiency of the lysosomal enzyme α-galactosidase A, which leads to glycosphingolipid accumulation in many cell types. Neuropathic pain is an early and severely debilitating symptom in patients with Fabry disease, but the cellular and molecular mechanisms that cause the pain are unknown. We generated a rat model of Fabry disease, the first nonmouse model to our knowledge. Fabry rats had substantial serum and tissue accumulation of α-galactosyl glycosphingolipids and had pronounced mechanical pain behavior. Additionally, Fabry rat dorsal root ganglia displayed global N-glycan alterations, sensory neurons were laden with inclusions, and sensory neuron somata exhibited prominent sensitization to mechanical force. We found that the cation channel transient receptor potential ankyrin 1 (TRPA1) is sensitized in Fabry rat sensory neurons and that TRPA1 antagonism reversed the behavioral mechanical sensitization. This study points toward TRPA1 as a potentially novel target to treat the pain experienced by patients with Fabry disease. PMID:29563343

Latent Herpes Simplex Virus Infection of Sensory Neurons Alters Neuronal Gene Expression

PubMed Central

Kramer, Martha F.; Cook, W. James; Roth, Frederick P.; Zhu, Jia; Holman, Holly; Knipe, David M.; Coen, Donald M.

2003-01-01

The persistence of herpes simplex virus (HSV) and the diseases that it causes in the human population can be attributed to the maintenance of a latent infection within neurons in sensory ganglia. Little is known about the effects of latent infection on the host neuron. We have addressed the question of whether latent HSV infection affects neuronal gene expression by using microarray transcript profiling of host gene expression in ganglia from latently infected versus mock-infected mouse trigeminal ganglia. 33P-labeled cDNA probes from pooled ganglia harvested at 30 days postinfection or post-mock infection were hybridized to nylon arrays printed with 2,556 mouse genes. Signal intensities were acquired by phosphorimager. Mean intensities (n = 4 replicates in each of three independent experiments) of signals from mock-infected versus latently infected ganglia were compared by using a variant of Student's t test. We identified significant changes in the expression of mouse neuronal genes, including several with roles in gene expression, such as the Clk2 gene, and neurotransmission, such as genes encoding potassium voltage-gated channels and a muscarinic acetylcholine receptor. We confirmed the neuronal localization of some of these transcripts by using in situ hybridization. To validate the microarray results, we performed real-time reverse transcriptase PCR analyses for a selection of the genes. These studies demonstrate that latent HSV infection can alter neuronal gene expression and might provide a new mechanism for how persistent viral infection can cause chronic disease. PMID:12915567

Developmental and hormonal regulation of thermosensitive neuron potential activity in rat brain.

PubMed

Belugin, S; Akino, K; Takamura, N; Mine, M; Romanovsky, D; Fedoseev, V; Kubarko, A; Kosaka, M; Yamashita, S

1999-08-01

To understand the involvement of thyroid hormone on the postnatal development of hypothalamic thermosensitive neurons, we focused on the analysis of thermosensitive neuronal activity in the preoptic and anterior hypothalamic (PO/AH) regions of developing rats with and without hypothyroidism. In euthyroid rats, the distribution of thermosensitive neurons in PO/AH showed that in 3-week-old rats (46 neurons tested), 19.5% were warm-sensitive and 80.5% were nonsensitive. In 5- to 12-week-old euthyroid rats (122 neurons), 33.6% were warm-sensitive and 66.4% were nonsensitive. In 5- to 12-week-old hypothyroid rats (108 neurons), however, 18.5% were warm-sensitive and 81.5% were nonsensitive. Temperature thresholds of warm-sensitive neurons were lower in 12-week-old euthyroid rats (36.4+/-0.2 degrees C, n = 15, p<0.01,) than in 3-week-old and in 5-week-old euthyroid rats (38.5+/-0.5 degrees C, n = 9 and 38.0+/-0.3 degrees C, n = 15, respectively). The temperature thresholds of warm-sensitive neurons in 12-week-old hypothyroid rats (39.5+/-0.3 degrees C, n = 8) were similar to that of warm-sensitive neurons of 3-week-old raats (euthyroid and hypothyroid). In contrast, there was no difference in the thresholds of warm-sensitive neurons between hypothyroid and euthyroid rats at the age of 3-5 weeks. In conclusion, monitoring the thermosensitive neuronal tissue activity demonstrated the evidence that thyroid hormone regulates the maturation of warm-sensitive hypothalamic neurons in developing rat brain by electrophysiological analysis.

Making sense of the sensory regulation of hunger neurons.

PubMed

Chen, Yiming; Knight, Zachary A

2016-04-01

AgRP and POMC neurons are two key cell types that regulate feeding in response to hormones and nutrients. Recently, it was discovered that these neurons are also rapidly modulated by the mere sight and smell of food. This rapid sensory regulation "resets" the activity of AgRP and POMC neurons before a single bite of food has been consumed. This surprising and counterintuitive discovery challenges longstanding assumptions about the function and regulation of these cells. Here we review these recent findings and discuss their implications for our understanding of feeding behavior. We propose several alternative hypotheses for how these new observations might be integrated into a revised model of the feeding circuit, and also highlight some of the key questions that remain to be answered. © 2016 WILEY Periodicals, Inc.

Making sense of the sensory regulation of hunger neurons

PubMed Central

Chen, Yiming; Knight, Zachary A.

2016-01-01

AgRP and POMC neurons are two key cell types that regulate feeding in response to hormones and nutrients. Recently, it was discovered that these neurons are also rapidly modulated by the mere sight and smell of food. This rapid sensory regulation “resets” the activity of AgRP and POMC neurons before a single bite of food has been consumed. This surprising and counterintuitive discovery challenges longstanding assumptions about the function and regulation of these cells. Here we review these recent findings and discuss their implications for our understanding of feeding behavior. We propose several alternative hypotheses for how these new observations might be integrated into a revised model of the feeding circuit, and also highlight some of the key questions that remain to be answered. PMID:26898524

Characterizing human stem cell-derived sensory neurons at the single-cell level reveals their ion channel expression and utility in pain research.

PubMed

Young, Gareth T; Gutteridge, Alex; Fox, Heather DE; Wilbrey, Anna L; Cao, Lishuang; Cho, Lily T; Brown, Adam R; Benn, Caroline L; Kammonen, Laura R; Friedman, Julia H; Bictash, Magda; Whiting, Paul; Bilsland, James G; Stevens, Edward B

2014-08-01

The generation of human sensory neurons by directed differentiation of pluripotent stem cells opens new opportunities for investigating the biology of pain. The inability to generate this cell type has meant that up until now their study has been reliant on the use of rodent models. Here, we use a combination of population and single-cell techniques to perform a detailed molecular, electrophysiological, and pharmacological phenotyping of sensory neurons derived from human embryonic stem cells. We describe the evolution of cell populations over 6 weeks of directed differentiation; a process that results in the generation of a largely homogeneous population of neurons that are both molecularly and functionally comparable to human sensory neurons derived from mature dorsal root ganglia. This work opens the prospect of using pluripotent stem-cell-derived sensory neurons to study human neuronal physiology and as in vitro models for drug discovery in pain and sensory disorders.

Experience-Related Changes in Place Cell Responses to New Sensory Configuration That Does Not Occur in the Natural Environment in the Rat Hippocampus

PubMed Central

Zou, Dan; Nishimaru, Hiroshi; Matsumoto, Jumpei; Takamura, Yusaku; Ono, Taketoshi; Nishijo, Hisao

2017-01-01

The hippocampal formation (HF) is implicated in a comparator that detects sensory conflict (mismatch) among convergent inputs. This suggests that new place cells encoding the new configuration with sensory mismatch develop after the HF learns to accept the new configuration as a match. To investigate this issue, HF CA1 place cell activity in rats was analyzed after the adaptation of the rats to the same sensory mismatch condition. The rats were placed on a treadmill on a stage that was translocated in a figure 8-shaped pathway. We recorded HF neuronal activities under three conditions; (1) an initial control session, in which both the stage and the treadmill moved forward, (2) a backward (mismatch) session, in which the stage was translocated backward while the rats locomoted forward on the treadmill, and (3) the second control session. Of the 161 HF neurons, 56 place-differential activities were recorded from the HF CA1 subfield. These place-differential activities were categorized into four types; forward-related, backward-related, both-translocation-related, and session-dependent. Forward-related activities showed predominant spatial firings in the forward sessions, while backward-related activities showed predominant spatial firings in the backward sessions. Both-translocation-related activities showed consistent spatial firings in both the forward and backward conditions. On the other hand, session-dependent activities showed different spatial firings across the sessions. Detailed analyses of the place fields indicated that mean place field sizes were larger in the forward-related, backward-related, and both-translocation-related activities than in the session-dependent activities. Furthermore, firing rate distributions in the place fields were negatively skewed and asymmetric, which is similar to place field changes that occur after repeated experience. These results demonstrate that the HF encodes a naturally impossible new configuration of sensory inputs

Connectivity of Pacemaker Neurons in the Neonatal Rat Superficial Dorsal Horn

PubMed Central

Ford, Neil C.; Arbabi, Shahriar; Baccei, Mark L.

2014-01-01

Pacemaker neurons with an intrinsic ability to generate rhythmic burst-firing have been characterized in lamina I of the neonatal spinal cord, where they are innervated by high-threshold sensory afferents. However, little is known about the output of these pacemakers, as the neuronal populations which are targeted by pacemaker axons have yet to be identified. The present study combines patch clamp recordings in the intact neonatal rat spinal cord with tract-tracing to demonstrate that lamina I pacemaker neurons contact multiple spinal motor pathways during early life. Retrograde labeling of premotor interneurons with the trans-synaptic virus PRV-152 revealed the presence of burst-firing in PRV-infected lamina I neurons, thereby confirming that pacemakers are synaptically coupled to motor networks in the spinal ventral horn. Notably, two classes of pacemakers could be distinguished in lamina I based on cell size and the pattern of their axonal projections. While small pacemaker neurons possessed ramified axons which contacted ipsilateral motor circuits, large pacemaker neurons had unbranched axons which crossed the midline and ascended rostrally in the contralateral white matter. Recordings from identified spino-parabrachial and spino-PAG neurons indicated the presence of pacemaker activity within neonatal lamina I projection neurons. Overall, these results show that lamina I pacemakers are positioned to regulate both the level of activity in developing motor circuits as well as the ascending flow of nociceptive information to the brain, thus highlighting a potential role for pacemaker activity in the maturation of pain and sensorimotor networks in the CNS. PMID:25380417

Brn3a/Pou4f1 Regulates Dorsal Root Ganglion Sensory Neuron Specification and Axonal Projection into the Spinal Cord

PubMed Central

Zou, Min; Li, Shengguo; Klein, William H.; Xiang, Mengqing

2012-01-01

The sensory neurons of the dorsal root ganglia (DRG) must project accurately to their central targets to convey proprioceptive, nociceptive and mechanoreceptive information to the spinal cord. How these different sensory modalities and central connectivities are specified and coordinated still remains unclear. Given the expression of the POU homeodomain transcription factors Brn3a/Pou4f1 and Brn3b/Pou4f2 in DRG and spinal cord sensory neurons, we determined the subtype specification of DRG and spinal cord sensory neurons as well as DRG central projections in Brn3a and Brn3b single and double mutant mice. Inactivation of either or both genes causes no gross abnormalities in early spinal cord neurogenesis; however, in Brn3a single and Brn3a;Brn3b double mutant mice, sensory afferent axons from the DRG fail to form normal trajectories in the spinal cord. The TrkA+ afferents remain outside the dorsal horn and fail to extend into the spinal cord, while the projections of TrkC+ proprioceptive afferents into the ventral horn are also impaired. Moreover, Brn3a mutant DRGs are defective in sensory neuron specification, as marked by the excessive generation of TrkB+ and TrkC+ neurons as well as TrkA+/TrkB+ and TrkA+/TrkC+ double positive cells at early embryonic stages. At later stages in the mutant, TrkB+, TrkC+ and parvalbumin+ neurons diminish while there is a significant increase of CGRP+ and c-ret+ neurons. In addition, Brn3a mutant DRGs display a dramatic down-regulation of Runx1 expression, suggesting that the regulation of DRG sensory neuron specification by Brn3a is mediated in part by Runx1. Our results together demonstrate a critical role for Brn3a in generating DRG sensory neuron diversity and regulating sensory afferent projections to the central targets. PMID:22326227

Histochemistry of nerve fibres double labelled with anti-TRPV2 antibodies and sensory nerve marker AM1-43 in the dental pulp of rat molars.

PubMed

Nishikawa, Sumio

2008-09-01

AM1-43 can label sensory nerve fibres and sensory neurons. Permeation of non-selective cation channels of the nerve cell membrane is suggested to be the mechanism responsible for labelling. To identify these channels, two candidates, TRPV1 and TRPV2 were examined by immunocytochemistry in the dental pulp and trigeminal ganglion of rats injected with AM1-43. A part of AM1-43-labelled nerve fibres was also positive for anti-TRPV2 antibody but negative for anti-TRPV1 antibody in the dental pulp. In the trigeminal ganglion, a part of the neuron showed both bright AM1-43 labelling and anti-TRPV2 immunolabelling, but neurons double labelled with AM1-43 and TRPV1 were rare. These results suggest that TRPV2 channels, but not TRPV1 channels, contribute to the fluorescent labelling of AM1-43 in the dental pulp.

Functional crosstalk in culture between macrophages and trigeminal sensory neurons of a mouse genetic model of migraine

PubMed Central

2012-01-01

Background Enhanced activity of trigeminal ganglion neurons is thought to underlie neuronal sensitization facilitating the onset of chronic pain attacks, including migraine. Recurrent headache attacks might establish a chronic neuroinflammatory ganglion profile contributing to the hypersensitive phenotype. Since it is difficult to study this process in vivo, we investigated functional crosstalk between macrophages and sensory neurons in primary cultures from trigeminal sensory ganglia of wild-type (WT) or knock-in (KI) mice expressing the Cacna1a gene mutation (R192Q) found in familial hemiplegic migraine-type 1. After studying the number and morphology of resident macrophages in culture, the consequences of adding host macrophages on macrophage phagocytosis and membrane currents mediated by pain-transducing P2X3 receptors on sensory neurons were examined. Results KI ganglion cultures constitutively contained a larger number of active macrophages, although no difference in P2X3 receptor expression was found. Co-culturing WT or KI ganglia with host macrophages (active as much as resident cells) strongly stimulated single cell phagocytosis. The same protocol had no effect on P2X3 receptor expression in WT or KI co-cultures, but it largely enhanced WT neuron currents that grew to the high amplitude constitutively seen for KI neurons. No further potentiation of KI neuronal currents was observed. Conclusions Trigeminal ganglion cultures from a genetic mouse model of migraine showed basal macrophage activation together with enhanced neuronal currents mediated by P2X3 receptors. This phenotype could be replicated in WT cultures by adding host macrophages, indicating an important functional crosstalk between macrophages and sensory neurons. PMID:23171280

Local subcutaneous injection of chlorogenic acid inhibits the nociceptive trigeminal spinal nucleus caudalis neurons in rats.

PubMed

Kakita, Kaede; Tsubouchi, Hirona; Adachi, Mayu; Takehana, Shiori; Shimazu, Yoshihito; Takeda, Mamoru

2017-11-29

Acute administration of chlorogenic acid (CGA) in vitro was recently shown to modulate potassium channel conductance and acid-sensing ion channels (ASICs) in the primary sensory neurons; however, in vivo peripheral effects of CGA on the nociceptive mechanical stimulation of trigeminal neuronal activity remains to be determined. The present study investigated whether local administration of CGA in vivo attenuates mechanical stimulation-induced excitability of trigeminal spinal nucleus caudalis neuronal (SpVc) activity in rats. Extracellular single-unit recordings were made of SpVc wide-dynamic range (WDR) neuronal activity elicited by non-noxious and noxious orofacial mechanical stimulation in pentobarbital anesthetized rats. The mean number of SpVc WDR neuronal firings responding to both non-noxious and noxious mechanical stimuli were significantly and dose-dependently inhibited by local subcutaneous administration of CGA (0.1-10mM), with the maximal inhibition of discharge frequency revealed within 10min and reversed after approximately 30min. The mean frequency of SpVc neuronal discharge inhibition by CGA was comparable to that by a local anesthetic, the sodium channel blocker, 1% lidocaine. These results suggest that local CGA injection into the peripheral receptive field suppresses the excitability of SpVc neurons, possibly via the activation of voltage-gated potassium channels and modulation of ASICs in the nociceptive nerve terminal of trigeminal ganglion neurons. Therefore, local injection of CGA could contribute to local anesthetic agents for the treatment of trigeminal nociceptive pain. Copyright © 2017 Elsevier Ireland Ltd and Japan Neuroscience Society. All rights reserved.

Synaptic inputs from stroke-injured brain to grafted human stem cell-derived neurons activated by sensory stimuli.

PubMed

Tornero, Daniel; Tsupykov, Oleg; Granmo, Marcus; Rodriguez, Cristina; Grønning-Hansen, Marita; Thelin, Jonas; Smozhanik, Ekaterina; Laterza, Cecilia; Wattananit, Somsak; Ge, Ruimin; Tatarishvili, Jemal; Grealish, Shane; Brüstle, Oliver; Skibo, Galina; Parmar, Malin; Schouenborg, Jens; Lindvall, Olle; Kokaia, Zaal

2017-03-01

Transplanted neurons derived from stem cells have been proposed to improve function in animal models of human disease by various mechanisms such as neuronal replacement. However, whether the grafted neurons receive functional synaptic inputs from the recipient's brain and integrate into host neural circuitry is unknown. Here we studied the synaptic inputs from the host brain to grafted cortical neurons derived from human induced pluripotent stem cells after transplantation into stroke-injured rat cerebral cortex. Using the rabies virus-based trans-synaptic tracing method and immunoelectron microscopy, we demonstrate that the grafted neurons receive direct synaptic inputs from neurons in different host brain areas located in a pattern similar to that of neurons projecting to the corresponding endogenous cortical neurons in the intact brain. Electrophysiological in vivo recordings from the cortical implants show that physiological sensory stimuli, i.e. cutaneous stimulation of nose and paw, can activate or inhibit spontaneous activity in grafted neurons, indicating that at least some of the afferent inputs are functional. In agreement, we find using patch-clamp recordings that a portion of grafted neurons respond to photostimulation of virally transfected, channelrhodopsin-2-expressing thalamo-cortical axons in acute brain slices. The present study demonstrates, for the first time, that the host brain regulates the activity of grafted neurons, providing strong evidence that transplanted human induced pluripotent stem cell-derived cortical neurons can become incorporated into injured cortical circuitry. Our findings support the idea that these neurons could contribute to functional recovery in stroke and other conditions causing neuronal loss in cerebral cortex. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Reconstruction of Sensory Stimuli Encoded with Integrate-and-Fire Neurons with Random Thresholds

PubMed Central

Lazar, Aurel A.; Pnevmatikakis, Eftychios A.

2013-01-01

We present a general approach to the reconstruction of sensory stimuli encoded with leaky integrate-and-fire neurons with random thresholds. The stimuli are modeled as elements of a Reproducing Kernel Hilbert Space. The reconstruction is based on finding a stimulus that minimizes a regularized quadratic optimality criterion. We discuss in detail the reconstruction of sensory stimuli modeled as absolutely continuous functions as well as stimuli with absolutely continuous first-order derivatives. Reconstruction results are presented for stimuli encoded with single as well as a population of neurons. Examples are given that demonstrate the performance of the reconstruction algorithms as a function of threshold variability. PMID:24077610

Characterizing Human Stem Cell–derived Sensory Neurons at the Single-cell Level Reveals Their Ion Channel Expression and Utility in Pain Research

PubMed Central

Young, Gareth T; Gutteridge, Alex; Fox, Heather DE; Wilbrey, Anna L; Cao, Lishuang; Cho, Lily T; Brown, Adam R; Benn, Caroline L; Kammonen, Laura R; Friedman, Julia H; Bictash, Magda; Whiting, Paul; Bilsland, James G; Stevens, Edward B

2014-01-01

The generation of human sensory neurons by directed differentiation of pluripotent stem cells opens new opportunities for investigating the biology of pain. The inability to generate this cell type has meant that up until now their study has been reliant on the use of rodent models. Here, we use a combination of population and single-cell techniques to perform a detailed molecular, electrophysiological, and pharmacological phenotyping of sensory neurons derived from human embryonic stem cells. We describe the evolution of cell populations over 6 weeks of directed differentiation; a process that results in the generation of a largely homogeneous population of neurons that are both molecularly and functionally comparable to human sensory neurons derived from mature dorsal root ganglia. This work opens the prospect of using pluripotent stem-cell–derived sensory neurons to study human neuronal physiology and as in vitro models for drug discovery in pain and sensory disorders. PMID:24832007

Transient receptor potential ion channels in primary sensory neurons as targets for novel analgesics

PubMed Central

Sousa-Valente, J; Andreou, A P; Urban, L; Nagy, I

2014-01-01

The last decade has witnessed an explosion in novel findings relating to the molecules involved in mediating the sensation of pain in humans. Transient receptor potential (TRP) ion channels emerged as the greatest group of molecules involved in the transduction of various physical stimuli into neuronal signals in primary sensory neurons, as well as, in the development of pain. Here, we review the role of TRP ion channels in primary sensory neurons in the development of pain associated with peripheral pathologies and possible strategies to translate preclinical data into the development of effective new analgesics. Based on available evidence, we argue that nociception-related TRP channels on primary sensory neurons provide highly valuable targets for the development of novel analgesics and that, in order to reduce possible undesirable side effects, novel analgesics should prevent the translocation from the cytoplasm to the cell membrane and the sensitization of the channels rather than blocking the channel pore or binding sites for exogenous or endogenous activators. LINKED ARTICLES This article is part of a themed section on the pharmacology of TRP channels. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-10 PMID:24283624

The Stimulus-Dependent Gradient of Cyp26B1+ Olfactory Sensory Neurons Is Necessary for the Functional Integrity of the Olfactory Sensory Map.

PubMed

Login, Hande; Håglin, Sofia; Berghard, Anna; Bohm, Staffan

2015-10-07

Stimulus-dependent expression of the retinoic acid-inactivating enzyme Cyp26B1 in olfactory sensory neurons (OSNs) forms a dorsomedial (DM)-ventrolateral (VL) gradient in the mouse olfactory epithelium. The gradient correlates spatially with different rates of OSN turnover, as well as the functional organization of the olfactory sensory map, into overlapping zones of OSNs that express different odorant receptors (ORs). Here, we analyze transgenic mice that, instead of a stimulus-dependent Cyp26B1 gradient, have constitutive Cyp26B1 levels in all OSNs. Starting postnatally, OSN differentiation is decreased and progenitor proliferation is increased. Initially, these effects are selective to the VL-most zone and correlate with reduced ATF5 expression and accumulation of OSNs that do not express ORs. Transcription factor ATF5 is known to stabilize OR gene choice via onset of the stimulus-transducing enzyme adenylyl cyclase type 3. During further postnatal development of Cyp26B1 mice, an anomalous DM(high)-VL(low) expression gradient of adenylyl cyclase type 3 appears, which coincides with altered OR frequencies and OR zones. All OR zones expand ventrolaterally except for the VL-most zone, which contracts. The expansion results in an increased zonal overlap that is also evident in the innervation pattern of OSN axon terminals in olfactory bulbs. These findings together identify a mechanism by which postnatal sensory-stimulated vitamin A metabolism modifies the generation of spatially specified neurons and their precise topographic connectivity. The distributed patterns of vitamin A-metabolizing enzymes in the nervous system suggest the possibility that the mechanism may also regulate neuroplasticity in circuits other than the olfactory sensory map. The mouse olfactory sensory map is functionally wired according to precise axonal projections of spatially organized classes of olfactory sensory neurons in the nose. The genetically controlled mechanisms that regulate the

Populations of striatal medium spiny neurons encode vibrotactile frequency in rats: modulation by slow wave oscillations

PubMed Central

Hawking, Thomas G.

2013-01-01

Dorsolateral striatum (DLS) is implicated in tactile perception and receives strong projections from somatosensory cortex. However, the sensory representations encoded by striatal projection neurons are not well understood. Here we characterized the contribution of DLS to the encoding of vibrotactile information in rats by assessing striatal responses to precise frequency stimuli delivered to a single vibrissa. We applied stimuli in a frequency range (45–90 Hz) that evokes discriminable percepts and carries most of the power of vibrissa vibration elicited by a range of complex fine textures. Both medium spiny neurons and evoked potentials showed tactile responses that were modulated by slow wave oscillations. Furthermore, medium spiny neuron population responses represented stimulus frequency on par with previously reported behavioral benchmarks. Our results suggest that striatum encodes frequency information of vibrotactile stimuli which is dynamically modulated by ongoing brain state. PMID:23114217

Transient receptor potential channels in sensory neurons are targets of the antimycotic agent clotrimazole.

PubMed

Meseguer, Victor; Karashima, Yuji; Talavera, Karel; D'Hoedt, Dieter; Donovan-Rodríguez, Tansy; Viana, Felix; Nilius, Bernd; Voets, Thomas

2008-01-16

Clotrimazole (CLT) is a widely used drug for the topical treatment of yeast infections of skin, vagina, and mouth. Common side effects of topical CLT application include irritation and burning pain of the skin and mucous membranes. Here, we provide evidence that transient receptor potential (TRP) channels in primary sensory neurons underlie these unwanted effects of CLT. We found that clinically relevant CLT concentrations activate heterologously expressed TRPV1 and TRPA1, two TRP channels that act as receptors of irritant chemical and/or thermal stimuli in nociceptive neurons. In line herewith, CLT stimulated a subset of capsaicin-sensitive and mustard oil-sensitive trigeminal neurons, and evoked nocifensive behavior and thermal hypersensitivity with intraplantar injection in mice. Notably, CLT-induced pain behavior was suppressed by the TRPV1-antagonist BCTC [(N-(-4-tertiarybutylphenyl)-4-(3-cholorpyridin-2-yl)tetrahydropyrazine-1(2H)-carboxamide)] and absent in TRPV1-deficient mice. In addition, CLT inhibited the cold and menthol receptor TRPM8, and blocked menthol-induced responses in capsaicin- and mustard oil-insensitive trigeminal neurons. The concentration for 50% inhibition (IC50) of inward TRPM8 current was approximately 200 nM, making CLT the most potent known TRPM8 antagonist and a useful tool to discriminate between TRPM8- and TRPA1-mediated responses. Together, our results identify TRP channels in sensory neurons as molecular targets of CLT, and offer means to develop novel CLT preparations with fewer unwanted sensory side effects.

Characterization of Glutamatergic Neurons in the Rat Atrial Intrinsic Cardiac Ganglia that Project to the Cardiac Ventricular Wall

PubMed Central

Wang, Ting; Miller, Kenneth E.

2016-01-01

The intrinsic cardiac nervous system modulates cardiac function by acting as an integration site for regulating autonomic efferent cardiac output. This intrinsic system is proposed to be composed of a short cardio-cardiac feedback control loop within the cardiac innervation hierarchy. For example, electrophysiological studies have postulated the presence of sensory neurons in intrinsic cardiac ganglia for regional cardiac control. There is still a knowledge gap, however, about the anatomical location and neurochemical phenotype of sensory neurons inside intrinsic cardiac ganglia. In the present study, rat intrinsic cardiac ganglia neurons were characterized neurochemically with immunohistochemistry using glutamatergic markers: vesicular glutamate transporters 1 and 2 (VGLUT1; VGLUT2), and glutaminase (GLS), the enzyme essential for glutamate production. Glutamatergic neurons (VGLUT1/VGLUT2/GLS) in the ICG that have axons to the ventricles were identified by retrograde tracing of wheat germ agglutinin-horseradish peroxidase (WGA-HRP) injected in the ventricular wall. Co-labeling of VGLUT1, VGLUT2, and GLS with the vesicular acetylcholine transporter (VAChT) was used to evaluate the relationship between post-ganglionic autonomic neurons and glutamatergic neurons. Sequential labeling of VGLUT1 and VGLUT2 in adjacent tissue sections was used to evaluate the co-localization of VGLUT1 and VGLUT2 in ICG neurons. Our studies yielded the following results: (1) intrinsic cardiac ganglia contain glutamatergic neurons with GLS for glutamate production and VGLUT1 and 2 for transport of glutamate into synaptic vesicles; (2) atrial intrinsic cardiac ganglia contain neurons that project to ventricle walls and these neurons are glutamatergic; (3) many glutamatergic ICG neurons also were cholinergic, expressing VAChT. (4) VGLUT1 and VGLUT2 co-localization occurred in ICG neurons with variation of their protein expression level. Investigation of both glutamatergic and cholinergic ICG

Characterization of glutamatergic neurons in the rat atrial intrinsic cardiac ganglia that project to the cardiac ventricular wall.

PubMed

Wang, Ting; Miller, Kenneth E

2016-08-04

The intrinsic cardiac nervous system modulates cardiac function by acting as an integration site for regulating autonomic efferent cardiac output. This intrinsic system is proposed to be composed of a short cardio-cardiac feedback control loop within the cardiac innervation hierarchy. For example, electrophysiological studies have postulated the presence of sensory neurons in intrinsic cardiac ganglia (ICG) for regional cardiac control. There is still a knowledge gap, however, about the anatomical location and neurochemical phenotype of sensory neurons inside ICG. In the present study, rat ICG neurons were characterized neurochemically with immunohistochemistry using glutamatergic markers: vesicular glutamate transporters 1 and 2 (VGLUT1; VGLUT2), and glutaminase (GLS), the enzyme essential for glutamate production. Glutamatergic neurons (VGLUT1/VGLUT2/GLS) in the ICG that have axons to the ventricles were identified by retrograde tracing of wheat germ agglutinin-horseradish peroxidase (WGA-HRP) injected in the ventricular wall. Co-labeling of VGLUT1, VGLUT2, and GLS with the vesicular acetylcholine transporter (VAChT) was used to evaluate the relationship between post-ganglionic autonomic neurons and glutamatergic neurons. Sequential labeling of VGLUT1 and VGLUT2 in adjacent tissue sections was used to evaluate the co-localization of VGLUT1 and VGLUT2 in ICG neurons. Our studies yielded the following results: (1) ICG contain glutamatergic neurons with GLS for glutamate production and VGLUT1 and 2 for transport of glutamate into synaptic vesicles; (2) atrial ICG contain neurons that project to ventricle walls and these neurons are glutamatergic; (3) many glutamatergic ICG neurons also were cholinergic, expressing VAChT; (4) VGLUT1 and VGLUT2 co-localization occurred in ICG neurons with variation of their protein expression level. Investigation of both glutamatergic and cholinergic ICG neurons could help in better understanding the function of the intrinsic cardiac

Perinatal choline deficiency produces abnormal sensory inhibition in Sprague-Dawley rats

PubMed Central

Stevens, Karen E.; Adams, Catherine E.; Mellott, Tiffany J.; Robbins, Emily; Kisley, Michael A.

2008-01-01

Adequate choline levels in rodents during gestation have been shown to be critical to several functions, including certain learning and memory functions, when tested at adulthood. Choline is a selective agonist for the α7 nicotinic receptor which appears in development before acetylcholine is present. Normal sensory inhibition is dependent, in part, upon sufficient numbers of this receptor in the hippocampus. The present study assessed sensory inhibition in Sprague-Dawley rats gestated on normal (1.1 g/kg), deficient (0 g/kg) or supplemented (5 g/kg) choline in the maternal diet during the critical period for cholinergic cell development (E12-18). Rats gestated on deficient choline showed abnormal sensory inhibition when tested at adulthood, while rats gestated on normal or supplemented choline showed normal sensory inhibition. Assessment of hippocampal α-bungarotoxin to visualize nicotinic α7 receptors revealed no difference between the gestational choline levels. These data suggest that attention to maternal choline levels for human pregnancy may be important to the normal functioning of the offspring. PMID:18778692

Perinatal choline deficiency produces abnormal sensory inhibition in Sprague-Dawley rats.

PubMed

Stevens, Karen E; Adams, Catherine E; Mellott, Tiffany J; Robbins, Emily; Kisley, Michael A

2008-10-27

Adequate choline levels in rodents during gestation have been shown to be critical to several functions, including certain learning and memory functions, when tested at adulthood. Choline is a selective agonist for the alpha7 nicotinic receptor which appears in development before acetylcholine is present. Normal sensory inhibition is dependent, in part, upon sufficient numbers of this receptor in the hippocampus. The present study assessed sensory inhibition in Sprague-Dawley rats gestated on normal (1.1 g/kg), deficient (0 g/kg) or supplemented (5 g/kg) choline in the maternal diet during the critical period for cholinergic cell development (E12-18). Rats gestated on deficient choline showed abnormal sensory inhibition when tested at adulthood, while rats gestated on normal or supplemented choline showed normal sensory inhibition. Assessment of hippocampal alpha-bungarotoxin to visualize nicotinic alpha7 receptors revealed no difference between the gestational choline levels. These data suggest that attention to maternal choline levels for human pregnancy may be important to the normal functioning of the offspring.

Neurotrophic Factors NGF, GDNF and NTN Selectively Modulate HSV1 and HSV2 Lytic Infection and Reactivation in Primary Adult Sensory and Autonomic Neurons

PubMed Central

Yanez, Andy A.; Harrell, Telvin; Sriranganathan, Heather J.; Ives, Angela M.; Bertke, Andrea S.

2017-01-01

Herpes simplex viruses (HSV1 and HSV2) establish latency in peripheral ganglia after ocular or genital infection, and can reactivate to produce different patterns and frequencies of recurrent disease. Previous studies showed that nerve growth factor (NGF) maintains HSV1 latency in embryonic sympathetic and sensory neurons. However, adult sensory neurons are no longer dependent on NGF for survival, some populations cease expression of NGF receptors postnatally, and the viruses preferentially establish latency in different populations of sensory neurons responsive to other neurotrophic factors (NTFs). Thus, NGF may not maintain latency in adult sensory neurons. To identify NTFs important for maintaining HSV1 and HSV2 latency in adult neurons, we investigated acute and latently-infected primary adult sensory trigeminal (TG) and sympathetic superior cervical ganglia (SCG) after NTF removal. NGF and glial cell line-derived neurotrophic factor (GDNF) deprivation induced HSV1 reactivation in adult sympathetic neurons. In adult sensory neurons, however, neurturin (NTN) and GDNF deprivation induced HSV1 and HSV2 reactivation, respectively, while NGF deprivation had no effects. Furthermore, HSV1 and HSV2 preferentially reactivated from neurons expressing GFRα2 and GFRα1, the high affinity receptors for NTN and GDNF, respectively. Thus, NTN and GDNF play a critical role in selective maintenance of HSV1 and HSV2 latency in primary adult sensory neurons. PMID:28178213

Neurotrophic Factors NGF, GDNF and NTN Selectively Modulate HSV1 and HSV2 Lytic Infection and Reactivation in Primary Adult Sensory and Autonomic Neurons.

PubMed

Yanez, Andy A; Harrell, Telvin; Sriranganathan, Heather J; Ives, Angela M; Bertke, Andrea S

2017-02-07

Herpes simplex viruses (HSV1 and HSV2) establish latency in peripheral ganglia after ocular or genital infection, and can reactivate to produce different patterns and frequencies of recurrent disease. Previous studies showed that nerve growth factor (NGF) maintains HSV1 latency in embryonic sympathetic and sensory neurons. However, adult sensory neurons are no longer dependent on NGF for survival, some populations cease expression of NGF receptors postnatally, and the viruses preferentially establish latency in different populations of sensory neurons responsive to other neurotrophic factors (NTFs). Thus, NGF may not maintain latency in adult sensory neurons. To identify NTFs important for maintaining HSV1 and HSV2 latency in adult neurons, we investigated acute and latently-infected primary adult sensory trigeminal (TG) and sympathetic superior cervical ganglia (SCG) after NTF removal. NGF and glial cell line-derived neurotrophic factor (GDNF) deprivation induced HSV1 reactivation in adult sympathetic neurons. In adult sensory neurons, however, neurturin (NTN) and GDNF deprivation induced HSV1 and HSV2 reactivation, respectively, while NGF deprivation had no effects. Furthermore, HSV1 and HSV2 preferentially reactivated from neurons expressing GFRα2 and GFRα1, the high affinity receptors for NTN and GDNF, respectively. Thus, NTN and GDNF play a critical role in selective maintenance of HSV1 and HSV2 latency in primary adult sensory neurons.

Asymmetric localization of natural antisense RNA of neuropeptide sensorin in Aplysia sensory neurons during aging and activity.

PubMed

Kadakkuzha, Beena M; Liu, Xin-An; Narvaez, Maria; Kaye, Alexandra; Akhmedov, Komolitdin; Puthanveettil, Sathyanarayanan V

2014-01-01

Despite the advances in our understanding of transcriptome, regulation and function of its non-coding components continue to be poorly understood. Here we searched for natural antisense transcript for sensorin (NAT-SRN), a neuropeptide expressed in the presynaptic sensory neurons of gill-withdrawal reflex of the marine snail Aplysia californica. Sensorin (SRN) has a key role in learning and long-term memory storage in Aplysia. We have now identified NAT-SRN in the central nervous system (CNS) and have confirmed its expression by northern blotting and fluorescent RNA in situ hybridization. Quantitative analysis of NAT-SRN in micro-dissected cell bodies and processes of sensory neurons suggest that NAT-SRN is present in the distal neuronal processes along with sense transcripts. Importantly, aging is associated with reduction in levels of NAT-SRN in sensory neuron processes. Furthermore, we find that forskolin, an activator of CREB signaling, differentially alters the distribution of SRN and NAT-SRN. These studies reveal novel insights into physiological regulation of natural antisense RNAs.

Effect of nitric oxide synthase inhibitor on increase in nasal mucosal blood flow induced by sensory and parasympathetic nerve stimulation in rats.

PubMed

Ogawa, Fumio; Hanamitsu, Masakazu; Ayajiki, Kazuhide; Aimi, Yoshinari; Okamura, Tomio; Shimizu, Takeshi

2010-06-01

Neural control of nasal blood flow (NBF) has not been systematically investigated. The aim of the present study was to evaluate the effect of electrical stimulation of both sensory and parasympathetic nerves innervating the nasal mucosal arteries on NBF in rats. In anesthetized rats, nasociliary (sensory) nerves and postganglionic (parasympathetic) nerves derived from the right sphenopalatine ganglion were electrically stimulated. We measured NBF with a laser-Doppler flowmeter. The nerve stimulation increased NBF on both sides and increased the mean arterial blood pressure. The increase in NBF was larger on the ipsilateral side than on the contralateral side. Hexamethonium bromide, a ganglion blocker, abolished the stimulation-induced pressure effect and the increase in NBF on the contralateral side, but did not abolish the increase in NBF on the ipsilateral side. The remaining increase in NBF was abolished by N(G)-nitro-L-arginine, a nitric oxide synthase inhibitor. Histochemical analysis with nicotinamide adenine dinucleotide phosphate-diaphorase showed neuronal nitric oxide synthase-containing nerves that innervate nasal mucosal arteries. Nitric oxide released from parasympathetic nitrergic nerves may contribute to an increase in NBF in rats. The afferent impulses induced by sensory nerve stimulation may lead to an increase in mean arterial blood pressure that is partly responsible for the increase in NBF.

Stimulus encoding and feature extraction by multiple sensory neurons.

PubMed

Krahe, Rüdiger; Kreiman, Gabriel; Gabbiani, Fabrizio; Koch, Christof; Metzner, Walter

2002-03-15

Neighboring cells in topographical sensory maps may transmit similar information to the next higher level of processing. How information transmission by groups of nearby neurons compares with the performance of single cells is a very important question for understanding the functioning of the nervous system. To tackle this problem, we quantified stimulus-encoding and feature extraction performance by pairs of simultaneously recorded electrosensory pyramidal cells in the hindbrain of weakly electric fish. These cells constitute the output neurons of the first central nervous stage of electrosensory processing. Using random amplitude modulations (RAMs) of a mimic of the fish's own electric field within behaviorally relevant frequency bands, we found that pyramidal cells with overlapping receptive fields exhibit strong stimulus-induced correlations. To quantify the encoding of the RAM time course, we estimated the stimuli from simultaneously recorded spike trains and found significant improvements over single spike trains. The quality of stimulus reconstruction, however, was still inferior to the one measured for single primary sensory afferents. In an analysis of feature extraction, we found that spikes of pyramidal cell pairs coinciding within a time window of a few milliseconds performed significantly better at detecting upstrokes and downstrokes of the stimulus compared with isolated spikes and even spike bursts of single cells. Coincident spikes can thus be considered "distributed bursts." Our results suggest that stimulus encoding by primary sensory afferents is transformed into feature extraction at the next processing stage. There, stimulus-induced coincident activity can improve the extraction of behaviorally relevant features from the stimulus.

Inhibition of acid-sensing ion channels by levo-tetrahydropalmatine in rat dorsal root ganglion neurons.

PubMed

Liu, Ting-Ting; Qu, Zu-Wei; Qiu, Chun-Yu; Qiu, Fang; Ren, Cuixia; Gan, Xiong; Peng, Fang; Hu, Wang-Ping

2015-02-01

Levo-tetrahydropalmatine (l-THP), a main bioactive Chinese herbal constituent from the genera Stephania and Corydalis, has been in use in clinical practice for years in China as a traditional analgesic agent. However, the mechanism underlying the analgesic action of l-THP is poorly understood. This study shows that l-THP can exert an inhibitory effect on the functional activity of native acid-sensing ion channels (ASICs), which are believed to mediate pain caused by extracellular acidification. l-THP dose dependently decreased the amplitude of proton-gated currents mediated by ASICs in rat dorsal root ganglion (DRG) neurons. l-THP shifted the proton concentration-response curve downward, with a decrease of 40.93% ± 8.45% in the maximum current response to protons, with no significant change in the pH0.5 value. Moreover, l-THP can alter the membrane excitability of rat DRG neurons to acid stimuli. It significantly decreased the number of action potentials and the amplitude of the depolarization induced by an extracellular pH drop. Finally, peripherally administered l-THP inhibited the nociceptive response to intraplantar injection of acetic acid in rats. These results indicate that l-THP can inhibit the functional activity of ASICs in dissociated primary sensory neurons and relieve acidosis-evoked pain in vivo, which for the first time provides a novel peripheral mechanism underlying the analgesic action of l-THP. © 2014 Wiley Periodicals, Inc.

Interhemispheric correlations of slow spontaneous neuronal fluctuations revealed in human sensory cortex

PubMed Central

Nir, Yuval; Mukamel, Roy; Dinstein, Ilan; Privman, Eran; Harel, Michal; Fisch, Lior; Gelbard-Sagiv, Hagar; Kipervasser, Svetlana; Andelman, Fani; Neufeld, Miri Y; Kramer, Uri; Arieli, Amos; Fried, Itzhak; Malach, Rafael

2009-01-01

Animal studies have shown robust electrophysiological activity in the sensory cortex in the absence of stimuli or tasks. Similarly, recent human functional magnetic resonance imaging (fMRI) revealed widespread, spontaneously emerging cortical fluctuations. However, it is unknown what neuronal dynamics underlie this spontaneous activity in the human brain. Here we studied this issue by combining bilateral single-unit, local field potentials (LFPs) and intracranial electrocorticography (ECoG) recordings in individuals undergoing clinical monitoring. We found slow (<0.1 Hz, following 1/f-like profiles) spontaneous fluctuations of neuronal activity with significant interhemispheric correlations. These fluctuations were evident mainly in neuronal firing rates and in gamma (40–100 Hz) LFP power modulations. Notably, the interhemispheric correlations were enhanced during rapid eye movement and stage 2 sleep. Multiple intracranial ECoG recordings revealed clear selectivity for functional networks in the spontaneous gamma LFP power modulations. Our results point to slow spontaneous modulations in firing rate and gamma LFP as the likely correlates of spontaneous fMRI fluctuations in the human sensory cortex. PMID:19160509

Population rate dynamics and multineuron firing patterns in sensory cortex

PubMed Central

Okun, Michael; Yger, Pierre; Marguet, Stephan; Gerard-Mercier, Florian; Benucci, Andrea; Katzner, Steffen; Busse, Laura; Carandini, Matteo; Harris, Kenneth D.

2012-01-01

Cortical circuits encode sensory stimuli through the firing of neuronal ensembles, and also produce spontaneous population patterns in the absence of sensory drive. This population activity is often characterized experimentally by the distribution of multineuron “words” (binary firing vectors), and a match between spontaneous and evoked word distributions has been suggested to reflect learning of a probabilistic model of the sensory world. We analyzed multineuron word distributions in sensory cortex of anesthetized rats and cats, and found that they are dominated by fluctuations in population firing rate rather than precise interactions between individual units. Furthermore, cortical word distributions change when brain state shifts, and similar behavior is seen in simulated networks with fixed, random connectivity. Our results suggest that similarity or dissimilarity in multineuron word distributions could primarily reflect similarity or dissimilarity in population firing rate dynamics, and not necessarily the precise interactions between neurons that would indicate learning of sensory features. PMID:23197704

Adipose-derived stromal cells enhance auditory neuron survival in an animal model of sensory hearing loss.

PubMed

Schendzielorz, Philipp; Vollmer, Maike; Rak, Kristen; Wiegner, Armin; Nada, Nashwa; Radeloff, Katrin; Hagen, Rudolf; Radeloff, Andreas

2017-10-01

A cochlear implant (CI) is an electronic prosthesis that can partially restore speech perception capabilities. Optimum information transfer from the cochlea to the central auditory system requires a proper functioning auditory nerve (AN) that is electrically stimulated by the device. In deafness, the lack of neurotrophic support, normally provided by the sensory cells of the inner ear, however, leads to gradual degeneration of auditory neurons with undesirable consequences for CI performance. We evaluated the potential of adipose-derived stromal cells (ASCs) that are known to produce neurotrophic factors to prevent neural degeneration in sensory hearing loss. For this, co-cultures of ASCs with auditory neurons have been studied, and autologous ASC transplantation has been performed in a guinea pig model of gentamicin-induced sensory hearing loss. In vitro ASCs were neuroprotective and considerably increased the neuritogenesis of auditory neurons. In vivo transplantation of ASCs into the scala tympani resulted in an enhanced survival of auditory neurons. Specifically, peripheral AN processes that are assumed to be the optimal activation site for CI stimulation and that are particularly vulnerable to hair cell loss showed a significantly higher survival rate in ASC-treated ears. ASC transplantation into the inner ear may restore neurotrophic support in sensory hearing loss and may help to improve CI performance by enhanced AN survival. Copyright © 2017 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

Knockdown of sodium channel NaV1.6 blocks mechanical pain and abnormal bursting activity of afferent neurons in inflamed sensory ganglia

PubMed Central

Xie, Wenrui; Strong, Judith A.; Ye, Ling; Mao, Ju-Xian; Zhang, Jun-Ming

2013-01-01

Inflammatory processes in the sensory ganglia contribute to many forms of chronic pain. We previously showed that local inflammation of the lumbar sensory ganglia rapidly leads to prolonged mechanical pain behaviors and high levels of spontaneous bursting activity in myelinated cells. Abnormal spontaneous activity of sensory neurons occurs early in many preclinical pain models, and initiates many other pathological changes, but its molecular basis is not well understood. The sodium channel isoform NaV1.6 can underlie repetitive firing and excitatory persistent and resurgent currents. We used in vivo knockdown of this channel via local injection of siRNA to examine its role in chronic pain following local inflammation of the rat lumbar sensory ganglia. In normal DRG, quantitative PCR showed that cells capable of firing repetitively had significantly higher relative expression of NaV1.6. In inflamed DRG, spontaneously active bursting cells expressed high levels of NaV1.6′ immunoreactivity. In vivo knockdown of NaV1.6 locally in the lumbar DRG at the time of DRG inflammation completely blocked development of pain behaviors and abnormal spontaneous activity, while having only minor effects on unmyelinated C-cells. Current research on isoform-specific sodium channel blockers for chronic pain is largely focused on NaV1.8, because it is present primarily in unmyelinated C fiber nociceptors, or on NaV1.7, because lack of this channel causes congenital indifference to pain. However, the results suggest that NaV1.6 may be a useful therapeutic target for chronic pain, and that some pain conditions may be primarily mediated by myelinated A-fiber sensory neurons. PMID:23622763

The pattern of thalamocortical and brain stem projections to the vibrissae-related sensory and motor cortices in de-whiskered congenital hypothyroid rats.

PubMed

Afarinesh, Mohammad Reza; Behzadi, Gila

2017-08-01

The present study is designed to investigate the plastic organization of the thalamo-cortical (TC) and brain stem afferents of whisker primary sensory (wS1) and motor (wM1) cortical areas in congenital hypothyroid (CH) pups following whisker deprivation (WD) from neonatal to adolescence period. Maternal hypothyroidism was induced by adding propylthiouracil (PTU) to the drinking water from early embryonic day 16 to postnatal day (PND) 60. Pregnant rats were divided into intact and CH groups (n = 8). In each group, the total whiskers of pups (4 of 8) were trimmed continuously from PND 1 to PND 60. Retrograde tracing technique with WGA-HRP was performed in the present study. Retrogradely labeled neurons were observed in the specific thalamic nuclei (VPM and VL) following separately WGA-HRP injections into wS1/M1 cortical areas. The number of labeled cells in the VPM, VL, VM and PO nuclei of the thalamus significantly decreased in CH offsprings rats (P < 0.05). Neonatal WD did not show any significant effects on the number of VPM, VL, VM and PO labeled projection neurons to wS1 and wM1 cortical areas. In addition, retrogradely labeled neurons in dorsal raphe (DR) and locus coeruleus (LC) nuclei were observed in all experimental groups. The number of DR and LC labeled neurons were higher in the CH and whisker deprived groups compared to their matching controls (P < 0.05). Upon our results, CH and WD had no synergic or additive effects on the TC and brain stem afferent patterns of barrel sensory and motor cortices.

Distribution of histaminergic neuronal cluster in the rat and mouse hypothalamus.

PubMed

Moriwaki, Chinatsu; Chiba, Seiichi; Wei, Huixing; Aosa, Taishi; Kitamura, Hirokazu; Ina, Keisuke; Shibata, Hirotaka; Fujikura, Yoshihisa

2015-10-01

Histidine decarboxylase (HDC) catalyzes the biosynthesis of histamine from L-histidine and is expressed throughout the mammalian nervous system by histaminergic neurons. Histaminergic neurons arise in the posterior mesencephalon during the early embryonic period and gradually develop into two histaminergic substreams around the lateral area of the posterior hypothalamus and the more anterior peri-cerebral aqueduct area before finally forming an adult-like pattern comprising five neuronal clusters, E1, E2, E3, E4, and E5, at the postnatal stage. This distribution of histaminergic neuronal clusters in the rat hypothalamus appears to be a consequence of neuronal development and reflects the functional differentiation within each neuronal cluster. However, the close linkage between the locations of histaminergic neuronal clusters and their physiological functions has yet to be fully elucidated because of the sparse information regarding the location and orientation of each histaminergic neuronal clusters in the hypothalamus of rats and mice. To clarify the distribution of the five-histaminergic neuronal clusters more clearly, we performed an immunohistochemical study using the anti-HDC antibody on serial sections of the rat hypothalamus according to the brain maps of rat and mouse. Our results confirmed that the HDC-immunoreactive (HDCi) neuronal clusters in the hypothalamus of rats and mice are observed in the ventrolateral part of the most posterior hypothalamus (E1), ventrolateral part of the posterior hypothalamus (E2), ventromedial part from the medial to the posterior hypothalamus (E3), periventricular part from the anterior to the medial hypothalamus (E4), and diffusely extended part of the more dorsal and almost entire hypothalamus (E5). The stereological estimation of the total number of HDCi neurons of each clusters revealed the larger amount of the rat than the mouse. The characterization of histaminergic neuronal clusters in the hypothalamus of rats and

Neurochemical differences between target-specific populations of rat dorsal raphe projection neurons.

PubMed

Prouty, Eric W; Chandler, Daniel J; Waterhouse, Barry D

2017-11-15

Serotonin (5-HT)-containing neurons in the dorsal raphe (DR) nucleus project throughout the forebrain and are implicated in many physiological processes and neuropsychiatric disorders. Diversity among these neurons has been characterized in terms of their neurochemistry and anatomical organization, but a clear sense of whether these attributes align with specific brain functions or terminal fields is lacking. DR 5-HT neurons can co-express additional neuroactive substances, increasing the potential for individualized regulation of target circuits. The goal of this study was to link DR neurons to a specific functional role by characterizing cells according to both their neurotransmitter expression and efferent connectivity; specifically, cells projecting to the medial prefrontal cortex (mPFC), a region implicated in cognition, emotion, and responses to stress. Following retrograde tracer injection, brainstem sections from Sprague-Dawley rats were immunohistochemically stained for markers of serotonin, glutamate, GABA, and nitric oxide (NO). 98% of the mPFC-projecting serotonergic neurons co-expressed the marker for glutamate, while the markers for NO and GABA were observed in 60% and less than 1% of those neurons, respectively. To identify potential target-specific differences in co-transmitter expression, we also characterized DR neurons projecting to a visual sensory structure, the lateral geniculate nucleus (LGN). The proportion of serotonergic neurons co-expressing NO was greater amongst cells targeting the mPFC vs LGN (60% vs 22%). The established role of 5-HT in affective disorders and the emerging role of NO in stress signaling suggest that the impact of 5-HT/NO co-localization in DR neurons that regulate mPFC circuit function may be clinically relevant. Copyright © 2017 Elsevier B.V. All rights reserved.

Origins, actions and dynamic expression patterns of the neuropeptide VGF in rat peripheral and central sensory neurones following peripheral nerve injury

PubMed Central

Moss, Andrew; Ingram, Rachel; Koch, Stephanie; Theodorou, Andria; Low, Lucie; Baccei, Mark; Hathway, Gareth J; Costigan, Michael; Salton, Stephen R; Fitzgerald, Maria

2008-01-01

Background The role of the neurotrophin regulated polypeptide, VGF, has been investigated in a rat spared injury model of neuropathic pain. This peptide has been shown to be associated with synaptic strengthening and learning in the hippocampus and while it is known that VGFmRNA is upregulated in dorsal root ganglia following peripheral nerve injury, the role of this VGF peptide in neuropathic pain has yet to be investigated. Results Prolonged upregulation of VGF mRNA and protein was observed in injured dorsal root ganglion neurons, central terminals and their target dorsal horn neurons. Intrathecal application of TLQP-62, the C-terminal active portion of VGF (5–50 nmol) to naïve rats caused a long-lasting mechanical and cold behavioral allodynia. Direct actions of 50 nM TLQP-62 upon dorsal horn neuron excitability was demonstrated in whole cell patch recordings in spinal cord slices and in receptive field analysis in intact, anesthetized rats where significant actions of VGF were upon spontaneous activity and cold evoked responses. Conclusion VGF expression is therefore highly modulated in nociceptive pathways following peripheral nerve injury and can cause dorsal horn cell excitation and behavioral hypersensitivity in naïve animals. Together the results point to a novel and powerful role for VGF in neuropathic pain. PMID:19077191

Differential expression of VGLUT1 or VGLUT2 in the trigeminothalamic or trigeminocerebellar projection neurons in the rat.

PubMed

Ge, Shun-Nan; Li, Zhi-Hong; Tang, Jun; Ma, Yunfei; Hioki, Hiroyuki; Zhang, Ting; Lu, Ya-Cheng; Zhang, Fu-Xing; Mizuno, Noboru; Kaneko, Takeshi; Liu, Ying-Ying; Lung, Mandy Siu Yu; Gao, Guo-Dong; Li, Jin-Lian

2014-01-01

The vesicular glutamate transporters, VGLUT1 and VGLUT2, reportedly display complementary distribution in the rat brain. However, co-expression of them in single neurons has been reported in some brain areas. We previously found co-expression of VGLUT1 and VGLUT2 mRNAs in a number of single neurons in the principal sensory trigeminal nucleus (Vp) of the adult rat; the majority of these neurons sent their axons to the thalamic regions around the posteromedial ventral nucleus (VPM) and the posterior nuclei (Po). It is well known that trigeminothalamic (T-T) projection fibers arise not only from the Vp but also from the spinal trigeminal nucleus (Vsp), and that trigeminocerebellar (T-C) projection fibers take their origins from both of the Vp and Vsp. Thus, in the present study, we examined the expression of VGLUT1 and VGLUT2 in Vp and Vsp neurons that sent their axons to the VPM/Po regions or the cortical regions of the cerebellum. For this purpose, we combined fluorescence in situ hybridization (FISH) histochemistry with retrograde tract-tracing; immunofluorescence histochemistry was also combined with anterograde tract-tracing. The results indicate that glutamatergic Vsp neurons sending their axons to the cerebellar cortical regions mainly express VGLUT1, whereas glutamatergic Vsp neurons sending their axons to the thalamic regions express VGLUT2. The present data, in combination with those of our previous study, indicate that glutamatergic Vp neurons projecting to the cerebellar cortical regions express mainly VGLUT1, whereas the majority of glutamatergic Vp neurons projecting to the thalamus co-express VGLUT1 and VGLUT2.

Progranulin overexpression in sensory neurons attenuates neuropathic pain in mice: Role of autophagy.

PubMed

Altmann, Christine; Hardt, Stefanie; Fischer, Caroline; Heidler, Juliana; Lim, Hee-Young; Häussler, Annett; Albuquerque, Boris; Zimmer, Béla; Möser, Christine; Behrends, Christian; Koentgen, Frank; Wittig, Ilka; Schmidt, Mirko H H; Clement, Albrecht M; Deller, Thomas; Tegeder, Irmgard

2016-12-01

Peripheral or central nerve injury is a frequent cause of chronic pain and the mechanisms are not fully understood. Using newly generated transgenic mice we show that progranulin overexpression in sensory neurons attenuates neuropathic pain after sciatic nerve injury and accelerates nerve healing. A yeast-2-hybrid screen revealed putative interactions of progranulin with autophagy-related proteins, ATG12 and ATG4b. This was supported by colocalization and proteomic studies showing regulations of ATG13 and ATG4b and other members of the autophagy network, lysosomal proteins and proteins involved in endocytosis. The association of progranulin with the autophagic pathway was functionally confirmed in primary sensory neurons. Autophagy and survival were impaired in progranulin-deficient neurons and improved in progranulin overexpressing neurons. Nerve injury in vivo caused an accumulation of LC3b-EGFP positive bodies in neurons of the dorsal root ganglia and nerves suggesting an impairment of autophagic flux. Overexpression of progranulin in these neurons was associated with a reduction of the stress marker ATF3, fewer protein aggregates in the injured nerve and enhanced stump healing. At the behavioral level, further inhibition of the autophagic flux by hydroxychloroquine intensified cold and heat nociception after sciatic nerve injury and offset the pain protection provided by progranulin. We infer that progranulin may assist in removal of protein waste and thereby helps to resolve neuropathic pain after nerve injury. Copyright © 2016 Elsevier Inc. All rights reserved.

Sensory Coding by Cerebellar Mossy Fibres through Inhibition-Driven Phase Resetting and Synchronisation

PubMed Central

Holtzman, Tahl; Jörntell, Henrik

2011-01-01

Temporal coding of spike-times using oscillatory mechanisms allied to spike-time dependent plasticity could represent a powerful mechanism for neuronal communication. However, it is unclear how temporal coding is constructed at the single neuronal level. Here we investigate a novel class of highly regular, metronome-like neurones in the rat brainstem which form a major source of cerebellar afferents. Stimulation of sensory inputs evoked brief periods of inhibition that interrupted the regular firing of these cells leading to phase-shifted spike-time advancements and delays. Alongside phase-shifting, metronome cells also behaved as band-pass filters during rhythmic sensory stimulation, with maximal spike-stimulus synchronisation at frequencies close to the idiosyncratic firing frequency of each neurone. Phase-shifting and band-pass filtering serve to temporally align ensembles of metronome cells, leading to sustained volleys of near-coincident spike-times, thereby transmitting synchronised sensory information to downstream targets in the cerebellar cortex. PMID:22046297

Expression of vesicular glutamate transporters in sensory and autonomic neurons innervating the mouse bladder.

PubMed

Brumovsky, Pablo R; Seal, Rebecca P; Lundgren, Kerstin H; Seroogy, Kim B; Watanabe, Masahiko; Gebhart, G F

2013-06-01

VGLUTs, which are essential for loading glutamate into synaptic vesicles, are present in various neuronal systems. However, to our knowledge the expression of VGLUTs in neurons innervating the bladder has not yet been analyzed. We studied VGLUT1, VGLUT2 and VGLUT3 in mouse bladder neurons. We analyzed the expression of VGLUT1, VGLUT2 and calcitonin gene-related peptide by immunohistochemistry in the retrograde labeled primary afferent and autonomic neurons of BALB/c mice after injecting fast blue in the bladder wall. To study VGLUT3 we traced the bladder of transgenic mice, in which VGLUT3 is identified by enhanced green fluorescent protein detection. Most bladder dorsal root ganglion neurons expressed VGLUT2. A smaller percentage of neurons also expressed VGLUT1 or VGLUT3. Co-expression with calcitonin gene-related peptide was only observed for VGLUT2. Occasional VGLUT2 immunoreactive neurons were seen in the major pelvic ganglia. Abundant VGLUT2 immunoreactive nerves were detected in the bladder dome and trigone, and the urethra. VGLUT1 immunoreactive nerves were discretely present. We present what are to our knowledge novel data on VGLUT expression in sensory and autonomic neurons innervating the mouse bladder. The frequent association of VGLUT2 and calcitonin gene-related peptide in sensory neurons suggests interactions between glutamatergic and peptidergic neurotransmissions, potentially influencing commonly perceived sensations in the bladder, such as discomfort and pain. Copyright © 2013 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Error-based analysis of optimal tuning functions explains phenomena observed in sensory neurons.

PubMed

Yaeli, Steve; Meir, Ron

2010-01-01

Biological systems display impressive capabilities in effectively responding to environmental signals in real time. There is increasing evidence that organisms may indeed be employing near optimal Bayesian calculations in their decision-making. An intriguing question relates to the properties of optimal encoding methods, namely determining the properties of neural populations in sensory layers that optimize performance, subject to physiological constraints. Within an ecological theory of neural encoding/decoding, we show that optimal Bayesian performance requires neural adaptation which reflects environmental changes. Specifically, we predict that neuronal tuning functions possess an optimal width, which increases with prior uncertainty and environmental noise, and decreases with the decoding time window. Furthermore, even for static stimuli, we demonstrate that dynamic sensory tuning functions, acting at relatively short time scales, lead to improved performance. Interestingly, the narrowing of tuning functions as a function of time was recently observed in several biological systems. Such results set the stage for a functional theory which may explain the high reliability of sensory systems, and the utility of neuronal adaptation occurring at multiple time scales.

Thy1.2 YFP-16 Transgenic Mouse Labels a Subset of Large-Diameter Sensory Neurons that Lack TRPV1 Expression

PubMed Central

Taylor-Clark, Thomas E.; Wu, Kevin Y.; Thompson, Julie-Ann; Yang, Kiseok; Bahia, Parmvir K.; Ajmo, Joanne M.

2015-01-01

The Thy1.2 YFP-16 mouse expresses yellow fluorescent protein (YFP) in specific subsets of peripheral and central neurons. The original characterization of this model suggested that YFP was expressed in all sensory neurons, and this model has been subsequently used to study sensory nerve structure and function. Here, we have characterized the expression of YFP in the sensory ganglia (DRG, trigeminal and vagal) of the Thy1.2 YFP-16 mouse, using biochemical, functional and anatomical analyses. Despite previous reports, we found that YFP was only expressed in approximately half of DRG and trigeminal neurons and less than 10% of vagal neurons. YFP-expression was only found in medium and large-diameter neurons that expressed neurofilament but not TRPV1. YFP-expressing neurons failed to respond to selective agonists for TRPV1, P2X2/3 and TRPM8 channels in Ca2+ imaging assays. Confocal analysis of glabrous skin, hairy skin of the back and ear and skeletal muscle indicated that YFP was expressed in some peripheral terminals with structures consistent with their presumed non-nociceptive nature. In summary, the Thy1.2 YFP-16 mouse expresses robust YFP expression in only a subset of sensory neurons. But this mouse model is not suitable for the study of nociceptive nerves or the function of such nerves in pain and neuropathies. PMID:25746468

Induction of sensory neurons from neuroepithelial stem cells by the ISX9 small molecule

PubMed Central

Ali, Rouknuddin Qasim; Blomberg, Evelina; Falk, Anna; Ährlund-Richter, Lars; Ulfendahl, Mats

2016-01-01

Hearing impairment most often involves loss of sensory hair cells and auditory neurons. As this loss is permanent in humans, a cell therapy approach has been suggested to replace damaged cells. It is thus of interest to generate lineage restricted progenitor cells appropriate for cell based therapies. Human long-term self-renewing neuroepithelial stem (lt-NES) cell lines exhibit in vitro a developmental potency to differentiate into CNS neural lineages, and importantly lack this potency in vivo, i.e do not form teratomas. Small-molecules-driven differentiation is today an established route obtain specific cell derivatives from stem cells. In this study, we have investigated the effects of three small molecules SB431542, ISX9 and Metformin to direct differentiation of lt-NES cells into sensory neurons. Exposure of lt-NES cells to Metformin or SB431542 did not induce any marked induction of markers for sensory neurons. However, a four days exposure to the ISX9 small molecule resulted in reduced expression of NeuroD1 mRNA as well as enhanced mRNA levels of GATA3, a marker and important player in auditory neuron specification and development. Subsequent culture in the presence of the neurotrophic factors BDNF and NT3 for another seven days yielded a further increase of mRNA expression for GATA3. This regimen resulted in a frequency of up to 25-30% of cells staining positive for Brn3a/Tuj1. We conclude that an approach with ISX9 small molecule induction of lt-NES cells into auditory like neurons may thus be an attractive route for obtaining safe cell replacement therapy of sensorineural hearing loss. PMID:27335699

Facilitation of TRPV4 by TRPV1 is required for itch transmission in some sensory neuron populations

PubMed Central

Kim, Seungil; Barry, Devin M.; Liu, Xian-Yu; Yin, Shijin; Munanairi, Admire; Meng, Qing-Tao; Cheng, Wei; Mo, Ping; Wan, Li; Liu, Shen-Bin; Ratnayake, Kasun; Zhao, Zhong-Qiu; Gautam, Narasimhan; Zheng, Jie; Ajith Karunarathne, W. K.; Chen, Zhou-Feng

2017-01-01

The transient receptor potential channels (TRPs) respond to chemical irritants and temperature. TRPV1 responds to the itch-inducing endogenous signal histamine, and TRPA1 responds to the itch-inducing chemical chloroquine. We showed that, in sensory neurons, TRPV4 is important for both chloroquine-and histamine-induced itch and that TRPV1 has a role in chloroquine-induced itch. Chloroquine-induced scratching was reduced in mice in which TRPV1 was knocked down or pharmacologically inhibited. Both TRPV4 and TRPV1 were present in some sensory neurons. Pharmacological blockade of either TRPV4 or TRPV1 significantly attenuated the Ca2+ response of sensory neurons exposed to histamine or chloroquine. Knockout of Trpv1 impaired Ca2+ responses and reduced scratching behavior evoked by a TRPV4 agonist, whereas knockout of Trpv4 did not alter TRPV1-mediated capsaicin responses. Electrophysiological analysis of human embryonic kidney (HEK) 293 cells coexpressing TRPV4 and TRPV1 revealed that the presence of both channels enhanced the activation kinetics of TRPV4 but not of TRPV1. Biochemical and biophysical studies suggested a close proximity between TRPV4 and TRPV1 in dorsal root ganglion neurons and in cultured cells. Thus, our studies identified TRPV4 as a channel that contributes to both histamine- and chloroquine-induced itch and indicated that the function of TRPV4 in itch signaling involves TRPV1-mediated facilitation. TRP facilitation through the formation of heteromeric complexes could be a prevalent mechanism by which the vast array of somatosensory information is encoded in sensory neurons. PMID:27436359

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

PubMed

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

2006-09-15

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

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

PubMed Central

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

2007-01-01

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

Adrenergic receptors inhibit TRPV1 activity in the dorsal root ganglion neurons of rats.

PubMed

Matsushita, Yumi; Manabe, Miki; Kitamura, Naoki; Shibuya, Izumi

2018-01-01

Transient receptor potential vanilloid type 1 (TRPV1) is a polymodal receptor channel that responds to multiple types of stimuli, such as heat, acid, mechanical pressure and some vanilloids. Capsaicin is the most commonly used vanilloid to stimulate TRPV1. TRPV1 channels are expressed in dorsal root ganglion neurons that extend to Aδ- and C-fibers and have a role in the transduction of noxious inputs to the skin into the electrical signals of the sensory nerve. Although noradrenergic nervous systems, including the descending antinociceptive system and the sympathetic nervous system, are known to modulate pain sensation, the functional association between TRPV1 and noradrenaline in primary sensory neurons has rarely been examined. In the present study, we examined the effects of noradrenaline on capsaicin-evoked currents in cultured dorsal root ganglion neurons of the rat by the whole-cell voltage clamp method. Noradrenaline at concentrations higher than 0.1 pM significantly reduced the amplitudes of the inward capsaicin currents recorded at -60 mV holding potential. This inhibitory action was reversed by either yohimbine (an α2 antagonist, 10 nM) or propranolol (a β antagonist, 10 nM). The α2 agonists, clonidine (1 pM) and dexmedetomidine (1 pM) inhibited capsaicin currents, and yohimbine (1 nM) reversed the effects of clonidine. The inhibitory action of noradrenaline was not seen in the neurons pretreated with pertussis toxin (100 μg/ml for 24 h) and the neurons dialyzed intracellularly with guanosine 5'- [β-thio] diphosphate (GDPβS, 200 μM), the catalytic subunit of protein kinase A (250 U/ml) or okadaic acid (1 μM). These results suggest that noradrenaline directly acts on dorsal root ganglion neurons to inhibit the activity of TRPV1 depending on the activation of α2-adrenoceptors followed by the inhibition of the adenylate cyclase/cAMP/protein kinase A pathway.

TrpA1 activation in peripheral sensory neurons underlies the ionic basis of pain hypersensitivity in response to vinca alkaloids

PubMed Central

Boiko, Nina; Medrano, Geraldo; Montano, Elizabeth; Jiang, Nan; Williams, Claire R.; Madungwe, Ngonidzashe B.; Bopassa, Jean C.; Kim, Charles C.; Parrish, Jay Z.; Hargreaves, Kenneth M.

2017-01-01

Chemotherapy induced peripheral neuropathy (CIPN), a side effect of many anti-cancer drugs including the vinca alkaloids, is characterized by a severe pain syndrome that compromises treatment in many patients. Currently there are no effective treatments for this pain syndrome except for the reduction of anti-cancer drug dose. Existing data supports the model that the pain associated with CIPN is the result of anti-cancer drugs augmenting the function of the peripheral sensory nociceptors but the cellular mechanisms underlying the effects of anti-cancer drugs on sensory neuron function are not well described. Studies from animal models have suggested a number of disease etiologies including mitotoxicity, axonal degeneration, immune signaling, and reduced sensory innervations but these outcomes are the result of prolonged treatment paradigms and do not necessarily represent the early formative events associated with CIPN. Here we show that acute exposure to vinca alkaloids results in an immediate pain syndrome in both flies and mice. Furthermore, we demonstrate that exposure of isolated sensory neurons to vinca alkaloids results in the generation of an inward sodium current capable of depolarizing these neurons to threshold resulting in neuronal firing. These neuronal effects of vinca alkaloids require the transient receptor potential ankyrin-1 (TrpA1) channel, and the hypersensitization to painful stimuli in response to the acute exposure to vinca alkaloids is reduced in TrpA1 mutant flies and mice. These findings demonstrate the direct excitation of sensory neurons by CIPN-causing chemotherapy drugs, and identify TrpA1 as an important target during the pathogenesis of CIPN. PMID:29084244

Capsaicin-induced reactivation of latent herpes simplex virus type 1 in sensory neurons in culture.

PubMed

Hunsperger, Elizabeth A; Wilcox, Christine L

2003-05-01

Herpes simplex virus type 1 (HSV-1) produces a life-long latent infection in neurons of the peripheral nervous system, primarily in the trigeminal and dorsal root ganglia. Neurons of these ganglia express high levels of the capsaicin receptor, also known as the vanilloid receptor-1 (VR-1). VR-1 is a non-selective ion channel, found on sensory neurons, that primarily fluxes Ca(2+) ions in response to various stimuli, including physiologically acidic conditions, heat greater than 45 degrees C and noxious compounds such as capsaicin. Using an in vitro neuronal model to study HSV-1 latency and reactivation, we found that agonists of the VR-1 channel - capsaicin and heat - resulted in reactivation of latent HSV-1. Capsaicin-induced reactivation of HSV-1 latently infected neurons was dose-dependent. Additionally, activation of VR-1 at its optimal temperature of 46 degrees C caused a significant increase in virus titres, which could be attenuated with the VR-1 antagonist, capsazepine. VR-1 activation that resulted in HSV-1 reactivation was calcium-dependent, since the calcium chelator BAPTA significantly reduced reactivation following treatment with caspsaicin and forskolin. Taken together, these results suggest that activation of the VR-1 channel, often associated with increases in intracellular calcium, results in HSV-1 reactivation in sensory neurons.

Distinct requirements for TrkB and TrkC signaling in target innervation by sensory neurons

NASA Technical Reports Server (NTRS)

Postigo, Antonio; Calella, Anna Maria; Fritzsch, Bernd; Knipper, Marlies; Katz, David; Eilers, Andreas; Schimmang, Thomas; Lewin, Gary R.; Klein, Rudiger; Minichiello, Liliana

2002-01-01

Signaling by brain-derived neurotrophic factor (BDNF) via the TrkB receptor, or by neurotrophin-3 (NT3) through the TrkC receptor support distinct populations of sensory neurons. The intracellular signaling pathways activated by Trk (tyrosine kinase) receptors, which in vivo promote neuronal survival and target innervation, are not well understood. Using mice with TrkB or TrkC receptors lacking the docking site for Shc adaptors (trkB(shc/shc) and trkC(shc/shc) mice), we show that TrkB and TrkC promote survival of sensory neurons mainly through Shc site-independent pathways, suggesting that these receptors use similar pathways to prevent apoptosis. In contrast, the regulation of target innervation appears different: in trkB(shc/shc) mice neurons lose target innervation, whereas in trkC(shc/shc) mice the surviving TrkC-dependent neurons maintain target innervation and function. Biochemical analysis indicates that phosphorylation at the Shc site positively regulates autophosphorylation of TrkB, but not of TrkC. Our findings show that although TrkB and TrkC signals mediating survival are largely similar, TrkB and TrkC signals required for maintenance of target innervation in vivo are regulated by distinct mechanisms.

Multiple blocks of intermittent and continuous theta-burst stimulation applied via transcranial magnetic stimulation differently affect sensory responses in rat barrel cortex.

PubMed

Thimm, Andreas; Funke, Klaus

2015-02-15

Theta-burst stimulation (TBS) applied via transcranial magnetic stimulation is able to modulate human cortical excitability. Here we investigated in a rat model how two different forms of TBS, intermittent (iTBS) and continuous (cTBS), affect sensory responses in rat barrel cortex. We found that iTBS but less cTBS promoted late (>18 ms) sensory response components while not affecting the earliest response (8-18 ms). The effect increased with each of the five iTBS blocks applied. cTBS somewhat reduced the early response component after the first block but had a similar effect as iTBS after four to five blocks. We conclude that iTBS primarly modulates the activity of (inhibitory) cortical interneurons while cTBS may first reduce general neuronal excitability with a single block but reverse to iTBS-like effects with application of several blocks. Cortical sensory processing varies with cortical state and the balance of inhibition to excitation. Repetitive transcranial magnetic stimulation (rTMS) has been shown to modulate human cortical excitability. In a rat model, we recently showed that intermittent theta-burst stimulation (iTBS) applied to the corpus callosum, to activate primarily supragranular cortical pyramidal cells but fewer subcortical neurons, strongly reduced the cortical expression of parvalbumin (PV), indicating reduced activity of fast-spiking interneurons. Here, we used the well-studied rodent barrel cortex system to test how iTBS and continuous TBS (cTBS) modulate sensory responses evoked by either single or double stimuli applied to the principal (PW) and/or adjacent whisker (AW) in urethane-anaesthetized rats. Compared to sham stimulation, iTBS but not cTBS particularly enhanced late (>18 ms) response components of multi-unit spiking and local field potential responses in layer 4 but not the very early response (<18 ms). Similarly, only iTBS diminished the suppression of the second response evoked by paired PW or AW-PW stimulation at 20�

Thrombospondin-4 divergently regulates voltage-gated Ca2+ channel subtypes in sensory neurons after nerve injury.

PubMed

Pan, Bin; Guo, Yuan; Wu, Hsiang-En; Park, John; Trinh, Van Nancy; Luo, Z David; Hogan, Quinn H

2016-09-01

Loss of high-voltage-activated (HVA) calcium current (ICa) and gain of low-voltage-activated (LVA) ICa after painful peripheral nerve injury cause elevated excitability in sensory neurons. Nerve injury is also accompanied by increased expression of the extracellular matrix glycoprotein thrombospondin-4 (TSP4), and interruption of TSP4 function can reverse or prevent behavioral hypersensitivity after injury. We therefore investigated TSP4 regulation of ICa in dorsal root ganglion (DRG) neurons. During depolarization adequate to activate HVA ICa, TSP4 decreases both N- and L-type ICa and the associated intracellular calcium transient. In contrast, TSP4 increases ICa and the intracellular calcium signal after low-voltage depolarization, which we confirmed is due to ICa through T-type channels. These effects are blocked by gabapentin, which ameliorates neuropathic pain by targeting the α2δ1 calcium subunit. Injury-induced changes of HVA and LVA ICa are attenuated in TSP4 knockout mice. In the neuropathic pain model of spinal nerve ligation, TSP4 application did not further regulate ICa of injured DRG neurons. Taken together, these findings suggest that elevated TSP4 after peripheral nerve injury may contribute to hypersensitivity of peripheral sensory systems by decreasing HVA and increasing LVA in DRG neurons by targeting the α2δ1 calcium subunit. Controlling TSP4 overexpression in peripheral sensory neurons may be a target for analgesic drug development for neuropathic pain.

Dynamics of human subthalamic neuron phase-locking to motor and sensory cortical oscillations during movement.

PubMed

Lipski, Witold J; Wozny, Thomas A; Alhourani, Ahmad; Kondylis, Efstathios D; Turner, Robert S; Crammond, Donald J; Richardson, Robert Mark

2017-09-01

Coupled oscillatory activity recorded between sensorimotor regions of the basal ganglia-thalamocortical loop is thought to reflect information transfer relevant to movement. A neuronal firing-rate model of basal ganglia-thalamocortical circuitry, however, has dominated thinking about basal ganglia function for the past three decades, without knowledge of the relationship between basal ganglia single neuron firing and cortical population activity during movement itself. We recorded activity from 34 subthalamic nucleus (STN) neurons, simultaneously with cortical local field potentials and motor output, in 11 subjects with Parkinson's disease (PD) undergoing awake deep brain stimulator lead placement. STN firing demonstrated phase synchronization to both low- and high-beta-frequency cortical oscillations, and to the amplitude envelope of gamma oscillations, in motor cortex. We found that during movement, the magnitude of this synchronization was dynamically modulated in a phase-frequency-specific manner. Importantly, we found that phase synchronization was not correlated with changes in neuronal firing rate. Furthermore, we found that these relationships were not exclusive to motor cortex, because STN firing also demonstrated phase synchronization to both premotor and sensory cortex. The data indicate that models of basal ganglia function ultimately will need to account for the activity of populations of STN neurons that are bound in distinct functional networks with both motor and sensory cortices and code for movement parameters independent of changes in firing rate. NEW & NOTEWORTHY Current models of basal ganglia-thalamocortical networks do not adequately explain simple motor functions, let alone dysfunction in movement disorders. Our findings provide data that inform models of human basal ganglia function by demonstrating how movement is encoded by networks of subthalamic nucleus (STN) neurons via dynamic phase synchronization with cortex. The data also

Effects of 14 days of spaceflight and nine days of recovery on cell body size and succinate dehydrogenase activity of rat dorsal root ganglion neurons

NASA Technical Reports Server (NTRS)

Ishihara, A.; Ohira, Y.; Roy, R. R.; Nagaoka, S.; Sekiguchi, C.; Hinds, W. E.; Edgerton, V. R.

1997-01-01

The cross-sectional areas and succinate dehydrogenase activities of L5 dorsal root ganglion neurons in rats were determined after 14 days of spaceflight and after nine days of recovery. The mean and distribution of the cross-sectional areas were similar to age-matched, ground-based controls for both the spaceflight and for the spaceflight plus recovery groups. The mean succinate dehydrogenase activity was significantly lower in spaceflight compared to aged-matched control rats, whereas the mean succinate dehydrogenase activity was similar in age-matched control and spaceflight plus recovery rats. The mean succinate dehydrogenase activity of neurons with cross-sectional areas between 1000 and 2000 microns2 was lower (between 7 and 10%) in both the spaceflight and the spaceflight plus recovery groups compared to the appropriate control groups. The reduction in the oxidative capacity of a subpopulation of sensory neurons having relatively large cross-sectional areas immediately following spaceflight and the sustained depression for nine days after returning to 1 g suggest that the 0 g environment induced significant alterations in proprioceptive function.

Finding and Not Finding Rat Perirhinal Neuronal Responses to Novelty

PubMed Central

Muller, Robert U.; Brown, Malcolm W.

2016-01-01

ABSTRACT There is much evidence that the perirhinal cortex of both rats and monkeys is important for judging the relative familiarity of visual stimuli. In monkeys many studies have found that a proportion of perirhinal neurons respond more to novel than familiar stimuli. There are fewer studies of perirhinal neuronal responses in rats, and those studies based on exploration of objects, have raised into question the encoding of stimulus familiarity by rat perirhinal neurons. For this reason, recordings of single neuronal activity were made from the perirhinal cortex of rats so as to compare responsiveness to novel and familiar stimuli in two different behavioral situations. The first situation was based upon that used in “paired viewing” experiments that have established rat perirhinal differences in immediate early gene expression for novel and familiar visual stimuli displayed on computer monitors. The second situation was similar to that used in the spontaneous object recognition test that has been widely used to establish the involvement of rat perirhinal cortex in familiarity discrimination. In the first condition 30 (25%) of 120 perirhinal neurons were visually responsive; of these responsive neurons 19 (63%) responded significantly differently to novel and familiar stimuli. In the second condition eight (53%) of 15 perirhinal neurons changed activity significantly in the vicinity of objects (had “object fields”); however, for none (0%) of these was there a significant activity change related to the familiarity of an object, an incidence significantly lower than for the first condition. Possible reasons for the difference are discussed. It is argued that the failure to find recognition‐related neuronal responses while exploring objects is related to its detectability by the measures used, rather than the absence of all such signals in perirhinal cortex. Indeed, as shown by the results, such signals are found when a different methodology is used. �

Experience-dependent increase in spine calcium evoked by backpropagating action potentials in layer 2/3 pyramidal neurons in rat somatosensory cortex.

PubMed

Krieger, Patrik

2009-11-01

In spines on basal dendrites of layer 2/3 pyramidal neurons in somatosensory barrel cortex, calcium transients evoked by back-propagating action potentials (bAPs) were investigated (i) along the length of the basal dendrite, (ii) with postnatal development and (iii) with sensory deprivation during postnatal development. Layer 2/3 pyramidal neurons were investigated at three different ages. At all ages [postnatal day (P)8, P14, P21] the bAP-evoked calcium transient amplitude increased with distance from the soma with a peak at around 50 microm, followed by a gradual decline in amplitude. The effect of sensory deprivation on the bAP-evoked calcium was investigated using two different protocols. When all whiskers on one side of the rat snout were trimmed daily from P8 to P20-24 there was no difference in the bAP-evoked calcium transient between cells in the contralateral hemisphere, lacking sensory input from the whisker, and cells in the ipsilateral barrel cortex, with intact whisker activation. When, however, only the D-row whiskers on one side were trimmed the distribution of bAP-evoked calcium transients in spines was shifted towards larger amplitudes in cells located in the deprived D-column. In conclusion, (i) the bAP-evoked calcium transient gradient along the dendrite length is established at P8, (ii) the calcium transient increases in amplitude with age and (iii) this increase is enhanced in layer 2/3 pyramidal neurons located in a sensory-deprived barrel column that is bordered by non-deprived barrel columns.

Peripheral Sensory Neurons Expressing Melanopsin Respond to Light

PubMed Central

Matynia, Anna; Nguyen, Eileen; Sun, Xiaoping; Blixt, Frank W.; Parikh, Sachin; Kessler, Jason; Pérez de Sevilla Müller, Luis; Habib, Samer; Kim, Paul; Wang, Zhe Z.; Rodriguez, Allen; Charles, Andrew; Nusinowitz, Steven; Edvinsson, Lars; Barnes, Steven; Brecha, Nicholas C.; Gorin, Michael B.

2016-01-01

The ability of light to cause pain is paradoxical. The retina detects light but is devoid of nociceptors while the trigeminal sensory ganglia (TG) contain nociceptors but not photoreceptors. Melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs) are thought to mediate light-induced pain but recent evidence raises the possibility of an alternative light responsive pathway independent of the retina and optic nerve. Here, we show that melanopsin is expressed in both human and mouse TG neurons. In mice, they represent 3% of small TG neurons that are preferentially localized in the ophthalmic branch of the trigeminal nerve and are likely nociceptive C fibers and high-threshold mechanoreceptor Aδ fibers based on a strong size-function association. These isolated neurons respond to blue light stimuli with a delayed onset and sustained firing, similar to the melanopsin-dependent intrinsic photosensitivity observed in ipRGCs. Mice with severe bilateral optic nerve crush exhibit no light-induced responses including behavioral light aversion until treated with nitroglycerin, an inducer of migraine in people and migraine-like symptoms in mice. With nitroglycerin, these same mice with optic nerve crush exhibit significant light aversion. Furthermore, this retained light aversion remains dependent on melanopsin-expressing neurons. Our results demonstrate a novel light-responsive neural function independent of the optic nerve that may originate in the peripheral nervous system to provide the first direct mechanism for an alternative light detection pathway that influences motivated behavior. PMID:27559310

Expression of the P/Q (Cav2.1) calcium channel in nodose sensory neurons and arterial baroreceptors.

PubMed

Tatalovic, Milos; Glazebrook, Patricia A; Kunze, Diana L

2012-06-27

The predominant calcium current in nodose sensory neurons, including the subpopulation of baroreceptor neurons, is the N-type channel, Cav2.2. It is also the primary calcium channel responsible for transmitter release at their presynaptic terminals in the nucleus of the solitary tract in the brainstem. The P/Q channel, Cav2.1, the other major calcium channel responsible for transmitter release at mammalian synapses, represents only 15-20% of total calcium current in the general population of sensory neurons and makes a minor contribution to transmitter release at the presynaptic terminal. In the present study we identified a subpopulation of the largest nodose neurons (capacitance>50pF) in which, surprisingly, Cav2.1 represents over 50% of the total calcium current, differing from the remainder of the population. Consistent with these electrophysiological data, anti-Cav2.1 antibody labeling was more membrane delimited in a subgroup of the large neurons in slices of nodose ganglia. Data reported in other synapses in the central nervous system assign different roles in synaptic information transfer to the P/Q-type versus N-type calcium channels. The study raises the possibility that the P/Q channel which has been associated with high fidelity transmission at other central synapses serves a similar function in this group of large myelinated sensory afferents, including arterial baroreceptors where a high frequency regular discharge pattern signals the pressure pulse. This contrasts to the irregular lower frequency discharge of the unmyelinated fibers that make up the majority of the sensory population and that utilize the N-type channel in synaptic transmission. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Dynamic synchronization of ongoing neuronal activity across spinal segments regulates sensory information flow

PubMed Central

Contreras-Hernández, E; Chávez, D; Rudomin, P

2015-01-01

Previous studies on the correlation between spontaneous cord dorsum potentials recorded in the lumbar spinal segments of anaesthetized cats suggested the operation of a population of dorsal horn neurones that modulates, in a differential manner, transmission along pathways mediating Ib non-reciprocal postsynaptic inhibition and pathways mediating primary afferent depolarization and presynaptic inhibition. In order to gain further insight into the possible neuronal mechanisms that underlie this process, we have measured changes in the correlation between the spontaneous activity of individual dorsal horn neurones and the cord dorsum potentials associated with intermittent activation of these inhibitory pathways. We found that high levels of neuronal synchronization within the dorsal horn are associated with states of incremented activity along the pathways mediating presynaptic inhibition relative to pathways mediating Ib postsynaptic inhibition. It is suggested that ongoing changes in the patterns of functional connectivity within a distributed ensemble of dorsal horn neurones play a relevant role in the state-dependent modulation of impulse transmission along inhibitory pathways, among them those involved in the central control of sensory information. This feature would allow the same neuronal network to be involved in different functional tasks. Key points We have examined, in the spinal cord of the anaesthetized cat, the relationship between ongoing correlated fluctuations of dorsal horn neuronal activity and state-dependent activation of inhibitory reflex pathways. We found that high levels of synchronization between the spontaneous activity of dorsal horn neurones occur in association with the preferential activation of spinal pathways leading to primary afferent depolarization and presynaptic inhibition relative to activation of pathways mediating Ib postsynaptic inhibition. It is suggested that changes in synchronization of ongoing activity within a

Mycolactone-mediated neurite degeneration and functional effects in cultured human and rat DRG neurons: Mechanisms underlying hypoalgesia in Buruli ulcer.

PubMed

Anand, U; Sinisi, M; Fox, M; MacQuillan, A; Quick, T; Korchev, Y; Bountra, C; McCarthy, T; Anand, P

2016-01-01

Mycolactone is a polyketide toxin secreted by the mycobacterium Mycobacterium ulcerans, responsible for the extensive hypoalgesic skin lesions characteristic of patients with Buruli ulcer. A recent pre-clinical study proposed that mycolactone may produce analgesia via activation of the angiotensin II type 2 receptor (AT2R). In contrast, AT2R antagonist EMA401 has shown analgesic efficacy in animal models and clinical trials for neuropathic pain. We therefore investigated the morphological and functional effects of mycolactone in cultured human and rat dorsal root ganglia (DRG) neurons and the role of AT2R using EMA401. Primary sensory neurons were prepared from avulsed cervical human DRG and rat DRG; 24 h after plating, neurons were incubated for 24 to 96 h with synthetic mycolactone A/B, followed by immunostaining with antibodies to PGP9.5, Gap43, β tubulin, or Mitotracker dye staining. Acute functional effects were examined by measuring capsaicin responses with calcium imaging in DRG neuronal cultures treated with mycolactone. Morphological effects: Mycolactone-treated cultures showed dramatically reduced numbers of surviving neurons and non-neuronal cells, reduced Gap43 and β tubulin expression, degenerating neurites and reduced cell body diameter, compared with controls. Dose-related reduction of neurite length was observed in mycolactone-treated cultures. Mitochondria were distributed throughout the length of neurites and soma of control neurons, but clustered in the neurites and soma of mycolactone-treated neurons. Functional effects: Mycolactone-treated human and rat DRG neurons showed dose-related inhibition of capsaicin responses, which were reversed by calcineurin inhibitor cyclosporine and phosphodiesterase inhibitor 3-isobutyl-1-Methylxanthine, indicating involvement of cAMP/ATP reduction. The morphological and functional effects of mycolactone were not altered by Angiotensin II or AT2R antagonist EMA401. Mycolactone induces toxic effects in DRG

Pharmacological reversal of a pain phenotype in iPSC-derived sensory neurons and patients with inherited erythromelalgia.

PubMed

Cao, Lishuang; McDonnell, Aoibhinn; Nitzsche, Anja; Alexandrou, Aristos; Saintot, Pierre-Philippe; Loucif, Alexandre J C; Brown, Adam R; Young, Gareth; Mis, Malgorzata; Randall, Andrew; Waxman, Stephen G; Stanley, Philip; Kirby, Simon; Tarabar, Sanela; Gutteridge, Alex; Butt, Richard; McKernan, Ruth M; Whiting, Paul; Ali, Zahid; Bilsland, James; Stevens, Edward B

2016-04-20

In common with other chronic pain conditions, there is an unmet clinical need in the treatment of inherited erythromelalgia (IEM). TheSCN9Agene encoding the sodium channel Nav1.7 expressed in the peripheral nervous system plays a critical role in IEM. A gain-of-function mutation in this sodium channel leads to aberrant sensory neuronal activity and extreme pain, particularly in response to heat. Five patients with IEM were treated with a new potent and selective compound that blocked the Nav1.7 sodium channel resulting in a decrease in heat-induced pain in most of the patients. We derived induced pluripotent stem cell (iPSC) lines from four of five subjects and produced sensory neurons that emulated the clinical phenotype of hyperexcitability and aberrant responses to heat stimuli. When we compared the severity of the clinical phenotype with the hyperexcitability of the iPSC-derived sensory neurons, we saw a trend toward a correlation for individual mutations. The in vitro IEM phenotype was sensitive to Nav1.7 blockers, including the clinical test agent. Given the importance of peripherally expressed sodium channels in many pain conditions, our approach may have broader utility for a wide range of pain and sensory conditions. Copyright © 2016, American Association for the Advancement of Science.

Serotonergic innervation of mesencephalic trigeminal nucleus neurons: a light and electron microscopic study in the rat.

PubMed

Li, J; Xiong, K H; Li, Y Q; Kaneko, T; Mizuno, N

2000-06-01

Neurons of the mesencephalic trigeminal nucleus (MTN) are considered to be homologous to mechanosensitive neurons in the sensory ganglia. The sites of origin of serotonin (5HT)-immunoreactive axons on neuronal cell bodies in the MTN were studied in the rat by combining immunofluorescence histochemical techniques with retrograde tracing of Fluoro-Gold (FG) and anterograde tracing of biotin-conjugated dextran amine (BDA). The tracing studies, which were combined with multiple-labeling immunohistochemistry and confocal microscopy, indicated that 5HT-immunoreactive axon terminals on the cell bodies of MTN neurons originated from the medullary raphe nuclei, such as the nucleus raphes magmus (RMg), alpha part of the nucleus reticularis gigantocellularis (GiA) and nucleus raphes obscurus (ROb), as well as from the mesopontine raphe nuclei, such as the nucleus raphes dorsalis (DR), nucleus raphes pontis (PnR) and nucleus raphes medianus (MnR); mainly from the RMg, GiA and DR, and additionally from the ROb, PnR and MnR. The cell bodies in close apposition to 5HT-immunoreactive axon terminals were found through the whole rostrocaudal extent of the MTN. Electron microscopically a number of axon terminals that were labeled with BDA injected into the raphe nuclei were confirmed to be in asymmetric synaptic contact with the cell bodies of MTN neurons. It was also indicated that substance P existed in some of the 5HT-containing axosomatic terminals arising from the ROb, RMg and GiA. The present results indicated that proprioceptive sensory signals from the muscle spindles or periodontal ligament might be modulated at the level of the primary afferent cell bodies in the MTN by 5HT-containing axons from the mesopontine and medullary raphe nuclei including the GiA.

Prostaglandin potentiates 5-HT responses in stomach and ileum innervating visceral afferent sensory neurons

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

Kim, Sojin; Jin, Zhenhua; Lee, Goeun

2015-01-02

Highlights: • Prostaglandin E2 (PGE{sub 2}) effect was tested on visceral afferent neurons. • PGE{sub 2} did not evoke response but potentiated serotonin (5-HT) currents up to 167%. • PGE{sub 2}-induced potentiation was blocked by E-prostanoid type 4 receptors antagonist. • PGE{sub 2} effect on 5-HT response was also blocked by protein kinase A inhibitor KT5720. • Thus, PGE{sub 2} modulate visceral afferent neurons via synergistic signaling with 5-HT. - Abstract: Gastrointestinal disorder is a common symptom induced by diverse pathophysiological conditions that include food tolerance, chemotherapy, and irradiation for therapy. Prostaglandin E{sub 2} (PGE{sub 2}) level increase was oftenmore » reported during gastrointestinal disorder and prostaglandin synthetase inhibitors has been used for ameliorate the symptoms. Exogenous administration of PGE{sub 2} induces gastrointestinal disorder, however, the mechanism of action is not known. Therefore, we tested PGE{sub 2} effect on visceral afferent sensory neurons of the rat. Interestingly, PGE{sub 2} itself did not evoked any response but enhanced serotonin (5-HT)-evoked currents up to 167% of the control level. The augmented 5-HT responses were completely inhibited by a 5-HT type 3 receptor antagonist, ondansetron. The PGE{sub 2}-induced potentiation were blocked by a selective E-prostanoid type4 (EP{sub 4}) receptors antagonist, L-161,982, but type1 and 2 receptor antagonist AH6809 has no effect. A membrane permeable protein kinase A (PKA) inhibitor, KT5720 also inhibited PGE{sub 2} effects. PGE{sub 2} induced 5-HT current augmentation was observed on 15% and 21% of the stomach and ileum projecting neurons, respectively. Current results suggest a synergistic signaling in visceral afferent neurons underlying gastrointestinal disorder involving PGE{sub 2} potentiation of 5-HT currents. Our findings may open a possibility for screen a new type drugs with lower side effects than currently using steroidal

Allergen challenge sensitizes TRPA1 in vagal sensory neurons and afferent C-fiber subtypes in guinea pig esophagus.

PubMed

Liu, Zhenyu; Hu, Youtian; Yu, Xiaoyun; Xi, Jiefeng; Fan, Xiaoming; Tse, Chung-Ming; Myers, Allen C; Pasricha, Pankaj J; Li, Xingde; Yu, Shaoyong

2015-03-15

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. Copyright © 2015 the American Physiological Society.

Allergen challenge sensitizes TRPA1 in vagal sensory neurons and afferent C-fiber subtypes in guinea pig esophagus

PubMed Central

Liu, Zhenyu; Hu, Youtian; Yu, Xiaoyun; Xi, Jiefeng; Fan, Xiaoming; Tse, Chung-Ming; Myers, Allen C.; Pasricha, Pankaj J.; Li, Xingde

2015-01-01

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

Mutant TDP-43 in motor neurons promotes the onset and progression of ALS in rats

PubMed Central

Huang, Cao; Tong, Jianbin; Bi, Fangfang; Zhou, Hongxia; Xia, Xu-Gang

2011-01-01

Amyotrophic lateral sclerosis (ALS) is characterized by progressive motor neuron degeneration, which ultimately leads to paralysis and death. Mutation of TAR DNA binding protein 43 (TDP-43) has been linked to the development of an inherited form of ALS. Existing TDP-43 transgenic animals develop a limited loss of motor neurons and therefore do not faithfully reproduce the core phenotype of ALS. Here, we report the creation of multiple lines of transgenic rats in which expression of ALS-associated mutant human TDP-43 is restricted to either motor neurons or other types of neurons and skeletal muscle and can be switched on and off. All of these rats developed progressive paralysis reminiscent of ALS when the transgene was switched on. Rats expressing mutant TDP-43 in motor neurons alone lost more spinal motor neurons than rats expressing the disease gene in varying neurons and muscle cells, although these rats all developed remarkable denervation atrophy of skeletal muscles. Intriguingly, progression of the disease was halted after transgene expression was switched off; in rats with limited loss of motor neurons, we observed a dramatic recovery of motor function, but in rats with profound loss of motor neurons, we only observed a moderate recovery of motor function. Our finding suggests that mutant TDP-43 in motor neurons is sufficient to promote the onset and progression of ALS and that motor neuron degeneration is partially reversible, at least in mutant TDP-43 transgenic rats. PMID:22156203

Protocol for culturing sympathetic neurons from rat superior cervical ganglia (SCG).

PubMed

Zareen, Neela; Greene, Lloyd A

2009-01-30

The superior cervical ganglia (SCG) in rats are small, glossy, almond-shaped structures that contain sympathetic neurons. These neurons provide sympathetic innervations for the head and neck regions and they constitute a well-characterized and relatively homogeneous population (4). Sympathetic neurons are dependent on nerve growth factor (NGF) for survival, differentiation and axonal growth and the wide-spread availability of NGF facilitates their culture and experimental manipulation (2, 3, 6). For these reasons, cultured sympathetic neurons have been used in a wide variety of studies including neuronal development and differentiation, mechanisms of programmed and pathological cell death, and signal transduction (1, 2, 5, and 6). Dissecting out the SCG from newborn rats and culturing sympathetic neurons is not very complicated and can be mastered fairly quickly. In this article, we will describe in detail how to dissect out the SCG from newborn rat pups and to use them to establish cultures of sympathetic neurons. The article will also describe the preparatory steps and the various reagents and equipment that are needed to achieve this.

Immunohistochemical localization of two types of choline acetyltransferase in neurons and sensory cells of the octopus arm.

PubMed

Sakaue, Yuko; Bellier, Jean-Pierre; Kimura, Shin; D'Este, Loredana; Takeuchi, Yoshihiro; Kimura, Hiroshi

2014-01-01

Cholinergic structures in the arm of the cephalopod Octopus vulgaris were studied by immunohistochemistry using specific antisera for two types (common and peripheral) of acetylcholine synthetic enzyme choline acetyltransferase (ChAT): antiserum raised against the rat common type ChAT (cChAT), which is cross-reactive with molluscan cChAT, and antiserum raised against the rat peripheral type ChAT (pChAT), which has been used to delineate peripheral cholinergic structures in vertebrates, but not previously in invertebrates. Western blot analysis of octopus extracts revealed a single pChAT-positive band, suggesting that pChAT antiserum is cross-reactive with an octopus counterpart of rat pChAT. In immunohistochemistry, only neuronal structures of the octopus arm were stained by cChAT and pChAT antisera, although the pattern of distribution clearly differed between the two antisera. cChAT-positive varicose nerve fibers were observed in both the cerebrobrachial tract and neuropil of the axial nerve cord, while pChAT-positive varicose fibers were detected only in the neuropil of the axial nerve cord. After epitope retrieval, pChAT-positive neuronal cells and their processes became visible in all ganglia of the arm, including the axial and intramuscular nerve cords, and in ganglia of suckers. Moreover, pChAT-positive structures also became detectable in nerve fibers connecting the different ganglia, in smooth nerve fibers among muscle layers and dermal connective tissues, and in sensory cells of the suckers. These results suggest that the octopus arm has two types of cholinergic nerves: cChAT-positive nerves from brain ganglia and pChAT-positive nerves that are intrinsic to the arm.

Nociceptor sensory neurons suppress neutrophil and γδ T cell responses in bacterial lung infections and lethal pneumonia.

PubMed

Baral, Pankaj; Umans, Benjamin D; Li, Lu; Wallrapp, Antonia; Bist, Meghna; Kirschbaum, Talia; Wei, Yibing; Zhou, Yan; Kuchroo, Vijay K; Burkett, Patrick R; Yipp, Bryan G; Liberles, Stephen D; Chiu, Isaac M

2018-05-01

Lung-innervating nociceptor sensory neurons detect noxious or harmful stimuli and consequently protect organisms by mediating coughing, pain, and bronchoconstriction. However, the role of sensory neurons in pulmonary host defense is unclear. Here, we found that TRPV1 + nociceptors suppressed protective immunity against lethal Staphylococcus aureus pneumonia. Targeted TRPV1 + -neuron ablation increased survival, cytokine induction, and lung bacterial clearance. Nociceptors suppressed the recruitment and surveillance of neutrophils, and altered lung γδ T cell numbers, which are necessary for immunity. Vagal ganglia TRPV1 + afferents mediated immunosuppression through release of the neuropeptide calcitonin gene-related peptide (CGRP). Targeting neuroimmunological signaling may be an effective approach to treat lung infections and bacterial pneumonia.

Developmental emergence of different forms of neuromodulation in Aplysia sensory neurons.

PubMed

Marcus, E A; Carew, T J

1998-04-14

The capacity for neuromodulation and biophysical plasticity is a defining feature of most mature neuronal cell types. In several cases, modulation at the level of the individual neuron has been causally linked to changes in the functional output of a neuronal circuit and subsequent adaptive changes in the organism's behavioral responses. Understanding how such capacity for neuromodulation develops therefore may provide insights into the mechanisms both of neuronal development and learning and memory. We have examined the development of multiple forms of neuromodulation triggered by a common neurotransmitter, serotonin, in the pleural sensory neurons of Aplysia californica. We have found that multiple signaling cascades within a single neuron develop sequentially, with some being expressed only very late in development. In addition, our data suggest a model in which, within a single neuromodulatory pathway, the elements of the signaling cascade are developmentally expressed in a "retrograde" manner with the ionic channel that is modulated appearing early in development, functional elements in the second messenger cascade appearing later, and finally, coupling of the second messenger cascade to the serotonin receptor appearing quite late. These studies provide the characterization of the development of neuromodulation at the level of an identified cell type and offer insights into the potential roles of neuromodulatory processes in development and adult plasticity.

Aging and amyloid β oligomers enhance TLR4 expression, LPS-induced Ca2+ responses, and neuron cell death in cultured rat hippocampal neurons.

PubMed

Calvo-Rodríguez, María; de la Fuente, Carmen; García-Durillo, Mónica; García-Rodríguez, Carmen; Villalobos, Carlos; Núñez, Lucía

2017-01-31

Toll-like receptors (TLRs) are transmembrane pattern-recognition receptors of the innate immune system recognizing diverse pathogen-derived and tissue damage-related ligands. It has been suggested that TLR signaling contributes to the pathogenesis of age-related, neurodegenerative diseases, including Alzheimer's disease (AD). AD is associated to oligomers of the amyloid β peptide (Aβo) that cause intracellular Ca 2+ dishomeostasis and neuron cell death in rat hippocampal neurons. Here we assessed the interplay between inflammation and Aβo in long-term cultures of rat hippocampal neurons, an in vitro model of neuron aging and/or senescence. Ca 2+ imaging and immunofluorescence against annexin V and TLR4 were applied in short- and long-term cultures of rat hippocampal neurons to test the effects of TLR4-agonist LPS and Aβo on cytosolic [Ca 2+ ] and on apoptosis as well as on expression of TLR4. LPS increases cytosolic [Ca 2+ ] and promotes apoptosis in rat hippocampal neurons in long-term culture considered aged and/or senescent neurons, but not in short-term cultured neurons considered young neurons. TLR4 antagonist CAY10614 prevents both effects. TLR4 expression in rat hippocampal neurons is significantly larger in aged hippocampal cultures. Treatment of aged hippocampal cultures with Aβo increases TLR4 expression and enhances LPS-induced Ca 2+ responses and neuron cell death. Aging and amyloid β oligomers, the neurotoxin involved in Alzheimer's disease, enhance TLR4 expression as well as LPS-induced Ca 2+ responses and neuron cell death in rat hippocampal neurons aged in vitro.

[Effect of spontaneous firing of injured dorsal root ganglion neuron on excitability of wide dynamic range neuron in rat spinal dorsal horn].

PubMed

Song, Ying; Zhang, Yong-Mei; Xu, Jie; Wu, Jing-Ru; Qin, Xia; Hua, Rong

2013-10-25

The aim of the paper is to study the effect of spontaneous firing of injured dorsal root ganglion (DRG) neuron in chronic compression of DRG (CCD) model on excitability of wide dynamic range (WDR) neuron in rat spinal dorsal horn. In vivo intracellular recording was done in DRG neurons and in vivo extracellular recording was done in spinal WDR neurons. After CCD, incidence of spontaneous discharge and firing frequency enhanced to 59.46% and (4.30 ± 0.69) Hz respectively from 22.81% and (0.60 ± 0.08) Hz in normal control group (P < 0.05). Local administration of 50 nmol/L tetrodotoxin (TTX) on DRG neuron in CCD rats decreased the spontaneous activities of WDR neurons from (191.97 ± 45.20)/min to (92.50 ± 30.32)/min (P < 0.05). On the other side, local administration of 100 mmol/L KCl on DRG neuron evoked spontaneous firing in a reversible way (n = 5) in silent WDR neurons of normal rats. There was 36.36% (12/33) WDR neuron showing after-discharge in response to innocuous mechanical stimuli on cutaneous receptive field in CCD rats, while after-discharge was not seen in control rats. Local administration of TTX on DRG with a concentration of 50 nmol/L attenuated innocuous electric stimuli-evoked after-discharge of WDR neurons in CCD rats in a reversible manner, and the frequency was decreased from (263 ± 56.5) Hz to (117 ± 30) Hz (P < 0.05). The study suggests that the excitability of WDR neurons is influenced by spontaneous firings of DRG neurons after CCD.

Impaired adenosine monophosphate-activated protein kinase signalling in dorsal root ganglia neurons is linked to mitochondrial dysfunction and peripheral neuropathy in diabetes.

PubMed

Roy Chowdhury, Subir K; Smith, Darrell R; Saleh, Ali; Schapansky, Jason; Marquez, Alexandra; Gomes, Suzanne; Akude, Eli; Morrow, Dwane; Calcutt, Nigel A; Fernyhough, Paul

2012-06-01

Mitochondrial dysfunction occurs in sensory neurons and may contribute to distal axonopathy in animal models of diabetic neuropathy. The adenosine monophosphate-activated protein kinase and peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) signalling axis senses the metabolic demands of cells and regulates mitochondrial function. Studies in muscle, liver and cardiac tissues have shown that the activity of adenosine monophosphate-activated protein kinase and PGC-1α is decreased under hyperglycaemia. In this study, we tested the hypothesis that deficits in adenosine monophosphate-activated protein kinase/PGC-1α signalling in sensory neurons underlie impaired axonal plasticity, suboptimal mitochondrial function and development of neuropathy in rodent models of type 1 and type 2 diabetes. Phosphorylation and expression of adenosine monophosphate-activated protein kinase/PGC-1α and mitochondrial respiratory chain complex proteins were downregulated in dorsal root ganglia of both streptozotocin-diabetic rats and db/db mice. Adenoviral-mediated manipulation of endogenous adenosine monophosphate-activated protein kinase activity using mutant proteins modulated neurotrophin-directed neurite outgrowth in cultures of sensory neurons derived from adult rats. Addition of resveratrol to cultures of sensory neurons derived from rats after 3-5 months of streptozotocin-induced diabetes, significantly elevated adenosine monophosphate-activated protein kinase levels, enhanced neurite outgrowth and normalized mitochondrial inner membrane polarization in axons. The bioenergetics profile (maximal oxygen consumption rate, coupling efficiency, respiratory control ratio and spare respiratory capacity) was aberrant in cultured sensory neurons from streptozotocin-diabetic rats and was corrected by resveratrol treatment. Finally, resveratrol treatment for the last 2 months of a 5-month period of diabetes reversed thermal hypoalgesia and attenuated foot skin

Impaired adenosine monophosphate-activated protein kinase signalling in dorsal root ganglia neurons is linked to mitochondrial dysfunction and peripheral neuropathy in diabetes

PubMed Central

Smith, Darrell R.; Saleh, Ali; Schapansky, Jason; Marquez, Alexandra; Gomes, Suzanne; Akude, Eli; Morrow, Dwane; Calcutt, Nigel A.; Fernyhough, Paul

2012-01-01

Mitochondrial dysfunction occurs in sensory neurons and may contribute to distal axonopathy in animal models of diabetic neuropathy. The adenosine monophosphate-activated protein kinase and peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) signalling axis senses the metabolic demands of cells and regulates mitochondrial function. Studies in muscle, liver and cardiac tissues have shown that the activity of adenosine monophosphate-activated protein kinase and PGC-1α is decreased under hyperglycaemia. In this study, we tested the hypothesis that deficits in adenosine monophosphate-activated protein kinase/PGC-1α signalling in sensory neurons underlie impaired axonal plasticity, suboptimal mitochondrial function and development of neuropathy in rodent models of type 1 and type 2 diabetes. Phosphorylation and expression of adenosine monophosphate-activated protein kinase/PGC-1α and mitochondrial respiratory chain complex proteins were downregulated in dorsal root ganglia of both streptozotocin-diabetic rats and db/db mice. Adenoviral-mediated manipulation of endogenous adenosine monophosphate-activated protein kinase activity using mutant proteins modulated neurotrophin-directed neurite outgrowth in cultures of sensory neurons derived from adult rats. Addition of resveratrol to cultures of sensory neurons derived from rats after 3–5 months of streptozotocin-induced diabetes, significantly elevated adenosine monophosphate-activated protein kinase levels, enhanced neurite outgrowth and normalized mitochondrial inner membrane polarization in axons. The bioenergetics profile (maximal oxygen consumption rate, coupling efficiency, respiratory control ratio and spare respiratory capacity) was aberrant in cultured sensory neurons from streptozotocin-diabetic rats and was corrected by resveratrol treatment. Finally, resveratrol treatment for the last 2 months of a 5-month period of diabetes reversed thermal hypoalgesia and attenuated foot skin

Proper development of relay somatic sensory neurons and D2/D4 interneurons requires homeobox genes Rnx/Tlx-3 and Tlx-1

PubMed Central

Qian, Ying; Shirasawa, Senji; Chen, Chih-Li; Cheng, Leping; Ma, Qiufu

2002-01-01

Trigeminal nuclei and the dorsal spinal cord are first-order relay stations for processing somatic sensory information such as touch, pain, and temperature. The origins and development of these neurons are poorly understood. Here we show that relay somatic sensory neurons and D2/D4 dorsal interneurons likely derive from Mash1-positive neural precursors, and depend on two related homeobox genes, Rnx and Tlx-1, for proper formation. Rnx and Tlx-1 maintain expression of Drg11, a homeobox gene critical for the development of pain circuitry, and are essential for the ingrowth of trkA+ nociceptive/thermoceptive sensory afferents to their central targets. We showed previously that Rnx is necessary for proper formation of the nucleus of solitary tract, the target for visceral sensory afferents. Together, our studies demonstrate a central role for Rnx and Tlx-1 in the development of two major classes of relay sensory neurons, somatic and visceral. PMID:12023301

Proper development of relay somatic sensory neurons and D2/D4 interneurons requires homeobox genes Rnx/Tlx-3 and Tlx-1.

PubMed

Qian, Ying; Shirasawa, Senji; Chen, Chih-Li; Cheng, Leping; Ma, Qiufu

2002-05-15

Trigeminal nuclei and the dorsal spinal cord are first-order relay stations for processing somatic sensory information such as touch, pain, and temperature. The origins and development of these neurons are poorly understood. Here we show that relay somatic sensory neurons and D2/D4 dorsal interneurons likely derive from Mash1-positive neural precursors, and depend on two related homeobox genes, Rnx and Tlx-1, for proper formation. Rnx and Tlx-1 maintain expression of Drg11, a homeobox gene critical for the development of pain circuitry, and are essential for the ingrowth of trkA+ nociceptive/thermoceptive sensory afferents to their central targets. We showed previously that Rnx is necessary for proper formation of the nucleus of solitary tract, the target for visceral sensory afferents. Together, our studies demonstrate a central role for Rnx and Tlx-1 in the development of two major classes of relay sensory neurons, somatic and visceral.

Ensemble Recordings in Awake Rats: Achieving Behavioral Regularity during Multimodal Stimulus Processing and Discriminative Learning

ERIC Educational Resources Information Center

Lee, Eunjeong; Oliveira-Ferreira, Ana I.; de Water, Ed; Gerritsen, Hans; Bakker, Mattijs C.; Kalwij, Jan A. W.; van Goudoever, Tjerk; Buster, Wietze H.; Pennartz, Cyriel M. A.

2009-01-01

To meet an increasing need to examine the neurophysiological underpinnings of behavior in rats, we developed a behavioral system for studying sensory processing, attention and discrimination learning in rats while recording firing patterns of neurons in one or more brain areas of interest. Because neuronal activity is sensitive to variations in…

CHARACTERIZATION OF UPPER THORACIC SPINAL NEURONS RESPONDING TO ESOPHAGEAL DISTENSION IN DIABETIC RATS

PubMed Central

Qin, Chao; Ghorbani, Marie L. M.; Wu, Mingyuan; Farber, Jay P.; Ma, Jianxin; Foreman, Robert D.

2009-01-01

The aim of this study was to examine spinal neuronal processing of innocuous and noxious mechanical inputs from the esophagus in diabetic rats. Streptozotocin (50 mg/kg, ip) was used to induce diabetes in 15 male Sprague-Dawley rats, and vehicle (10 mM citrate buffer) was injected into 15 rats as control. Four to eleven weeks after injections, extracellular potentials of single thoracic (T3) spinal neurons were recorded in pentobarbital anesthetized, paralyzed, and ventilated rats. Esophageal distensions (ED, 0.2, 0.4 ml, 20s) were produced by water inflation of a latex balloon in the thoracic esophagus. Noxious ED (0.4 ml, 20 s) altered activity of 44% (55/126) and 38% (50/132) of spinal neurons in diabetic and control rats, respectively. The short-lasting excitatory responses to ED were encountered more frequently in diabetic rats (27/42 vs 15/41, P<0.05). Spinal neurons with low threshold for excitatory responses to ED were more frequently encountered in diabetic rats (33/42 vs 23/41, P<0.05). However, mean excitatory responses and duration of responses to noxious ED were significantly reduced for high-threshold neurons in diabetic rats (7.4±1.1 vs 13.9±3.3 imp/s; 19.0±2.3 vs 31.2±5.5 s; P<0.05). In addition, more large size somatic receptive fields were found for spinal neurons with esophageal input in diabetic rats than in control rats (28/42 vs 19/45, P<0.05). These results suggested that diabetes influenced response characteristics of thoracic spinal neurons receiving mechanical esophageal input, which might indicate an altered spinal visceroceptive processing underlying diabetic esophageal neuropathy. PMID:19027368

Possible involvement of transient receptor potential ankyrin 1 in Ca2+ signaling via T-type Ca2+ channel in mouse sensory neurons.

PubMed

Nishizawa, Yuki; Takahashi, Kenji; Oguma, Naoko; Tominaga, Makoto; Ohta, Toshio

2018-05-01

T-type Ca 2+ channels and TRPA1 are expressed in sensory neurons and both are associated with pain transmission, but their functional interaction is unclear. Here we demonstrate that pharmacological evidence of the functional relation between T-type Ca 2+ channels and TRPA1 in mouse sensory neurons. Low concentration of KCl at 15 mM (15K) evoked increases of intracellular Ca 2+ concentration ([Ca 2+ ] i ), which were suppressed by selective T-type Ca 2+ channel blockers. RT-PCR showed that mouse sensory neurons expressed all subtypes of T-type Ca 2+ channel. The magnitude of 15K-induced [Ca 2+ ] i increase was significantly larger in neurons sensitive to allylisothiocyanate (AITC, a TRPA1 agonist) than in those insensitive to it, and in TRPA1 -/- mouse sensory neurons. TRPA1 blockers diminished the [Ca 2+ ] i responses to 15K in neurons sensitive to AITC, but failed to inhibit 40 mM KCl-induced [Ca 2+ ] i increases even in AITC-sensitive neurons. TRPV1 blockers did not inhibit the 15K-induced [Ca 2+ ] i increase regardless of the sensitivity to capsaicin. [Ca 2+ ] i responses to TRPA1 agonist were enhanced by co-application with 15K. These pharmacological data suggest the possibility of functional interaction between T-type Ca 2+ channels and TRPA1 in sensory neurons. Since TRPA1 channel is activated by intracellular Ca 2+ , we hypothesize that Ca 2+ entered via T-type Ca 2+ channel activation may further stimulate TRPA1, resulting in an enhancement of nociceptive signaling. Thus, T-type Ca 2+ channel may be a potential target for TRPA1-related pain. © 2017 Wiley Periodicals, Inc.

Rehabilitation modality and onset differentially influence whisker sensory hypersensitivity after diffuse traumatic brain injury in the rat.

PubMed

Thomas, Theresa Currier; Stockhausen, Ellen Magee; Law, L Matthew; Khodadad, Aida; Lifshitz, Jonathan

2017-01-01

As rehabilitation strategies advance as therapeutic interventions, the modality and onset of rehabilitation after traumatic brain injury (TBI) are critical to optimize treatment. Our laboratory has detected and characterized a late-onset, long-lasting sensory hypersensitivity to whisker stimulation in diffuse brain-injured rats; a deficit that is comparable to visual or auditory sensory hypersensitivity in humans with an acquired brain injury. We hypothesize that the modality and onset of rehabilitation therapies will differentially influence sensory hypersensitivity in response to the Whisker Nuisance Task (WNT) as well as WNT-induced corticosterone (CORT) stress response in diffuse brain-injured rats and shams. After midline fluid percussion brain injury (FPI) or sham surgery, rats were assigned to one of four rehabilitative interventions: (1) whisker sensory deprivation during week one or (2) week two or (3) whisker stimulation during week one or (4) week two. At 28 days following FPI and sham procedures, sensory hypersensitivity was assessed using the WNT. Plasma CORT was evaluated immediately following the WNT (aggravated levels) and prior to the pre-determined endpoint 24 hours later (non-aggravated levels). Deprivation therapy during week two elicited significantly greater sensory hypersensitivity to the WNT compared to week one (p < 0.05), and aggravated CORT levels in FPI rats were significantly lower than sham levels. Stimulation therapy during week one resulted in low levels of sensory hypersensitivity to the WNT, similar to deprivation therapy and naïve controls, however, non-aggravated CORT levels in FPI rats were significantly higher than sham. These data indicate that modality and onset of sensory rehabilitation can differentially influence FPI and sham rats, having a lasting impact on behavioral and stress responses to the WNT, emphasizing the necessity for continued evaluation of modality and onset of rehabilitation after TBI.

Stress Hormones Epinephrine and Corticosterone Selectively Modulate Herpes Simplex Virus 1 (HSV-1) and HSV-2 Productive Infections in Adult Sympathetic, but Not Sensory, Neurons

PubMed Central

Ives, Angela M.

2017-01-01

ABSTRACT Herpes simplex viruses 1 and 2 (HSV-1 and HSV-2) infect and establish latency in peripheral neurons, from which they can reactivate to cause recurrent disease throughout the life of the host. Stress is associated with the exacerbation of clinical symptoms and the induction of recurrences in humans and animal models. The viruses preferentially replicate and establish latency in different subtypes of sensory neurons, as well as in neurons of the autonomic nervous system that are highly responsive to stress hormones. To determine if stress-related hormones modulate productive HSV-1 and HSV-2 infections within sensory and autonomic neurons, we analyzed viral DNA and the production of viral progeny after treatment of primary adult murine neuronal cultures with the stress hormones epinephrine and corticosterone. Both sensory trigeminal ganglion (TG) and sympathetic superior cervical ganglion (SCG) neurons expressed adrenergic receptors (activated by epinephrine) and the glucocorticoid receptor (activated by corticosterone). Productive HSV infection colocalized with these receptors in SCG but not in TG neurons. In productively infected neuronal cultures, epinephrine treatment significantly increased the levels of HSV-1 DNA replication and production of viral progeny in SCG neurons, but no significant differences were found in TG neurons. In contrast, corticosterone significantly decreased the levels of HSV-2 DNA replication and production of viral progeny in SCG neurons but not in TG neurons. Thus, the stress-related hormones epinephrine and corticosterone selectively modulate acute HSV-1 and HSV-2 infections in autonomic, but not sensory, neurons. IMPORTANCE Stress exacerbates acute disease symptoms resulting from HSV-1 and HSV-2 infections and is associated with the appearance of recurrent skin lesions in millions of people. Although stress hormones are thought to impact HSV-1 and HSV-2 through immune system suppression, sensory and autonomic neurons that

Damage of hippocampal neurons in rats with chronic alcoholism.

PubMed

Du, Ailin; Jiang, Hongbo; Xu, Lei; An, Na; Liu, Hui; Li, Yinsheng; Zhang, Ruiling

2014-09-01

Chronic alcoholism can damage the cytoskeleton and aggravate neurological deficits. However, the effect of chronic alcoholism on hippocampal neurons remains unclear. In this study, a model of chronic alcoholism was established in rats that were fed with 6% alcohol for 42 days. Endogenous hydrogen sulfide content and cystathionine-beta-synthase activity in the hippocampus of rats with chronic alcoholism were significantly increased, while F-actin expression was decreased. Hippocampal neurons in rats with chronic alcoholism appeared to have a fuzzy nuclear membrane, mitochondrial edema, and ruptured mitochondrial crista. These findings suggest that chronic alcoholism can cause learning and memory decline in rats, which may be associated with the hydrogen sulfide/cystathionine-beta-synthase system, mitochondrial damage and reduced expression of F-actin.

Expression of vesicular glutamate transporters in transient receptor potential ankyrin 1 (TRPA1)-positive neurons in the rat trigeminal ganglion.

PubMed

Kim, Yun Sook; Kim, Sung Kuk; Lee, Jae Sik; Ko, Sang Jin; Bae, Yong Chul

2018-07-01

Transient receptor potential ankyrin 1 (TRPA1), a cold receptor in sensory neurons activated by a variety of stimuli, is implicated in nociception and mechanotransduction. To help understand the vesicular glutamate transporter (VGLUT)-mediated glutamate signaling in TRPA1-immunopositive (+) neurons, we examined the expression of VGLUT1 and VGLUT2 in the TRPA1+ neurons in the male rat trigeminal ganglion (n = 19) under normal conditions and following experimental inflammation in the vibrissal pad by light microscopic immunohistochemistry (n = 11), western blot (n = 8), and quantitative analysis. One half (50.8%, 250/492) of the TRPA1+ neurons expressed VGLUT2, and a small fraction (8.3%, 57/683) also expressed VGLUT1. The majority of the VGLUT2-expressing TRPA1+ (VGLUT2+/TRPA1+) neurons coexpressed the markers of peptidergic and non-peptidergic neurons, CGRP, IB4, and TRPV1 but not the markers of neurons with myelinated fibers, NF200 and parvalbumin. In contrast, most VGLUT1+/TRPA1+ neurons coexpressed NF200 and parvalbumin but rarely expressed CGRP, IB4, or TRPV1. Following experimental inflammation, the fraction of VGLUT2+ (experimental vs. control: 34.7% vs. 22.3%), TRPA1+ (39.3% vs. 25.3%), and VGLUT2+/TRPA1+ (60.7% vs. 49.7%) neurons and the protein levels for TRPA1 and VGLUT2 increased significantly, compared to control, whereas the fraction of VGLUT1+ and VGLUT1+/TRPA1+ neurons and the protein level for VGLUT1 remained unchanged. These findings suggest that both VGLUT1 and VGLUT2 are involved in the glutamate signaling in TRPA1+ neurons under normal conditions in the male rats, and raise a possibility that VGLUT2 may play a role in the TRPA1-induced hypersensitivity following inflammation. Copyright © 2018 Elsevier B.V. All rights reserved.

Botulinum toxin decreases hyperalgesia and inhibits P2X3 receptor over-expression in sensory neurons induced by ventral root transection in rats.

PubMed

Xiao, Lizu; Cheng, Jianguo; Dai, Juanli; Zhang, Deren

2011-09-01

We aim to determine the effects of Botulinum toxin type A (BTX-A) on neuropathic pain behavior and the expression of P2X(3) receptor in dorsal root ganglion (DRG) in rats with neuropathic pain induced by L5 ventral root transection (L5 VRT). Neuropathic pain was induced by L5 VRT in male Sprague-Dawley rats. Either saline or BTX-A was administered to the plantar surface. Behavioral tests were conducted preoperatively and at predefined postoperative days. The expression of P2X(3) receptors in DRG neurons was detected by immunoreactivity at postoperative days 3, 7, 14, and 21. The number of positive P2X(3) neurons in the ipsilateral L5 DRG increased significantly after L5 VRT (P<0.001). This increase persisted for at least 3 weeks after the operation. No significant changes in P2X(3) expression were detected in the contralateral L5, or in the L4 DRGs bilaterally. Subcutaneous administration of BTX-A, performed on the left hindpaw at days 4, 8, or 16 post VRT surgery, significantly reduced mechanical allodynia bilaterally and inhibited P2X(3) over-expression induced by L5 VRT. L5 VRT led to over-expression of P2X(3) receptors in the L5 DRG and bilateral mechanical allodynia in rats. Subcutaneous injection of BTX-A significantly reversed the neuropathic pain behavior and the over-expression of P2X(3) receptor in nociceptive neurons. These data not only show over-expression of purinergic receptors in the VRT model of neuropathic pain but also reveal a novel mechanism of botulinum toxin action on nociceptive neurons. Wiley Periodicals, Inc.

Motion makes sense: an adaptive motor-sensory strategy underlies the perception of object location in rats.

PubMed

Saraf-Sinik, Inbar; Assa, Eldad; Ahissar, Ehud

2015-06-10

Tactile perception is obtained by coordinated motor-sensory processes. We studied the processes underlying the perception of object location in freely moving rats. We trained rats to identify the relative location of two vertical poles placed in front of them and measured at high resolution the motor and sensory variables (19 and 2 variables, respectively) associated with this whiskers-based perceptual process. We found that the rats developed stereotypic head and whisker movements to solve this task, in a manner that can be described by several distinct behavioral phases. During two of these phases, the rats' whiskers coded object position by first temporal and then angular coding schemes. We then introduced wind (in two opposite directions) and remeasured their perceptual performance and motor-sensory variables. Our rats continued to perceive object location in a consistent manner under wind perturbations while maintaining all behavioral phases and relatively constant sensory coding. Constant sensory coding was achieved by keeping one group of motor variables (the "controlled variables") constant, despite the perturbing wind, at the cost of strongly modulating another group of motor variables (the "modulated variables"). The controlled variables included coding-relevant variables, such as head azimuth and whisker velocity. These results indicate that consistent perception of location in the rat is obtained actively, via a selective control of perception-relevant motor variables. Copyright © 2015 the authors 0270-6474/15/358777-13$15.00/0.

Dying neurons in thalamus of asphyxiated term newborns and rats are autophagic.

PubMed

Ginet, Vanessa; Pittet, Marie P; Rummel, Coralie; Osterheld, Maria Chiara; Meuli, Reto; Clarke, Peter G H; Puyal, Julien; Truttmann, Anita C

2014-11-01

Neonatal hypoxic-ischemic encephalopathy (HIE) still carries a high burden by its mortality and long-term neurological morbidity in survivors. Apart from hypothermia, there is no acknowledged therapy for HIE, reflecting the lack of mechanistic understanding of its pathophysiology. (Macro)autophagy, a physiological intracellular process of lysosomal degradation, has been proposed to be excessively activated in excitotoxic conditions such as HIE. The present study examines whether neuronal autophagy in the thalamus of asphyxiated human newborns or P7 rats is enhanced and related to neuronal death processes. Neuronal autophagy and cell death were evaluated in the thalamus (frequently injured in severe HIE) of both human newborns who died after severe HIE (n = 5) and P7 hypoxic-ischemic rats (Rice-Vannuci model). Autophagic (LC3, p62), lysosomal (LAMP1, cathepsins), and cell death (TUNEL, caspase-3) markers were studied by immunohistochemistry in human and rat brain sections, and by additional methods in rats (immunoblotting, histochemistry, and electron microscopy). Following severe perinatal asphyxia in both humans and rats, thalamic neurons displayed up to 10-fold (p < 0.001) higher numbers of autophagosomes and lysosomes, implying an enhanced autophagic flux. The highly autophagic neurons presented strong features of apoptosis. These findings were confirmed and elucidated in more detail in rats. These results show for the first time that autophagy is enhanced in severe HIE in dying thalamic neurons of human newborns, as in rats. Experimental neuroprotective strategies targeting autophagy could thus be a promising lead to follow for the development of future therapeutic approaches. © 2014 American Neurological Association.

Chronic hypoxia suppresses the CO2 response of solitary complex (SC) neurons from rats.

PubMed

Nichols, Nicole L; Wilkinson, Katherine A; Powell, Frank L; Dean, Jay B; Putnam, Robert W

2009-09-30

We studied the effect of chronic hypobaric hypoxia (CHx; 10-11% O(2)) on the response to hypercapnia (15% CO(2)) of individual solitary complex (SC) neurons from adult rats. We simultaneously measured the intracellular pH and firing rate responses to hypercapnia of SC neurons in superfused medullary slices from control and CHx-adapted adult rats using the blind whole cell patch clamp technique and fluorescence imaging microscopy. We found that CHx caused the percentage of SC neurons inhibited by hypercapnia to significantly increase from about 10% up to about 30%, but did not significantly alter the percentage of SC neurons activated by hypercapnia (50% in control vs. 35% in CHx). Further, the magnitudes of the responses of SC neurons from control rats (chemosensitivity index for activated neurons of 166+/-11% and for inhibited neurons of 45+/-15%) were the same in SC neurons from CHx-adapted rats. This plasticity induced in chemosensitive SC neurons by CHx appears to involve intrinsic changes in neuronal properties since they were the same in synaptic blockade medium.

Tissue engineering the mechanosensory circuit of the stretch reflex arc: sensory neuron innervation of intrafusal muscle fibers.

PubMed

Rumsey, John W; Das, Mainak; Bhalkikar, Abhijeet; Stancescu, Maria; Hickman, James J

2010-11-01

The sensory circuit of the stretch reflex arc, composed of specialized intrafusal muscle fibers and type Ia proprioceptive sensory neurons, converts mechanical information regarding muscle length and stretch to electrical action potentials and relays them to the central nervous system. Utilizing a non-biological substrate, surface patterning photolithography and a serum-free medium formulation a co-culture system was developed that facilitated functional interactions between intrafusal muscle fibers and sensory neurons. The presence of annulospiral wrappings (ASWs) and flower-spray endings (FSEs), both physiologically relevant morphologies in sensory neuron-intrafusal fiber interactions, were demonstrated and quantified using immunocytochemistry. Furthermore, two proposed components of the mammalian mechanosensory transduction system, BNaC1 and PICK1, were both identified at the ASWs and FSEs. To verify functionality of the mechanoreceptor elements the system was integrated with a MEMS cantilever device, and Ca(2+) currents were imaged along the length of an axon innervating an intrafusal fiber when stretched by cantilever deflection. This system provides a platform for examining the role of this mechanosensory complex in the pathology of myotonic and muscular dystrophies, peripheral neuropathy, and spasticity inducing diseases like Parkinson's. These studies will also assist in engineering fine motor control for prosthetic devices by improving our understanding of mechanosensitive feedback. Copyright (c) 2010 Elsevier Ltd. All rights reserved.

The Molecular Motor KIF1A Transports the TrkA Neurotrophin Receptor and Is Essential for Sensory Neuron Survival and Function.

PubMed

Tanaka, Yosuke; Niwa, Shinsuke; Dong, Ming; Farkhondeh, Atena; Wang, Li; Zhou, Ruyun; Hirokawa, Nobutaka

2016-06-15

KIF1A is a major axonal transport motor protein, but its functional significance remains elusive. Here we show that KIF1A-haploinsufficient mice developed sensory neuropathy. We found progressive loss of TrkA(+) sensory neurons in Kif1a(+/-) dorsal root ganglia (DRGs). Moreover, axonal transport of TrkA was significantly disrupted in Kif1a(+/-) neurons. Live imaging and immunoprecipitation assays revealed that KIF1A bound to TrkA-containing vesicles through the adaptor GTP-Rab3, suggesting that TrkA is a cargo of the KIF1A motor. Physiological measurements revealed a weaker capsaicin response in Kif1a(+/-) DRG neurons. Moreover, these neurons were hyposensitive to nerve growth factor, which could explain the reduced neuronal survival and the functional deficiency of the pain receptor TRPV1. Because phosphatidylinositol 3-kinase (PI3K) signaling significantly rescued these phenotypes and also increased Kif1a mRNA, we propose that KIF1A is essential for the survival and function of sensory neurons because of the TrkA transport and its synergistic support of the NGF/TrkA/PI3K signaling pathway. Copyright © 2016 Elsevier Inc. All rights reserved.

Stable olfactory sensory neuron in vivo physiology during normal aging.

PubMed

Kass, Marley D; Czarnecki, Lindsey A; McGann, John P

2018-05-08

Normal aging is associated with a number of smell impairments that are paralleled by age-dependent changes in the peripheral olfactory system, including decreases in olfactory sensory neurons (OSNs) and in the regenerative capacity of the epithelium. Thus, an age-dependent degradation of sensory input to the brain is one proposed mechanism for the loss of olfactory function in older populations. Here, we tested this hypothesis by performing in vivo optical neurophysiology in 6-, 12-, 18-, and 24-month-old mice. We visualized odor-evoked neurotransmitter release from populations of OSNs into olfactory bulb glomeruli, and found that these sensory inputs are actually quite stable during normal aging. Specifically, the magnitude and number of odor-evoked glomerular responses were comparable across all ages, and there was no effect of age on the sensitivity of OSN responses to odors or on the neural discriminability of different sensory maps. These results suggest that the brain's olfactory bulbs do not receive deteriorated input during aging and that local bulbar circuitry might adapt to maintain stable nerve input. Copyright © 2018 Elsevier Inc. All rights reserved.

Endosome-mediated retrograde axonal transport of P2X3 receptor signals in primary sensory neurons

PubMed Central

Chen, Xu-Qiao; Wang, Bin; Wu, Chengbiao; Pan, Jin; Yuan, Bo; Su, Yuan-Yuan; Jiang, Xing-Yu; Zhang, Xu; Bao, Lan

2012-01-01

Neurotrophins and their receptors adopt signaling endosomes to transmit retrograde signals. However, the mechanisms of retrograde signaling for other ligand/receptor systems are poorly understood. Here, we report that the signals of the purinergic (P)2X3 receptor, an ATP-gated ion channel, are retrogradely transported in dorsal root ganglion (DRG) neuron axons. We found that Rab5, a small GTPase, controls the early sorting of P2X3 receptors into endosomes, while Rab7 mediates the fast retrograde transport of P2X3 receptors. Intraplantar injection and axonal application into the microfluidic chamber of α, β-methylene-ATP (α, β-MeATP), a P2X selective agonist, enhanced the endocytosis and retrograde transport of P2X3 receptors. The α, β-MeATP-induced Ca2+ influx activated a pathway comprised of protein kinase C, rat sarcoma viral oncogene and extracellular signal-regulated protein kinase (ERK), which associated with endocytic P2X3 receptors to form signaling endosomes. Disruption of the lipid rafts abolished the α, β-MeATP-induced ERK phosphorylation, endocytosis and retrograde transport of P2X3 receptors. Furthermore, treatment of peripheral axons with α, β-MeATP increased the activation level of ERK and cAMP response element-binding protein in the cell bodies of DRG neurons and enhanced neuronal excitability. Impairment of either microtubule-based axonal transport in vivo or dynein function in vitro blocked α, β-MeATP-induced retrograde signals. These results indicate that P2X3 receptor-activated signals are transmitted via retrogradely transported endosomes in primary sensory neurons and provide a novel signaling mechanism for ligand-gated channels. PMID:22157653

Endosome-mediated retrograde axonal transport of P2X3 receptor signals in primary sensory neurons.

PubMed

Chen, Xu-Qiao; Wang, Bin; Wu, Chengbiao; Pan, Jin; Yuan, Bo; Su, Yuan-Yuan; Jiang, Xing-Yu; Zhang, Xu; Bao, Lan

2012-04-01

Neurotrophins and their receptors adopt signaling endosomes to transmit retrograde signals. However, the mechanisms of retrograde signaling for other ligand/receptor systems are poorly understood. Here, we report that the signals of the purinergic (P)2X(3) receptor, an ATP-gated ion channel, are retrogradely transported in dorsal root ganglion (DRG) neuron axons. We found that Rab5, a small GTPase, controls the early sorting of P2X(3) receptors into endosomes, while Rab7 mediates the fast retrograde transport of P2X(3) receptors. Intraplantar injection and axonal application into the microfluidic chamber of α, β-methylene-ATP (α, β-MeATP), a P2X selective agonist, enhanced the endocytosis and retrograde transport of P2X(3) receptors. The α, β-MeATP-induced Ca(2+) influx activated a pathway comprised of protein kinase C, rat sarcoma viral oncogene and extracellular signal-regulated protein kinase (ERK), which associated with endocytic P2X(3) receptors to form signaling endosomes. Disruption of the lipid rafts abolished the α, β-MeATP-induced ERK phosphorylation, endocytosis and retrograde transport of P2X(3) receptors. Furthermore, treatment of peripheral axons with α, β-MeATP increased the activation level of ERK and cAMP response element-binding protein in the cell bodies of DRG neurons and enhanced neuronal excitability. Impairment of either microtubule-based axonal transport in vivo or dynein function in vitro blocked α, β-MeATP-induced retrograde signals. These results indicate that P2X(3) receptor-activated signals are transmitted via retrogradely transported endosomes in primary sensory neurons and provide a novel signaling mechanism for ligand-gated channels.

A BMP-mediated transcriptional cascade involving Cash1 and Tlx-3 specifies first-order relay sensory neurons in the developing hindbrain.

PubMed

Hornbruch, Amata; Ma, Grace; Ballermann, Mark A; Tumova, Katerina; Liu, Dan; Cairine Logan, C

2005-07-01

The divergent homeobox-containing transcription factor, Tlx-3 (also known as Hox11L2/Rnx), is required for proper formation of first-order relay sensory neurons in the developing vertebrate brainstem. To date, however, the inductive signals and transcriptional regulatory cascade underlying their development are poorly understood. We previously isolated the chick Tlx-3 homologue and showed it is expressed early (i.e. beginning at HH15) in distinct subcomponents of both the trigeminal/solitary and vestibular nuclei. Here we show via in vivo rhombomere inversions that expression of Tlx-3 is under control of local environmental signals. Our RNA in situ analysis shows expression of the BMP-specific receptor, Bmpr-1b, correlates well with Tlx-3. Furthermore, manipulation of the BMP signaling pathway in vivo via electroporation of expression vectors encoding either BMP or NOGGIN coupled with MASH1 gain-of-function experiments demonstrate that a BMP-mediated transcriptional cascade involving Cash1 and Tlx-3 specifies first-order relay sensory neurons in the developing brainstem. Notably, high-level Noggin misexpression results in an increase in newly differentiated Tlx-3+ neurons that correlates with a corresponding increase in the number of Calretinin+ neurons in vestibular nuclei at later developmental stages strongly suggesting that Tlx-3, in addition to being required for proper formation of somatic as well as visceral sensory neurons in the trigeminal and solitary nuclei, respectively, is sufficient for proper formation of special somatic sensory neurons in vestibular nuclei.

The "waiting period" of sensory and motor axons in early chick hindlimb: its role in axon pathfinding and neuronal maturation.

PubMed

Wang, G; Scott, S A

2000-07-15

During embryonic development motor axons in the chick hindlimb grow out slightly before sensory axons and wait in the plexus region at the base of the limb for approximately 24 hr before invading the limb itself (Tosney and Landmesser, 1985a). We have investigated the role of this waiting period by asking, Is the arrest of growth cones in the plexus region a general property of both sensory and motor axons? Why do axons wait? Does eliminating the waiting period affect the further development of motor and sensory neurons? Here we show that sensory axons, like motor axons, pause in the plexus region and that neither sensory nor motor axons require cues from the other population to wait in or exit from the plexus region. By transplanting older or younger donor limbs to host embryos, we show that host axons innervate donor limbs on a schedule consistent with the age of the grafted limbs. Thus, axons wait in the plexus region for maturational changes to occur in the limb rather than in the neurons themselves. Both sensory and motor axons innervate their appropriate peripheral targets when the waiting period is eliminated by grafting older donor limbs. Therefore, axons do not require a prolonged period in the plexus region to sort out and project appropriately. Eliminating the waiting period does, however, accelerate the onset of naturally occurring cell death, but it does not enhance the development of central projections or the biochemical maturation of sensory neurons.

Transient voltage-dependent potassium currents are reduced in NTS neurons isolated from renal wrap hypertensive rats.

PubMed

Belugin, Sergei; Mifflin, Steve

2005-12-01

Whole cell patch-clamp measurements were made in neurons enzymatically dispersed from the nucleus of the solitary tract (NTS) to determine if alterations occur in voltage-dependent potassium channels from rats made hypertensive (HT) by unilateral nephrectomy/renal wrap for 4 wk. Some rats had the fluorescent tracer DiA applied to the aortic nerve before the experiment to identify NTS neurons receiving monosynaptic baroreceptor afferent inputs. Mean arterial pressure (MAP) was greater in 4-wk HT (165 +/- 5 mmHg, n = 26, P < 0.001) rats compared with normotensive (NT) rats (109 +/- 3 mmHg measured in 10 of 69 rats). Transient outward currents (TOCs) were observed in 67-82% of NTS neurons from NT and HT rats. At activation voltages from -10 to +10 mV, TOCs were significantly less in HT neurons compared with those observed in NT neurons (P < 0.001). There were no differences in the voltage-dependent activation kinetics, the voltage dependence of steady-state inactivation, and the rise and decay time constants of the TOCs comparing neurons isolated from NT and HT rats. The 4-aminopyridine-sensitive component of the TOC was significantly less in neurons from HT compared with NT rats (P < 0.001), whereas steady-state outward currents, whether or not sensitive to 4-aminopyridine or tetraethylammonium, were not different. Delayed excitation, studied under current clamp, was observed in 60-80% of NTS neurons from NT and HT rats and was not different comparing neurons from NT and HT rats. However, examination of the subset of NTS neurons exhibiting somatic DiA fluorescence revealed that DiA-labeled neurons from HT rats had a significantly shorter duration delayed excitation (n = 8 cells, P = 0.022) than DiA-labeled neurons from NT rats (n = 7 cells). Neurons with delayed excitation from HT rats had a significantly broader first action potential (AP) and a slower maximal downstroke velocity of repolarization compared with NT neurons with delayed excitation (P = 0.016 and P = 0

Communication between mast cells and rat submucosal neurons.

PubMed

Bell, Anna; Althaus, Mike; Diener, Martin

2015-08-01

Histamine is a mast cell mediator released e.g. during food allergy. The aim of the project was to identify the effect of histamine on rat submucosal neurons and the mechanisms involved. Cultured submucosal neurons from rat colon express H1, H2 and H3 receptors as shown by immunocytochemical staining confirmed by reverse transcriptase polymerase chain reaction (RT-PCR) with messenger RNA (mRNA) isolated from submucosal homogenates as starting material. Histamine evoked a biphasic rise of the cytosolic Ca(2+) concentration in cultured submucosal neurons, consisting in a release of intracellularly stored Ca(2+) followed by an influx from the extracellular space. Although agonists of all three receptor subtypes evoked an increase in the cytosolic Ca(2+) concentration, experiments with antagonists revealed that mainly H1 (and to a lesser degree H2) receptors mediate the response to histamine. In coculture experiments with RBL-2H3 cells, a mast cell equivalent, compound 48/80, evoked an increase in the cytosolic Ca(2+) concentration of neighbouring neurons. Like the response to native histamine, the neuronal response to the mast cell degranulator was strongly inhibited by the H1 receptor antagonist pyrilamine and reduced by the H2 receptor antagonist cimetidine. In rats sensitized against ovalbumin, exposure to the antigen induced a rise in short-circuit current (I sc) across colonic mucosa-submucosa preparations without a significant increase in paracellular fluorescein fluxes. Pyrilamine strongly inhibited the increase in I sc, a weaker inhibition was observed after blockade of protease receptors or 5-lipoxygenase. Consequently, H1 receptors on submucosal neurons seem to play a pivotal role in the communication between mast cells and the enteric nervous system.

Calcium buffering properties of calbindin D28k and parvalbumin in rat sensory neurones.

PubMed Central

Chard, P S; Bleakman, D; Christakos, S; Fullmer, C S; Miller, R J

1993-01-01

1. We have examined the ability of the Ca(2+)-binding proteins (CABP) calbindin D28k and paravalbumin to modulate increases in the intracellular free Ca2+ concentration ([Ca2+]i), produced by brief depolarizations, in rat dorsal root ganglion (DRG) neurones. 2. In order to obtain good voltage control, we replated DRG neurones prior to performing these experiments. Immunocytochemical staining of these cells revealed that approximately 10% stained for CABPs. 3. Using fluorescently labelled parvalbumin, we demonstrated that in the whole-cell voltage clamp mode the protein freely entered the cell soma with a mean half-life t0.5 of 6 min 22 s +/- 54 s. 4. Analysis of the effects of calbindin D28k (370 microM) and parvalbumin (1 mM) on Ca2+ currents in the whole-cell voltage clamp mode, revealed that neither protein changed the rate of inactivation of the Ca2+ current or its rate of run-down. 5. Introducing either calbindin D28k (370 microM) or parvalbumin (1 mM) into the cell soma did not significantly alter the basal [Ca2+]i when compared to control cells. 6. Compared to control cells, both CABPs significantly reduced the peak [Ca2+]i obtained for a Ca2+ influx of an equivalent charge density, whereas lysozyme (1 mM), a protein with low affinity for Ca2+, failed to do so. 7. Calbindin D28k caused an 8-fold decrease in the rate of rise in [Ca2+]i and altered the kinetics of decay of [Ca2+]i to a single slow component. Parvalbumin also slowed the rate of rise in [Ca2+]i. Parvalbumin selectively increased a fast component in the decay of the Ca2+ signal. 8. These data demonstrate that both calbindin D28k and paravalbumin effectively buffer Ca2+ in a cellular environment and may therefore regulate Ca(2+)-dependent aspects of neuronal function. Images Fig. 1 PMID:8145149

A-type voltage-gated K+ currents influence firing properties of isolectin B4-positive but not isolectin B4-negative primary sensory neurons.

PubMed

Vydyanathan, Amaresh; Wu, Zi-Zhen; Chen, Shao-Rui; Pan, Hui-Lin

2005-06-01

Voltage-gated K+ channels (Kv) in primary sensory neurons are important for regulation of neuronal excitability. The dorsal root ganglion (DRG) neurons are heterogeneous, and the types of native Kv currents in different groups of nociceptive DRG neurons are not fully known. In this study, we determined the difference in the A-type Kv current and its influence on the firing properties between isolectin B4 (IB4)-positive and -negative DRG neurons. Whole cell voltage- and current-clamp recordings were performed on acutely dissociated small DRG neurons of rats. The total Kv current density was significantly higher in IB+-positive than that in IB(4)-negative neurons. Also, 4-aminopyridine (4-AP) produced a significantly greater reduction in Kv currents in IB4-positive than in IB4-negative neurons. In contrast, IB4-negative neurons exhibited a larger proportion of tetraethylammonium-sensitive Kv currents. Furthermore, IB4-positive neurons showed a longer latency of firing and required a significantly larger amount of current injection to evoke action potentials. 4-AP significantly decreased the latency of firing and increased the firing frequency in IB4-positive but not in IB4-negative neurons. Additionally, IB4-positive neurons are immunoreactive to Kv1.4 but not to Kv1.1 and Kv1.2 subunits. Collectively, this study provides new information that 4-AP-sensitive A-type Kv currents are mainly present in IB4-positive DRG neurons and preferentially dampen the initiation of action potentials of this subpopulation of nociceptors. The difference in the density of A-type Kv currents contributes to the distinct electrophysiological properties of IB4-positive and -negative DRG neurons.

Sensory specificity and speciation: a potential neuronal pathway for host fruit odour discrimination in Rhagoletis pomonella

PubMed Central

Batra, Srishti; Ramaswamy, Sree Subha; Feder, Jeffrey L.

2016-01-01

Behavioural changes in habitat or mate choice can trigger population divergence, leading to speciation. However, little is known about the neurological bases for such changes. Rhagoletis pomonella (Diptera: Tephritidae) is a model for ecological speciation via host plant shifts. Within the past 180 years, Rhagoletis flies infesting hawthorn (Crataegus spp.) shifted to attack domesticated apple (Malus pumila). The two populations differ in their olfactory preferences for apple versus hawthorn fruit. Here, we looked for patterns of sensory organization that may have contributed to this shift by characterizing the morphology, specificity and distribution of olfactory sensory neurons (OSNs) on the antennae of Rhagoletis responding to host fruit and non-host volatiles. Of 28 OSN classes identified, two colocalized OSN pairs were found that specifically responded to the major behavioural attractant and antagonist volatiles for each fly population. A reversal in the response of these OSNs to fruit volatiles, either through a switch in receptor expression between these paired neurons or changes in neuronal projections in the brain, could therefore account for the behavioural difference between apple and hawthorn flies. The finding supports the hypothesis that relatively minor changes in olfactory sensory pathways may contribute to rapid host shifting and divergence in Rhagoletis. PMID:28003447

Decoy peptide targeted to Toll-IL-1R domain inhibits LPS and TLR4-active metabolite morphine-3 glucuronide sensitization of sensory neurons.

PubMed

Allette, Yohance M; Kim, Youngsook; Randolph, Aaron L; Smith, Jared A; Ripsch, Matthew S; White, Fletcher A

2017-06-16

Accumulating evidence indicates that Toll-like receptor (TLR) signaling adapter protein interactions with Toll/Interleukin-1 Receptor (TIR) domains present in sensory neurons may modulate neuropathic pain states. Following ligand interaction with TLRs, TIR serves to both initiate intracellular signaling and facilitate recruitment of signaling adapter proteins to the intracytoplasmic domain. Although TLR TIR is central to a number of TLR signaling cascades, its role in sensory neurons is poorly understood. In this study we investigated the degree to which TLR TIR decoy peptide modified to include a TAT sequence (Trans-Activator of Transcription gene in HIV; TAT-4BB) affected LPS-induced intracellular calcium flux and excitation in sensory neurons, and behavioral changes due to TLR4 active metabolite, morphine-3-glucuronide (M3G) exposure in vivo. TAT-4BB inhibited LPS-induced calcium changes in a majority of sensory neurons and decreased LPS-dependent neuronal excitability in small diameter neurons. Acute systemic administration of the TAT-4BB reversed M3G-induced tactile allodynia in a dose-dependent manner but did not affect motor activity, anxiety or responses to noxious thermal stimulus. These data suggest that targeting TLR TIR domains may provide novel pharmacological targets to reduce or reverse TLR4-dependent pain behavior in the rodent.

Intracellular activity of cortical and thalamic neurones during high-voltage rhythmic spike discharge in Long-Evans rats in vivo

PubMed Central

Polack, Pierre-Olivier; Charpier, Stéphane

2006-01-01

Spontaneous high-voltage rhythmic spike (HVRS) discharges at 6–12 Hz have been widely described in the electrocorticogram (EcoG) of Long-Evans rats. These ECoG oscillations have been proposed to reflect a state of attentive immobility allowing the optimization of sensory integration within the corticothalamic pathway. This hypothesis has been challenged by recent studies emphasizing similarities between HVRS discharges and spike-and-wave discharges (SWDs) in well-established rat genetic models of absence epilepsy. Here, we made in vivo intracellular recordings to determine, for the first time, the cellular mechanisms responsible for the synchronized oscillations in the corticothalamic loop during HVRS discharges in the Long-Evans rats. We show that HVRS discharges are associated in corticothalamic neurones with rhythmic suprathreshold synaptic depolarizations superimposed on a tonic hyperpolarization, likely due to a process of synaptic disfacilitation. Simultaneously, thalamocortical neurones exhibit a large-amplitude ‘croissant’-shaped membrane hyperpolarization with a voltage sensitivity suggesting a potassium-dependent mechanism. This thalamic hyperpolarizing envelope was associated with a membrane oscillation resulting from interactions between excitatory synaptic inputs, a chloride-dependent inhibitory conductance and voltage-gated intrinsic currents. These cortical and thalamic cellular mechanisms underlying HVRS activity in Long-Evans rats are remarkably similar to those previously described in the thalamocortical networks during SWDs. Thus, the present study provides an additional support to the hypothesis that HVRS activity in Long-Evans rats is an absence-like seizure activity. PMID:16410284

Assessing sensory versus optogenetic network activation by combining (o)fMRI with optical Ca2+ recordings.

PubMed

Schmid, Florian; Wachsmuth, Lydia; Schwalm, Miriam; Prouvot, Pierre-Hugues; Jubal, Eduardo Rosales; Fois, Consuelo; Pramanik, Gautam; Zimmer, Claus; Faber, Cornelius; Stroh, Albrecht

2016-11-01

Encoding of sensory inputs in the cortex is characterized by sparse neuronal network activation. Optogenetic stimulation has previously been combined with fMRI (ofMRI) to probe functional networks. However, for a quantitative optogenetic probing of sensory-driven sparse network activation, the level of similarity between sensory and optogenetic network activation needs to be explored. Here, we complement ofMRI with optic fiber-based population Ca 2+ recordings for a region-specific readout of neuronal spiking activity in rat brain. Comparing Ca 2+ responses to the blood oxygenation level-dependent signal upon sensory stimulation with increasing frequencies showed adaptation of Ca 2+ transients contrasted by an increase of blood oxygenation level-dependent responses, indicating that the optical recordings convey complementary information on neuronal network activity to the corresponding hemodynamic response. To study the similarity of optogenetic and sensory activation, we quantified the density of cells expressing channelrhodopsin-2 and modeled light propagation in the tissue. We estimated the effectively illuminated volume and numbers of optogenetically stimulated neurons, being indicative of sparse activation. At the functional level, upon either sensory or optogenetic stimulation we detected single-peak short-latency primary Ca 2+ responses with similar amplitudes and found that blood oxygenation level-dependent responses showed similar time courses. These data suggest that ofMRI can serve as a representative model for functional brain mapping. © The Author(s) 2015.

GluN2B N-methyl-D-aspartate receptor and excitatory amino acid transporter 3 are upregulated in primary sensory neurons after 7 days of morphine administration in rats: implication for opiate-induced hyperalgesia.

PubMed

Gong, Kerui; Bhargava, Aditi; Jasmin, Luc

2016-01-01

The contribution of the peripheral nervous system to opiate-induced hyperalgesia (OIH) is not well understood. In this study, we determined the changes in excitability of primary sensory neurons after sustained morphine administration for 7 days. Changes in the expression of glutamate receptors and glutamate transporters after morphine administration were ascertained in dorsal root ganglions. Patch clamp recordings from intact dorsal root ganglions (ex vivo preparation) of morphine-treated rats showed increased excitability of small diameter (≤30 μm) neurons with respect to rheobase and membrane threshold, whereas the excitability of large diameter (>30 μm) neurons remained unchanged. Small diameter neurons also displayed increased responses to glutamate, which were mediated mainly by GluN2B containing N-methyl-D-aspartate (NMDA) receptors, and to a lesser degree by the neuronal excitatory amino acid transporter 3/excitatory amino acid carrier 1. Coadministration in vivo of the GluN2B selective antagonist Ro 25-6981 with morphine for 7 days prevented the appearance of OIH and increased morphine-induced analgesia. Administration of morphine for 7 days led to an increased expression of GluN2B and excitatory amino acid transporter 3/excitatory amino acid carrier 1, but not of the α-amino-3-hydroxy-5-methyl-4-isoxazole propionate, kainate, or group I metabotropic glutamate receptors, or of the vesicular glutamate transporter 2. These results suggest that peripheral glutamatergic neurotransmission contributes to OIH and that GluN2B subunit of NMDA receptors in the periphery may be a target for therapy.

Repeated cycles of restricted food intake and binge feeding disrupt sensory-specific satiety in the rat.

PubMed

Ahn, Soyon; Phillips, Anthony G

2012-06-01

The relationship between food restriction and subsequent dysregulation of food intake is complex, variable and long-lasting. The present study investigated in rats whether repeated cycles of food restriction and binge feeding opportunities may alter regulation of food intake by employing a test for sensory-specific satiety. Rats that experienced repeated food restriction-binge cycles maintained heavier body weights compared to rats that remained on continuous food restriction. In contrast to the control subjects, rats that alternated between food restriction and binge feeding failed to display sensory-specific satiety. During the first meal, there was a gradual decrease in the amount of food intake over a 40 min period. When presented with a second meal of the same food, these rats responded to the familiar food in a manner similar as to a novel food (i.e., comparable quantities of both types of food were consumed). Food restriction-binge feeding cycles may be considered as a form of stress, which in turn is associated with cross-sensitization to numerous behavioral responses. Therefore, we propose that stress-induced disruption of sensory-specific satiety reflects a sensitized response to food, in which the interaction between sensory and satiety factors are no longer the key regulators of food choice and meal cessation. Furthermore, a role for sensory-specific satiety in terminating food intake appeared to decline with the progression of the cycles, thereby contributing to a steady increase in body weight of rats that experienced restriction with bouts of binge feeding opportunities. Copyright © 2012 Elsevier B.V. All rights reserved.

Morphological and electrophysiological examination of olfactory sensory neurons during the early developmental prolarval stage of the sea lamprey Petromyzon marinus L

USGS Publications Warehouse

Zielinski, B.S.; Fredricks, Keith; McDonald, R.; Zaidi, A.U.

2005-01-01

This study examined olfactory sensory neuron morphology and physiological responsiveness in newly hatched sea lamprey, Petromyzon marinus L. These prolarvae hatch shortly after neural tube formation, and stay within nests for approximately 18 days, before moving downstream to silty areas where they burrow, feed and pass to the larval stage. To explore the possibility that the olfactory system is functioning during this prolarval stage, morphological and physiological development of olfactory sensory neurons was examined. The nasal cavity contained an olfactory epithelium with ciliated olfactory sensory neurons. Axons formed aggregates in the basal portion of the olfactory epithelium and spanned the narrow distance between the olfactory epithelium and the brain. The presence of asymmetric synapses with agranular vesicles within fibers in the brain, adjacent to the olfactory epithelium suggests that there was synaptic connectivity between olfactory sensory axons and the brain. Neural recordings from the surface of the olfactory epithelium showed responses following the application of L-arginine, taurocholic acid, petromyzonol sulfate (a lamprey migratory pheromone), and water conditioned by conspecifics. These results suggest that lampreys may respond to olfactory sensory input during the prolarval stage. ?? 2006 Springer Science + Business Media, LLC.

[Changes in ingestive behavior during growth affects the functional maturation of temporomandibular joint nociceptive neurons of rats].

PubMed

Hiranuma, Maya

2013-03-01

Temporomandibular joint (TMJ) loading during development promotes its growth and maintains normal structure/function. Continuous change in diet consistency is related to development and maturation of the peripheral nervous system, including the nociceptive system. However, the functional modulation of TMJ-nociceptive neurons under different ingestive behavior is unclear. We fed growing rats a liquid diet to investigate the effects of low TMJ loading on the response properties of neurons in the trigeminal spinal tract subnucleus caudalis (Sp5C). Forty 2-week-old male rats were used. They were fed chow pellets (n = 20, C group) or a liquid diet (n = 20, LD group) soon after weaning. Firing activities of single sensory units in response to TMJ pressure stimuli were recorded at 4, 5, 7 and 9 weeks. In TMJ-nociceptive neurons, the firing threshold (FT) in the LD group was significantly lower than that in the C group at each recording age. The FT in the C group remained unchanged throughout the recording period, whereas that in the LD group was the highest at 4 weeks, and gradually decreased. On the other hand, the initial firing frequency (IFF) was significantly higher in the LD group than in the C group at each recording age. The IFF in the C group remained unchanged throughout the experimental period, whereas that in the LD group was at its lowest at 4 weeks, and gradually increased. Based on these findings, ingestive behavior that results from continuous changes in the physical consistency of the diet during growth may affect the functional maturation of TMJ-nociceptive neurons.

Attenuated plasma extravasation to sensory neuropeptides in diabetic rats.

PubMed

Mathison, R; Davison, J S

1993-01-01

The effects of either substance P (SP) or a metabolically stable SP analogue, [pGlu5,Me-Phe8,Sar9]SP(5-11), alone or in combination with calcitonin gene-related peptide (CGRP) on blood pressure (BP) and extravasation of serum albumin were examined in normal and diabetic rats. CGRP (12 ng/kg) modified neither BP nor vascular permeability in control and diabetic rats. Both SP and its analogue (74 ng/kg) produced hypotension, and increased plasma extravasation in the respiratory tissues, urinary bladder and skin. The simultaneous injection of CGRP and SP resulted in modest potentiation of the vascular permeability actions of SP in control and diabetic rats. However, extravasation induced by [pGlu5,Me-Phe8,Sar9]SP(5-11) was potentiated by CGRP in control animals, but not in diabetic rats. Defective neurogenic inflammatory responses in diabetic rats may result from decreased responses in the effector tissues of diabetic rats to the neuropeptides released from sensory nerves.

Analysis of variance study of the rat cortical layer 4 barrel and layer 5b neurones

PubMed Central

Ito, Muneyuki; Kato, Miyuki

2002-01-01

Unique formation of rodent cortical barrels by layer 4 neurones attracts study of the sensory function of cortical input stage neurones (layer 4) compared with that of output stage neurones (layer 5). We have recorded extracellular responses from rat somatosensory cortical neurones to deflections of contralateral vibrissae. Thirty-two layer 4 barrel neurones and 29 layer 5b neurones were studied. Whisker stimulations were ramp-and-hold deflections with one of six different ramp velocities (100–2.5 mm s−1) and one of four different plateau amplitudes (2000–200 μm). Twenty-four (6 × 4) different stimulus forms were applied to the tip of a whisker trimmed to 10 mm in a predetermined order in stimulus cycles of 20–50 repetitions. Spike counts for a period of 2560 ms in 10 ms bins were summed to construct a matrix of 24 peristimulus histograms for each neurone. Twenty-four amplitude and 24 velocity values were computed from counts during the plateau and ramp phases, respectively. To determine the amplitude- and velocity dependence of a neurone, an amplitude F value (the ratio of variations among-/within-amplitude of the amplitude value) and a velocity F value (ratio of variations among-/within-velocity of the velocity value) were derived by analysis of variance. The amplitude F value of the layer 4 barrel neurones was greater than that of the layer 5b neurones (P < 0.0001). The velocity F value of the barrel neurones was smaller than that of the layer 5b neurones (P = 0.0226). The results suggests that barrel neurones and layer 5b neurones tend to detect amplitude and velocity components of whisker deflection, respectively. PMID:11882683

Sec71 functions as a GEF for the small GTPase Arf1 to govern dendrite pruning of Drosophila sensory neurons.

PubMed

Wang, Yan; Zhang, Heng; Shi, Meng; Liou, Yih-Cherng; Lu, Lei; Yu, Fengwei

2017-05-15

Pruning, whereby neurons eliminate their excess neurites, is central for the maturation of the nervous system. In Drosophila , sensory neurons, ddaCs, selectively prune their larval dendrites without affecting their axons during metamorphosis. However, it is unknown whether the secretory pathway plays a role in dendrite pruning. Here, we show that the small GTPase Arf1, an important regulator of the secretory pathway, is specifically required for dendrite pruning of ddaC/D/E sensory neurons but dispensable for apoptosis of ddaF neurons. Analyses of the GTP- and GDP-locked forms of Arf1 indicate that the cycling of Arf1 between GDP-bound and GTP-bound forms is essential for dendrite pruning. We further identified Sec71 as a guanine nucleotide exchange factor for Arf1 that preferentially interacts with its GDP-bound form. Like Arf1, Sec71 is also important for dendrite pruning, but not for apoptosis, of sensory neurons. Arf1 and Sec71 are interdependent for their localizations on Golgi. Finally, we show that the Sec71/Arf1-mediated trafficking process is a prerequisite for Rab5-dependent endocytosis to facilitate endocytosis and degradation of the cell-adhesion molecule Neuroglian (Nrg). © 2017. Published by The Company of Biologists Ltd.

A New Regulatory Mechanism for Kv7.2 Protein During Neuropathy: Enhanced Transport from the Soma to Axonal Terminals of Injured Sensory Neurons.

PubMed

Cisneros, Elsa; Roza, Carolina; Jackson, Nieka; López-García, José Antonio

2015-01-01

Kv7.2 channel expression has been reported to decrease in dorsal root ganglia (DRG) following the induction of a peripheral neuropathy while other experiments show that Kv7.2 accumulates in peripheral neuromas. The mechanisms underlying these novel expression patterns are poorly understood. Here we use immunofluorescence methods to analyze Kv7.2 protein expression changes in sensory neurons following peripheral axotomy and the potential role of axonal transport. Results indicate that DRG neurons express Kv7.2 in ~16% of neurons and that this number decreases by about 65% after axotomy. Damaged neurons were identified in DRG by application of the tracer Fluoro-ruby at the site of injury during surgery. Reduction of Kv7.2 expression was particularly strong in damaged neurons although some loss was also found in putative uninjured neurons. In parallel to the decrease in the soma of axotomized sensory neurons, Kv7.2 accumulated at neuromatose fiber endings. Blockade of axonal transport with either vinblastine (VLB) or colchicine (COL) abolished Kv7.2 redistribution in neuropathic animals. Channel distribution rearrangements did not occur following induction of inflammation in the hind paw. Behavioral tests indicate that protein rearrangements within sensory afferents are essential to the development of allodynia under neuropathic conditions. These results suggest that axotomy enhances axonal transport in injured sensory neurons, leading to a decrease of somatic expression of Kv7.2 protein and a concomitant accumulation in damaged fiber endings. Localized changes in channel expression patterns under pathological conditions may create novel opportunities for Kv7.2 channel openers to act as analgesics.

Enhanced responses of the anterior cingulate cortex neurones to colonic distension in viscerally hypersensitive rats

PubMed Central

Gao, Jun; Wu, Xiaoyin; Owyang, Chung; Li, Ying

2006-01-01

The anterior cingulate cortex (ACC) is critically involved in processing the affective component of pain sensation. Visceral hypersensitivity is a characteristic of irritable bowel syndrome. Electrophysiological activity of the ACC with regard to visceral sensitization has not been characterized. Single ACC neuronal activities in response to colorectal distension (CRD) were recorded in control, sham-treated rats and viscerally hypersensitive (EA) rats (induced by chicken egg albumin injection, i.p). The ACC neurones of controls failed to respond to 10 or 30 mmHg CRD; only 22% were activated by 50 mmHg CRD. Among the latter, 16.4% exhibited an excitatory response to CRD and were labelled ‘CRD-excited’ neurones. In contrast, CRD (10, 30 and 50 mmHg) markedly increased ACC neuronal responses of EA rats (10%, 28% and 47%, respectively). CRD produced greater pressure-dependent increases in ACC spike firing rates in EA rats compared with controls. Splanchnicectomy combined with pelvic nerve section abolished ACC responses to CRD in EA rats. Spontaneous activity in CRD-excited ACC neurones was significantly higher in EA rats than in controls. CRD-excited ACC neurones in control and EA rats (7 of 16 (42%) and 8 of 20 (40%), respectively) were activated by transcutaneous electrical and thermal stimuli. However, ACC neuronal activity evoked by noxious cutaneous stimuli did not change significantly in EA rats. This study identifies CRD-responsive neurones in the ACC and establishes for the first time that persistence of a heightened visceral afferent nociceptive input to the ACC induces ACC sensitization, characterized by increased spontaneous activity of CRD-excited neurones, decreased CRD pressure threshold, and increased response magnitude. Enhanced ACC nociceptive transmission in viscerally hypersensitive rats is restricted to visceral afferent input. PMID:16239277

Prior activity of olfactory receptor neurons is required for proper sensory processing and behavior in Drosophila larvae.

PubMed

Utashiro, Nao; Williams, Claire R; Parrish, Jay Z; Emoto, Kazuo

2018-06-05

Animal responses to their environment rely on activation of sensory neurons by external stimuli. In many sensory systems, however, neurons display basal activity prior to the external stimuli. This prior activity is thought to modulate neural functions, yet its impact on animal behavior remains elusive. Here, we reveal a potential role for prior activity in olfactory receptor neurons (ORNs) in shaping larval olfactory behavior. We show that prior activity in larval ORNs is mediated by the olfactory receptor complex (OR complex). Mutations of Orco, an odorant co-receptor required for OR complex function, cause reduced attractive behavior in response to optogenetic activation of ORNs. Calcium imaging reveals that Orco mutant ORNs fully respond to optogenetic stimulation but exhibit altered temporal patterns of neural responses. These findings together suggest a critical role for prior activity in information processing upon ORN activation in Drosophila larvae, which in turn contributes to olfactory behavior control.

The Postnatal Development of Spinal Sensory Processing

NASA Astrophysics Data System (ADS)

Fitzgerald, Maria; Jennings, Ernest

1999-07-01

The mechanisms by which infants and children process pain should be viewed within the context of a developing sensory nervous system. The study of the neurophysiological properties and connectivity of sensory neurons in the developing spinal cord dorsal horn of the intact postnatal rat has shed light on the way in which the newborn central nervous system analyzes cutaneous innocuous and noxious stimuli. The receptive field properties and evoked activity of newborn dorsal horn cells to single repetitive and persistent innocuous and noxious inputs are developmentally regulated and reflect the maturation of excitatory transmission within the spinal cord. These changes will have an important influence on pain processing in the postnatal period.

Functional recovery of neuronal activity in rat whisker-barrel cortex sensory pathway from freezing injury after transplantation of adult bone marrow stromal cells.

PubMed

Mori, Kentaro; Iwata, Junko; Miyazaki, Masahiro; Nakao, Yasuaki; Maeda, Minoru

2005-07-01

The effect of transplantation of adult bone marrow stromal cells (MSCs) into the freeze-lesioned left barrel field cortex in the rat was investigated by measurement of local cerebral glucose utilization (lCMR(glc)) in the anatomic structures of the whisker-to-barrel cortex sensory pathway. Bone marrow stromal cells or phosphate-buffered saline (PBS) were injected intracerebrally into the boundary zone 1 h after induction of the freezing cortical lesion. Three weeks after surgery, the 2-[(14)C]deoxyglucose method was used to measure lCMR(glc) during right whisker stimulation. The volume of the primary necrotic freezing lesion was significantly reduced (P<0.05), and secondary retrograde degeneration in the left ventral posteromedial (VPM) thalamic nucleus was diminished in the MSC-treated group. Local cerebral glucose utilization measurements showed that the freezing cortical lesion did not alter the metabolic responses to stimulation in the brain stem trigeminal nuclei, but eliminated the responses in the left VPM nucleus and periphery of the barrel cortex in the PBS-treated group. The left/right (stimulated/unstimulated) lCMR(glc) ratios were significantly improved in both the VPM nucleus and periphery of the barrel cortex in the MSC-treated group compared with the PBS-treated group (P<0.05). These results indicate that MSC transplantation in adults may stimulate metabolic and functional recovery in injured neuronal pathways.

Cevimeline enhances the excitability of rat superior salivatory neurons.

PubMed

Ueda, Hirotaka; Mitoh, Yoshihiro; Ichikawa, Hiroyuki; Kobashi, Motoi; Yamashiro, Takashi; Matsuo, Ryuji

2009-01-01

Cevimeline, a therapeutic drug for xerostomia, is an agonist of muscarinic acetylcholine receptors (mAChRs), and directly stimulates the peripheral mAChRs of the salivary glands. Since cevimeline is distributed in the brain after its oral administration, it is possible that it affects the central nervous system. However, it is unknown how cevimeline affects the superior salivatory (SS) neurons, which control submandibular salivation. In the present study, we examined the effects of cevimeline on the SS neurons using the whole-cell patch-clamp technique in brain slices. In Wistar rats (6-10 days), the SS neurons were retrogradely labeled by Texas Red applied to the chorda-lingual nerve. Two days after injection, whole-cell recordings were obtained from the labeled cells, and miniature excitatory postsynaptic currents (mEPSCs) were examined. Cevimeline induced the inward currents dose-dependently and increased the frequency of mEPSCs. Therefore, it is suggested that cevimeline enhances the excitability via post- and presynaptic muscarinic receptors in the rat SS neurons. In conclusion, cevimeline may enhance the excitability of the SS neurons.

Hmx1 is required for the normal development of somatosensory neurons in the geniculate ganglion

PubMed Central

Quina, Lely A.; Tempest, Lynne; Hsu, Yun-Wei A.; Cox, Timothy C.; Turner, Eric E.

2012-01-01

Hmx1 is a variant homeodomain transcription factor expressed in the developing sensory nervous system, retina, and craniofacial mesenchyme. Recently, mutations at the Hmx1 locus have been linked to craniofacial defects in humans, rats, and mice, but its role in nervous system development is largely unknown. Here we show that Hmx1 is expressed in a subset of sensory neurons in the cranial and dorsal root ganglia which does not correspond to any specific sensory modality. Sensory neurons in the dorsal root and trigeminal ganglia of Hmx1dm/dm mouse embryos have no detectable Hmx1 protein, yet they undergo neurogenesis and express sensory subtype markers normally, demonstrating that Hmx1 is not globally required for the specification of sensory neurons from neural crest precursors. Loss of Hmx1 expression has no obvious effect on the early development of the trigeminal (V), superior (IX/X), or dorsal root ganglia neurons in which it is expressed, but results in marked defects in the geniculate (VII) ganglion. Hmx1dm/dm mouse embryos possess only a vestigial posterior auricular nerve, and general somatosensory neurons in the geniculate ganglion are greatly reduced by mid-gestation. Although Hmx1 is expressed in geniculate neurons prior to cell cycle exit, it does not appear to be required for neurogenesis, and the loss of geniculate neurons is likely to be the result of increased cell death. Fate mapping of neural crest-derived tissues indicates that Hmx1-expressing somatosensory neurons at different axial levels may be derived from either the neural crest or the neurogenic placodes. PMID:22586713

A5-positive primary sensory neurons are nonpermissive for productive infection with herpes simplex virus 1 in vitro.

PubMed

Bertke, Andrea S; Swanson, Sophia M; Chen, Jenny; Imai, Yumi; Kinchington, Paul R; Margolis, Todd P

2011-07-01

Herpes simplex viruses 1 and 2 (HSV-1 and HSV-2) establish latency and express the latency-associated transcript (LAT) preferentially in different murine sensory neuron populations, with most HSV-1 LAT expression in A5(+) neurons and most HSV-2 LAT expression in KH10(+) neurons. To study the mechanisms regulating the establishment of HSV latency in specific subtypes of neurons, cultured dissociated adult murine trigeminal ganglion (TG) neurons were assessed for relative permissiveness for productive infection. In contrast to that for neonatal TG, the relative distribution of A5(+) and KH10(+) neurons in cultured adult TG was similar to that seen in vivo. Productive infection with HSV was restricted, and only 45% of cultured neurons could be productively infected with either HSV-1 or HSV-2. A5(+) neurons supported productive infection with HSV-2 but were selectively nonpermissive for productive infection with HSV-1, a phenomenon that was not due to restricted viral entry or DNA uncoating, since HSV-1 expressing β-galactosidase under the control of the neurofilament promoter was detected in ∼90% of cultured neurons, with no preference for any neuronal subtype. Infection with HSV-1 reporter viruses expressing enhanced green fluorescent protein (EGFP) from immediate early (IE), early, and late gene promoters indicated that the block to productive infection occurred before IE gene expression. Trichostatin A treatment of quiescently infected neurons induced productive infection preferentially from non-A5(+) neurons, demonstrating that the nonpermissive neuronal subtype is also nonpermissive for reactivation. Thus, HSV-1 is capable of entering the majority of sensory neurons in vitro; productive infection occurs within a subset of these neurons; and this differential distribution of productive infection is determined at or before the expression of the viral IE genes.

A5-Positive Primary Sensory Neurons Are Nonpermissive for Productive Infection with Herpes Simplex Virus 1 In Vitro▿

PubMed Central

Bertke, Andrea S.; Swanson, Sophia M.; Chen, Jenny; Imai, Yumi; Kinchington, Paul R.; Margolis, Todd P.

2011-01-01

Herpes simplex viruses 1 and 2 (HSV-1 and HSV-2) establish latency and express the latency-associated transcript (LAT) preferentially in different murine sensory neuron populations, with most HSV-1 LAT expression in A5+ neurons and most HSV-2 LAT expression in KH10+ neurons. To study the mechanisms regulating the establishment of HSV latency in specific subtypes of neurons, cultured dissociated adult murine trigeminal ganglion (TG) neurons were assessed for relative permissiveness for productive infection. In contrast to that for neonatal TG, the relative distribution of A5+ and KH10+ neurons in cultured adult TG was similar to that seen in vivo. Productive infection with HSV was restricted, and only 45% of cultured neurons could be productively infected with either HSV-1 or HSV-2. A5+ neurons supported productive infection with HSV-2 but were selectively nonpermissive for productive infection with HSV-1, a phenomenon that was not due to restricted viral entry or DNA uncoating, since HSV-1 expressing β-galactosidase under the control of the neurofilament promoter was detected in ∼90% of cultured neurons, with no preference for any neuronal subtype. Infection with HSV-1 reporter viruses expressing enhanced green fluorescent protein (EGFP) from immediate early (IE), early, and late gene promoters indicated that the block to productive infection occurred before IE gene expression. Trichostatin A treatment of quiescently infected neurons induced productive infection preferentially from non-A5+ neurons, demonstrating that the nonpermissive neuronal subtype is also nonpermissive for reactivation. Thus, HSV-1 is capable of entering the majority of sensory neurons in vitro; productive infection occurs within a subset of these neurons; and this differential distribution of productive infection is determined at or before the expression of the viral IE genes. PMID:21507969

Implant-derived magnesium induces local neuronal production of CGRP to improve bone-fracture healing in rats

PubMed Central

Zhang, Yifeng; Xu, Jiankun; Ruan, Ye Chun; Yu, Mei Kuen; O’Laughlin, Micheal; Wise, Helen; Chen, Di; Tian, Li; Shi, Dufang; Wang, Jiali; Chen, Sihui; Feng, Jian Q; Chow, Dick Ho Kiu; Xie, Xinhui; Zheng, Lizhen; Huang, Le; Huang, Shuo; Leung, Kwoksui; Lu, Na; Zhao, Lan; Li, Huafang; Zhao, Dewei; Guo, Xia; Chan, Kaiming; Witte, Frank; Chan, Hsiao Chang; Zheng, Yufeng; Qin, Ling

2017-01-01

Orthopedic implants containing biodegradable magnesium have been used for fracture repair with considerable efficacy; however, the underlying mechanisms by which these implants improve fracture healing remain elusive. Here we show the formation of abundant new bone at peripheral cortical sites after intramedullary implantation of a pin containing ultrapure magnesium into the intact distal femur in rats. This response was accompanied by substantial increases of neuronal calcitonin gene-related polypeptide-α (CGRP) in both the peripheral cortex of the femur and the ipsilateral dorsal root ganglia (DRG). Surgical removal of the periosteum, capsaicin denervation of sensory nerves or knockdown in vivo of the CGRP-receptor-encoding genes Calcrl or Ramp1 substantially reversed the magnesium-induced osteogenesis that we observed in this model. Overexpression of these genes, however, enhanced magnesium-induced osteogenesis. We further found that an elevation of extracellular magnesium induces magnesium transporter 1 (MAGT1)-dependent and transient receptor potential cation channel, subfamily M, member 7 (TRPM7)-dependent magnesium entry, as well as an increase in intracellular adenosine triphosphate (ATP) and the accumulation of terminal synaptic vesicles in isolated rat DRG neurons. In isolated rat periosteum-derived stem cells, CGRP induces CALCRL-and RAMP1-dependent activation of cAMP-responsive element binding protein 1 (CREB1) and SP7 (also known as osterix), and thus enhances osteogenic differentiation of these stem cells. Furthermore, we have developed an innovative, magnesium-containing intramedullary nail that facilitates femur fracture repair in rats with ovariectomy-induced osteoporosis. Taken together, these findings reveal a previously undefined role of magnesium in promoting CGRP-mediated osteogenic differentiation, which suggests the therapeutic potential of this ion in orthopedics. PMID:27571347

Active signal conduction through the sensory dendrite of a spider mechanoreceptor neuron.

PubMed

Gingl, Ewald; French, Andrew S

2003-07-09

Rapid responses to sensory stimulation are crucial for survival. This must be especially true for mechanical stimuli containing temporal information, such as vibration. Sensory transduction occurs at the tips of relatively long sensory dendrites in many mechanoreceptors of both vertebrates and invertebrates, but little is known about the electrical properties of these crucial links between transduction and action potential generation. The VS-3 slit-sense organ of the spider Cupiennius salei contains bipolar mechanosensory neurons that allow voltage-clamp recording from the somata, whereas mechanotransduction occurs at the tips of 100- to 200-microm-long sensory dendrites. We studied the properties of VS-3 sensory dendrites using three approaches. Voltage-jump experiments measured the spread of voltage outward from the soma by observing total mechanically transduced charge recovered at the soma as a function of time after a voltage jump. Frequency-response measurements between pseudorandom mechanical stimulation and somatic membrane potential estimated the passive cable properties of the dendrite for voltage spread in the opposite direction. Both of these sets of data indicated that the dendritic cable would significantly attenuate and retard a passively propagated receptor potential. Finally, current-clamp observations of receptor potentials and action potentials indicated that action potentials normally start at the distal dendrites and propagate regeneratively to the soma, reducing the temporal delay of passive conduction.

Gabapentin Inhibits Protein Kinase C Epsilon Translocation in Cultured Sensory Neurons with Additive Effects When Coapplied with Paracetamol (Acetaminophen).

PubMed

Vellani, Vittorio; Giacomoni, Chiara

2017-01-01

Gabapentin is a well-established anticonvulsant drug which is also effective for the treatment of neuropathic pain. Although the exact mechanism leading to relief of allodynia and hyperalgesia caused by neuropathy is not known, the blocking effect of gabapentin on voltage-dependent calcium channels has been proposed to be involved. In order to further evaluate its analgesic mechanisms, we tested the efficacy of gabapentin on protein kinase C epsilon (PKC ε ) translocation in cultured peripheral neurons isolated from rat dorsal root ganglia (DRGs). We found that gabapentin significantly reduced PKC ε translocation induced by the pronociceptive peptides bradykinin and prokineticin 2, involved in both inflammatory and chronic pain. We recently showed that paracetamol (acetaminophen), a very commonly used analgesic drug, also produces inhibition of PKC ε . We tested the effect of the combined use of paracetamol and gabapentin, and we found that the inhibition of translocation adds up. Our study provides a novel mechanism of action for gabapentin in sensory neurons and suggests a mechanism of action for the combined use of paracetamol and gabapentin, which has recently been shown to be effective, with a cumulative behavior, in the control of postoperative pain in human patients.

Turmeric extract inhibits apoptosis of hippocampal neurons of trimethyltin-exposed rats.

PubMed

Yuliani, S; Widyarini, S; Mustofa; Partadiredja, G

2017-01-01

The aim of the present study was to reveal the possible antiapoptotic effect of turmeric (Curcuma longa Linn.) on the hippocampal neurons of rats exposed to trimethyltin (TMT). Oxidative damage in the hippocampus can induce the apoptosis of neurons associated with the pathogenesis of dementiaMETHODS. The ethanolic turmeric extract and a citicoline (as positive control) solution were administered to the TMT-exposed rats for 28 days. The body weights of rats were recorded once a week. The hippocampal weights and imumunohistochemical expression of caspase 3 proteins in the CA1 and CA2-CA3 regions of the hippocampi were examined at the end of the experiment. Immunohistochemical analysis showed that the injection of TMT increased the expression of caspase 3 in the CA1 and CA2-CA3 regions of hippocampus. TMT also decreased the body and hippocampal weights. Furthermore, the administration of 200 mg/kg bw dose of turmeric extract decreased the caspase 3 expression in the CA2-CA3 pyramidal neurons but not in the CA1 neurons. It also prevented the decrease of the body and hippocampal weights. We suggest that the 200 mg/kg bw dose of turmeric extract may exert antiapoptotic effect on the hippocampal neurons of the TMT-exposed rats (Tab. 1, Fig. 3, Ref. 49).

A New Regulatory Mechanism for Kv7.2 Protein During Neuropathy: Enhanced Transport from the Soma to Axonal Terminals of Injured Sensory Neurons

PubMed Central

Cisneros, Elsa; Roza, Carolina; Jackson, Nieka; López-García, José Antonio

2015-01-01

Kv7.2 channel expression has been reported to decrease in dorsal root ganglia (DRG) following the induction of a peripheral neuropathy while other experiments show that Kv7.2 accumulates in peripheral neuromas. The mechanisms underlying these novel expression patterns are poorly understood. Here we use immunofluorescence methods to analyze Kv7.2 protein expression changes in sensory neurons following peripheral axotomy and the potential role of axonal transport. Results indicate that DRG neurons express Kv7.2 in ~16% of neurons and that this number decreases by about 65% after axotomy. Damaged neurons were identified in DRG by application of the tracer Fluoro-ruby at the site of injury during surgery. Reduction of Kv7.2 expression was particularly strong in damaged neurons although some loss was also found in putative uninjured neurons. In parallel to the decrease in the soma of axotomized sensory neurons, Kv7.2 accumulated at neuromatose fiber endings. Blockade of axonal transport with either vinblastine (VLB) or colchicine (COL) abolished Kv7.2 redistribution in neuropathic animals. Channel distribution rearrangements did not occur following induction of inflammation in the hind paw. Behavioral tests indicate that protein rearrangements within sensory afferents are essential to the development of allodynia under neuropathic conditions. These results suggest that axotomy enhances axonal transport in injured sensory neurons, leading to a decrease of somatic expression of Kv7.2 protein and a concomitant accumulation in damaged fiber endings. Localized changes in channel expression patterns under pathological conditions may create novel opportunities for Kv7.2 channel openers to act as analgesics. PMID:26696829

Voltage-gated currents in identified rat olfactory receptor neurons.

PubMed

Trombley, P Q; Westbrook, G L

1991-02-01

Whole-cell recording techniques were used to characterize voltage-gated membrane currents in neonatal rat olfactory receptor neurons (ORNs) in cell culture. Mature ORNs were identified in culture by their characteristic bipolar morphology, by retrograde labeling techniques, and by olfactory marker protein (OMP) immunoreactivity. ORNs did not have spontaneous activity, but fired action potentials to depolarizing current pulses. Action potentials were blocked by tetrodotoxin (TTX), which contrasts with the TTX-resistant action potentials in salamander olfactory receptor cells (e.g., Firestein and Werblin, 1987). Prolonged, suprathreshold current pulses evoked only a single action potential; however, repetitive firing up to 35 Hz could be elicited by a series of brief depolarizing pulses. Under voltage clamp, the TTX-sensitive sodium current had activation and inactivation properties similar to other excitable cells. In TTX and 20 mM barium, sustained inward current were evoked by voltage steps positive to -30 mV. This current was blocked by Cd (100 microM) and by nifedipine (IC50 = 368 nM) consistent with L-type calcium channels in other neurons. No T-type calcium current was observed. Voltage steps positive to -20 mV also evoked an outward current that did not inactivate during 100-msec depolarizations. Tail current analysis of this current was consistent with a selective potassium conductance. The outward current was blocked by external tetraethylammonium but was unaffected by Cd or 4-aminopyridine (4-AP) or by removal of external calcium. A transient outward current was not observed. The 3 voltage-dependent conductances in cultured rat ORNs appear to be sufficient for 2 essential functions: action potential generation and transmitter release. As a single odorant-activated channel can trigger an action potential (e.g., Lynch and Barry, 1989), the repetitive firing seen with brief depolarizing pulses suggests that ORNs do not integrate sensory input, but rather act

Oxytocin Modulates Expression of Neuron and Glial Markers in the Rat Hippocampus.

PubMed

Havránek, T; Lešťanová, Z; Mravec, B; Štrbák, V; Bakoš, J; Bačová, Z

2017-01-01

Neuropeptides including oxytocin belong to the group of factors that may play a role in the control of neuronal cell survival, proliferation and differentiation. The aim of the present study was to investigate potential contribution of oxytocin to neuronal differentiation by measuring gene and protein expression of specific neuron and glial markers in the brain. Neonatal and adult oxytocin administration was used to reveal developmental and/or acute effects of oxytocin in Wistar rats. Gene and protein expression of neuron-specific enolase (NSE) in the hippocampus was increased in 21-day and 2-month old rats in response to neonatal oxytocin administration. Neonatal oxytocin treatment induced a significant increase of gene and protein expression of the marker of astrocytes - glial fibrillary acid protein (GFAP). Oxytocin treatment resulted in a decrease of oligodendrocyte marker mRNA - 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase) - in 21-day and 2-month old rats, while no change of CD68 mRNA, marker of microglia, was observed. Central oxytocin administration in adult rats induced a significant increase of gene expression of NSE and CNPase. The present study provides the first data revealing the effect of oxytocin on the expression of neuron and glial markers in the brain. It may be suggested that the oxytocin system is involved in the regulation of development of neuronal precursor cells in the brain.

Genomics of Mature and Immature Olfactory Sensory Neurons

PubMed Central

Nickell, Melissa D.; Breheny, Patrick; Stromberg, Arnold J.; McClintock, Timothy S.

2014-01-01

The continuous replacement of neurons in the olfactory epithelium provides an advantageous model for investigating neuronal differentiation and maturation. By calculating the relative enrichment of every mRNA detected in samples of mature mouse olfactory sensory neurons (OSNs), immature OSNs, and the residual population of neighboring cell types, and then comparing these ratios against the known expression patterns of >300 genes, enrichment criteria that accurately predicted the OSN expression patterns of nearly all genes were determined. We identified 847 immature OSN-specific and 691 mature OSN-specific genes. The control of gene expression by chromatin modification and transcription factors, and neurite growth, protein transport, RNA processing, cholesterol biosynthesis, and apoptosis via death domain receptors, were overrepresented biological processes in immature OSNs. Ion transport (ion channels), presynaptic functions, and cilia-specific processes were overrepresented in mature OSNs. Processes overrepresented among the genes expressed by all OSNs were protein and ion transport, ER overload response, protein catabolism, and the electron transport chain. To more accurately represent gradations in mRNA abundance and identify all genes expressed in each cell type, classification methods were used to produce probabilities of expression in each cell type for every gene. These probabilities, which identified 9,300 genes expressed in OSNs, were 96% accurate at identifying genes expressed in OSNs and 86% accurate at discriminating genes specific to mature and immature OSNs. This OSN gene database not only predicts the genes responsible for the major biological processes active in OSNs, but also identifies thousands of never before studied genes that support OSN phenotypes. PMID:22252456

Laminin promotes neuritic regeneration from cultured peripheral and central neurons

PubMed Central

1983-01-01

The ability of axons to grow through tissue in vivo during development or regeneration may be regulated by the availability of specific neurite-promoting macromolecules located within the extracellular matrix. We have used tissue culture methods to examine the relative ability of various extracellular matrix components to elicit neurite outgrowth from dissociated chick embryo parasympathetic (ciliary ganglion) neurons in serum-free monolayer culture. Purified laminin from both mouse and rat sources, as well as a partially purified polyornithine-binding neurite promoting factor (PNPF-1) from rat Schwannoma cells all stimulate neurite production from these neurons. Laminin and PNPF-1 are also potent stimulators of neurite growth from cultured neurons obtained from other peripheral as well as central neural tissues, specifically avian sympathetic and sensory ganglia and spinal cord, optic tectum, neural retina, and telencephalon, as well as from sensory ganglia of the neonatal mouse and hippocampal, septal, and striatal tissues of the fetal rat. A quantitative in vitro bioassay method using ciliary neurons was used to (a) measure and compare the specific neurite-promoting activities of these agents, (b) confirm that during the purification of laminin, the neurite-promoting activity co- purifies with the laminin protein, and (c) compare the influences of antilaminin antibodies on the neurite-promoting activity of laminin and PNPF-1. We conclude that laminin and PNPF-1 are distinct macromolecules capable of expressing their neurite-promoting activities even when presented in nanogram amounts. This neurite-promoting bioassay currently represents the most sensitive test for the biological activity of laminin. PMID:6643580

Acetylcholine and lobster sensory neurones

PubMed Central

Barker, David L.; Herbert, Edward; Hildebrand, John G.; Kravitz, Edward A.

1972-01-01

Experiments are presented in support of the hypothesis that acetylcholine functions as a sensory transmitter in the lobster nervous system. 1. Several different peripheral sensory structures incorporate radioactive choline into acetylcholine. The preparation most enriched in sensory as opposed to other nervous elements (the antennular sense organs of the distal outer flagellum) does not incorporate significant amounts of glutamate, tyrosine or tryptophan into any of the other major transmitter candidates. 2. There is a parallel between the distribution of the enzyme choline acetyltransferase and the proportion of sensory fibres in nervous tissue from many parts of the lobster nervous system. 3. Isolated sensory axons contain at least 500 times as much choline acetyltransferase per cm of axon as do efferent excitatory and inhibitory fibres. 4. Abdominal ganglia and root stumps show a decline in the rate of incorporation of choline into acetylcholine 2 to 8 weeks after severing the first and second roots bilaterally (leaving the connectives and third roots intact). Extracts of the root stumps exhibit a significantly lower level of choline acetyltransferase 2 weeks after this operation. 5. Curare and atropine partially block an identified sensory synapse in the lobster abdominal ganglion. ImagesText-fig. 4Text-fig. 5Plate 1 PMID:4343316

Motor Neuron Rescue in Spinal Muscular Atrophy Mice Demonstrates That Sensory-Motor Defects Are a Consequence, Not a Cause, of Motor Neuron Dysfunction

PubMed Central

Gogliotti, Rocky G.; Quinlan, Katharina A.; Barlow, Courtenay B.; Heier, Christopher R.; Heckman, C. J.

2012-01-01

The loss of motor neurons (MNs) is a hallmark of the neuromuscular disease spinal muscular atrophy (SMA); however, it is unclear whether this phenotype autonomously originates within the MN. To address this question, we developed an inducible mouse model of severe SMA that has perinatal lethality, decreased motor function, motor unit pathology, and hyperexcitable MNs. Using an Hb9-Cre allele, we increased Smn levels autonomously within MNs and demonstrate that MN rescue significantly improves all phenotypes and pathologies commonly described in SMA mice. MN rescue also corrects hyperexcitability in SMA motor neurons and prevents sensory-motor synaptic stripping. Survival in MN-rescued SMA mice is extended by only 5 d, due in part to failed autonomic innervation of the heart. Collectively, this work demonstrates that the SMA phenotype autonomously originates in MNs and that sensory-motor synapse loss is a consequence, not a cause, of MN dysfunction. PMID:22423102

Necroptosis contributes to methamphetamine-induced cytotoxicity in rat cortical neurons.

PubMed

Xiong, Kun; Liao, Huidan; Long, Lingling; Ding, Yanjun; Huang, Jufang; Yan, Jie

2016-09-01

Necroptosis, a programmed necrosis, is involved in various types of neurodegenerative diseases. In this study, we investigated whether necroptosis contributed to neuronal damage in a methamphetamine injury model. Primary cultures of embryonic cortical neurons from Sprague-Dawley rats were subjected to different doses of methamphetamine with/without pre-treatment with a specific necroptosis inhibitor, Necrostatin-1. Necrosis was assessed by determining lactate dehydrogenase release and by Annexin V/propidium iodide double staining, while the neuronal ultra-structure was examined by electron microscopy. Tumor necrosis factor-α protein levels were determined by enzyme-linked immunosorbent assay. At early stages (12h) of post-treatment with methamphetamine, significant necrosis occurred and the viability of neurons decreased in a dose- and time-dependent manner in this model of acute neuronal injury. Pretreatment with Necrostatin-1 led to significant neuronal preservation compared with the methamphetamine-treated groups. Furthermore, tumor necrosis factor-α expression increased in a dose-dependent manner following methamphetamine exposure. Methamphetamine induced necrosis in rat cortical neurons in vitro, both time and dose dependently, and necroptosis may be an important newly identified mode of cortical neuronal death caused by single high-dose methamphetamine administration. Copyright © 2016 Elsevier B.V. All rights reserved.

Methylphenidate modulates dorsal raphe neuronal activity: Behavioral and neuronal recordings from adolescent rats.

PubMed

Kharas, Natasha; Whitt, Holly; Reyes-Vasquez, Cruz; Dafny, Nachum

2017-01-01

Methylphenidate (MPD) is a widely prescribed psychostimulants used for the treatment of attention deficit hyperactive disorder (ADHD). Unlike the psychostimulants cocaine and amphetamine, MPD does not exhibit direct actions on the serotonin transporter, however there is evidence suggesting that the therapeutic effects of MPD may be mediated in part by alterations in serotonin transmission. This study aimed to investigate the role of the dorsal raphe (DR) nucleus, one of the major sources of serotonergic innervation in the mammalian brain, in the response to MPD exposure. Freely behaving adolescent rats previously implanted bilaterally with permanent electrodes were used. An open field assay and a wireless neuronal recording system were used to concomitantly record behavioral and DR electrophysiological activity following acute and chronic MPD exposure. Four groups were used: one control (saline) and three experimental groups treated with 0.6, 2.5, and 10.0mg/kg MPD respectively. Animals received daily MPD or saline injections on experimental days 1-6, followed by 3 washout days and MPD rechallenge dose on experimental day (ED)10. The same chronic dose of MPD resulted in either behavioral sensitization or tolerance, and we found that neuronal activity recorded from the DR neuronal units of rats expressing behavioral sensitization to chronic MPD exposure responded significantly differently to MPD rechallenge on ED10 compared to the DR unit activity recorded from animals that expressed behavioral tolerance. This correlation between behavioral response and DR neuronal activity following chronic MPD exposure provides evidence that the DR is involved in the acute effects as well as the chronic effects of MPD in adolescent rats. Copyright © 2016 Elsevier Inc. All rights reserved.

Environmental enrichment of young adult rats (Rattus norvegicus) in different sensory modalities has long-lasting effects on their ability to learn via specific sensory channels.

PubMed

Dolivo, Vassilissa; Taborsky, Michael

2017-05-01

Sensory modalities individuals use to obtain information from the environment differ among conspecifics. The relative contributions of genetic divergence and environmental plasticity to this variance remain yet unclear. Numerous studies have shown that specific sensory enrichments or impoverishments at the postnatal stage can shape neural development, with potential lifelong effects. For species capable of adjusting to novel environments, specific sensory stimulation at a later life stage could also induce specific long-lasting behavioral effects. To test this possibility, we enriched young adult Norway rats with either visual, auditory, or olfactory cues. Four to 8 months after the enrichment period we tested each rat for their learning ability in 3 two-choice discrimination tasks, involving either visual, auditory, or olfactory stimulus discrimination, in a full factorial design. No sensory modality was more relevant than others for the proposed task per se, but rats performed better when tested in the modality for which they had been enriched. This shows that specific environmental conditions encountered during early adulthood have specific long-lasting effects on the learning abilities of rats. Furthermore, we disentangled the relative contributions of genetic and environmental causes of the response. The reaction norms of learning abilities in relation to the stimulus modality did not differ between families, so interindividual divergence was mainly driven by environmental rather than genetic factors. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

Noise Enhances Action Potential Generation in Mouse Sensory Neurons via Stochastic Resonance

PubMed Central

Onorato, Irene; D'Alessandro, Giuseppina; Di Castro, Maria Amalia; Renzi, Massimiliano; Dobrowolny, Gabriella; Musarò, Antonio; Salvetti, Marco; Limatola, Cristina; Crisanti, Andrea; Grassi, Francesca

2016-01-01

Noise can enhance perception of tactile and proprioceptive stimuli by stochastic resonance processes. However, the mechanisms underlying this general phenomenon remain to be characterized. Here we studied how externally applied noise influences action potential firing in mouse primary sensory neurons of dorsal root ganglia, modelling a basic process in sensory perception. Since noisy mechanical stimuli may cause stochastic fluctuations in receptor potential, we examined the effects of sub-threshold depolarizing current steps with superimposed random fluctuations. We performed whole cell patch clamp recordings in cultured neurons of mouse dorsal root ganglia. Noise was added either before and during the step, or during the depolarizing step only, to focus onto the specific effects of external noise on action potential generation. In both cases, step + noise stimuli triggered significantly more action potentials than steps alone. The normalized power norm had a clear peak at intermediate noise levels, demonstrating that the phenomenon is driven by stochastic resonance. Spikes evoked in step + noise trials occur earlier and show faster rise time as compared to the occasional ones elicited by steps alone. These data suggest that external noise enhances, via stochastic resonance, the recruitment of transient voltage-gated Na channels, responsible for action potential firing in response to rapid step-wise depolarizing currents. PMID:27525414

Noise Enhances Action Potential Generation in Mouse Sensory Neurons via Stochastic Resonance.

PubMed

Onorato, Irene; D'Alessandro, Giuseppina; Di Castro, Maria Amalia; Renzi, Massimiliano; Dobrowolny, Gabriella; Musarò, Antonio; Salvetti, Marco; Limatola, Cristina; Crisanti, Andrea; Grassi, Francesca

2016-01-01

Noise can enhance perception of tactile and proprioceptive stimuli by stochastic resonance processes. However, the mechanisms underlying this general phenomenon remain to be characterized. Here we studied how externally applied noise influences action potential firing in mouse primary sensory neurons of dorsal root ganglia, modelling a basic process in sensory perception. Since noisy mechanical stimuli may cause stochastic fluctuations in receptor potential, we examined the effects of sub-threshold depolarizing current steps with superimposed random fluctuations. We performed whole cell patch clamp recordings in cultured neurons of mouse dorsal root ganglia. Noise was added either before and during the step, or during the depolarizing step only, to focus onto the specific effects of external noise on action potential generation. In both cases, step + noise stimuli triggered significantly more action potentials than steps alone. The normalized power norm had a clear peak at intermediate noise levels, demonstrating that the phenomenon is driven by stochastic resonance. Spikes evoked in step + noise trials occur earlier and show faster rise time as compared to the occasional ones elicited by steps alone. These data suggest that external noise enhances, via stochastic resonance, the recruitment of transient voltage-gated Na channels, responsible for action potential firing in response to rapid step-wise depolarizing currents.

Neurochemical phenotype of cytoglobin-expressing neurons in the rat hippocampus.

PubMed

Hundahl, Christian Ansgar; Fahrenkrug, Jan; Hannibal, Jens

2014-09-01

Cytoglobin (Cygb), a novel oxygen-binding protein, is expressed in the majority of tissues and has been proposed to function in nitric oxide (NO) metabolism in the vasculature and to have cytoprotective properties. However, the overall functions of Cygb remain elusive. Cygb is also expressed in a subpopulation of brain neurons. Recently, it has been shown that stress upregulates Cygb expression in the brain and the majority of neuronal nitric oxide synthase (nNOS)-positive neurons, an enzyme that produces NO, co-express Cygb. However, there are more neurons expressing Cygb than nNOS, thus a large number of Cygb neurons remain uncharacterized by the neurochemical content. The aim of the present study was to provide an additional and more detailed neurochemical phenotype of Cygb-expressing neurons in the rat hippocampus. The rat hippocampus was chosen due to the abundance of Cygb, as well as this limbic structure being an important target in a number of neurodegenerative diseases. Using triple immunohistochemistry, it was demonstrated that nearly all the parvalbumin- and heme oxygenase 1-positive neurons co-express Cygb and to a large extent, these neuron populations are distinct from the population of Cygb neurons co-expressing nNOS. Furthermore, it was shown that the majority of neurons expressing somastostatin and vasoactive intestinal peptide also co-express Cygb and nNOS. Detailed information regarding the neurochemical phenotype of Cygb neurons in the hippocampus can be a valuable tool in determining the function of Cygb in the brain.

Early-Life Social Isolation Impairs the Gonadotropin-Inhibitory Hormone Neuronal Activity and Serotonergic System in Male Rats.

PubMed

Soga, Tomoko; Teo, Chuin Hau; Cham, Kai Lin; Idris, Marshita Mohd; Parhar, Ishwar S

2015-01-01

Social isolation in early life deregulates the serotonergic system of the brain, compromising reproductive function. Gonadotropin-inhibitory hormone (GnIH) neurons in the dorsomedial hypothalamic nucleus are critical to the inhibitory regulation of gonadotropin-releasing hormone neuronal activity in the brain and release of luteinizing hormone by the pituitary gland. Although GnIH responds to stress, the role of GnIH in social isolation-induced deregulation of the serotonin system and reproductive function remains unclear. We investigated the effect of social isolation in early life on the serotonergic-GnIH neuronal system using enhanced green fluorescent protein (EGFP)-tagged GnIH transgenic rats. Socially isolated rats were observed for anxious and depressive behaviors. Using immunohistochemistry, we examined c-Fos protein expression in EGFP-GnIH neurons in 9-week-old adult male rats after 6 weeks post-weaning isolation or group housing. We also inspected serotonergic fiber juxtapositions in EGFP-GnIH neurons in control and socially isolated male rats. Socially isolated rats exhibited anxious and depressive behaviors. The total number of EGFP-GnIH neurons was the same in control and socially isolated rats, but c-Fos expression in GnIH neurons was significantly reduced in socially isolated rats. Serotonin fiber juxtapositions on EGFP-GnIH neurons were also lower in socially isolated rats. In addition, levels of tryptophan hydroxylase mRNA expression in the dorsal raphe nucleus were significantly attenuated in these rats. These results suggest that social isolation in early-life results in lower serotonin levels, which reduce GnIH neuronal activity and may lead to reproductive failure.

Hindbrain Catecholamine Neurons Activate Orexin Neurons During Systemic Glucoprivation in Male Rats.

PubMed

Li, Ai-Jun; Wang, Qing; Elsarelli, Megan M; Brown, R Lane; Ritter, Sue

2015-08-01

Hindbrain catecholamine neurons are required for elicitation of feeding responses to glucose deficit, but the forebrain circuitry required for these responses is incompletely understood. Here we examined interactions of catecholamine and orexin neurons in eliciting glucoprivic feeding. Orexin neurons, located in the perifornical lateral hypothalamus (PeFLH), are heavily innervated by hindbrain catecholamine neurons, stimulate food intake, and increase arousal and behavioral activation. Orexin neurons may therefore contribute importantly to appetitive responses, such as food seeking, during glucoprivation. Retrograde tracing results showed that nearly all innervation of the PeFLH from the hindbrain originated from catecholamine neurons and some raphe nuclei. Results also suggested that many catecholamine neurons project collaterally to the PeFLH and paraventricular hypothalamic nucleus. Systemic administration of the antiglycolytic agent, 2-deoxy-D-glucose, increased food intake and c-Fos expression in orexin neurons. Both responses were eliminated by a lesion of catecholamine neurons innervating orexin neurons using the retrogradely transported immunotoxin, anti-dopamine-β-hydroxylase saporin, which is specifically internalized by dopamine-β-hydroxylase-expressing catecholamine neurons. Using designer receptors exclusively activated by designer drugs in transgenic rats expressing Cre recombinase under the control of tyrosine hydroxylase promoter, catecholamine neurons in cell groups A1 and C1 of the ventrolateral medulla were activated selectively by peripheral injection of clozapine-N-oxide. Clozapine-N-oxide injection increased food intake and c-Fos expression in PeFLH orexin neurons as well as in paraventricular hypothalamic nucleus neurons. In summary, catecholamine neurons are required for the activation of orexin neurons during glucoprivation. Activation of orexin neurons may contribute to appetitive responses required for glucoprivic feeding.

Two Heteromeric Kinesin Complexes in Chemosensory Neurons and Sensory Cilia of Caenorhabditis elegans

PubMed Central

Signor, Dawn; Wedaman, Karen P.; Rose, Lesilee S.; Scholey, Jonathan M.

1999-01-01

Chemosensation in the nervous system of the nematode Caenorhabditis elegans depends on sensory cilia, whose assembly and maintenance requires the transport of components such as axonemal proteins and signal transduction machinery to their site of incorporation into ciliary structures. Members of the heteromeric kinesin family of microtubule motors are prime candidates for playing key roles in these transport events. Here we describe the molecular characterization and partial purification of two heteromeric kinesin complexes from C. elegans, heterotrimeric CeKinesin-II and dimeric CeOsm-3. Transgenic worms expressing green fluorescent protein driven by endogenous heteromeric kinesin promoters reveal that both CeKinesin-II and CeOsm-3 are expressed in amphid, inner labial, and phasmid chemosensory neurons. Additionally, immunolocalization experiments on fixed worms show an intense concentration of CeKinesin-II and CeOsm-3 polypeptides in the ciliated endings of these chemosensory neurons and a punctate localization pattern in the corresponding cell bodies and dendrites. These results, together with the phenotypes of known mutants in the pathway of sensory ciliary assembly, suggest that CeKinesin-II and CeOsm-3 drive the transport of ciliary components required for sequential steps in the assembly of chemosensory cilia. PMID:9950681

In Vitro Analysis of the Role of Schwann Cells on Axonal Degeneration and Regeneration Using Sensory Neurons from Dorsal Root Ganglia.

PubMed

López-Leal, Rodrigo; Diaz, Paula; Court, Felipe A

2018-01-01

Sensory neurons from dorsal root ganglion efficiently regenerate after peripheral nerve injuries. These neurons are widely used as a model system to study degenerative mechanisms of the soma and axons, as well as regenerative axonal growth in the peripheral nervous system. This chapter describes techniques associated to the study of axonal degeneration and regeneration using explant cultures of dorsal root ganglion sensory neurons in vitro in the presence or absence of Schwann cells. Schwann cells are extremely important due to their involvement in tissue clearance during axonal degeneration as well as their known pro-regenerative effect during regeneration in the peripheral nervous system. We describe methods to induce and study axonal degeneration triggered by axotomy (mechanical separation of the axon from its soma) and treatment with vinblastine (which blocks axonal transport), which constitute clinically relevant mechanical and toxic models of axonal degeneration. In addition, we describe three different methods to evaluate axonal regeneration using quantitative methods. These protocols constitute a valuable tool to analyze in vitro mechanisms associated to axonal degeneration and regeneration of sensory neurons and the role of Schwann cells in these processes.

Purification and culture of adult rat dorsal root ganglia neurons.

PubMed

Delree, P; Leprince, P; Schoenen, J; Moonen, G

1989-06-01

To study the trophic requirements of adult rat dorsal root ganglia neurons (DRG) in vitro, we developed a purification procedure that yields highly enriched neuronal cultures. Forty to fifty ganglia are dissected from the spinal column of an adult rat. After enzymatic and mechanical dissociation of the ganglia, myelin debris are eliminated by centrifugation on a Percoll gradient. The resulting cell suspension is layered onto a nylon mesh with a pore size of 10 microns. Most of the neurons, the diameter of which ranged from 17 microns to greater than 100 microns, are retained on the upper surface of the sieve; most of the non-neuronal cells with a caliber of less than 10 microns after trypsinization go through it. Recovery of neurons is achieved by reversing the mesh onto a Petri dish containing culture medium. Neurons to non-neurons ratio is 1 to 10 in the initial cell suspension and 1 to 1 after separation. When these purified neurons are seeded at a density of 3,000 neurons/cm2 in 6 mm polyornithine-laminin (PORN-LAM) coated wells, neuronal survival (assessed by the ability to extend neurites), measured after 48 hr of culture, is very low (from 0 to 16%). Addition of nerve growth factor (NGF) does not improve neuronal survival. However, when neurons are cultured in the presence of medium conditioned (CM) by astrocytes or Schwann cells, 60-80% of the seeded, dye-excluding neurons survive. So, purified adult DRG neurons require for their short-term survival and regeneration in culture, a trophic support that is present in conditioned medium from PNS or CNS glia.(ABSTRACT TRUNCATED AT 250 WORDS)

Glucose-dependent trafficking of 5-HT3 receptors in rat gastrointestinal vagal afferent neurons

PubMed Central

Babic, Tanja; Troy, Amanda E; Fortna, Samuel R; Browning, Kirsteen N

2012-01-01

Background Intestinal glucose induces gastric relaxation via vagally mediated sensory-motor reflexes. Glucose can alter the activity of gastrointestinal (GI) vagal afferent (sensory) neurons directly, via closure of ATP-sensitive potassium channels, as well as indirectly, via the release of 5-hydroxytryptamine (5-HT) from mucosal enteroendocrine cells. We hypothesized that glucose may also be able to modulate the ability of GI vagal afferent neurons to respond to the released 5-HT, via regulation of neuronal 5-HT3 receptors. Methods Whole cell patch clamp recordings were made from acutely dissociated GI-projecting vagal afferent neurons exposed to equiosmolar Krebs’ solution containing different concentrations of D-glucose (1.25–20mM) and the response to picospritz application of 5-HT assessed. The distribution of 5-HT3 receptors in neurons exposed to different glucose concentrations was also assessed immunohistochemically. Key Results Increasing or decreasing extracellular D-glucose concentration increased or decreased, respectively, the 5-HT-induced inward current as well as the proportion of 5-HT3 receptors associated with the neuronal membrane. These responses were blocked by the Golgi-disrupting agent Brefeldin-A (5µM) suggesting involvement of a protein trafficking pathway. Furthermore, L-glucose did not mimic the response of D-glucose implying that metabolic events downstream of neuronal glucose uptake are required in order to observe the modulation of 5-HT3 receptor mediated responses. Conclusions & Inferences These results suggest that, in addition to inducing the release of 5-HT from enterochromaffin cells, glucose may also increase the ability of GI vagal sensory neurons to respond to the released 5-HT, providing a means by which the vagal afferent signal can be amplified or prolonged. PMID:22845622

Effect of knockout of α2δ-1 on action potentials in mouse sensory neurons.

PubMed

Margas, Wojciech; Ferron, Laurent; Nieto-Rostro, Manuela; Schwartz, Arnold; Dolphin, Annette C

2016-08-05

Gene deletion of the voltage-gated calcium channel auxiliary subunit α2δ-1 has been shown previously to have a cardiovascular phenotype, and a reduction in mechano- and cold sensitivity, coupled with delayed development of neuropathic allodynia. We have also previously shown that dorsal root ganglion (DRG) neuron calcium channel currents were significantly reduced in α2δ-1 knockout mice. To extend our findings in these sensory neurons, we have examined here the properties of action potentials (APs) in DRG neurons from α2δ-1 knockout mice in comparison to their wild-type (WT) littermates, in order to dissect how the calcium channels that are affected by α2δ-1 knockout are involved in setting the duration of individual APs and their firing frequency. Our main findings are that there is reduced Ca(2+) entry on single AP stimulation, particularly in the axon proximal segment, reduced AP duration and reduced firing frequency to a 400 ms stimulation in α2δ-1 knockout neurons, consistent with the expected role of voltage-gated calcium channels in these events. Furthermore, lower intracellular Ca(2+) buffering also resulted in reduced AP duration, and a lower frequency of AP firing in WT neurons, mimicking the effect of α2δ-1 knockout. By contrast, we did not obtain any consistent evidence for the involvement of Ca(2+)-activation of large conductance calcium-activated potassium (BK) and small conductance calcium-activated potassium (SK) channels in these events. In conclusion, the reduced Ca(2+) elevation as a result of single AP stimulation is likely to result from the reduced duration of the AP in α2δ-1 knockout sensory neurons.This article is part of the themed issue 'Evolution brings Ca(2+) and ATP together to control life and death'. © 2016 The Authors.

Male sexual behavior is associated with LHRH neuron number in middle-aged rats.

PubMed

Tsai, Y F; Tsai, H W; Tai, M Y; Huang, R L; Peng, M T

1997-11-21

LHRH administration is reported to facilitate male sexual behavior. The aim of the present study was to investigate whether male sexual behavior is associated with the number of LHRH neurons in the forebrain in middle-aged rats. Male Long-Evans rats (18-19 months) were assigned to three groups on the basis of sexual performance: (1) group MEI consisted of rats showing complete copulatory patterns, including mounts, intromissions and ejaculations, (2) group MI was composed of rats showing mounts and intromissions, but no ejaculation and (3) group NC were non-copulators, i.e. they did not show any copulatory behavior. Young adult rats (4-5 months), displaying sexual behavior, were used as controls. Following the sexual behavior tests, the number of LHRH neurons in the medial septum (MS), organum vasculosum of the lamina terminalis (OVLT), preoptic area (POA) and anterior hypothalamus (AH) was determined by immunocytochemistry. No difference was seen in the total number of LHRH neurons in these combined brain areas between group MIE and young controls. In the three middle-aged groups, the total number of LHRH neurons was greatest in group MIE, less in group MI, and lowest in group NC. In general, a similar trend was seen separately in the MS, OVLT and POA. These results suggest that changes in the number of LHRH neurons in the forebrain, in most cases, are age-related, at least in the middle-aged rats, but they also seem to be associated with male sexual performance.

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

PubMed Central

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

2008-01-01

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

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

PubMed

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

2008-08-18

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

Early-Life Social Isolation Impairs the Gonadotropin-Inhibitory Hormone Neuronal Activity and Serotonergic System in Male Rats

PubMed Central

Soga, Tomoko; Teo, Chuin Hau; Cham, Kai Lin; Idris, Marshita Mohd; Parhar, Ishwar S.

2015-01-01

Social isolation in early life deregulates the serotonergic system of the brain, compromising reproductive function. Gonadotropin-inhibitory hormone (GnIH) neurons in the dorsomedial hypothalamic nucleus are critical to the inhibitory regulation of gonadotropin-releasing hormone neuronal activity in the brain and release of luteinizing hormone by the pituitary gland. Although GnIH responds to stress, the role of GnIH in social isolation-induced deregulation of the serotonin system and reproductive function remains unclear. We investigated the effect of social isolation in early life on the serotonergic–GnIH neuronal system using enhanced green fluorescent protein (EGFP)-tagged GnIH transgenic rats. Socially isolated rats were observed for anxious and depressive behaviors. Using immunohistochemistry, we examined c-Fos protein expression in EGFP–GnIH neurons in 9-week-old adult male rats after 6 weeks post-weaning isolation or group housing. We also inspected serotonergic fiber juxtapositions in EGFP–GnIH neurons in control and socially isolated male rats. Socially isolated rats exhibited anxious and depressive behaviors. The total number of EGFP–GnIH neurons was the same in control and socially isolated rats, but c-Fos expression in GnIH neurons was significantly reduced in socially isolated rats. Serotonin fiber juxtapositions on EGFP–GnIH neurons were also lower in socially isolated rats. In addition, levels of tryptophan hydroxylase mRNA expression in the dorsal raphe nucleus were significantly attenuated in these rats. These results suggest that social isolation in early-life results in lower serotonin levels, which reduce GnIH neuronal activity and may lead to reproductive failure. PMID:26617573

How do neurons work together? Lessons from auditory cortex.

PubMed

Harris, Kenneth D; Bartho, Peter; Chadderton, Paul; Curto, Carina; de la Rocha, Jaime; Hollender, Liad; Itskov, Vladimir; Luczak, Artur; Marguet, Stephan L; Renart, Alfonso; Sakata, Shuzo

2011-01-01

Recordings of single neurons have yielded great insights into the way acoustic stimuli are represented in auditory cortex. However, any one neuron functions as part of a population whose combined activity underlies cortical information processing. Here we review some results obtained by recording simultaneously from auditory cortical populations and individual morphologically identified neurons, in urethane-anesthetized and unanesthetized passively listening rats. Auditory cortical populations produced structured activity patterns both in response to acoustic stimuli, and spontaneously without sensory input. Population spike time patterns were broadly conserved across multiple sensory stimuli and spontaneous events, exhibiting a generally conserved sequential organization lasting approximately 100 ms. Both spontaneous and evoked events exhibited sparse, spatially localized activity in layer 2/3 pyramidal cells, and densely distributed activity in larger layer 5 pyramidal cells and putative interneurons. Laminar propagation differed however, with spontaneous activity spreading upward from deep layers and slowly across columns, but sensory responses initiating in presumptive thalamorecipient layers, spreading rapidly across columns. In both unanesthetized and urethanized rats, global activity fluctuated between "desynchronized" state characterized by low amplitude, high-frequency local field potentials and a "synchronized" state of larger, lower-frequency waves. Computational studies suggested that responses could be predicted by a simple dynamical system model fitted to the spontaneous activity immediately preceding stimulus presentation. Fitting this model to the data yielded a nonlinear self-exciting system model in synchronized states and an approximately linear system in desynchronized states. We comment on the significance of these results for auditory cortical processing of acoustic and non-acoustic information. © 2010 Elsevier B.V. All rights reserved.

BKCa currents are enriched in a subpopulation of adult rat cutaneous nociceptive dorsal root ganglion neurons

PubMed Central

Zhang, Xiu-Lin; Mok, Lee-Peng; Katz, Elizabeth J; Gold, Michael S.

2010-01-01

The biophysical properties and distribution of voltage-dependent, Ca2+-modulated K+ (BKCa) currents among subpopulations of acutely dissociated DiI labeled cutaneous sensory neurons from the adult rat were characterized with whole cell patch clamp techniques. BKCa currents were isolated from total K+ current with iberiotoxin, charybdotoxin, or paxilline. There was considerable variability in biophysical properties of BKCa currents. There was also variability in the distribution of BKCa current among subpopulations of cutaneous DRG neurons. While present in each of the subpopulations defined by cell body size, IB4 binding or capsaicin sensitivity, BKCa current was present in vast majority (>90%) of small diameter IB4+ neurons but was present in only a minority of neurons in subpopulations defined by other criteria (i.e., small diameter IB4−). Current clamp analysis indicated that in IB4+ neurons, BKCa currents contribute to the repolarization of the action potential and adaptation in response to sustained membrane depolarization, while playing little role in the determination of action potential threshold. RT-PCR analysis of mRNA collected from whole DRG revealed the presence of multiple splice variants of the BKCa channel α-subunit, rslo and all 4 of the accessory β subunits, suggesting that heterogeneity in the biophysical and pharmacological properties of BKCa current in cutaneous neurons, reflects, at least in part, the differential distribution of splice variants and/or β subunits. Because even a small decrease in BKCa current appears to have a dramatic influence on excitability, modulation of this current may contribute to sensitization of nociceptive afferents observed following tissue injury. PMID:20105244

Competition model for aperiodic stochastic resonance in a Fitzhugh-Nagumo model of cardiac sensory neurons.

PubMed

Kember, G C; Fenton, G A; Armour, J A; Kalyaniwalla, N

2001-04-01

Regional cardiac control depends upon feedback of the status of the heart from afferent neurons responding to chemical and mechanical stimuli as transduced by an array of sensory neurites. Emerging experimental evidence shows that neural control in the heart may be partially exerted using subthreshold inputs that are amplified by noisy mechanical fluctuations. This amplification is known as aperiodic stochastic resonance (ASR). Neural control in the noisy, subthreshold regime is difficult to see since there is a near absence of any correlation between input and the output, the latter being the average firing (spiking) rate of the neuron. This lack of correlation is unresolved by traditional energy models of ASR since these models are unsuitable for identifying "cause and effect" between such inputs and outputs. In this paper, the "competition between averages" model is used to determine what portion of a noisy, subthreshold input is responsible, on average, for the output of sensory neurons as represented by the Fitzhugh-Nagumo equations. A physiologically relevant conclusion of this analysis is that a nearly constant amount of input is responsible for a spike, on average, and this amount is approximately independent of the firing rate. Hence, correlation measures are generally reduced as the firing rate is lowered even though neural control under this model is actually unaffected.

Rapid Integration of Artificial Sensory Feedback during Operant Conditioning of Motor Cortex Neurons.

PubMed

Prsa, Mario; Galiñanes, Gregorio L; Huber, Daniel

2017-02-22

Neuronal motor commands, whether generating real or neuroprosthetic movements, are shaped by ongoing sensory feedback from the displacement being produced. Here we asked if cortical stimulation could provide artificial feedback during operant conditioning of cortical neurons. Simultaneous two-photon imaging and real-time optogenetic stimulation were used to train mice to activate a single neuron in motor cortex (M1), while continuous feedback of its activity level was provided by proportionally stimulating somatosensory cortex. This artificial signal was necessary to rapidly learn to increase the conditioned activity, detect correct performance, and maintain the learned behavior. Population imaging in M1 revealed that learning-related activity changes are observed in the conditioned cell only, which highlights the functional potential of individual neurons in the neocortex. Our findings demonstrate the capacity of animals to use an artificially induced cortical channel in a behaviorally relevant way and reveal the remarkable speed and specificity at which this can occur. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Consistent relationships between sensory properties of savory snack foods and calories influence food intake in rats.

PubMed

Swithers, S E; Doerflinger, A; Davidson, T L

2006-11-01

Determine the influence of experience with consistent or inconsistent relationships between the sensory properties of snack foods and their caloric consequences on the control of food intake or body weight in rats. Rats received plain and BBQ flavored potato chips as a dietary supplement, along with ad lib rat chow. For some rats the potato chips were a consistent source of high fat and high calories (regular potato chips). For other rats, the chips provided high fat and high calories on some occasions (regular potato chips) and provided no digestible fat and fewer calories at other times (light potato chips manufactured with a fat substitute). Thus, animals in the first group were given experiences that the sensory properties of potato chips were strong predictors of high calories, while animals in the second group were given experiences that the sensory properties of potato chips were not predictors of high calories. Juvenile and adult male Sprague-Dawley rats. Following exposure to varying potato chip-calorie contingencies, intake of a novel, high-fat snack food and subsequent chow intake were assessed. Body weight gain and body composition as measured by DEXA were also measured. In juvenile animals, exposure to a consistent relationship between potato chips and calories resulted in reduced chow intake, both when no chips were provided and following consumption of a novel high-fat, high-calorie snack chip. Long-term experience with these contingencies did not affect body weight gain or body composition in juveniles. In adult rats, exposure to an inconsistent relationship between potato chips and calories resulted in increased consumption of a novel high-fat, high-calorie snack chip premeal along with impaired compensation for the calories contained in the premeal. Consumption of foods in which the sensory properties are poor predictors of caloric consequences may alter subsequent food intake.

Responses in Rat Core Auditory Cortex are Preserved during Sleep Spindle Oscillations

PubMed Central

Sela, Yaniv; Vyazovskiy, Vladyslav V.; Cirelli, Chiara; Tononi, Giulio; Nir, Yuval

2016-01-01

Study Objectives: Sleep is defined as a reversible state of reduction in sensory responsiveness and immobility. A long-standing hypothesis suggests that a high arousal threshold during non-rapid eye movement (NREM) sleep is mediated by sleep spindle oscillations, impairing thalamocortical transmission of incoming sensory stimuli. Here we set out to test this idea directly by examining sensory-evoked neuronal spiking activity during natural sleep. Methods: We compared neuronal (n = 269) and multiunit activity (MUA), as well as local field potentials (LFP) in rat core auditory cortex (A1) during NREM sleep, comparing responses to sounds depending on the presence or absence of sleep spindles. Results: We found that sleep spindles robustly modulated the timing of neuronal discharges in A1. However, responses to sounds were nearly identical for all measured signals including isolated neurons, MUA, and LFPs (all differences < 10%). Furthermore, in 10% of trials, auditory stimulation led to an early termination of the sleep spindle oscillation around 150–250 msec following stimulus onset. Finally, active ON states and inactive OFF periods during slow waves in NREM sleep affected the auditory response in opposite ways, depending on stimulus intensity. Conclusions: Responses in core auditory cortex are well preserved regardless of sleep spindles recorded in that area, suggesting that thalamocortical sensory relay remains functional during sleep spindles, and that sensory disconnection in sleep is mediated by other mechanisms. Citation: Sela Y, Vyazovskiy VV, Cirelli C, Tononi G, Nir Y. Responses in rat core auditory cortex are preserved during sleep spindle oscillations. SLEEP 2016;39(5):1069–1082. PMID:26856904

Characteristics of sensory neuronal groups in CGRP-cre-ER reporter mice: Comparison to Nav1.8-cre, TRPV1-cre and TRPV1-GFP mouse lines.

PubMed

Patil, Mayur J; Hovhannisyan, Anahit H; Akopian, Armen N

2018-01-01

Peptidergic sensory neurons play a critical role in nociceptive pathways. To precisely define the function and plasticity of sensory neurons in detail, new tools such as transgenic mouse models are needed. We employed electrophysiology and immunohistochemistry to characterize in detail dorsal root ganglion (DRG) neurons expressing an inducible CGRPcre-ER (CGRP-cre+); and compared them to DRG neurons expressing Nav1.8cre (Nav1.8-cre+), TRPV1cre (TRPV1-cre+) and TRPV1-GFP (V1-GFP+). Tamoxifen effectively induced CGRPcre-ER production in DRG. ≈87% of CGRPcre-ER-expressing neurons were co-labeled CGRP antibody. Three small and two medium-large-sized (5HT3a+/NPY2R- and NPY2R+) neuronal groups with unique electrophysiological profiles were CGRP-cre+. Nav1.8-cre+ neurons were detected in all CGRP-cre+ groups, as well as in 5 additional neuronal groups: MrgprD+/TRPA1-, MrgprD+/TRPA1+, TRPV1+/CGRP-, vGLUT3+ and ≈30% of trkC+ neurons. Differences between TRPV1cre and Nav1.8cre reporters were that unlike TRPV1-cre+, Nav1.8-cre+ expression was detected in non-nociceptive vGLUT3+ and trkC+ populations. Many TRPV1-cre+ neurons did not respond to capsaicin. In contrast, V1-GFP+ neurons were in 4 groups, each of which was capsaicin-sensitive. Finally, none of the analyzed reporter lines showed cre-recombination in trkB+, calbindin+, 70% of trkC+ or parvalbumin+ neurons, which together encompassed ≈20% of Nav1.8-cre- DRG neurons. The data presented here increases our knowledge of peptidergic sensory neuron characteristics, while showing the efficiency and specificity manipulation of peptidergic neurons by the CGRPcre-ER reporter. We also demonstrate that manipulation of all C- and A-nociceptors is better achieved with TRPV1-cre reporter. Finally, the described approach for detailed characterization of sensory neuronal groups can be applied to a variety of reporter mice.

Potentiation of transient receptor potential V1 functions by the activation of metabotropic 5-HT receptors in rat primary sensory neurons

PubMed Central

Ohta, Toshio; Ikemi, Yuki; Murakami, Matsuka; Imagawa, Toshiaki; Otsuguro, Ken-ichi; Ito, Shigeo

2006-01-01

5-Hydroxytryptamine (5-HT) is one of the major chemical mediators released in injured and inflamed tissue and is capable of inducing hyperalgesia in vivo. However, the cellular mechanisms of 5-HT-induced hyperalgesia remain unclear. Transient receptor potential V1 (TRPV1) plays a pivotal role in nociceptive receptors. In the present study, we determined whether 5-HT changes TRPV1 functions in cultured dorsal root ganglion (DRG) neurons isolated from neonatal rats, using Ca2+ imaging and whole-cell patch-clamp techniques. In more than 70% of DRG neurons, 5-HT potentiated the increases of [Ca2+]i induced by capsaicin, protons and noxious heat. Capsaicin-induced current and depolarizing responses, and proton-induced currents were also augmented by 5-HT. RT-PCR analysis revealed the expression of 5-HT2A and 5-HT7 receptors in rat DRG neurons. Agonists for 5-HT2A and 5-HT7 receptors mimicked the potentiating effect of 5-HT, and their antagonists decreased it. In DRG ipsilateral to the complete Freund's adjuvant-injected inflammation side, expression levels of 5-HT2A and 5-HT7 mRNAs increased, and the potentiating effect of 5-HT was more prominent than in the contralateral control side. These results suggest that the PKC- and PKA-mediated signalling pathways are involved in the potentiating effect of 5-HT on TRPV1 functions through the activation of 5-HT2A and 5-HT7 receptors, respectively. Under inflammatory conditions, the increases of the biosynthesis of these 5-HT receptors may lead to further potentiation of TRPV1 functions, resulting in the generation of inflammatory hyperalgesia in vivo. PMID:16901936

Sensory Neuron Fates Are Distinguished by a Transcriptional Switch that Regulates Dendrite Branch Stabilization

PubMed Central

Smith, Cody J.; O’Brien, Timothy; Chatzigeorgiou, Marios; Spencer, W. Clay; Feingold-Link, Elana; Husson, Steven J.; Hori, Sayaka; Mitani, Shohei; Gottschalk, Alexander; Schafer, William R.; Miller, David M.

2013-01-01

SUMMARY Sensory neurons adopt distinct morphologies and functional modalities to mediate responses to specific stimuli. Transcription factors and their downstream effectors orchestrate this outcome but are incompletely defined. Here, we show that different classes of mechanosensory neurons in C. elegans are distinguished by the combined action of the transcription factors MEC-3, AHR-1, and ZAG-1. Low levels of MEC-3 specify the elaborate branching pattern of PVD nociceptors, whereas high MEC-3 is correlated with the simple morphology of AVM and PVM touch neurons. AHR-1 specifies AVM touch neuron fate by elevating MEC-3 while simultaneously blocking expression of nociceptive genes such as the MEC-3 target, the claudin-like membrane protein HPO-30, that promotes the complex dendritic branching pattern of PVD. ZAG-1 exercises a parallel role to prevent PVM from adopting the PVD fate. The conserved dendritic branching function of the Drosophila AHR-1 homolog, Spineless, argues for similar pathways in mammals. PMID:23889932

The HMX/NKX homeodomain protein MLS-2 specifies the identity of the AWC sensory neuron type via regulation of the ceh-36 Otx gene in C. elegans

PubMed Central

Kim, Kyuhyung; Kim, Rinho; Sengupta, Piali

2010-01-01

The differentiated features of postmitotic neurons are dictated by the expression of specific transcription factors. The mechanisms by which the precise spatiotemporal expression patterns of these factors are regulated are poorly understood. In C. elegans, the ceh-36 Otx homeobox gene is expressed in the AWC sensory neurons throughout postembryonic development, and regulates terminal differentiation of this neuronal subtype. Here, we show that the HMX/NKX homeodomain protein MLS-2 regulates ceh-36 expression specifically in the AWC neurons. Consequently, the AWC neurons fail to express neuron type-specific characteristics in mls-2 mutants. mls-2 is expressed transiently in postmitotic AWC neurons, and directly initiates ceh-36 expression. CEH-36 subsequently interacts with a distinct site in its cis-regulatory sequences to maintain its own expression, and also directly regulates the expression of AWC-specific terminal differentiation genes. We also show that MLS-2 acts in additional neuron types to regulate their development and differentiation. Our analysis describes a transcription factor cascade that defines the unique postmitotic characteristics of a sensory neuron subtype, and provides insights into the spatiotemporal regulatory mechanisms that generate functional diversity in the sensory nervous system. PMID:20150279

The molecular basis of neurosensory cell formation in ear development: a blueprint for hair cell and sensory neuron regeneration?

PubMed Central

Fritzsch, Bernd; Beisel, Kirk W.; Hansen, Laura

2014-01-01

Summary The inner ear of mammals uses neurosensory cells derived from the embryonic ear for mechanoelectric transduction of vestibular and auditory stimuli (the hair cells) and conducts this information to the brain via sensory neurons. As with most other neurons of mammals, lost hair cells and sensory neurons are not spontaneously replaced and result instead in age-dependent progressive hearing loss. We review the molecular basis of neurosensory development in the mouse ear to provide a blueprint for possible enhancement of therapeutically useful transformation of stem cells into lost neurosensory cells. We identify several readily available adult sources of stem cells that express, like the ectoderm-derived ear, genes known to be essential for ear development. Use of these stem cells combined with molecular insights into neurosensory cell specification and proliferation regulation of the ear, might allow for neurosensory regeneration of mammalian ears in the near future. PMID:17120192

Persistent Genital Hyperinnervation Following Progesterone Administration to Adolescent Female Rats1

PubMed Central

Liao, Zhaohui; Smith, Peter G.

2014-01-01

ABSTRACT Provoked vestibulodynia, a female pelvic pain syndrome affecting substantial numbers of women, is characterized by genital hypersensitivity and sensory hyperinnervation. Previous studies have shown that the risk of developing provoked vestibulodynia is markedly elevated following adolescent use of oral contraceptives with high progesterone content. We hypothesized that progesterone, a steroid hormone with known neurotropic properties, may alter genital innervation through direct or indirect actions. Female Sprague Dawley rats received progesterone (20 mg/kg subcutaneously) from Days 20–27; tissue was removed for analysis in some rats on Day 28, while others were ovariectomized on Day 43 and infused for 7 days with vehicle or 17beta estradiol. Progesterone resulted in overall increases in vaginal innervation at both Day 28 and 50 due to proliferation of peptidergic sensory and sympathetic (but not parasympathetic) axons. Estradiol reduced innervation in progesterone-treated and untreated groups. To assess the mechanisms of sensory hyperinnervation, we cultured dissociated dorsal root ganglion neurons and found that progesterone increases neurite outgrowth by small unmyelinated (but not myelinated) sensory neurons, it was receptor mediated, and it was nonadditive with NGF. Pretreatment of ganglion with progesterone also increased neurite outgrowth in response to vaginal target explants. However, pretreatment of vaginal target with progesterone did not improve outgrowth. We conclude that adolescent progesterone exposure may contribute to provoked vestibulodynia by eliciting persistent genital hyperinnervation via a direct effect on unmyelinated sensory nociceptor neurons and that estradiol, a well-documented therapeutic, may alleviate symptoms in part by reducing progesterone-induced sensory hyperinnervation. PMID:25359899

[Changes in the expression of large-conductance calcium-activated potassium channels in dorsal root ganglion neurons after electrical injury in rats' sciatic nerves and its influence on sensory conduction function].

PubMed

Wang, Guangning; Li, Xueyong; Xu, Xiaoli; Ren, Pan

2016-06-01

To study the changes in the expression of large-conductance calcium-activated potassium (BKCa) channels in dorsal root ganglion (DRG) neurons after electrical injury in rats' sciatic nerves and its influence on sensory conduction function. One-hundred and thirty-six adult SD rats were divided into normal control group, sham electrical injury group, and 75, 100, 125 V electrical injury groups according to the random number table, with 8 rats in normal control group and 32 rats in each of the rest 4 groups. Rats in normal control group were routinely fed without any treatment. Blunt dissection of the sciatic nerves of left hind leg of rats was performed in sham electrical injury group, while sciatic nerves of left hind leg of rats in electrical injury groups were electrically injured with corresponding voltage. Eight rats of normal control group fed for one week, and 8 rats from each of the rest four groups on post injury day (PID) 3 and in post injury week (PIW) 1, 2, 3 respectively were collected to detect the paw withdrawal mechanical threshold (PWMT). In addition, rats of 100 V electrical injury group in PIW 1 were collected and intrathecally injected with NS1619 after former PWMT detection, and PWMT was detected per 30 minutes within three hours post injection. The rats in each group at each time point were sacrificed after PWMT detection. The DRG of L4 to L6 segments of spinal cord was sampled to observe the BKCa channels distribution with immunohistochemical staining and to detect the protein and mRNA expressions of BKCa channels with Western blotting and reverse transcription-polymerase chain reaction respectively. Data were processed with one-way analysis of variance, analysis of variance of factorial design, and SNK test. (1) The PWMT values of rats in 75 and 100 V electrical injury groups on PID 3 and in PIW 1, 2, 3 were (5.8±0.6), (5.0±0.8), (4.2±0.3), (5.9±1.1) g; (5.3±1.3), (5.9±2.0), (4.5±2.7), (4.3±1.3) g, respectively, which were

Genes that act downstream of sensory neurons to influence longevity, dauer formation, and pathogen responses in Caenorhabditis elegans.

PubMed

Gaglia, Marta M; Jeong, Dae-Eun; Ryu, Eun-A; Lee, Dongyeop; Kenyon, Cynthia; Lee, Seung-Jae

2012-01-01

The sensory systems of multicellular organisms are designed to provide information about the environment and thus elicit appropriate changes in physiology and behavior. In the nematode Caenorhabditis elegans, sensory neurons affect the decision to arrest during development in a diapause state, the dauer larva, and modulate the lifespan of the animals in adulthood. However, the mechanisms underlying these effects are incompletely understood. Using whole-genome microarray analysis, we identified transcripts whose levels are altered by mutations in the intraflagellar transport protein daf-10, which result in impaired development and function of many sensory neurons in C. elegans. In agreement with existing genetic data, the expression of genes regulated by the transcription factor DAF-16/FOXO was affected by daf-10 mutations. In addition, we found altered expression of transcriptional targets of the DAF-12/nuclear hormone receptor in the daf-10 mutants and showed that this pathway influences specifically the dauer formation phenotype of these animals. Unexpectedly, pathogen-responsive genes were repressed in daf-10 mutant animals, and these sensory mutants exhibited altered susceptibility to and behavioral avoidance of bacterial pathogens. Moreover, we found that a solute transporter gene mct-1/2, which was induced by daf-10 mutations, was necessary and sufficient for longevity. Thus, sensory input seems to influence an extensive transcriptional network that modulates basic biological processes in C. elegans. This situation is reminiscent of the complex regulation of physiology by the mammalian hypothalamus, which also receives innervations from sensory systems, most notably the visual and olfactory systems.

Diminished A-type potassium current and altered firing properties in presympathetic PVN neurones in renovascular hypertensive rats

PubMed Central

Sonner, Patrick M; Filosa, Jessica A; Stern, Javier E

2008-01-01

Accumulating evidence supports a contribution of the hypothalamic paraventricular nucleus (PVN) to sympathoexcitation and elevated blood pressure in renovascular hypertension. However, the underlying mechanisms resulting in altered neuronal function in hypertensive rats remain largely unknown. Here, we aimed to address whether the transient outward potassium current (IA) in identified rostral ventrolateral medulla (RVLM)-projecting PVN neurones is altered in hypertensive rats, and whether such changes affected single and repetitive action potential properties and associated changes in intracellular Ca2+ levels. Patch-clamp recordings obtained from PVN-RVLM neurons showed a reduction in IA current magnitude and single channel conductance, and an enhanced steady-state current inactivation in hypertensive rats. Morphometric reconstructions of intracellularly labelled PVN-RVLM neurons showed a diminished dendritic surface area in hypertensive rats. Consistent with a diminished IA availability, action potentials in PVN-RVLM neurons in hypertensive rats were broader, decayed more slowly, and were less sensitive to the K+ channel blocker 4-aminopyridine. Simultaneous patch clamp recordings and confocal Ca2+ imaging demonstrated enhanced action potential-evoked intracellular Ca2+ transients in hypertensive rats. Finally, spike broadening during repetitive firing discharge was enhanced in PVN-RVLM neurons from hypertensive rats. Altogether, our results indicate that diminished IA availability constitutes a contributing mechanism underlying aberrant central neuronal function in renovascular hypertension. PMID:18238809

Human neural progenitors differentiate into astrocytes and protect motor neurons in aging rats.

PubMed

Das, Melanie M; Avalos, Pablo; Suezaki, Patrick; Godoy, Marlesa; Garcia, Leslie; Chang, Christine D; Vit, Jean-Philippe; Shelley, Brandon; Gowing, Genevieve; Svendsen, Clive N

2016-06-01

Age-associated health decline presents a significant challenge to healthcare, although there are few animal models that can be used to test potential treatments. Here, we show that there is a significant reduction in both spinal cord motor neurons and motor function over time in the aging rat. One explanation for this motor neuron loss could be reduced support from surrounding aging astrocytes. Indeed, we have previously shown using in vitro models that aging rat astrocytes are less supportive to rat motor neuron function and survival over time. Here, we test whether rejuvenating the astrocyte niche can improve the survival of motor neurons in an aging spinal cord. We transplanted fetal-derived human neural progenitor cells (hNPCs) into the aging rat spinal cord and found that the cells survive and differentiate into astrocytes with a much higher efficiency than when transplanted into younger animals, suggesting that the aging environment stimulates astrocyte maturation. Importantly, the engrafted astrocytes were able to protect against motor neuron loss associated with aging, although this did not result in an increase in motor function based on behavioral assays. We also transplanted hNPCs genetically modified to secrete glial cell line-derived neurotrophic factor (GDNF) into the aging rat spinal cord, as this combination of cell and protein delivery can protect motor neurons in animal models of ALS. During aging, GDNF-expressing hNPCs protected motor neurons, though to the same extent as hNPCs alone, and again had no effect on motor function. We conclude that hNPCs can survive well in the aging spinal cord, protect motor neurons and mature faster into astrocytes when compared to transplantation into the young spinal cord. While there was no functional improvement, there were no functional deficits either, further supporting a good safety profile of hNPC transplantation even into the older patient population. Copyright © 2016 Elsevier Inc. All rights reserved.

Motor–sensory convergence in object localization: a comparative study in rats and humans

PubMed Central

Horev, Guy; Saig, Avraham; Knutsen, Per Magne; Pietr, Maciej; Yu, Chunxiu; Ahissar, Ehud

2011-01-01

In order to identify basic aspects in the process of tactile perception, we trained rats and humans in similar object localization tasks and compared the strategies used by the two species. We found that rats integrated temporally related sensory inputs (‘temporal inputs’) from early whisk cycles with spatially related inputs (‘spatial inputs’) to align their whiskers with the objects; their perceptual reports appeared to be based primarily on this spatial alignment. In a similar manner, human subjects also integrated temporal and spatial inputs, but relied mainly on temporal inputs for object localization. These results suggest that during tactile object localization, an iterative motor–sensory process gradually converges on a stable percept of object location in both species. PMID:21969688

Development of sensory innervation in rat tibia: co-localization of CGRP and substance P with growth-associated protein 43 (GAP-43)

PubMed Central

Gajda, Mariusz; Litwin, Jan A; Cichocki, Tadeusz; Timmermans, Jean-Pierre; Adriaensen, Dirk

2005-01-01

The development of sensory innervation in long bones was investigated in rat tibia in fetuses on gestational days (GD) 16–21 and in neonates and juvenile individuals on postnatal days (PD) 1–28. A double immunostaining method was applied to study the co-localization of the neuronal growth marker growth-associated protein 43 (GAP-43) and the pan-neuronal marker protein gene product 9.5 (PGP 9.5) as well as that of two sensory fibre-associated neuropeptides, calcitonin gene-related peptide (CGRP) and substance P (SP). The earliest, not yet chemically coded, nerve fibres were observed on GD17 in the perichondrium of the proximal epiphysis. Further development of the innervation was characterized by the successive appearance of nerve fibres in the perichondrium/periosteum of the shaft (GD19), the bone marrow cavity and intercondylar eminence (GD21), the metaphyses (PD1), the cartilage canals penetrating into the epiphyses (PD7), and finally in the secondary ossification centres (PD10) and epiphyseal bone marrow (PD14). Maturation of the fibres, manifested by their immunoreactivity for CGRP and SP, was visible on GD21 in the epiphyseal perichondrium, the periosteum of the shaft and the bone marrow, on PD1 in the intercondylar eminence and the metaphyses, on PD7 in the cartilage canals, on PD10 in the secondary ossification centres and on PD14 in the epiphyseal bone marrow. The temporal and topographic pattern of nerve fibre appearance corresponds with the development of regions characterized by active mineralization and bone remodelling, suggesting a possible involvement of the sensory innervation in these processes. PMID:16050900

Preferential Enhancement of Sensory and Motor Axon Regeneration by Combining Extracellular Matrix Components with Neurotrophic Factors

PubMed Central

Santos, Daniel; González-Pérez, Francisco; Giudetti, Guido; Micera, Silvestro; Udina, Esther; Del Valle, Jaume; Navarro, Xavier

2016-01-01

After peripheral nerve injury, motor and sensory axons are able to regenerate but inaccuracy of target reinnervation leads to poor functional recovery. Extracellular matrix (ECM) components and neurotrophic factors (NTFs) exert their effect on different neuronal populations creating a suitable environment to promote axonal growth. Here, we assessed in vitro and in vivo the selective effects of combining different ECM components with NTFs on motor and sensory axons regeneration and target reinnervation. Organotypic cultures with collagen, laminin and nerve growth factor (NGF)/neurotrophin-3 (NT3) or collagen, fibronectin and brain-derived neurotrophic factor (BDNF) selectively enhanced sensory neurite outgrowth of DRG neurons and motor neurite outgrowth from spinal cord slices respectively. For in vivo studies, the rat sciatic nerve was transected and repaired with a silicone tube filled with a collagen and laminin matrix with NGF/NT3 encapsulated in poly(lactic-co-glycolic acid) (PLGA) microspheres (MP) (LM + MP.NGF/NT3), or a collagen and fibronectin matrix with BDNF in PLGA MPs (FN + MP.BDNF). Retrograde labeling and functional tests showed that LM + MP.NGF/NT3 increased the number of regenerated sensory neurons and improved sensory functional recovery, whereas FN + MP.BDNF preferentially increased regenerated motoneurons and enhanced motor functional recovery. Therefore, combination of ECM molecules with NTFs may be a good approach to selectively enhance motor and sensory axons regeneration and promote appropriate target reinnervation. PMID:28036084

Selenomethionine protects against neuronal degeneration by methylmercury in the developing rat cerebrum.

PubMed

Sakamoto, Mineshi; Yasutake, Akira; Kakita, Akiyoshi; Ryufuku, Masae; Chan, Hing Man; Yamamoto, Megumi; Oumi, Sanae; Kobayashi, Sayaka; Watanabe, Chiho

2013-03-19

Although many experimental studies have shown that selenium protects against methylmercury (MeHg) toxicity at different end points, the direct interactive effects of selenium and MeHg on neurons in the brain remain unknown. Our goal is to confirm the protective effects of selenium against neuronal degeneration induced by MeHg in the developing postnatal rat brain using a postnatal rat model that is suitable for extrapolating the effects of MeHg to the fetal brain of humans. As an exposure source of selenium, we used selenomethionine (SeMet), a food-originated selenium. Wistar rats of postnatal days 14 were orally administered with vehicle (control), MeHg (8 mg Hg/kg/day), SeMet (2 mg Se/kg/day), or MeHg plus SeMet coexposure for 10 consecutive days. Neuronal degeneration and reactive astrocytosis were observed in the cerebral cortex of the MeHg-group but the symptoms were prevented by coexposure to SeMet. These findings serve as a proof that dietary selenium can directly protect neurons against MeHg toxicity in the mammalian brain, especially in the developing cerebrum.

Activation of phenotypically-distinct neuronal subpopulations of the rat amygdala following exposure to predator odor.

PubMed

Butler, R K; Sharko, A C; Oliver, E M; Brito-Vargas, P; Kaigler, K F; Fadel, J R; Wilson, M A

2011-02-23

Exposure of rats to an odor of a predator can elicit an innate fear response. In addition, such exposure has been shown to activate limbic brain regions such as the amygdala. However, there is a paucity of data on the phenotypic characteristics of the activated amygdalar neurons following predator odor exposure. In the current experiments, rats were exposed to cloth which contained either ferret odor, butyric acid, or no odor for 30 min. Ferret odor-exposed rats displayed an increase in defensive burying versus control rats. Sections of the brains were prepared for dual-labeled immunohistochemistry and counts of c-Fos co-localized with Ca(2+)/calmodulin-dependent protein kinase II (CaMKII), parvalbumin, or calbindin were made in the basolateral (BLA), central (CEA), and medial (MEA) nucleus of the amygdala. Dual-labeled immunohistochemistry showed a significant increase in the percentage of CaMKII-positive neurons also immunoreactive for c-Fos in the BLA, CEA and MEA of ferret odor-exposed rats compared to control and butyric acid-exposed groups. Further results showed a significant decrease in calbindin-immunoreactive neurons that were also c-Fos-positive in the anterior portion of the BLA of ferret odor-exposed rats compared to control and butyric acid-exposed rats, whereas the MEA expressed a significant decrease in calbindin/c-Fos dual-labeled neurons in butyric acid-exposed rats compared to controls and ferret odor-exposed groups. These results enhance our understanding of the functioning of the amygdala following exposure to predator threats by showing phenotypic characteristics of activated amygdalar neurons. With this knowledge, specific neuronal populations could be targeted to further elucidate the fundamental underpinnings of anxiety and could possibly indicate new targets for the therapeutic treatment of anxiety. Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.

Danger Changes the Way the Mammalian Brain Stores Information About Innocuous Events: A Study of Sensory Preconditioning in Rats

PubMed Central

Qureshi, Omar A.; Killcross, Simon

2018-01-01

Abstract The amygdala is a critical substrate for learning about cues that signal danger. Less is known about its role in processing innocuous or background information. The present study addressed this question using a sensory preconditioning protocol in male rats. In each experiment, rats were exposed to pairings of two innocuous stimuli in stage 1, S2 and S1, and then to pairings of S1 and shock in stage 2. As a consequence of this training, control rats displayed defensive reactions (freezing) when tested with both S2 and S1. The freezing to S2 is a product of two associations formed in training: an S2-S1 association in stage 1 and an S1-shock association in stage 2. We examined the roles of two medial temporal lobe (MTL) structures in consolidation of the S2-S1 association: the perirhinal cortex (PRh) and basolateral complex of the amygdala (BLA). When the S2-S1 association formed in a safe context, its consolidation required neuronal activity in the PRh (but not BLA), including activation of AMPA receptors and MAPK signaling. In contrast, when the S2-S1 association formed in a dangerous context, or when the context was rendered dangerous immediately after the association had formed, its consolidation required neuronal activity in the BLA (but not PRh), including activation of AMPA receptors and MAPK signaling. These roles of the PRh and BLA show that danger changes the way the mammalian brain stores information about innocuous events. They are discussed with respect to danger-induced changes in stimulus processing. PMID:29464195

Enhancement of basolateral amygdaloid neuronal dendritic arborization following Bacopa monniera extract treatment in adult rats.

PubMed

Vollala, Venkata Ramana; Upadhya, Subramanya; Nayak, Satheesha

2011-01-01

In the ancient Indian system of medicine, Ayurveda, Bacopa monniera is classified as Medhya rasayana, which includes medicinal plants that rejuvenate intellect and memory. Here, we investigated the effect of a standardized extract of Bacopa monniera on the dendritic morphology of neurons in the basolateral amygdala, a region that is concerned with learning and memory. The present study was conducted on 2½-month-old Wistar rats. The rats were divided into 2-, 4- and 6-week treatment groups. Rats in each of these groups were further divided into 20 mg/kg, 40 mg/kg and 80 mg/kg dose groups (n = 8 for each dose). After the treatment period, treated rats and age-matched control rats were subjected to spatial learning (T-maze) and passive avoidance tests. Subsequently, these rats were killed by decapitation, the brains were removed, and the amygdaloid neurons were impregnated with silver nitrate (Golgi staining). Basolateral amygdaloid neurons were traced using camera lucida, and dendritic branching points (a measure of dendritic arborization) and dendritic intersections (a measure of dendritic length) were quantified. These data were compared with the data from the age-matched control rats. The results showed an improvement in spatial learning performance and enhanced memory retention in rats treated with Bacopa monniera extract. Furthermore, a significant increase in dendritic length and the number of dendritic branching points was observed along the length of the dendrites of the basolateral amygdaloid neurons of rats treated with 40 mg/kg and 80 mg/kg of Bacopa monniera (BM) for longer periods of time (i.e., 4 and 6 weeks). We conclude that constituents present in Bacopa monniera extract have neuronal dendritic growth-stimulating properties.

Substance P Differentially Modulates Firing Rate of Solitary Complex (SC) Neurons from Control and Chronic Hypoxia-Adapted Adult Rats

PubMed Central

Nichols, Nicole L.; Powell, Frank L.; Dean, Jay B.; Putnam, Robert W.

2014-01-01

NK1 receptors, which bind substance P, are present in the majority of brainstem regions that contain CO2/H+-sensitive neurons that play a role in central chemosensitivity. However, the effect of substance P on the chemosensitive response of neurons from these regions has not been studied. Hypoxia increases substance P release from peripheral afferents that terminate in the caudal nucleus tractus solitarius (NTS). Here we studied the effect of substance P on the chemosensitive responses of solitary complex (SC: NTS and dorsal motor nucleus) neurons from control and chronic hypoxia-adapted (CHx) adult rats. We simultaneously measured intracellular pH and electrical responses to hypercapnic acidosis in SC neurons from control and CHx adult rats using the blind whole cell patch clamp technique and fluorescence imaging microscopy. Substance P significantly increased the basal firing rate in SC neurons from control and CHx rats, although the increase was smaller in CHx rats. However, substance P did not affect the chemosensitive response of SC neurons from either group of rats. In conclusion, we found that substance P plays a role in modulating the basal firing rate of SC neurons but the magnitude of the effect is smaller for SC neurons from CHx adult rats, implying that NK1 receptors may be down regulated in CHx adult rats. Substance P does not appear to play a role in modulating the firing rate response to hypercapnic acidosis of SC neurons from either control or CHx adult rats. PMID:24516602

Hyperlipidemic Diet Causes Loss of Olfactory Sensory Neurons, Reduces Olfactory Discrimination, and Disrupts Odor-Reversal Learning

PubMed Central

Thiebaud, Nicolas; Johnson, Melissa C.; Butler, Jessica L.; Bell, Genevieve A.; Ferguson, Kassandra L.; Fadool, Andrew R.; Fadool, James C.; Gale, Alana M.; Gale, David S.

2014-01-01

Currently, 65% of Americans are overweight, which leads to well-supported cardiovascular and cognitive declines. Little, however, is known concerning obesity's impact on sensory systems. Because olfaction is linked with ingestive behavior to guide food choice, its potential dysfunction during obesity could evoke a positive feedback loop to perpetuate poor ingestive behaviors. To determine the effect of chronic energy imbalance and reveal any structural or functional changes associated with obesity, we induced long-term, diet-induced obesity by challenging mice to high-fat diets: (1) in an obesity-prone (C57BL/6J) and obesity-resistant (Kv1.3−/−) line of mice, and compared this with (2) late-onset, genetic-induced obesity in MC4R−/− mice in which diabetes secondarily precipitates after disruption of the hypothalamic axis. We report marked loss of olfactory sensory neurons and their axonal projections after exposure to a fatty diet, with a concomitant reduction in electro-olfactogram amplitude. Loss of olfactory neurons and associated circuitry is linked to changes in neuronal proliferation and normal apoptotic cycles. Using a computer-controlled, liquid-based olfactometer, mice maintained on fatty diets learn reward-reinforced behaviors more slowly, have deficits in reversal learning demonstrating behavioral inflexibility, and exhibit reduced olfactory discrimination. When obese mice are removed from their high-fat diet to regain normal body weight and fasting glucose, olfactory dysfunctions are retained. We conclude that chronic energy imbalance therefore presents long-lasting structural and functional changes in the operation of the sensory system designed to encode external and internal chemical information and leads to altered olfactory- and reward-driven behaviors. PMID:24828650

Experience-dependent development of spinal motor neurons

NASA Technical Reports Server (NTRS)

Inglis, F. M.; Zuckerman, K. E.; Kalb, R. G.; Walton, K. D. (Principal Investigator)

2000-01-01

Locomotor activity in many species undergoes pronounced alterations in early postnatal life, and environmental cues may be responsible for modifying this process. To determine how these events are reflected in the nervous system, we studied rats reared under two different conditions-the presence or absence of gravity-in which the performance of motor operations differed. We found a significant effect of rearing environment on the size and complexity of dendritic architecture of spinal motor neurons, particularly those that are likely to participate in postural control. These results provide evidence that neurons subserving motor function undergo activity-dependent maturation in early postnatal life in a manner analogous to sensory systems.

Enhanced excitability and down-regulated voltage-gated potassium channels in colonic drg neurons from neonatal maternal separation rats.

PubMed

Luo, Jia-Lie; Qin, Hong-Yan; Wong, Chun-Kit; Tsang, Suk-Ying; Huang, Yu; Bian, Zhao-Xiang

2011-05-01

Irritable bowel syndrome (IBS), characterized mainly by abdominal pain, is a functional bowel disorder. The present study aimed to examine changes in the excitability and the activity of the voltage-gated K(+) channel in dorsal root ganglia (DRG) neurons innervating the colon of rats subjected to neonatal maternal separation (NMS). Colonic DRG neurons from NMS rats as identified by FAST DiI™ labeling showed an increased cell size compared with those from nonhandled (NH) rats. Whole cell current-clamp recordings showed that colonic DRG neurons from NMS rats displayed: 1) depolarized resting membrane potential; 2) increased input resistance; 3) a dramatic reduction in rheobase; and 4) a significant increase in the number of action potentials evoked at twice rheobase. Whole cell voltage-clamp recordings revealed that neurons from both groups exhibited transient A-type (I(A)) and delayed rectifier (I(K)) K(+) currents. Compared with NH rat neurons, the averaged density of I(K) was significantly reduced in NMS rat neurons. Furthermore, the Kv1.2 expression was significantly decreased in NMS rat colonic DRG neurons. These results suggest that NMS increases the excitability of colonic DRG neurons mainly by suppressing the I(K) current, which is likely accounted for by the downregulation of the Kv1.2 expression and somal hypertrophy. This study demonstrates the alteration of delayed rectifier K current and Kv1.2 expression in DRG neurons from IBS model rats, representing a molecular mechanism underlying visceral pain and sensitization in IBS, suggesting the potential of Kv1.2 as a therapeutic target for the treatment of IBS. Copyright © 2011 American Pain Society. Published by Elsevier Inc. All rights reserved.

Treadmill exercise alleviates nigrostriatal dopaminergic loss of neurons and fibers in rotenone-induced Parkinson rats.

PubMed

Shin, Mal-Soon; Kim, Tae-Woon; Lee, Jae-Min; Ji, Eun-Sang; Lim, Baek-Vin

2017-02-01

Parkinson disease is one of the common brain diseases caused by dopaminergic neuronal loss in the substantia nigra and dopaminergic fiber loss in the striatum. In the present study, the effects of treadmill exercise on motor performance, dopaminergic loss of neurons and fibers, and α-synuclein expression in the nigrostriatum were evaluated using rotenone-induced Parkinson rats. For the induction of Parkinson rats, 3-mg/kg rotenone was injected, once a day for 14 consecutive days. Treadmill running was conducted for 30 min once a day during 14 consecutive days. Rota-rod test for motor balance and coordination and immunohistochemistry for tyrosine hydroxylase and α-synuclein in the nigrostriatum were performed. In the present study, motor balance and coordination was disturbed by induction of rotenone-induced Parkinson disease, in contrast, treadmill exercise alleviated motor dysfunction in the rotenone-induced Parkinson rats. Nigrostriatal dopaminergic loss of neurons and fibers was occurred by induction of rotenone-induced Parkinson disease, in contrast, treadmill exercise alleviated nigrostriatal dopaminergic loss of neurons and fibers in the rotenone-induced Parkinson rats. α-Synuclein expression in the nigrostriatum was enhanced by induction of rotenone-induced Parkinson disease, in contrast, treadmill exercise suppressed α-synuclein expression in the rotenone-induced Parkinson rats. Treadmill exercise improved motor function through preservation of nigrostriatal dopaminergic neurons and fibers and suppression of nigrostriatal formation of Lewy bodies in rotenone-induced Parkinson rats.

Pickpocket1 Is an Ionotropic Molecular Sensory Transducer*

PubMed Central

Boiko, Nina; Kucher, Volodymyr; Stockand, James D.; Eaton, Benjamin A.

2012-01-01

The molecular transformation of an external stimulus into changes in sensory neuron activity is incompletely described. Although a number of molecules have been identified that can respond to stimuli, evidence that these molecules can transduce stimulation into useful neural activity is lacking. Here we demonstrate that pickpocket1 (ppk1), a Drosophila homolog of mammalian Degenerin/epithelial sodium channels, encodes an acid-sensing sodium channel that conducts a transient depolarizing current in multidendritic sensory neurons of Drosophila melanogaster. Stimulation of Ppk1 is sufficient to bring these sensory neurons to threshold, eliciting a burst of action potentials. The transient nature of the neural activity produced by Ppk1 activation is the result of Ppk1 channel gating properties. This model is supported by the observation of enhanced bursting activity in neurons expressing a gain of function ppk1 mutant harboring the degenerin mutation. These findings demonstrate that Ppk1 can function as an ionotropic molecular sensory transducer capable of transforming the perception of a stimulus into phasic neuronal activity in sensory neurons. PMID:23033486

Reduced motor neuron excitability is an important contributor to weakness in a rat model of sepsis.

PubMed

Nardelli, Paul; Vincent, Jacob A; Powers, Randall; Cope, Tim C; Rich, Mark M

2016-08-01

The mechanisms by which sepsis triggers intensive care unit acquired weakness (ICUAW) remain unclear. We previously identified difficulty with motor unit recruitment in patients as a novel contributor to ICUAW. To study the mechanism underlying poor recruitment of motor units we used the rat cecal ligation and puncture model of sepsis. We identified striking dysfunction of alpha motor neurons during repetitive firing. Firing was more erratic, and often intermittent. Our data raised the possibility that reduced excitability of motor neurons was a significant contributor to weakness induced by sepsis. In this study we quantified the contribution of reduced motor neuron excitability and compared its magnitude to the contributions of myopathy, neuropathy and failure of neuromuscular transmission. We injected constant depolarizing current pulses (5s) into the soma of alpha motor neurons in the lumbosacral spinal cord of anesthetized rats to trigger repetitive firing. In response to constant depolarization, motor neurons in untreated control rats fired at steady and continuous firing rates and generated smooth and sustained tetanic motor unit force as expected. In contrast, following induction of sepsis, motor neurons were often unable to sustain firing throughout the 5s current injection such that force production was reduced. Even when firing, motor neurons from septic rats fired erratically and discontinuously, leading to irregular production of motor unit force. Both fast and slow type motor neurons had similar disruption of excitability. We followed rats after recovery from sepsis to determine the time course of resolution of the defect in motor neuron excitability. By one week, rats appeared to have recovered from sepsis as they had no piloerection and appeared to be in no distress. The defects in motor neuron repetitive firing were still striking at 2weeks and, although improved, were present at one month. We infer that rats suffered from weakness due to reduced

Responses to GABA(A) receptor activation are altered in NTS neurons isolated from chronic hypoxic rats.

PubMed

Tolstykh, Gleb; Belugin, Sergei; Mifflin, Steve

2004-04-23

The inhibitory amino acid GABA is released within the nucleus of the solitary tract (NTS) during hypoxia and modulates the respiratory response to hypoxia. To determine if responses of NTS neurons to activation of GABA(A) receptors are altered following exposure to chronic hypoxia, GABA(A) receptor-evoked whole cell currents were measured in enzymatically dispersed NTS neurons from normoxic and chronic hypoxic rats. Chronic hypoxic rats were exposed to 10% O(2) for 9-12 days. Membrane capacitance was the same in neurons from normoxic (6.9+/-0.5 pF, n=16) and hypoxic (6.3+/-0.5 pF, n=15) rats. The EC(50) for peak GABA-evoked current density was significantly greater in neurons from hypoxic (21.7+/-2.2 microM) compared to normoxic rats (12.2+/-0.9 microM) (p<0.001). Peak and 5-s adapted GABA currents evoked by 1, 3 and 10 microM were greater in neurons from normoxic compared to hypoxic rats (p<0.05) whereas peak and 5-s adapted responses to 30 and 100 microM GABA were not different comparing normoxic to hypoxic rats. Desensitization of GABA(A)-evoked currents was observed at concentrations greater than 3 microM and, measured as the ratio of the current 5 s after the onset of 100 microM GABA application to the peak GABA current, was the same in neurons from normoxic (0.37+/-0.03) and hypoxic rats (0.33+/-0.04). Reduced sensitivity to GABA(A) receptor-evoked inhibition in chronic hypoxia could influence chemoreceptor afferent integration by NTS neurons.

A calcium-permeable cGMP-activated cation conductance in hippocampal neurons

NASA Technical Reports Server (NTRS)

Leinders-Zufall, T.; Rosenboom, H.; Barnstable, C. J.; Shepherd, G. M.; Zufall, F.

1995-01-01

Whole-cell patch clamp recordings detected a previously unidentified cGMP-activated membrane conductance in cultured rat hippocampal neurons. This conductance is nonselectively permeable for cations and is completely but reversibly blocked by external Cd2+. The Ca2+ permeability of the hippocampal cGMP-activated conductance was examined in detail, indicating that the underlying ion channels display a high relative permeability for Ca2+. The results indicate that hippocampal neurons contain a cGMP-activated membrane conductance that has some properties similar to the cyclic nucleotide-gated channels previously shown in sensory receptor cells and retinal neurons. In hippocampal neurons this conductance similarly could mediate membrane depolarization and Ca2+ fluxes in response to intracellular cGMP elevation.

Maternal creatine supplementation affects the morpho-functional development of hippocampal neurons in rat offspring.

PubMed

Sartini, S; Lattanzi, D; Ambrogini, P; Di Palma, M; Galati, C; Savelli, D; Polidori, E; Calcabrini, C; Rocchi, M B L; Sestili, P; Cuppini, R

2016-01-15

Creatine supplementation has been shown to protect neurons from oxidative damage due to its antioxidant and ergogenic functions. These features have led to the hypothesis of creatine supplementation use during pregnancy as prophylactic treatment to prevent CNS damage, such as hypoxic-ischemic encephalopathy. Unfortunately, very little is known on the effects of creatine supplementation during neuron differentiation, while in vitro studies revealed an influence on neuron excitability, leaving the possibility of creatine supplementation during the CNS development an open question. Using a multiple approach, we studied the hippocampal neuron morphological and functional development in neonatal rats born by dams supplemented with 1% creatine in drinking water during pregnancy. CA1 pyramidal neurons of supplemented newborn rats showed enhanced dendritic tree development, increased LTP maintenance, larger evoked-synaptic responses, and higher intrinsic excitability in comparison to controls. Moreover, a faster repolarizing phase of action potential with the appearance of a hyperpolarization were recorded in neurons of the creatine-treated group. Consistently, CA1 neurons of creatine exposed pups exhibited a higher maximum firing frequency than controls. In summary, we found that creatine supplementation during pregnancy positively affects morphological and electrophysiological development of CA1 neurons in offspring rats, increasing neuronal excitability. Altogether, these findings emphasize the need to evaluate the benefits and the safety of maternal intake of creatine in humans. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

Neuronal hyperexcitability in the ventral posterior thalamus of neuropathic rats: modality selective effects of pregabalin

PubMed Central

Dickenson, Anthony H.

2016-01-01

Neuropathic pain represents a substantial clinical challenge; understanding the underlying neural mechanisms and back-translation of therapeutics could aid targeting of treatments more effectively. The ventral posterior thalamus (VP) is the major termination site for the spinothalamic tract and relays nociceptive activity to the somatosensory cortex; however, under neuropathic conditions, it is unclear how hyperexcitability of spinal neurons converges onto thalamic relays. This study aimed to identify neural substrates of hypersensitivity and the influence of pregabalin on central processing. In vivo electrophysiology was performed to record from VP wide dynamic range (WDR) and nociceptive-specific (NS) neurons in anesthetized spinal nerve-ligated (SNL), sham-operated, and naive rats. In neuropathic rats, WDR neurons had elevated evoked responses to low- and high-intensity punctate mechanical stimuli, dynamic brushing, and innocuous and noxious cooling, but less so to heat stimulation, of the receptive field. NS neurons in SNL rats also displayed increased responses to noxious punctate mechanical stimulation, dynamic brushing, noxious cooling, and noxious heat. Additionally, WDR, but not NS, neurons in SNL rats exhibited substantially higher rates of spontaneous firing, which may correlate with ongoing pain. The ratio of WDR-to-NS neurons was comparable between SNL and naive/sham groups, suggesting relatively few NS neurons gain sensitivity to low-intensity stimuli leading to a “WDR phenotype.” After neuropathy was induced, the proportion of cold-sensitive WDR and NS neurons increased, supporting the suggestion that changes in frequency-dependent firing and population coding underlie cold hypersensitivity. In SNL rats, pregabalin inhibited mechanical and heat responses but not cold-evoked or elevated spontaneous activity. PMID:27098028

Neuronal hyperexcitability in the ventral posterior thalamus of neuropathic rats: modality selective effects of pregabalin.

PubMed

Patel, Ryan; Dickenson, Anthony H

2016-07-01

Neuropathic pain represents a substantial clinical challenge; understanding the underlying neural mechanisms and back-translation of therapeutics could aid targeting of treatments more effectively. The ventral posterior thalamus (VP) is the major termination site for the spinothalamic tract and relays nociceptive activity to the somatosensory cortex; however, under neuropathic conditions, it is unclear how hyperexcitability of spinal neurons converges onto thalamic relays. This study aimed to identify neural substrates of hypersensitivity and the influence of pregabalin on central processing. In vivo electrophysiology was performed to record from VP wide dynamic range (WDR) and nociceptive-specific (NS) neurons in anesthetized spinal nerve-ligated (SNL), sham-operated, and naive rats. In neuropathic rats, WDR neurons had elevated evoked responses to low- and high-intensity punctate mechanical stimuli, dynamic brushing, and innocuous and noxious cooling, but less so to heat stimulation, of the receptive field. NS neurons in SNL rats also displayed increased responses to noxious punctate mechanical stimulation, dynamic brushing, noxious cooling, and noxious heat. Additionally, WDR, but not NS, neurons in SNL rats exhibited substantially higher rates of spontaneous firing, which may correlate with ongoing pain. The ratio of WDR-to-NS neurons was comparable between SNL and naive/sham groups, suggesting relatively few NS neurons gain sensitivity to low-intensity stimuli leading to a "WDR phenotype." After neuropathy was induced, the proportion of cold-sensitive WDR and NS neurons increased, supporting the suggestion that changes in frequency-dependent firing and population coding underlie cold hypersensitivity. In SNL rats, pregabalin inhibited mechanical and heat responses but not cold-evoked or elevated spontaneous activity. Copyright © 2016 the American Physiological Society.

Duodenal afferent input converges onto T9-T10 spinal neurons responding to gastric distension in rats.

PubMed

Qin, Chao; Chen, Jiande D Z; Zhang, Jing; Foreman, Robert D

2007-12-01

Clinically, the overlap of gastroduodenal symptoms, such as visceral pain or hypersensitivity, is often observed in functional gastrointestinal disorders. The underlying mechanism may be related to intraspinal neuronal processing of noxious convergent inputs from the stomach and the intestine. The purpose of this study was to examine whether single low thoracic (T9-T10) spinal neurons responded to both gastric and duodenal mechanical stimulation. Extracellular potentials of single T9-T10 spinal neurons were recorded in pentobarbital anesthetized, paralyzed, and ventilated male rats. Graded gastric distensions (GD, 20, 40, 60 mm Hg, 20 s) were induced by air inflation of a latex balloon surgically placed in the stomach. Graded duodenal distensions (DD, 0.2, 0.4, 0.6 ml, 20 s) were produced by water inflation of a latex balloon placed into the duodenum. Of 70 deeper (depth from dorsal surface of spinal cord: 0.3-1.2 mm) spinal neurons responsive to noxious GD (> or =40 mm Hg), 44(63%) also responded to noxious DD (> or =0.4 ml). Similarly, 13/17 (76%) superficial neurons (depth <0.3 mm) responded to both GD and DD. Of 57 gastroduodenal convergent neurons, 41 (72%) had excitatory and 6 had inhibitory responses to both GD and DD; the remaining neurons exhibited multiple patterns of excitation and inhibition. 43/57 (75%) gastroduodenal convergent neurons had low-threshold (< or =20 mm Hg) responses to GD, whereas 42/57 (74%) of these neurons had high-threshold (> or =0.4 ml) responses to DD. In addition, 34/40 (85%) gastroduodenal convergent neurons had somatic receptive fields on the back, flank, and medial/lateral abdominal areas. These results suggested that superficial and deeper T9-T10 spinal neurons received innocuous and/or noxious convergent inputs from mechanical stimulation of the stomach and duodenum. Gastroduodenal convergent spinal neurons might contribute to intraspinal sensory transmission for cross-organ afferent-afferent communication between the

Immunological cross-reactivity of cultured rat hippocampal neurons with goldfish brain proteins synthesized during memory consolidation.

PubMed

Schmidt, R; Löffler, F; Müller, H W; Seifert, W

1986-10-29

Ependymins are goldfish brain glycoproteins exhibiting a specifically enhanced rate of synthesis when the animals adopt a new pattern of swimming behavior. With specific antisera against ependymins it has become possible to look for ependymin-like immunoreactivity in other animal species, both qualitatively by immunofluorescence staining and quantitatively by radioimmunoassay. Ependymin-like immunoreactivity was detected not only in other fish but also in rat brain. In the rat radioimmunoassay measurements were highest for the hippocampal formation and for cultured neurons derived from the embryonic hippocampus. Immunofluorescence staining was performed on various cell culture systems derived from rat brain, in order to establish which cell type contains the antigen. Only neuronal cell populations reacted with the anti-ependymin antisera. Cells derived from embryonic rat brain hippocampus which resembled pyramidal neurons stained particularly bright for ependymin-like immunoreactivity. The antigenic material was distributed throughout the cytoplasm including the neuronal extensions. Various neuron-specific antisera have been used to counterstain the cells containing ependymin-like immunoreactivity.

Chloroquine inhibits autophagy and deteriorates the mitochondrial dysfunction and apoptosis in hypoxic rat neurons.

PubMed

Li, Peng; Hao, Lei; Guo, Yan-Yan; Yang, Guang-Lu; Mei, Hua; Li, Xiao-Hua; Zhai, Qiong-Xiang

2018-06-01

Mitochondrial dysfunction (MD) and apoptosis in the neurons are associated with neonatal hypoxic-ischemic (HI) encephalopathy (HIE). The present study was to explore the influence of autophagy on the induction of MD and apoptosis in the neurons in a neonatal HIE rats and in hypoxia-treated neurons in vitro. Ten-day-old HI rat pups were sacrificed for brain pathological examination and immunohistochemical analysis. The induction of autophagy, apoptosis and MD were also determined in the neurons under hypoxia, with or without autophagy inhibitor, chloroquine (CQ) treatment. HI treatment caused atrophy and apoptosis of neurons, with a significantly increased levels of apoptosis- and autophagy-associated proteins, such as cleaved caspase 3 and the B subunit of autophagy-related microtubule-associated protein 1 light chain 3 (LC3-B). in vitro experiments demonstrated that the hypoxia induced autophagy in neurons, as was inhibited by CQ. The hypoxia-induced cytochrome c release, cleaved caspase 3 and cleaved caspase 9 were aggravated by CQ. Moreover, there were higher levels of reactive oxygen species, more mitochondrial superoxide and less mitochondrial membrane potential in the CQ-treated neurons under hypoxia than in the neurons singularly under hypoxia. Apoptosis and autophagy were induced in HI neonatal rat neurons, autophagy inhibition deteriorates the hypoxia-induced neuron MD and apoptosis. It implies a neuroprotection of autophagy in the hypoxic-ischemic encephalopathy. Administration of autophagy inducer agents might be promising in HIE treatment. Copyright © 2018. Published by Elsevier Inc.