-
Experimental Physiology Nov 2019What is the topic of this review? In this review, we examine the evidence for control mechanisms underlying exercise hyperpnoea, giving attention to the feedback from... (Review)
Review
NEW FINDINGS
What is the topic of this review? In this review, we examine the evidence for control mechanisms underlying exercise hyperpnoea, giving attention to the feedback from thin-fibre skeletal muscle afferents, and highlight the frequently conflicting findings and difficulties encountered by researchers using a variety of experimental models. What advances does it highlight? There has been a recent resurgence of interest in the role of skeletal muscle afferent involvement, not only as a mechanism of healthy exercise hyperpnoea but also in the manifestation of breathlessness and exercise intolerance in chronic disease.
ABSTRACT
The ventilatory response to dynamic submaximal exercise is immediate and proportional to metabolic rate, which maintains isocapnia. How these respiratory responses are controlled remains poorly understood, given that the most tightly controlled variable (arterial partial pressure of CO /H ) provides no error signal for arterial chemoreceptors to trigger reflex increases in ventilation. This review discusses evidence for different postulated control mechanisms, with a focus on the feedback from group III/IV skeletal muscle mechanosensitive and metabosensitive afferents. This concept is attractive, because the stimulation of muscle mechanoreceptors might account for the immediate increase in ventilation at the onset of exercise, and signals from metaboreceptors might be proportional to metabolic rate. A variety of experimental models have been used to establish the contribution of thin-fibre muscle afferents in ventilatory control during exercise, with equivocal results. The inhibition of afferent feedback via the application of lumbar intrathecal fentanyl during exercise suppresses ventilation, which provides the most compelling supportive evidence to date. However, stimulation of afferent feedback at rest has no consistent effect on respiratory output. However, evidence is emerging for synergistic interactions between muscle afferent feedback and other stimulatory inputs to the central respiratory neuronal pool. These seemingly hyperadditive effects might explain the conflicting findings encountered when using different experimental models. We also discuss the increasing evidence that patients with certain chronic diseases exhibit exaggerated muscle afferent activation during exercise, resulting in enhanced cardiorespiratory responses. This might provide a neural link between the well-established limb muscle dysfunction and the associated exercise intolerance and exertional dyspnoea, which might offer therapeutic targets for these patients.
Topics: Animals; Exercise; Humans; Hypercapnia; Hyperventilation; Muscle Fibers, Skeletal; Neurons, Afferent; Pulmonary Ventilation; Respiration
PubMed: 31429500
DOI: 10.1113/EP087649 -
The Journal of Physiology Aug 2021We investigated hair-cell regeneration in the zebrafish lateral line following the application of the ototoxic compound copper. In early-larval zebrafish (<10 days...
KEY POINTS
We investigated hair-cell regeneration in the zebrafish lateral line following the application of the ototoxic compound copper. In early-larval zebrafish (<10 days post-fertilisation), regenerated hair cells drive action potentials (APs) in the afferent neurons 24 h post-copper treatment (24 hpt). Full regeneration of the early-larval neuromasts, the organs containing the hair cells, requires ∼48 h due to the progressive addition of hair cells and synaptic refinement. In older larval zebrafish, regenerated hair cells are active and drive afferent APs by 48 hpt, which is comparable to larvae, but the functional recovery of their neuromasts requires >120 hpt. Afferent terminals within the regenerating neuromast appear to initially contact supporting cells, and their complete ablation prevents the timely reappearance of supporting cells and hair cells. We conclude that the regeneration of zebrafish neuromasts is slower after the initial developmental stages, and that the afferent input plays a key role in driving this process.
ABSTRACT
Hair cells are mechanosensory receptors responsible for transducing auditory and vestibular information into electrical signals, which are then transmitted with remarkable precision to afferent neurons. Different from mammals, the hair cells of lower vertebrates, including those present in the neuromasts of the zebrafish lateral line, regenerate following environmental or chemical insults. Here we investigate the time course of regeneration of hair cells in vivo using electrophysiology, two-photon imaging and immunostaining applied to wild-type and genetically encoded fluorescent indicator zebrafish lines. Functional hair cells drive spontaneous action potentials in the posterior lateral line afferent fibres, the frequency of which progressively increases over the first 10 days post-fertilisation (dpf). Higher firing-rate fibres are only observed from ∼6 dpf. Following copper treatment, newly formed hair cells become functional and are able to drive APs in the afferent fibres within 48 h in both early-larval (≤8 dpf) and late-larval (12-17 dpf) zebrafish. However, the complete functional regeneration of the entire neuromast is delayed in late-larval compared to early-larval zebrafish. We propose that while individual regenerating hair cells can rapidly become active, the acquisition of fully functional neuromasts progresses faster at early-larval stages, a time when hair cells are still under development. At both ages, the afferent terminals in the regenerating neuromast appear to make initial contact with supporting cells. The ablation of the lateral line afferent neurons prevents the timely regeneration of supporting cells and hair cells. These findings indicate that the afferent system is likely to facilitate or promote the neuromast regeneration process.
Topics: Animals; Hair Cells, Auditory; Lateral Line System; Mechanoreceptors; Regeneration; Zebrafish
PubMed: 34143497
DOI: 10.1113/JP281522 -
Pain Oct 2022Despite being involved in a number of functions, such as nociception and locomotion, spinal lamina X remains one of the least studied central nervous system regions....
Despite being involved in a number of functions, such as nociception and locomotion, spinal lamina X remains one of the least studied central nervous system regions. Here, we show that Aδ- and C-afferent inputs to lamina X neurons are presynaptically inhibited by homo- and heterosegmental afferents as well as by descending fibers from the corticospinal tract, dorsolateral funiculus, and anterior funiculus. Activation of descending tracts suppresses primary afferent-evoked action potentials and also elicits excitatory (mono- and polysynaptic) and inhibitory postsynaptic responses in lamina X neurons. Thus, primary afferent input to lamina X is subject to both spinal and supraspinal control being regulated by at least 5 distinct pathways.
Topics: Action Potentials; Afferent Pathways; Excitatory Postsynaptic Potentials; Gray Matter; Neurons; Neurons, Afferent; Nociception; Spinal Cord
PubMed: 35297816
DOI: 10.1097/j.pain.0000000000002597 -
The Journal of Physiology Feb 2015Gastrointestinal (GI) vagal afferents are a key mediatory of food intake. Through a balance of responses to chemical and mechanical stimuli food intake can be tightly... (Review)
Review
Gastrointestinal (GI) vagal afferents are a key mediatory of food intake. Through a balance of responses to chemical and mechanical stimuli food intake can be tightly controlled via the ascending satiety signals initiated in the GI tract. However, vagal responses to both mechanical and chemical stimuli are modified in diet-induced obesity (DIO). Much of the research to date whilst in relatively isolated/controlled circumstances indicates a shift between a balance of orexigenic and anorexigenic vagal signals to blunted anorexigenic and potentiated orexigenic capacity. Although the mechanism responsible for the DIO shift in GI vagal afferent signalling is unknown, one possible contributing factor is the gut microbiota. Nevertheless, whatever the mechanism, the observed changes in gastrointestinal vagal afferent signalling may underlie the pathophysiological changes in food consumption that are pivotal for the development and maintenance of obesity.
Topics: Animals; Gastrointestinal Microbiome; Gastrointestinal Tract; Humans; Neurons, Afferent; Obesity; Vagus Nerve
PubMed: 25433079
DOI: 10.1113/jphysiol.2014.278226 -
Chemical Senses Apr 2019The gustatory system encodes information about chemical identity, nutritional value, and concentration of sensory stimuli before transmitting the signal from taste buds... (Review)
Review
The gustatory system encodes information about chemical identity, nutritional value, and concentration of sensory stimuli before transmitting the signal from taste buds to central neurons that process and transform the signal. Deciphering the coding logic for taste quality requires examining responses at each level along the neural axis-from peripheral sensory organs to gustatory cortex. From the earliest single-fiber recordings, it was clear that some afferent neurons respond uniquely and others to stimuli of multiple qualities. There is frequently a "best stimulus" for a given neuron, leading to the suggestion that taste exhibits "labeled line coding." In the extreme, a strict "labeled line" requires neurons and pathways dedicated to single qualities (e.g., sweet, bitter, etc.). At the other end of the spectrum, "across-fiber," "combinatorial," or "ensemble" coding requires minimal specific information to be imparted by a single neuron. Instead, taste quality information is encoded by simultaneous activity in ensembles of afferent fibers. Further, "temporal coding" models have proposed that certain features of taste quality may be embedded in the cadence of impulse activity. Taste receptor proteins are often expressed in nonoverlapping sets of cells in taste buds apparently supporting "labeled lines." Yet, taste buds include both narrowly and broadly tuned cells. As gustatory signals proceed to the hindbrain and on to higher centers, coding becomes more distributed and temporal patterns of activity become important. Here, we present the conundrum of taste coding in the light of current electrophysiological and imaging techniques at several levels of the gustatory processing pathway.
Topics: Animals; Humans; Neurons; Recognition, Psychology; Stimulation, Chemical; Taste; Taste Buds
PubMed: 30788507
DOI: 10.1093/chemse/bjz013 -
Brain Stimulation 2022Vagal reflexes regulate homeostasis in visceral organs and systems through afferent and efferent neurons and nerve fibers. Small, unmyelinated, C-type afferents comprise...
BACKGROUND
Vagal reflexes regulate homeostasis in visceral organs and systems through afferent and efferent neurons and nerve fibers. Small, unmyelinated, C-type afferents comprise over 80% of fibers in the vagus and form the sensory arc of autonomic reflexes of the gut, lungs, heart and vessels and the immune system. Selective bioelectronic activation of C-afferents could be used to mechanistically study and treat diseases of peripheral organs in which vagal reflexes are involved, but it has not been achieved.
METHODS
We stimulated the vagus in rats and mice using trains of kHz-frequency stimuli. Stimulation effects were assessed using neuronal c-Fos expression, physiological and nerve fiber responses, optogenetic and computational methods.
RESULTS
Intermittent kHz stimulation for 30 min activates specific motor and, preferentially, sensory vagus neurons in the brainstem. At sufficiently high frequencies (>5 kHz) and at intensities within a specific range (7-10 times activation threshold, T, in rats; 15-25 × T in mice), C-afferents are activated, whereas larger, A- and B-fibers, are blocked. This was determined by measuring fiber-specific acute physiological responses to kHz stimulus trains, and by assessing fiber excitability around kHz stimulus trains through compound action potentials evoked by probing pulses. Aspects of selective activation of C-afferents are explained in computational models of nerve fibers by how fiber size and myelin shape the response of sodium channels to kHz-frequency stimuli.
CONCLUSION
kHz stimulation is a neuromodulation strategy to robustly and selectively activate vagal C-afferents implicated in physiological homeostasis and disease, over larger vagal fibers.
Topics: Rats; Animals; Mice; Rats, Sprague-Dawley; Vagus Nerve; Nerve Fibers, Myelinated; Sensory Receptor Cells; Electric Stimulation; Neurons, Afferent
PubMed: 36241025
DOI: 10.1016/j.brs.2022.09.015 -
The Journal of Neuroscience : the... Apr 2022Cervical and trigeminal afferents innervate neighboring cranial territories, and their convergence on upper cervical dorsal horn neurons provides a potential substrate...
Cervical and trigeminal afferents innervate neighboring cranial territories, and their convergence on upper cervical dorsal horn neurons provides a potential substrate for pain referral in primary headache syndromes. Lamina I neurons are central to this mechanism, as they relay convergent nociceptive input to supraspinal pain centers. Unfortunately, little is known about the interactions between trigeminal and cervical afferents supplying Lamina I neurons. Here, we used rats of both sexes to show that cervical and trigeminal afferents interact via presynaptic inhibition, where monosynaptic inputs to Lamina I neurons undergo unidirectional as well as reciprocal presynaptic control. This means that afferent-driven presynaptic inhibition shapes the way trigeminal and cervical Aδ-fiber and C-fiber input reaches Lamina I projection neurons (PNs) and local-circuit neurons (LCNs). We propose that this inhibition provides a feedforward control of excitatory drive to Lamina I neurons that regulates their convergent and cervical-specific or trigeminal-specific processing modes. As a consequence, disruption of the trigeminal and cervical afferent-driven presynaptic inhibition may contribute to development of primary headache syndromes. Cervical and trigeminal afferents innervate neighboring cranial territories, and their convergence on upper cervical dorsal horn neurons provides a potential substrate for pain referral in primary headache syndromes. Lamina I neurons are central to this mechanism as they relay convergent nociceptive input to supraspinal pain centers. Here, we show that cervical and trigeminal afferents interact via presynaptic inhibition, where inputs to Lamina I neurons undergo unidirectional as well as reciprocal control. The afferent-driven presynaptic inhibition shapes the trigeminocervical Aδ-fiber and C-fiber input to Lamina I neurons. This inhibition provides control of excitatory drive to Lamina I neurons that regulates their convergent and cervical-specific or trigeminal-specific processing modes. Disruption of this control may contribute to development of primary headache syndromes.
Topics: Animals; Female; Headache Disorders; Male; Nerve Fibers, Unmyelinated; Neurons, Afferent; Nociception; Pain; Rats; Spinal Cord Dorsal Horn
PubMed: 35318285
DOI: 10.1523/JNEUROSCI.0025-22.2022 -
The Journal of Physiology Oct 2016This review highlights evidence for a role of the vagus nerve in the development of obesity and how targeting the vagus nerve with neuromodulation or pharmacology can be... (Review)
Review
This review highlights evidence for a role of the vagus nerve in the development of obesity and how targeting the vagus nerve with neuromodulation or pharmacology can be used as a therapeutic treatment of obesity. The vagus nerve innervating the gut plays an important role in controlling metabolism. It communicates peripheral information about the volume and type of nutrients between the gut and the brain. Depending on the nutritional status, vagal afferent neurons express two different neurochemical phenotypes that can inhibit or stimulate food intake. Chronic ingestion of calorie-rich diets reduces sensitivity of vagal afferent neurons to peripheral signals and their constitutive expression of orexigenic receptors and neuropeptides. This disruption of vagal afferent signalling is sufficient to drive hyperphagia and obesity. Furthermore neuromodulation of the vagus nerve can be used in the treatment of obesity. Although the mechanisms are poorly understood, vagal nerve stimulation prevents weight gain in response to a high-fat diet. In small clinical studies, in patients with depression or epilepsy, vagal nerve stimulation has been demonstrated to promote weight loss. Vagal blockade, which inhibits the vagus nerve, results in significant weight loss. Vagal blockade is proposed to inhibit aberrant orexigenic signals arising in obesity as a putative mechanism of vagal blockade-induced weight loss. Approaches and molecular targets to develop future pharmacotherapy targeted to the vagus nerve for the treatment of obesity are proposed. In conclusion there is strong evidence that the vagus nerve is involved in the development of obesity and it is proving to be an attractive target for the treatment of obesity.
Topics: Animals; Body Weight; Diet, High-Fat; Humans; Hyperphagia; Neurons, Afferent; Obesity; Vagus Nerve
PubMed: 26959077
DOI: 10.1113/JP271538 -
Molecular Pain 2021Aβ-afferents in maxillary or V2 trigeminal ganglion (TG) neurons are somatosensory neurons that may be involved in both non-nociceptive and nociceptive functions in...
Aβ-afferents in maxillary or V2 trigeminal ganglion (TG) neurons are somatosensory neurons that may be involved in both non-nociceptive and nociceptive functions in orofacial regions. However, electrophysiological properties of these V2 trigeminal Aβ-afferent neurons have not been well characterized so far. Here, we used rat trigeminal nerve preparations and applied patch-clamp recordings to large-sized V2 TG neurons to characterize their electrophysiological properties. All the cells recorded had afferent conduction velocities in the range of Aβ-afferent conduction speeds. However, these V2 trigeminal Aβ-afferent neurons displayed different action potential (AP) properties. APs showed fast kinetics in some cells but slow kinetics with shoulders in repolarization phases in other cells. Based on the derivatives of voltages in AP repolarization with time (dV/dt), we classified V2 trigeminal Aβ-afferent neurons into four types: type I, type II, type IIIa and type IIIb. Type I V2 trigeminal Aβ-afferent neurons had the largest dV/dt of repolarization, the fastest AP conduction velocities, the shortest AP and afterhyperpolarization (AHP) durations, and the highest AP success rates. In contrast, type IIIb V2 trigeminal Aβ-afferent neurons had the smallest dV/dt of AP repolarization, the slowest AP conduction velocities, the longest AP and AHP durations, and the lowest AP success rates. The type IIIb cells also had significantly lower voltage-activated K currents. For type II and type IIIa V2 trigeminal Aβ-afferent neurons, AP parameters were in the range between those of type I and type IIIb V2 trigeminal Aβ-afferent neurons. Our electrophysiological classification of V2 trigeminal Aβ-afferent neurons may be useful in future to study their non-nociceptive and nociceptive functions in orofacial regions.
Topics: Action Potentials; Animals; Membrane Potentials; Neurons, Afferent; Rats; Rats, Sprague-Dawley; Trigeminal Ganglion
PubMed: 34056968
DOI: 10.1177/17448069211021271 -
Handbook of Experimental Pharmacology 2018The functional diversity of primary afferent neurons of the dorsal root ganglia (DRG) generates a variety of qualitatively and quantitatively distinct somatosensory... (Review)
Review
The functional diversity of primary afferent neurons of the dorsal root ganglia (DRG) generates a variety of qualitatively and quantitatively distinct somatosensory experiences, from shooting pain to pleasant touch. In recent years, the identification of dozens of genetic markers specifically expressed by subpopulations of DRG neurons has dramatically improved our understanding of this diversity and provided the tools to manipulate their activity and uncover their molecular identity and function. Opioid receptors have long been known to be expressed by discrete populations of DRG neurons, in which they regulate cell excitability and neurotransmitter release. We review recent insights into the identity of the DRG neurons that express the delta opioid receptor (DOR) and the ion channel mechanisms that DOR engages in these cells to regulate sensory input. We highlight recent findings derived from DORGFP reporter mice and from in situ hybridization and RNA sequencing studies in wild-type mice that revealed DOR presence in cutaneous mechanosensory afferents eliciting touch and implicated in tactile allodynia. Mechanistically, we describe how DOR modulates opening of voltage-gated calcium channels (VGCCs) to control glutamatergic neurotransmission between somatosensory neurons and postsynaptic neurons in the spinal cord dorsal horn. We additionally discuss other potential signaling mechanisms, including those involving potassium channels, which DOR may engage to fine tune somatosensation. We conclude by discussing how this knowledge may explain the analgesic properties of DOR agonists against mechanical pain and uncovers an unanticipated specialized function for DOR in cutaneous mechanosensation.
Topics: Animals; Ganglia, Spinal; Humans; Neurons, Afferent; Pain; Receptors, Opioid, delta; Sensory Receptor Cells
PubMed: 28993838
DOI: 10.1007/164_2017_58