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American Journal of Physiology.... Aug 2021Bile acid reflux in the esophagus plays a role in the pathogenesis of certain esophageal disorders, where it can induce esophageal pain and heartburn. The present study...
Bile acid reflux in the esophagus plays a role in the pathogenesis of certain esophageal disorders, where it can induce esophageal pain and heartburn. The present study aimed to determine whether bile acid, deoxycholic acid (DCA), directly activates and sensitizes esophageal vagal nociceptive afferent C-fiber subtypes. DCA-elicited effects on vagal nodose and jugular neurons were studied by calcium imaging. Its effects on esophageal-labeled nodose and jugular neurons were then determined by patch-clamp recording. At nodose and jugular C-fiber nerve endings in the esophagus, DCA-evoked action potentials (APs) were compared by extracellular single-unit recordings in ex vivo esophageal-vagal preparations. DCA application induced calcium influxes in nodose and jugular neurons and elicited inward currents in esophageal-labeled nodose and jugular neurons. In the presence of DCA, the current densities elicited by capsaicin were enhanced in those labeled neurons. Consistently, DCA perfusion at nerve terminals in the esophagus evoked APs in about 50% of esophageal nodose and jugular C-fibers. In DCA-sensitive C-fibers, DCA perfusion also sensitized the fibers such that the subsequent response to capsaicin was amplified. Collectively, these results provide new evidence that DCA directly activates and sensitizes nociceptive nodose and jugular C-fibers in the esophagus. Such activation and sensitization effects may contribute to bile acid-induced esophageal nociceptive symptoms that are refractory to proton-pump inhibitor therapy. Bile acid reflux in the esophagus can induce pain and heartburn in certain esophageal disorders, but the underlying neuronal mechanism is still unclear. The present study demonstrated that bile acid, deoxycholic acid (DCA), directly activates esophageal vagal afferent nodose and jugular nociceptive C-fibers and sensitizes their response to capsaicin. Such effects may contribute to bile acid-induced esophageal nociceptive symptoms that refractory to proton-pump inhibitors (PPIs) therapy.
Topics: Action Potentials; Animals; Calcium Signaling; Cells, Cultured; Cholagogues and Choleretics; Deoxycholic Acid; Esophagus; Guinea Pigs; Nerve Fibers, Unmyelinated; Nociceptors; Vagus Nerve
PubMed: 34160291
DOI: 10.1152/ajpgi.00187.2021 -
Journal of Neurophysiology Nov 2021has a lateral line mechanosensory system throughout its full life cycle, and a previous study on prefeeding stage tadpoles revealed that it may play a role in motor...
has a lateral line mechanosensory system throughout its full life cycle, and a previous study on prefeeding stage tadpoles revealed that it may play a role in motor responses to both water suction and water jets. Here, we investigated the physiology of the anterior lateral line system in newly hatched tadpoles and the motor outputs induced by its activation in response to brief suction stimuli. High-speed videoing showed tadpoles tended to turn and swim away when strong suction was applied close to the head. The lateral line neuromasts were revealed by using DASPEI staining, and their inactivation with neomycin eliminated tadpole motor responses to suction. In immobilized preparations, suction or electrically stimulating the anterior lateral line nerve reliably initiated swimming but the motor nerve discharges implicating turning was observed only occasionally. The same stimulation applied during ongoing fictive swimming produced a halting response. The anterior lateral line nerve showed spontaneous afferent discharges at rest and increased activity during stimulation. Efferent activities were only recorded during tadpole fictive swimming and were largely synchronous with the ipsilateral motor nerve discharges. Finally, calcium imaging identified neurons with fluorescence increase time-locked with suction stimulation in the hindbrain and midbrain. A cluster of neurons at the entry point of the anterior lateral line nerve in the dorsolateral hindbrain had the shortest latency in their responses, supporting their potential sensory interneuron identity. Future studies need to reveal how the lateral line sensory information is processed by the central circuit to determine tadpole motor behavior. We studied tadpole motor responses to anterior lateral line stimulation using high-speed videos, electrophysiology and calcium imaging. Activating the lateral line reliably started swimming. At high stimulation intensities, turning was observed behaviorally but suitable motor nerve discharges were seen only occasionally in immobilized tadpoles. Suction applied during swimming produced a halting response. We analyzed afferent and efferent activities of the tadpole anterior lateral line nerve and located sensory interneurons using calcium imaging.
Topics: Animals; Behavior, Animal; Interneurons; Larva; Lateral Line System; Motor Activity; Neurons, Afferent; Neurons, Efferent; Rhombencephalon; Xenopus laevis
PubMed: 34705593
DOI: 10.1152/jn.00618.2020 -
Vision Research Nov 2021Following photopigment bleaching, the rhodopsin and cone-opsins show a characteristic exponential regeneration in the dark with a photocycle dependent on the retinal...
Following photopigment bleaching, the rhodopsin and cone-opsins show a characteristic exponential regeneration in the dark with a photocycle dependent on the retinal pigment epithelium. Melanopsin pigment regeneration in animal models requires different pathways to rods and cones. To quantify melanopsin-mediated light adaptation in humans, we first estimated its photopigment regeneration kinetics through the photo-bleach recovery of the intrinsic melanopsin pupil light response (PLR). An intense broadband light (~120,000 Td) bleached 43% of melanopsin compared to 86% of the cone-opsins. Recovery from a 43% bleach was 3.4X slower for the melanopsin than cone-opsin. Post-bleach melanopsin regeneration followed an exponential growth with a 2.5 min time-constant (τ) that required 11.2 min for complete recovery; the half-bleaching level (I) was ~ 4.47 log melanopic Td (16.10 log melanopsin effective photons.cm.s; 8.25 log photoisomerisations.photoreceptor.s). The effect on the cone-directed PLR of the level of the melanopsin excitation during continuous light adaptation was then determined. We observed that cone-directed pupil constriction amplitudes increased by ~ 10% when adapting lights had a higher melanopic excitation but the same mean photometric luminance. Our findings suggest that melanopsin light adaptation enhances cone signalling along the non-visual retina-brain axis. Parameters τ and I will allow estimation of the level of melanopsin bleaching in any light units; the data have implications for quantifying the relative contributions of putative melanopsin pathways to regulate the post-bleach photopigment regeneration and adaptation.
Topics: Adaptation, Ocular; Dark Adaptation; Humans; Light; Photobleaching; Retinal Cone Photoreceptor Cells; Retinal Rod Photoreceptor Cells; Rod Opsins
PubMed: 34315092
DOI: 10.1016/j.visres.2021.07.005 -
Journal of Neurophysiology Feb 2021Somatosensory input strength can be modulated by primary afferent depolarization (PAD) generated predominantly via presynaptic GABA receptors on afferent terminals. We...
Somatosensory input strength can be modulated by primary afferent depolarization (PAD) generated predominantly via presynaptic GABA receptors on afferent terminals. We investigated whether ionotropic nicotinic acetylcholine receptors (nAChRs) also provide modulatory actions, focusing on myelinated afferent excitability in in vitro murine spinal cord nerve-attached models. Primary afferent stimulation-evoked synaptic transmission was recorded in the deep dorsal horn as extracellular field potentials (EFPs), whereas concurrently recorded dorsal root potentials (DRPs) were used as an indirect measure of PAD. Changes in afferent membrane excitability were simultaneously measured as direct current (DC)-shifts in membrane polarization recorded in dorsal roots or peripheral nerves. The broad nAChR antagonist d-tubocurarine (d-TC) selectively and strongly depressed Aδ-evoked synaptic EFPs (36% of control) coincident with similarly depressed A-fiber DRP (43% of control), whereas afferent electrical excitability remained unchanged. In comparison, acetylcholine (ACh) and the nAChR agonists, epibatidine and nicotine, reduced afferent excitability by generating coincident depolarizing DC-shifts in peripheral axons and intraspinally. Progressive depolarization corresponded temporally with the emergence of spontaneous axonal spiking and reductions in the DRP and all afferent-evoked synaptic actions (31%-37% of control). Loss of evoked response was long-lasting, independent of DC repolarization, and likely due to mechanisms initiated by spontaneous C-fiber activity. DC-shifts were blocked with d-TC but not GABA receptor blockers and retained after tetrodotoxin block of voltage-gated Na channels. Notably, actions tested were comparable between three mouse strains, in rat, and when performed in different labs. Thus, nAChRs can regulate afferent excitability via two distinct mechanisms: by central Aδ-afferent actions, and by transient extrasynaptic axonal activation of high-threshold primary afferents. Primary afferents express many nicotinic ACh receptor (nAChR) subtypes but whether activation is linked to presynaptic inhibition, facilitation, or more complex and selective activity modulation is unknown. Recordings of afferent-evoked responses in the lumbar spinal cord identified two nAChR-mediated modulatory actions: ) selective control of Aδ afferent transmission and ) robust changes in axonal excitability initiated via extrasynaptic shifts in DC polarization. This work broadens the diversity of presynaptic modulation of primary afferents by nAChRs.
Topics: Animals; Ganglia, Spinal; Mice; Mice, Inbred BALB C; Neurons, Afferent; Nicotinic Agonists; Nicotinic Antagonists; Rats; Rats, Sprague-Dawley; Receptors, Nicotinic; Synaptic Potentials
PubMed: 33326305
DOI: 10.1152/jn.00228.2020 -
Cell Reports Jan 2021Recent studies reveal great diversity in the structure, function, and efferent innervation of afferent synaptic connections between the cochlear inner hair cells (IHCs)...
Recent studies reveal great diversity in the structure, function, and efferent innervation of afferent synaptic connections between the cochlear inner hair cells (IHCs) and spiral ganglion neurons (SGNs), which likely enables audition to process a wide range of sound pressures. By performing an extensive electron microscopic (EM) reconstruction of the neural circuitry in the mature mouse organ of Corti, we demonstrate that afferent SGN dendrites differ in abundance and composition of efferent innervation in a manner dependent on their afferent synaptic connectivity with IHCs. SGNs that sample glutamate release from several presynaptic ribbons receive more efferent innervation from lateral olivocochlear projections than those driven by a single ribbon. Next to the prevailing unbranched SGN dendrites, we found branched SGN dendrites that can contact several ribbons of 1-2 IHCs. Unexpectedly, medial olivocochlear neurons provide efferent innervation of SGN dendrites, preferring those forming single-ribbon, pillar-side synapses. We propose a fine-tuning of afferent and efferent SGN innervation.
Topics: Animals; Cochlea; Dendrites; Female; Hair Cells, Auditory, Inner; Imaging, Three-Dimensional; Male; Mice; Mice, Inbred C57BL; Mice, Inbred CBA; Microscopy, Electron; Neural Pathways; Neurons; Organ of Corti; Spiral Ganglion; Synapses
PubMed: 33406431
DOI: 10.1016/j.celrep.2020.108551 -
Annual Review of Vision Science Sep 2023Rod and cone photoreceptors degenerate in retinitis pigmentosa and age-related macular degeneration, robbing the visual system of light-triggered signals necessary for... (Review)
Review
Rod and cone photoreceptors degenerate in retinitis pigmentosa and age-related macular degeneration, robbing the visual system of light-triggered signals necessary for sight. However, changes in the retina do not stop with the photoreceptors. A stereotypical set of morphological and physiological changes, known as remodeling, occur in downstream retinal neurons. Some aspects of remodeling are homeostatic, with structural or functional changes compensating for partial loss of visual inputs. However, other aspects are nonhomeostatic, corrupting retinal information processing to obscure vision mediated naturally by surviving photoreceptors or artificially by vision-restoration technologies. In this review, I consider the mechanism of remodeling and its consequences for residual and restored visual function; discuss the role of retinoic acid, a critical molecular trigger of detrimental remodeling; and discuss strategies for suppressing retinoic acid biosynthesis or signaling as therapeutic possibilities for mitigating vision loss.
Topics: Humans; Vision Disorders; Retina; Retinal Cone Photoreceptor Cells; Retinal Neurons; Tretinoin
PubMed: 37713276
DOI: 10.1146/annurev-vision-112122-020957 -
Pain Jun 2023Neuronal N-type (Ca V 2.2) voltage-gated calcium channels are essential for neurotransmission from primary afferent terminals in the dorsal horn. In this study, we have...
Neuronal N-type (Ca V 2.2) voltage-gated calcium channels are essential for neurotransmission from primary afferent terminals in the dorsal horn. In this study, we have used a knockin mouse containing Ca V 2.2 with an inserted extracellular hemagglutinin tag (Ca V 2.2_HA), to visualise the pattern of expression of endogenous Ca V 2.2 in dorsal root ganglion (DRG) neurons and their primary afferents in the dorsal horn. We examined the effect of partial sciatic nerve ligation (PSNL) and found an increase in Ca V 2.2_HA only in large and medium dorsal root ganglion neurons and also in deep dorsal horn synaptic terminals. Furthermore, there is a parallel increase in coexpression with GFRα1, present in a population of low threshold mechanoreceptors, both in large DRG neurons and in their terminals. The increased expression of Ca V 2.2_HA in these DRG neurons and their terminals is dependent on the presence of the auxiliary subunit α 2 δ-1, which is required for channel trafficking to the cell surface and to synaptic terminals, and it likely contributes to enhanced synaptic transmission at these synapses following PSNL. By contrast, the increase in GFRα1 is not altered in α 2 δ-1-knockout mice. We also found that following PSNL, there is patchy loss of glomerular synapses immunoreactive for Ca V 2.2_HA and CGRP or IB4, restricted to the superficial layers of the dorsal horn. This reduction is not dependent on α 2 δ-1 and likely reflects partial deafferentation of C-nociceptor presynaptic terminals. Therefore, in this pain model, we can distinguish 2 different events affecting specific DRG terminals, with opposite consequences for Ca V 2.2_HA expression and function in the dorsal horn.
Topics: Animals; Mice; Rats; Ganglia, Spinal; Mechanoreceptors; Nociceptors; Peripheral Nervous System Diseases; Rats, Sprague-Dawley
PubMed: 36524581
DOI: 10.1097/j.pain.0000000000002846 -
Molecules and Cells Dec 2022Taste sensation is the process of converting chemical identities in food into a neural code of the brain. Taste information is initially formed in the taste buds on the... (Review)
Review
Taste sensation is the process of converting chemical identities in food into a neural code of the brain. Taste information is initially formed in the taste buds on the tongue, travels through the afferent gustatory nerves to the sensory ganglion neurons, and finally reaches the multiple taste centers of the brain. In the taste field, optical tools to observe cellular-level functions play a pivotal role in understanding how taste information is processed along a pathway. In this review, we introduce recent advances in the optical tools used to study the taste transduction pathways.
Topics: Taste; Taste Buds; Tongue; Taste Perception; Sensory Receptor Cells
PubMed: 36572557
DOI: 10.14348/molcells.2022.0116 -
Cell and Tissue Research Jun 2024Understanding how the gut communicates with the brain, via sensory nerves, is of significant interest to medical science. Enteroendocrine cells (EEC) that line the...
Understanding how the gut communicates with the brain, via sensory nerves, is of significant interest to medical science. Enteroendocrine cells (EEC) that line the mucosa of the gastrointestinal tract release neurochemicals, including the largest quantity of 5-hydroxytryptamine (5-HT). How the release of substances, like 5-HT, from enterochromaffin (EC) cells activates vagal afferent nerve endings is unresolved. We performed anterograde labelling from nodose ganglia in vivo and identified vagal afferent axons and nerve endings in the mucosa of whole-mount full-length preparations of mouse colon. We then determined the spatial relationship between mucosal-projecting vagal afferent nerve endings and EC cells in situ using 3D imaging. The mean distances between vagal afferent nerve endings in the mucosa, or nearest varicosities along vagal afferent axon branches, and the nearest EC cell were 29.6 ± 19.2 μm (n = 107, N = 6) and 25.7 ± 15.2 μm (n = 119, N = 6), respectively. No vagal afferent endings made close contacts with EC cells. The distances between EC cells and vagal afferent endings are many hundreds of times greater than known distances between pre- and post-synaptic membranes (typically 10-20 nm) that underlie synaptic transmission in vertebrates. The absence of any close physical contacts between 5-HT-containing EC cells and vagal afferent nerve endings in the mucosa leads to the inescapable conclusion that the mechanism by which 5-HT release from ECs in the colonic mucosa occurs in a paracrine fashion, to activate vagal afferents.
Topics: Animals; Enterochromaffin Cells; Colon; Vagus Nerve; Mice; Mice, Inbred C57BL; Male; Nerve Endings; Nodose Ganglion; Neurons, Afferent
PubMed: 38383905
DOI: 10.1007/s00441-024-03879-6 -
The Journal of Physiology Nov 2022
Topics: Retinal Rod Photoreceptor Cells; Retinal Cone Photoreceptor Cells; Electroretinography; Retina; Dark Adaptation
PubMed: 36083438
DOI: 10.1113/JP283652