Sensory Endings Research Articles

Role of Inflammation and Motility Disorders in the Development, Course and Consequences of Functional Gastrointestinal and Biliary Tract Diseases (Literature Review and Expert Panel Resolution)

Aim: to present the results of the Expert Panel with a discussion of modern concepts of the pathogenesis of functional gastrointestinal diseases and the possibilities of multitarget therapy with trimebutine. Key points. Low-grade inflammation can be considered as a morphological substrate of functional diseases with an increase in activated mastocytes and eosinophils, T-helpers 2 and T-helpers 17 in the gastrointestinal mucosa. In the development in the content of visceral hypersensitivity, the functional connection between mastocytes and TRPV1-positive sensory endings of the vagus nerve is of great importance. Proinflammatory cytokines and matrix metalloproteinases can enter the systemic circulation, provoking the development of systemic manifestations. Increased levels of proinflammatory cytokines are supported by altered intestinal permeability and microbiota. Functional diseases are believed to modify the symptoms and course of concomitant organic diseases of the gastrointestinal tract (for example, functional diseases of the biliary tract may contribute to the development of cholelithiasis, pancreatitis). The peripheral μ-, κ- and δ-receptor agonist trimebutine (Trimedat®) regulates the production of enterohormones, modulates motility throughout the gastrointestinal tract and normalizes visceral sensitivity. The effectiveness of trimebutine in the treatment of functional disorders has been shown in various studies. Trimebutine helps reduce the production of proinflammatory cytokines, including interleukin-6. Conclusion. In the treatment of functional diseases of the gastrointestinal tract, trimebutine can be considered as a multitarget agent, since the drug helps to normalize motility, reduces the degree of visceral hypersensitivity, exhibits anti-inflammatory and neuroregenerative effects, and can also increase the effectiveness of treatment of concomitant diseases.

Protein kinase C epsilon contributes to chronic mechanoreflex sensitization in rats with heart failure.

We investigated second-messenger signalling components linked to the stimulation of Gq protein-coupled receptors (e.g. thromboxane A2 and bradykinin B2 receptors) on the sensory endings of thin fibre muscle afferents in the chronic mechanoreflex sensitization in rats with myocardial infarction-induced heart failure with reduced ejection fraction (HF-rEF). We hypothesized that injection of either the inositol 1,4,5-trisphosphate (IP3) receptor antagonist xestospongin C (5µg) or the PKCε translocation inhibitor PKCe141 (45µg) into the arterial supply of the hindlimb would reduce the increase in renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) evoked during 30s of 1Hz dynamic hindlimb muscle stretch in decerebrate, unanaesthetized HF-rEF rats but not sham-operated controls (SHAM). Ejection fraction was significantly reduced in HF-rEF (45 (19)%) compared to SHAM (80 (9)%; P<0.001) rats. In HF-rEF rats (n=3M/2F), IP3 receptor blockade had no effect on the peak ΔRSNA (pre: 99 (74)%; post: 133 (79)%; P=0.974) or peak ΔMAP response to stretch (peak ΔMAP: pre: 32 (14) mmHg; post: 36 (21) mmHg; P=0.719). Conversely, in another group of HF-rEF rats (n=4M/3F), the PKCε translocation inhibitor reduced the peak ΔRSNA (pre: 110 (77)%; post: 62 (58)%; P=0.029) and peak ΔMAP response to stretch (pre: 30 (20) mmHg; post: 17 (16) mmHg; P=0.048). In SHAM counterparts, neither drug affected the mechanoreflex responses. Our findings highlight PKCε, but not IP3 receptors, as a significant second-messenger in the chronic mechanoreflex sensitization in HF-rEF which may play a crucial role in the exaggerated sympathetic response to exercise in this patient population. KEY POINTS: Skeletal muscle contraction results in an exaggerated reflex increase in sympathetic nerve activity in heart failure patients with reduced ejection fraction (HF-rEF) compared to healthy individuals, contributing to increased cardiovascular risk and impaired tolerance for mild exercise. The exaggerated reflex sympathetic responses in HF-rEF may be attributed to a chronic sensitization of mechanically sensitive thin fibre muscle afferents mediated, at least in part, by stimulation of Gq protein-coupled thromboxane A2 and bradykinin B2 receptors on muscle afferent sensory endings. The specific Gq protein-linked signalling mechanisms that produce the chronic mechanoreflex sensitization in HF-rEF have not been investigated but may involve inositol 1,4,5-trisphosphate (IP3) receptors and/or protein kinase C epsilon (PKCε). Here we demonstrate that PKCε, but not IP3 receptors, within the sensory endings of thin fibre muscle afferents plays a role in the sensitization of mechanically sensitive thin fibre muscle afferents in rats with HF-rEF.

First person – Maria Sharkova

ABSTRACT First Person is a series of interviews with the first authors of a selection of papers published in Journal of Cell Science, helping researchers promote themselves alongside their papers. Maria Sharkova is first author on ‘ Photoreceptor calyceal processes accompany the developing outer segment, adopting a stable length despite a dynamic core’, published in JCS. Maria is a PhD student in the lab of Dr Jennifer Hocking at the Department of Cell Biology, University of Alberta, Edmonton, Canada, investigating the role of microvilli surrounding the sensory ending of vertebrate photoreceptors.

Touch sensation requires the mechanically gated ion channel ELKIN1.

Touch perception is enabled by mechanically activated ion channels, the opening of which excites cutaneous sensory endings to initiate sensation. In this study, we identify ELKIN1 as an ion channel likely gated by mechanical force, necessary for normal touch sensitivity in mice. Touch insensitivity in Elkin1-/- mice was caused by a loss of mechanically activated currents (MA currents) in around half of all sensory neurons activated by light touch (low-threshold mechanoreceptors). Reintroduction of Elkin1 into sensory neurons from Elkin1-/- mice restored MA currents. Additionally, small interfering RNA-mediated knockdown of ELKIN1 from induced human sensory neurons substantially reduced indentation-induced MA currents, supporting a conserved role for ELKIN1 in human touch. Our data identify ELKIN1 as a core component of touch transduction in mice and potentially in humans.

NGF Signaling Exacerbates KOA Peripheral Hyperalgesia via the Increased TRPV1-Labeled Synovial Sensory Innervation in KOA Rats.

Knee osteoarthritis (KOA) pain is caused by nociceptors, which are actually sensory nerve fiber endings that can detect stimuli to produce and transmit pain signals, and high levels of NGF in synovial tissue led to peripheral hyperalgesia in KOA. The purpose of this study is to investigate how sensory nerve fibers respond to the NGF/TrKA signal pathway and mediate the peripheral hyperalgesia in KOA rats. Forty SD male rats were randomly divided into 4 groups: normal, KOA, KOA + NGF, and KOA + siRNA TrKA. KOA model rats were induced by anterior cruciate ligament transection (ACLT). Mechanical and cold withdrawal thresholds (MWT and CWT) were measured 4 times in each group. The synovial tissues were harvested on day 28, and the expressions of NGF, TrKA, TRPV1, IL-1β, and PGP9.5 were determined using western blot, qPCR, and immunofluorescence staining. The primary rat fibroblast-like synoviocytes (FLSs) and DRG cells were divided into 4 groups as in vivo. The expressions of NGF, TrKA, TRPV1, and CGRP in vitro were determined using western blot and qPCR. KOA and intra-articular injection with NGF protein increased both mRNA and protein levels, not only TRPV1, PGP 9.5, and IL-1β in the synovial tissue, but also TRPV1, PGP 9.5, and S100 in the DRG tissue, while above changes were partly reversed after siRNA TrKA intervention. Besides, siRNA TrKA could improve peripheral hyperalgesia and decreased the TRPV1 positive nerve fiber innervation in synovial tissue. The results in vitro were consistent with those in vivo. This study showed the activation of the NGF/TrKA signaling pathway in KOA promoted the release of pain mediators, increased the innervation of sensory nerve fibers in the synovium, and worsened peripheral hyperalgesia. It also showed increased TRPV1 positive sensory innervation in KOA was mediated by NGF/TrKA signaling and exacerbated peripheral hyperalgesia.

Individual word representations dissociate from linguistic context along a cortical unimodal to heteromodal gradient.

Language comprehension involves multiple hierarchical processing stages across time, space, and levels of representation. When processing a word, the sensory input is transformed into increasingly abstract representations that need to be integrated with the linguistic context. Thus, language comprehension involves both input-driven as well as context-dependent processes. While neuroimaging research has traditionally focused on mapping individual brain regions to the distinct underlying processes, recent studies indicate that whole-brain distributed patterns of cortical activation might be highly relevant for cognitive functions, including language. One such pattern, based on resting-state connectivity, is the 'principal cortical gradient', which dissociates sensory from heteromodal brain regions. The present study investigated the extent to which this gradient provides an organizational principle underlying language function, using a multimodal neuroimaging dataset of functional magnetic resonance imaging (fMRI) and magnetoencephalography (MEG) recordings from 102 participants during sentence reading. We found that the brain response to individual representations of a word (word length, orthographic distance, and word frequency), which reflect visual; orthographic; and lexical properties, gradually increases towards the sensory end of the gradient. Although these properties showed opposite effect directions in fMRI and MEG, their association with the sensory end of the gradient was consistent across both neuroimaging modalities. In contrast, MEG revealed that properties reflecting a word's relation to its linguistic context (semantic similarity and position within the sentence) involve the heteromodal end of the gradient to a stronger extent. This dissociation between individual word and contextual properties was stable across earlier and later time windows during word presentation, indicating interactive processing of word representations and linguistic context at opposing ends of the principal gradient. To conclude, our findings indicate that the principal gradient underlies the organization of a range of linguistic representations while supporting a gradual distinction between context-independent and context-dependent representations. Furthermore, the gradient reveals convergent patterns across neuroimaging modalities (similar location along the gradient) in the presence of divergent responses (opposite effect directions).

Microanatomy and ultrastructure of the nervous system of adult Renicola parvicaudatus (Digenea: Renicolidae).

The digenean complex life cycle includes various morphological forms with different locomotory and behavioral activities, and the functional specialization of their nervous system is of importance for the transmission of these parasites. Adult digeneans acquire many adaptive features associated with the final settlement in a vertebrate host. Our study describes the general morphology and ultrastructure of the nervous system of the adult renicolid digenean Renicola parvicaudatus parasitizing the renal tubules of herring gulls. Using immunocytochemical and electron microscopic methods, we identified the distinctive characteristics of ganglia and synapses in the studied species. A comparative analysis of the organization of the nervous system of adult individuals and their continuously-swimming stylet cercariae revealed a number of stage-related differences in the composition of ganglia, the distribution of serotonin- and FMRFamide-immunoreactive neurons, the cytomorphology of neuron somata and free sensory endings. Thus, in adults, the presence of FMRFamide-positive neuron somata, accessory muscle bundles in the ganglionic cortex, and eight types of neuronal vesicles was detected, but no glia-like elements were identified. Their neurons are characterized by a larger volume of cytoplasm and also show greater ultrastructural diversity. Although the sensory papillae of adults do not vary in their external morphology as much as those of larvae, their sensory bulbs are more diverse in cytomorphology. Following our previous data on the "support" cell processes related to various tissues of the larvae and considered as glia-like structures, we also briefly present the identified features of the parenchyma, attachment organs and excretory system of adult individuals. The excretory system of adult R. parvicaudatus is characterized by the presence of unique terminal cells with several flame tufts, which are not typical either for the larvae of this species or for other digeneans studied so far. We also used molecular phylogenetic analysis to clarify species identification.

THE ROLE OF MECHANOSENSORY NEURONS IN MUSCULOSKELETAL DISEASES

Distal arthrogryposis (DA) is a collection of rare developmental disorders characterized by congenital joint contractures. Most arthrogryposis mutations are in muscle- and joint-related genes, and the anatomical defects originate cell-autonomously within the musculoskeletal tissues. However, gain-of-function (GOF) mutations in PIEZO2, a principal mechanosensor in somatosensation, cause DA subtype 5 via unknown mechanisms. We show that expression of a GOF PIEZO2 mutation in proprioceptive sensory neurons mainly innervating muscle spindles and tendons is sufficient to induce DA5-like phenotypes in mice. Overactive PIEZO2 causes anatomical defects via increased activity within the peripheral nervous system during postnatal development. Surprisingly, overactive PIEZO2 is likely to cause joint abnormalities via increased exocytosis from sensory neuron endings without involving motor circuitry. This reveals a role for somatosensory neurons: excessive mechanosensation within these neurons disrupts musculoskeletal development. We also present proof-of-concept that Botox injection or dietary treatment can counteract the effect of overactive PIEZO2 function to evade DA-like phenotypes in mice when applied during a developmental critical period. These approaches might have clinical applications. Beyond this, our findings call attention to the importance of considering sensory mechanotransduction when diagnosing and treating other musculoskeletal disorders.Acknowledgements: Our work is supported by National Institutes of Health grant (R35 NS105067, R01 DE022358, R25 SC3GM127195, R25 GM07138, R01GM133845, intramural) and Howard Hughes Medical Institute.

An adeno-associated viral labeling approach to visualize the meso- and microanatomy of mechanosensory afferents and autonomic innervation of the rat urinary bladder.

The urinary bladder is supplied by a rich network of sensory and autonomic axons, commonly visualized by immunolabeling for neural markers. This approach demonstrates overall network patterning but is less suited to understanding the structure of individual motor and sensory terminals within these complex plexuses. There is a further limitation visualizing the lightly myelinated (A-delta) class of sensory axons that provides the primary mechanosensory drive for initiation of voiding. Whereas most unmyelinated sensory axons can be revealed by immunolabeling for specific neuropeptides, to date no unique neural marker has been identified to immunohistochemically label myelinated visceral afferents. We aimed to establish a non-surgical method to visualize and map myelinated afferents in the bladder in rats. We found that in rats, the adeno-associated virus (AAV), AAV-PHP.S, which shows a high tropism for the peripheral nervous system, primarily transduced myelinated dorsal root ganglion neurons, enabling us to identify the structure and regional distribution of myelinated (mechanosensory) axon endings within the muscle and lamina propria of the bladder. We further identified the projection of myelinated afferents within the pelvic nerve and lumbosacral spinal cord. A minority of noradrenergic and cholinergic neurons in pelvic ganglia were transduced, enabling visualization and regional mapping of both autonomic and sensory axon endings within the bladder. Our study identified a sparse labeling approach for investigating myelinated sensory and autonomic axon endings within the bladder and provides new insights into the nerve-bladder interface.

The Effects of Lithium on Proprioceptive Sensory Function and Nerve Conduction.

Animals are exposed to lithium (Li+) in the natural environment as well as by contact with industrial sources and therapeutic treatments. Low levels of exposure over time and high volumes of acute levels can be harmful and even toxic. The following study examines the effect of high-volume acute levels of Li+ on sensory nerve function and nerve conduction. A proprioceptive nerve in the limbs of a marine crab (Callinectes sapidus) was used as a model to address the effects on stretch-activated channels (SACs) and evoked nerve conduction. The substitution of Li+ for Na+ in the bathing saline slowed nerve conduction rapidly; however, several minutes were required before the SACs in sensory endings were affected. The evoked compound action potential slowed in conduction and slightly decreased in amplitude, while the frequency of nerve activity with joint movement and chordotonal organ stretching significantly decreased. Both altered responses could be partially restored with the return of a Na+-containing saline. Long-term exposure to Li+ may alter the function of SACs in organisms related to proprioception and nerve conduction, but it remains to be investigated.

An intraflagellar transport dependent negative feedback regulates the MAPKKK DLK-1 to protect cilia from degeneration

Primary cilia are specialized organelles supporting the development and function of cells and organisms. Intraflagellar transport (IFT) is essential for cilia formation, maintenance, and function. In C. elegans ciliated sensory neurons, IFT interacts with signaling molecules to generate distinct morphological and function features and also to maintain the integrity of cilia. Here, we report an IFT-dependent feedback control on the conserved MAPKKK DLK-1 in the ciliated sensory neurons. DLK proteins are widely known to act in synapse formation, axon regeneration, and degeneration, but their roles in other neuronal compartments are understudied. By forward genetic screening for altered expression of the endogenously tagged DLK-1 we identified multiple ift mutants showing increased DLK-1 accumulation in the defective sensory endings. We show that in response to acute IFT disruption, DLK-1 accumulates rapidly and reversibly. The expression levels of the transcription factor CEBP-1, known to act downstream of DLK-1 in the development and maintenance of synapses and axons, are also increased in the ciliated sensory neurons of ift mutants. Interestingly, the regulation of CEBP-1 expression shows sensory neuron-type dependency on DLK-1. Moreover, in the sensory neuron AWC, which has elaborate cilia morphology, up-regulated CEBP-1 represses DLK-1 at the transcription level, thereby dampening DLK-1 accumulation. Last, the IFT-dependent regulatory loop of DLK-1 and CEBP-1 offers neuroprotection in a cilia degeneration model. These findings uncover a surveillance mechanism in which tight control on the DLK-1 signaling protects cilia integrity in a context-specific manner.

The efficacy and neural mechanism of acupuncture therapy in the treatment of visceral hypersensitivity in irritable bowel syndrome.

Irritable Bowel Syndrome (IBS) is a complex functional gastrointestinal disorder primarily characterized by chronic abdominal pain, bloating, and altered bowel habits. Chronic abdominal pain caused by visceral Hypersensitivity (VH) is the main reason why patients with IBS seek medication. Significant research effort has been devoted to the efficacy of acupuncture as a non-drug alternative therapy for visceral-hyperalgesia-induced IBS. Herein, we examined the central and peripheral analgesic mechanisms of acupuncture in IBS treatment. Acupuncture can improve inflammation and relieve pain by reducing 5-hydroxytryptamine and 5-HT3A receptor expression and increasing 5-HT4 receptor expression in peripheral intestinal sensory endings. Moreover, acupuncture can also activate the transient receptor potential vanillin 1 channel, block the activity of intestinal glial cells, and reduce the secretion of local pain-related neurotransmitters, thereby weakening peripheral sensitization. Moreover, by inhibiting the activation of N-methyl-D-aspartate receptor ion channels in the dorsal horn of the spinal cord and anterior cingulate cortex or releasing opioids, acupuncture can block excessive stimulation of abnormal pain signals in the brain and spinal cord. It can also stimulate glial cells (through the P2X7 and prokinetic protein pathways) to block VH pain perception and cognition. Furthermore, acupuncture can regulate the emotional components of IBS by targeting hypothalamic-pituitary-adrenal axis-related hormones and neurotransmitters via relevant brain nuclei, hence improving the IBS-induced VH response. These findings provide a scientific basis for acupuncture as an effective clinical adjuvant therapy for IBS pain.

Sex-dependent attenuating effects of capsaicin administration on the mechanoreflex in healthy rats.

Stimulation of mechanically sensitive channels on the sensory endings of group III and IV thin fiber muscle afferents activates the mechanoreflex, which contributes to reflex increases in sympathetic nerve activity (SNA) and blood pressure during exercise. Accumulating evidence suggests that activation of the nonselective cation channel transient receptor potential vanilloid-1 (TRPV1) on the sensory endings of thin fiber afferents with capsaicin may attenuate mechanosensation. However, no study has investigated the effect of capsaicin on the mechanoreflex. We tested the hypothesis that in male and female decerebrate, unanesthetized rats, the injection of capsaicin (0.05 µg) into the arterial supply of the hindlimb reduces the pressor and renal SNA (RSNA) response to 30 s of 1 Hz rhythmic hindlimb muscle stretch (a model of isolated mechanoreflex activation). In male rats (n = 8), capsaicin injection significantly reduced the integrated blood pressure (blood pressure index or BPI: pre, 363 ± 78; post, 211 ± 88 mmHg·s; P = 0.023) and RSNA [∫ΔRSNA; pre, 687 ± 206; post, 216 ± 80 arbitrary units (au), P = 0.049] response to hindlimb muscle stretch. In female rats (n = 8), capsaicin injection had no significant effect on the pressor (BPI; pre: 277 ± 67; post: 207 ± 77 mmHg·s; P = 0.343) or RSNA (∫ΔRSNA: pre, 697 ± 123; post, 440 ± 183 au; P = 0.307) response to hindlimb muscle stretch. The data suggest that the injection of capsaicin into the hindlimb arterial supply to stimulate TRPV1 on the sensory endings of thin fiber muscle afferents attenuates the mechanoreflex in healthy male, but not female, rats. The findings may carry important implications for chronic conditions in which an exaggerated mechanoreflex contributes to aberrant sympathoexcitation during exercise.NEW & NOTEWORTHY Recent evidence in isolated sensory neurons indicates that capsaicin-induced stimulation of TRPV1 attenuates mechanosensitivity. Here we demonstrate for the first time that capsaicin exposure/administration reduces the reflex pressor and renal sympathetic nerve response to mechanoreflex activation in male rats, but not female rats, in vivo. Our data may carry important clinical implications for chronic diseases which have been linked to an exaggerated mechanoreflex, at least in males.

A Call for Discovery and Therapeutic Development for Cutaneous Neurofibromas

A Call for Discovery and Therapeutic Development for Cutaneous Neurofibromas

Visual processing in the fly, from photoreceptors to behavior.

Originally a genetic model organism, the experimental use of Drosophila melanogaster has grown to include quantitative behavioral analyses, sophisticated perturbations of neuronal function, and detailed sensory physiology. A highlight of these developments can be seen in the context of vision, where pioneering studies have uncovered fundamental and generalizable principles of sensory processing. Here we begin with an overview of vision-guided behaviors and common methods for probing visual circuits. We then outline the anatomy and physiology of brain regions involved in visual processing, beginning at the sensory periphery and ending with descending motor control. Areas of focus include contrast and motion detection in the optic lobe, circuits for visual feature selectivity, computations in support of spatial navigation, and contextual associative learning. Finally, we look to the future of fly visual neuroscience and discuss promising topics for further study.

Purinergic 2X Receptors Contribute to the Exaggerated Mechanoreflex in Rats with Heart Failure

Skeletal muscle contraction stimulates mechanically activated channels on the sensory endings of thin fiber muscle afferents which evokes reflex increases in sympathetic nerve activity and blood pressure. This reflex is termed the mechanoreflex and its activation in healthy populations plays a key role in facilitating oxygen delivery to contracting muscles and exercise performance. However, mechanoreflex activation in patients with heart failure with reduced ejection fraction (HF-rEF) results in excessive peripheral vasoconstriction and impaired limb blood flow during exercise. Recent evidence in a rat model of HF-rEF demonstrated that hindlimb arterial injection of PPADS, an antagonist for ATP-sensitive purinergic 2X (P2X) receptors, reduced thin fiber muscle afferent responsiveness to static hindlimb muscle stretch (a model of mechanoreflex activation isolated from contraction-induced metabolite production) to a greater extent in HF-rEF rats than in healthy counterparts. Those data suggest that, in HF-rEF, P2X receptor stimulation results in the sensitization of co-localized mechanically activated channels on the sensory endings of muscle afferents. To date, however, those electrophysiological findings have not been extended to reflex experiments investigating the cardiovascular consequences of mechanoreflex activation. Accordingly, we sought to determine the role played by P2X receptors in evoking the exaggerated blood pressure response to isolated mechanoreflex activation in HF-rEF rats. We hypothesized that hindlimb arterial injection of the P2X receptor antagonist PPADS (5mg) would reduce the integrated area under the blood pressure signal (the blood pressure index: BPI) evoked during 30 seconds of static hindlimb skeletal muscle stretch in decerebrate, unanesthetized HF-rEF rats to a greater extent than in healthy rats. Experiments were performed six to eight weeks following either a coronary artery ligation surgery to induce myocardial infarction and HF-rEF ( n=8M/2F; ejection fraction 37±6%) or a sham procedure ( n=1M/4F; ejection fraction 84±4; P&lt;0.01versus HF-rEF). In sham rats, P2X receptor blockade had no effect on the BPI response to hindlimb muscle stretch (control: 197±67, PPADS: 211±159mmHg⋅s; p=0.46). Conversely, in HF-rEF rats P2X receptor blockade reduced the BPI response to hindlimb muscle stretch (control: 425±60, PPADS: 257±83mmHg⋅s; p=0.01). The integrated area of the muscle tension signal during the stretch maneuver (tension-time-index; TTI) was not different between control and P2X receptor blockade conditions in either sham (control: 20±2, PPADS: 21±2kg·s; P=0.31) or HF-rEF (control: 24±2, PPADS: 25±2kg·s; P=0.09) rats. The data suggest that P2X receptors on the sensory endings of thin fiber muscle afferents do not play a role in the cardiovascular responses to mechanoreflex activation in health, but contribute importantly to the cardiovascular responses to mechanoreflex activation in HF-rEF. This work was supported by the National Institutes of Health (NIH) R01HL142877 to S.W.C. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Follicle-innervating Aδ-low threshold mechanoreceptive neurons form receptive fields through homotypic competition

The mammalian somatosensory system is comprised of multiple neuronal populations that form specialized, highly organized sensory endings in the skin. The organization of somatosensory endings is essential to their functions, yet the mechanisms which regulate this organization remain unclear. Using a combination of genetic and molecular labeling approaches, we examined the development of mouse hair follicle-innervating low-threshold mechanoreceptors (LTMRs) and explored competition for innervation targets as a mechanism involved in the patterning of their receptive fields. We show that follicle innervating neurons are present in the skin at birth and that LTMR receptive fields gradually add follicle-innervating endings during the first two postnatal weeks. Using a constitutive Bax knockout to increase the number of neurons in adult animals, we show that two LTMR subtypes have differential responses to an increase in neuronal population size: Aδ-LTMR neurons shrink their receptive fields to accommodate the increased number of neurons innervating the skin, while C-LTMR neurons do not. Our findings suggest that competition for hair follicles to innervate plays a role in the patterning and organization of follicle-innervating LTMR neurons.

Intrafusal-fiber LRP4 for muscle spindle formation and maintenance in adult and aged animals

Proprioception is sensed by muscle spindles for precise locomotion and body posture. Unlike the neuromuscular junction (NMJ) for muscle contraction which has been well studied, mechanisms of spindle formation are not well understood. Here we show that sensory nerve terminals are disrupted by the mutation of Lrp4, a gene required for NMJ formation; inducible knockout of Lrp4 in adult mice impairs sensory synapses and movement coordination, suggesting that LRP4 is required for spindle formation and maintenance. LRP4 is critical to the expression of Egr3 during development; in adult mice, it interacts in trans with APP and APLP2 on sensory terminals. Finally, spindle sensory endings and function are impaired in aged mice, deficits that could be diminished by LRP4 expression. These observations uncovered LRP4 as an unexpected regulator of muscle spindle formation and maintenance in adult and aged animals and shed light on potential pathological mechanisms of abnormal muscle proprioception.

Gut touch: Molecules, cells, circuits, and purpose.

Most animals conduct the entire digestive process within the GI tract while keeping the luminal contents entirely outside the body, separated by the tightly sealed GI epithelium. Therefore, like the skin and oral cavity, the GI tract must sense the chemical and physical properties of luminal contents at this interface to perfect function. Specialized sensory enteroendocrine cells (EECs) in the GI epithelium interact intimately with luminal contents. Recently, we discovered an EEC subpopulation that expresses mechanically gated ion channel Piezo2 and is developmentally and functionally like the population of skin's touch sensors - the Merkel cells. Given these similarities, we hypothesized that the gut has intrinsic tactile sensitivity, which we call gut touch. The Piezo2+ EEC mechanotransduction mechanism involves voltage-gated calcium and sodium ion channels and intracellular calcium stores to amplify and prolong the cytoplasmic calcium elevation, which drives the release of signaling molecules such as serotonin. The released EEC signaling molecules activate multiple downstream intrinsic sensory endings that drive intrinsic reflex motility and secretion circuits. I will end by exploring the physiologic purpose of gut touch and how gut touch disruptions lead to human disease.

There and back again: 50 years of wandering through terra incognita fusorum.

This paper is in two parts: 'There', which is a review of some of the major advances in the study of spindle structure and function during the past 50 years, serving as an introduction to the symposium entitled 'Mechanotransduction, Muscle Spindles and Proprioception' held in Munich in July 2022; and 'And Back Again', presenting new quantitative morphological results on the equatorial nuclei of intrafusal muscle fibres and of the primary sensory ending in relationship to passive stretch of the spindle.