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Journal of Neural Transmission (Vienna,... Apr 2020The trigeminal ganglion with its three trigeminal nerve tracts consists mainly of clusters of sensory neurons with their peripheral and central processes. Most neurons... (Review)
Review
The trigeminal ganglion with its three trigeminal nerve tracts consists mainly of clusters of sensory neurons with their peripheral and central processes. Most neurons are surrounded by satellite glial cells and the axons are wrapped by myelinating and non-myelinating Schwann cells. Trigeminal neurons express various neuropeptides, most notably, calcitonin gene-related peptide (CGRP), substance P, and pituitary adenylate cyclase-activating polypeptide (PACAP). Two types of CGRP receptors are expressed in neurons and satellite glia. A variety of other signal molecules like ATP, nitric oxide, cytokines, and neurotrophic factors are released from trigeminal ganglion neurons and signal to neighboring neurons or satellite glial cells, which can signal back to neurons with same or other mediators. This potential cross-talk of signals involves intracellular mechanisms, including gene expression, that can modulate mediators of sensory information, such as neuropeptides, receptors, and neurotrophic factors. From the ganglia cell bodies, which are outside the blood-brain barrier, the mediators are further distributed to peripheral sites and/or to the spinal trigeminal nucleus in the brainstem, where they can affect neural transmission. A major question is how the sensory neurons in the trigeminal ganglion differ from those in the dorsal root ganglion. Despite their functional overlap, there are distinct differences in their ontogeny, gene expression, signaling pathways, and responses to anti-migraine drugs. Consequently, drugs that modulate cross-talk in the trigeminal ganglion can modulate both peripheral and central sensitization, which may potentially be distinct from sensitization mediated in the dorsal root ganglion.
Topics: Animals; Ganglia, Spinal; Humans; Neurons, Afferent; Neuropeptides; Nociception; Signal Transduction; Trigeminal Ganglion
PubMed: 32088764
DOI: 10.1007/s00702-020-02161-7 -
Nature Communications Mar 2021Proprioceptive feedback mainly derives from groups Ia and II muscle spindle (MS) afferents and group Ib Golgi tendon organ (GTO) afferents, but the molecular correlates...
Proprioceptive feedback mainly derives from groups Ia and II muscle spindle (MS) afferents and group Ib Golgi tendon organ (GTO) afferents, but the molecular correlates of these three afferent subtypes remain unknown. We performed single cell RNA sequencing of genetically identified adult proprioceptors and uncovered five molecularly distinct neuronal clusters. Validation of cluster-specific transcripts in dorsal root ganglia and skeletal muscle demonstrates that two of these clusters correspond to group Ia MS afferents and group Ib GTO afferent proprioceptors, respectively, and suggest that the remaining clusters could represent group II MS afferents. Lineage analysis between proprioceptor transcriptomes at different developmental stages provides evidence that proprioceptor subtype identities emerge late in development. Together, our data provide comprehensive molecular signatures for groups Ia and II MS afferents and group Ib GTO afferents, enabling genetic interrogation of the role of individual proprioceptor subtypes in regulating motor output.
Topics: Animals; Calbindin 2; Electrophysiological Phenomena; Ion Channels; Mechanoreceptors; Mice, Transgenic; Muscle Spindles; Neurons; Neurons, Afferent; Proprioception; RNA, Messenger; Receptors, Neurotransmitter; Reproducibility of Results; Sequence Analysis, RNA; Single-Cell Analysis; Transcriptome
PubMed: 33649316
DOI: 10.1038/s41467-021-21880-3 -
The European Journal of Neuroscience Oct 2022The main question addressed in this study was whether the refractoriness of nerve fibres can be modulated by their depolarisation and, if so, whether depolarisation of...
The main question addressed in this study was whether the refractoriness of nerve fibres can be modulated by their depolarisation and, if so, whether depolarisation of nerve fibres evokes a long-term decrease in the duration of the refractory period as well as the previously demonstrated increase in their excitability. This was investigated on nerve fibres within the dorsal columns, dorsal roots and peripheral nerves in deeply anaesthetised rats in vivo. The results revealed major differences depending on the sites of fibre stimulation and polarisation. Firstly, the relative refractory period was found to be shorter in epidurally stimulated dorsal column fibres than in fibres stimulated at other sites. Secondly, the minimal effective interstimulus intervals reflecting the absolute refractory period were likewise shorter for nerve fibres within the dorsal columns even though action potentials evoked by the second of a pair of stimuli were similarly delayed with respect to the preceding action potentials at all the stimulation sites. Thirdly, the minimal interstimulus intervals were reduced by epidurally applied cathodal direct current polarisation but not at other stimulation sites. Consequently, higher proportions of dorsal column fibres could be excited at higher frequencies, especially following their depolarisation, at interstimulus intervals as short as 0.5-0.7 ms. The results demonstrate that epidural depolarisation results in long-lasting effects not only on the excitability but also on the refractoriness of dorsal column fibres. They also provide further evidence for specific features of afferent fibres traversing the dorsal columns previously linked to properties of their branching regions.
Topics: Action Potentials; Animals; Axons; Electric Stimulation; Nerve Fibers; Neurons, Afferent; Rats; Spinal Cord
PubMed: 35999192
DOI: 10.1111/ejn.15801 -
Neuron Aug 2016The nociceptive flexor withdrawal reflex has an august place in the history of neuroscience. In this issue of Neuron, Hilde et al. (2016) advance our understanding of...
The nociceptive flexor withdrawal reflex has an august place in the history of neuroscience. In this issue of Neuron, Hilde et al. (2016) advance our understanding of this reflex by characterizing the molecular identity and circuit connectivity of component interneurons. They assess how a DNA-binding factor Satb2 controls cell position, molecular identity, pre-and postsynaptic targeting, and function of a population of inhibitory sensory relay interneurons that serve to integrate both proprioceptive and nociceptive afferent information.
Topics: Interneurons; Motor Neurons; Neurons; Neurons, Afferent; Reflex
PubMed: 27537478
DOI: 10.1016/j.neuron.2016.08.005 -
Audiology & Neuro-otology 2020This paper discusses some of the concepts and major physiological issues in developing a means of electrically stimulating the otolithic system, with the final goal... (Review)
Review
BACKGROUND
This paper discusses some of the concepts and major physiological issues in developing a means of electrically stimulating the otolithic system, with the final goal being the electrical stimulation of the otoliths in human patients. It contrasts the challenges of electrical stimulation of the otolith organs as compared to stimulation of the semicircular canals. Electrical stimulation may consist of trains of short-duration pulses (e.g., 0.1 ms duration at 400 Hz) by selective electrodes on otolith maculae or otolithic afferents, or unselective maintained DC stimulation by large surface electrodes on the mastoids - surface galvanic stimulation.
SUMMARY
Recent anatomical and physiological results are summarized in order to introduce some of the unique issues in electrical stimulation of the otoliths. The first challenge is that each otolithic macula contains receptors with opposite polarization (opposing preferred directions of stimulation), unlike the uniform polarization of receptors in each semicircular canal crista. The puzzle is that in response to the one linear acceleration in the one macula, some otolithic afferents have an increased activation whereas others have decreased activation. Key Messages: At the vestibular nucleus this opposite receptor hair cell polarization and consequent opposite afferent input allow enhanced response to the one linear acceleration, via a "push-pull" neural mechanism in a manner analogous to the enhancement of semicircular canal responses to angular acceleration. Within each otolithic macula there is not just one uniform otolithic neural input to the brain - there are very distinctly different channels of otolithic neural inputs transferring the neural data to the brainstem. As a simplification these channels are characterized as the sustained and transient systems. Afferents in each system have different responses to stimulus onset and maintained stimulation and likely different projections, and most importantly different thresholds for activation by electrical stimulation and different adaptation rates to maintained stimulation. The implications of these differences are considered.
Topics: Animals; Electric Stimulation; Humans; Neurons, Afferent; Otolithic Membrane; Semicircular Canals
PubMed: 31553977
DOI: 10.1159/000502712 -
Biosensors May 2023The gut-brain axis embodies the bi-directional communication between the gastrointestinal tract and the central nervous system (CNS), where vagal afferent neurons (VANs)...
The gut-brain axis embodies the bi-directional communication between the gastrointestinal tract and the central nervous system (CNS), where vagal afferent neurons (VANs) serve as sensors for a variety of gut-derived signals. The gut is colonized by a large and diverse population of microorganisms that communicate via small (effector) molecules, which also act on the VAN terminals situated in the gut viscera and consequently influence many CNS processes. However, the convoluted in vivo environment makes it difficult to study the causative impact of the effector molecules on VAN activation or desensitization. Here, we report on a VAN culture and its proof-of-principle demonstration as a cell-based sensor to monitor the influence of gastrointestinal effector molecules on neuronal behavior. We initially compared the effect of surface coatings (poly-L-lysine vs. Matrigel) and culture media composition (serum vs. growth factor supplement) on neurite growth as a surrogate of VAN regeneration following tissue harvesting, where the Matrigel coating, but not the media composition, played a significant role in the increased neurite growth. We then used both live-cell calcium imaging and extracellular electrophysiological recordings to show that the VANs responded to classical effector molecules of endogenous and exogenous origin (cholecystokinin serotonin and capsaicin) in a complex fashion. We expect this study to enable platforms for screening various effector molecules and their influence on VAN activity, assessed by their information-rich electrophysiological fingerprints.
Topics: Neurons, Afferent; Vagus Nerve; Cholecystokinin; Neurons; Central Nervous System
PubMed: 37366967
DOI: 10.3390/bios13060601 -
Progress in Neurobiology Oct 2018The substantia gelatinosa Rolandi (SGR) was first described about two centuries ago. In the following decades an enormous amount of information has permitted us to... (Review)
Review
The substantia gelatinosa Rolandi (SGR) was first described about two centuries ago. In the following decades an enormous amount of information has permitted us to understand - at least in part - its role in the initial processing of pain and itch. Here, I will first provide a comprehensive picture of the histology, physiology, and neurochemistry of the normal SGR. Then, I will analytically discuss the SGR circuits that have been directly demonstrated or deductively envisaged in the course of the intensive research on this area of the spinal cord, with particular emphasis on the pathways connecting the primary afferent fibers and the intrinsic neurons. The perspective existence of neurochemically-defined sets of primary afferent neurons giving rise to these circuits will be also discussed, with the proposition that a cross-talk between different subsets of peptidergic fibers may be the structural and functional substrate of additional gating mechanisms in SGR. Finally, I highlight the role played by slow acting high molecular weight modulators in these gating mechanisms.
Topics: Animals; History, 19th Century; Humans; Mammals; Nerve Net; Neurochemistry; Spinal Cord; Substantia Gelatinosa
PubMed: 29981393
DOI: 10.1016/j.pneurobio.2018.06.012 -
Autonomic Neuroscience : Basic &... Mar 2015Group III and IV muscle afferents originating in exercising limb muscle play a significant role in the development of fatigue during exercise in humans. Feedback from... (Review)
Review
Group III and IV muscle afferents originating in exercising limb muscle play a significant role in the development of fatigue during exercise in humans. Feedback from these sensory neurons to the central nervous system (CNS) reflexively increases ventilation and central (cardiac output) and peripheral (limb blood flow) hemodynamic responses during exercise and thereby assures adequate muscle blood flow and O2 delivery. This response depicts a key factor in minimizing the rate of development of peripheral fatigue and in optimizing aerobic exercise capacity. On the other hand, the central projection of group III/IV muscle afferents impairs performance and limits the exercising human via its diminishing effect on the output from spinal motoneurons which decreases voluntary muscle activation (i.e. facilitates central fatigue). Accumulating evidence from recent animal studies suggests the existence of two subtypes of group III/IV muscle afferents. While one subtype only responds to physiological and innocuous levels of endogenous intramuscular metabolites (lactate, ATP, protons) associated with 'normal', predominantly aerobic exercise, the other subtype only responds to higher and concurrently noxious levels of metabolites present in muscle during ischemic contractions or following, for example, hypertonic saline infusions. This review discusses the mechanisms through which group III/IV muscle afferent feedback mediates both central and peripheral fatigue in exercising humans. We also briefly summarize the accumulating evidence from recent animal and human studies documenting the existence of two subtypes of group III/IV muscle afferents and the relevance of this discovery to the interpretation of previous work and the design of future studies.
Topics: Animals; Autonomic Nervous System; Exercise; Humans; Muscle Fatigue; Neurons, Afferent
PubMed: 25458423
DOI: 10.1016/j.autneu.2014.10.018 -
The Journal of Physiology Jun 2017Direct current stimulation (DCS) polarity specifically modulates synaptic efficacy during a continuous train of presynaptic inputs, despite synaptic depression. DCS...
KEY POINTS
Direct current stimulation (DCS) polarity specifically modulates synaptic efficacy during a continuous train of presynaptic inputs, despite synaptic depression. DCS polarizes afferent axons and postsynaptic neurons, boosting cooperativity between synaptic inputs. Polarization of afferent neurons in upstream brain regions may modulate activity in the target brain region during transcranial DCS (tDCS). A statistical theory of coincident activity predicts that the diffuse and weak profile of current flow can be advantageous in enhancing connectivity between co-active brain regions.
ABSTRACT
Transcranial direct current stimulation (tDCS) produces sustained and diffuse current flow in the brain with effects that are state dependent and outlast stimulation. A mechanistic explanation for tDCS should capture these spatiotemporal features. It remains unclear how sustained DCS affects ongoing synaptic dynamics and how modulation of afferent inputs by diffuse stimulation changes synaptic activity at the target brain region. We tested the effect of acute DCS (10-20 V m for 3-5 s) on synaptic dynamics with constant rate (5-40 Hz) and Poisson-distributed (4 Hz mean) trains of presynaptic inputs. Across tested frequencies, sustained synaptic activity was modulated by DCS with polarity-specific effects. Synaptic depression attenuates the sensitivity to DCS from 1.1% per V m to 0.55%. DCS applied during synaptic activity facilitates cumulative neuromodulation, potentially reversing endogenous synaptic depression. We establish these effects are mediated by both postsynaptic membrane polarization and afferent axon fibre polarization, which boosts cooperativity between synaptic inputs. This potentially extends the locus of neuromodulation from the nominal target to afferent brain regions. Based on these results we hypothesized the polarization of afferent neurons in upstream brain regions may modulate activity in the target brain region during tDCS. A multiscale model of transcranial electrical stimulation including a finite element model of brain current flow, numerical simulations of neuronal activity, and a statistical theory of coincident activity predicts that the diffuse and weak profile of current flow can be advantageous. Thus, we propose that specifically because tDCS is diffuse, weak and sustained it can boost connectivity between co-active brain regions.
Topics: Animals; Cerebral Cortex; Male; Neurons, Afferent; Rats; Rats, Wistar; Synaptic Transmission; Transcranial Direct Current Stimulation
PubMed: 28436038
DOI: 10.1113/JP273005 -
The Journal of Physiology Jun 2022The K 1/D-type potassium current (I ) is an important determinant of neuronal excitability. This study explored whether and how I channels regulate the activation of...
The K 1/D-type potassium current (I ) is an important determinant of neuronal excitability. This study explored whether and how I channels regulate the activation of bronchopulmonary vagal afferent nerves. The single-neuron RT-PCR assay revealed that nearly all mouse bronchopulmonary nodose neurons expressed the transcripts of α-dendrotoxin (α-DTX)-sensitive, I channel-forming K 1.1, K 1.2 and/or K 1.6 α-subunits, with the expression of K 1.6 being most prevalent. Patch-clamp recordings showed that I , defined as the α-DTX-sensitive K current, activated at voltages slightly more negative than the resting membrane potential in lung-specific nodose neurons and displayed little inactivation at subthreshold voltages. Inhibition of I channels by α-DTX depolarized the lung-specific nodose neurons and caused an increase in input resistance, decrease in rheobase, as well as increase in action potential number and firing frequency in response to suprathreshold current steps. Application of α-DTX to the lungs via trachea in the mouse ex vivo vagally innervated trachea-lungs preparation led to action potential discharges in nearly half of bronchopulmonary nodose afferent nerve fibres, including nodose C-fibres, as detected by the two-photon microscopic Ca imaging technique and extracellular electrophysiological recordings. In conclusion, I channels act as a critical brake on the activation of bronchopulmonary vagal afferent nerves by stabilizing the membrane potential, counterbalancing the subthreshold depolarization and promoting the adaptation of action potential firings. Down-regulation of I channels, as occurs in various inflammatory diseases, may contribute to the enhanced C-fibre activity in airway diseases that are associated with excessive coughing, dyspnoea, and reflex bronchospasm and secretions. KEY POINTS: The α-dendrotoxin (α-DTX)-sensitive D-type K current (I ) is an important determinant of neuronal excitability. Nearly all bronchopulmonary nodose afferent neurons in the mouse express I and the transcripts of α-DTX-sensitive, I channel-forming K 1.1, K 1.2 and/or K 1.6 α-subunits. Inhibition of I channels by α-DTX depolarizes the bronchopulmonary nodose neurons, reduces the minimal depolarizing current needed to evoke an action potential (AP) and increases AP number and AP firing frequency in response to suprathreshold stimulations. Application of α-DTX to the lungs ex vivo elicits AP discharges in about half of bronchopulmonary nodose C-fibre terminals. Our novel finding that I channels act as a critical brake on the activation of bronchopulmonary vagal afferent nerves suggests that their down-regulation, as occurs in various inflammatory diseases, may contribute to the enhanced C-fibre activity in airway inflammation associated with excessive respiratory symptoms.
Topics: Action Potentials; Animals; Membrane Potentials; Mice; Neurons, Afferent; Nodose Ganglion; Patch-Clamp Techniques; Potassium Channels; Vagus Nerve
PubMed: 35430729
DOI: 10.1113/JP282803