Afferent Innervation Research Articles

Choice-selective sequences dominate in cortical relative to thalamic inputs to NAc to support reinforcement learning.

SUMMARYHow are actions linked with subsequent outcomes to guide choices? The nucleus accumbens, which is implicated in this process, receives glutamatergic inputs from the prelimbic cortex and midline regions of the thalamus. However, little is known about whether and how representations differ across these input pathways. By comparing these inputs during a reinforcement learning task in mice, we discovered that prelimbic cortical inputs preferentially represent actions and choices, whereas midline thalamic inputs preferentially represent cues. Choice-selective activity in the prelimbic cortical inputs is organized in sequences that persist beyond the outcome. Through computational modeling, we demonstrate that these sequences can support the neural implementation of reinforcement-learning algorithms, in both a circuit model based on synaptic plasticity and one based on neural dynamics. Finally, we test and confirm a prediction of our circuit models by direct manipulation of nucleus accumbens input neurons.

Contributions of afferent and sympathetic renal nerves to cystogenesis and arterial pressure regulation in a preclinical model of autosomal recessive polycystic kidney disease.

Polycystic kidney disease (PKD) is the most common inheritable cause of kidney failure, and the underlying mechanisms remain incompletely uncovered. Renal nerves contribute to hypertension and chronic kidney disease-frequent complications of PKD. There is limited evidence that renal nerves may contribute to cardiorenal dysfunction in PKD and no investigations of the role of sympathetic versus afferent nerves in PKD. Afferent renal nerve activity (ARNA) is elevated in models of renal disease and fibrosis. However, it remains unknown if this is true in PKD. We tested the hypothesis that ARNA is elevated in a preclinical model of autosomal recessive PKD and that targeted renal nerve ablation would attenuate cystogenesis and cardiorenal dysfunction. We tested this by performing total renal denervation (T-RDNx) or afferent renal denervation (A-RDNx) denervation in 4-wk-old male and female PCK rats and then quantified renal and cardiovascular responses 6 wk following treatment. Cystogenesis was attenuated with A-RDNx and T-RDNx versus sham controls, highlighting a crucial role for renal afferent nerves in cystogenesis. In contrast, blood pressure was improved with T-RDNx but not A-RDNx. Importantly, treatments produced similar results in both males and females. Direct renal afferent nerve recordings revealed that ARNA was twofold greater in PCK rats versus noncystic controls and was directly correlated with cystic severity. To our knowledge, we are the first to demonstrate that PCK rats have greater ARNA than noncystic, age-matched controls. The findings of this study support a novel and crucial role for renal afferent innervation in cystogenesis in the PCK rat.NEW & NOTEWORTHY This is the first study to dissect the contributions of renal sympathetic and afferent innervation in the PCK rat, a preclinical model of autosomal recessive polycystic kidney disease. We demonstrated that resting afferent renal nerve activity is greater in the PCK rat than noncystic controls and that basal afferent renal nerve activity is directly correlated with the extent of renal cystogenesis.

Human Frontalis Muscle Innervation and Morphology.

Background:Due to its clinical importance and due to a suggestion regarding the afferent innervation, the microscopic appearance of the frontalis muscle was investigated.Methods:From seven human cadavers, serial sections of the frontalis muscle were studied using light microscopy. Immunhistochemistry was performed using antibodies against collagen XXII and neurofilament.Results:The macroscopic appearance of the muscle was in accordance with the literature. At both insertion sides, the muscle fiber endings expressed collagen XXII, a marker for myotendinous junctions, although no tendons were present at the origin side. Neuromuscular junctions were seen in the middle part of the muscle belly (insertion of the nerve fibers of the facialis nerve) and in the cranial part toward the galea aponeurotica (possible afferent fibers?).Conclusions:This study summarizes the microscopic appearance of the frontalis muscle. It is a first example that collagen XXII can be expressed even without tendon formation. It confirms the absence of corpuscular afferent neuronal structures within the muscle.

Orexin receptor type 2 agonism inhibits thermogenesis in brown adipose tissue by attenuating afferent innervation.

Orexin signaling has been associated with energy expenditure and brown adipose tissue (BAT) function. However, conflicting data exist in the field about how orexin signaling regulates BAT thermogenesis. In this study, we show that a specific orexin receptor type 2 (OX2R) agonist [Ala11, D-Leu15]-OxB (OB-Ala) inhibited intrascapular brown adipose tissue (iBAT) thermogenesis by reducing sympathetic output to iBAT. This effect is mediated by OX2Rs located on afferent nerve endings innervating iBAT instead of brown adipocyte itself. Microinjection of OB-Ala into iBAT inhibited iBAT thermogenesis in mice upon cold exposure and neuronal activity in the paraventricular nucleus. Findings suggest that OB-Ala could inhibit iBAT thermogenesis by attenuating sensory input thereby inhibiting the sympathetic-sensory iBAT feedback loop. Our study uncovers a novel primary action site of orexin in the regulation of energy balance.

Regional Targeting of Bladder and Urethra Afferents in the Lumbosacral Spinal Cord of Male and Female Rats: A Multiscale Analysis.

Sensorimotor circuits of the lumbosacral spinal cord are required for lower urinary tract (LUT) regulation as well as being engaged in pelvic pain states. To date, no molecular markers have been identified to enable specific visualization of LUT afferents, which are embedded within spinal cord segments that also subserve somatic functions. Moreover, previous studies have not fully investigated the patterning within or across spinal segments, compared afferent innervation of the bladder and urethra, or explored possible structural sex differences in these pathways. We have addressed these questions in adult Sprague Dawley rats, using intramural microinjection of the tract tracer, B subunit of cholera toxin (CTB). Afferent distribution was analyzed within individual sections and 3D reconstructions from sections across four spinal cord segments (L5-S2), and in cleared intact spinal cord viewed with light sheet microscopy. Simultaneous mapping of preganglionic neurons showed their location throughout S1 but restricted to the caudal half of L6. Afferents from both LUT regions extended from L5 to S2, even where preganglionic motor pathways were absent. In L6 and S1, most afferents were associated with the sacral preganglionic nucleus (SPN) and sacral dorsal commissural nucleus (SDCom), with very few in the superficial laminae of the dorsal horn. Spinal innervation patterns by bladder and urethra afferents were remarkably similar, likewise the patterning in male and female rats. In conclusion, microscale to macroscale mapping has identified distinct features of LUT afferent projections to the lumbosacral cord and provided a new anatomic approach for future studies on plasticity, injury responses, and modeling of these pathways.

Morphology and chemical characteristics of taste buds associated with P2X3-immunoreactive afferent nerve endings in the rat incisive papilla.

The present study investigated the cellular components and afferent innervations of taste buds in the rat incisive papilla by immunohistochemistry using confocal scanning laser microscopy. Taste buds containing guanine nucleotide-binding protein G(t), subunit α3 (GNAT3)-imunoreactive cells were densely distributed in the lateral wall of incisive papilla forming the opening of nasoincisor ducts. GNAT3-immunoreactive cells in the taste buds were slender in shape and the tips of apical processes gathered at one point at the surface of the epithelium. The number of taste buds was 56.8±4.5 in the incisive papilla. The incisive taste buds also contained ectonucleoside triphosphate diphosphohydrolase 2-immunoreactive cells and synaptotagmin-1-immunoreactive cells in addition to GNAT3-immunoreactive cells. Furthermore, GNAT3-immunoreactive cells were immunoreactive to taste transduction molecules such as phospholipase C, β2-subunit, and inositol 1,4,5-trisphosphate receptor, type 3. P2X3-immunoreactive subepithelial nerve fibers intruded into the taste buds and terminated with hederiform or calix-like nerve endings attached to GNAT3-immunoreactive cells and synaptosomal-associated protein, 25 kDa-immunoreactive cells. Some P2X3-immunoreactive endings were also weakly immunoreactive for P2X2. Furthermore, a retrograde tracing method using fast blue dye indicated that most of the P2X3-immunoreactive nerve endings originated from the geniculate ganglia (GG) of the facial nerve. These results suggest that incisive taste buds are morphologically and cellularly homologous to lingual taste buds and are innervated by P2X3-immunoreactive nerve endings derived from the GG. The incisive papilla may be the palatal taste papilla that transmits chemosensory information in the oral cavity to the GG via P2X3-immunoreactive afferent nerve endings.

Constitutive tumor necrosis factor (TNF)‐deficiency causes a reduction in spine density in mouse dentate granule cells accompanied by homeostatic adaptations of spine head size

The majority of excitatory synapses terminating on cortical neurons are found on dendritic spines. The geometry of spines, in particular the size of the spine head, tightly correlates with the strength of the excitatory synapse formed with the spine. Under conditions of synaptic plasticity, spine geometry may change, reflecting functional adaptations. Since the cytokine tumor necrosis factor (TNF) has been shown to influence synaptic transmission as well as Hebbian and homeostatic forms of synaptic plasticity, we speculated that TNF-deficiency may cause concomitant structural changes at the level of dendritic spines. To address this question, we analyzed spine density and spine head area of Alexa568-filled granule cells in the dentate gyrus of adult C57BL/6J and TNF-deficient (TNF-KO) mice. Tissue sections were double-stained for the actin-modulating and plasticity-related protein synaptopodin (SP), a molecular marker for strong and stable spines. Dendritic segments of TNF-deficient granule cells exhibited ∼20% fewer spines in the outer molecular layer of the dentate gyrus compared to controls, indicating a reduced afferent innervation. Of note, these segments also had larger spines containing larger SP-clusters. This pattern of changes is strikingly similar to the one seen after denervation-associated spine loss following experimental entorhinal denervation of granule cells: Denervated granule cells increase the SP-content and strength of their remaining spines to homeostatically compensate for those that were lost. Our data suggest a similar compensatory mechanism in TNF-deficient granule cells in response to a reduction in their afferent innervation.

Functional nitrergic innervation of smooth muscle structures in the mucosa of pig lower urinary tract.

Neurally released nitric oxide (NO) functions as an inhibitory neurotransmitter of urethral but not detrusor smooth muscles while relaxing bladder vasculature and muscularis mucosae (MM). Here, the distribution of nitrergic nerves was examined in the mucosa of pig lower urinary tract using immunohistochemistry, and their vasodilatory functions were studied by measuring arteriolar diameter changes. Properties of smooth muscle cells in the lamina propria (SMC-LP) of urethra and trigone were also investigated using florescence Ca2+ imaging. In the bladder mucosa, neuronal nitric oxide synthase (nNOS)-immunoreactive nitrergic fibres projected to suburothelial arterioles and venules. Perivascular nitrergic nerves were intermingled with but distinct from tyrosine hydroxylase (TH)-immunoreactive sympathetic or calcitonin gene-related peptide (CGRP)-immunoreactive afferent nerves. MM receive a nitrergic but not sympathetic or afferent innervation. In the mucosa of urethra and trigone, nitrergic nerves were in close apposition with sympathetic or afferent nerves around suburothelial vasculature but did not project to SMC-LP. In suburothelial arterioles of bladder and urethra, N ω-nitro-L-arginine (L-NA, 100μM), an NOS inhibitor, enhanced electrical field stimulation (EFS)-induced sympathetic vasoconstrictions, while tadalafil (10nM), a phosphodiesterase type 5 (PDE5) inhibitor, suppressed the vasoconstrictions. SMC-LP developed asynchronous spontaneous Ca2+ transients without responding to EFS. The spontaneous Ca2+ transients were enhanced by acetylcholine (1μM) and diminished by noradrenaline (1μM) but not SIN-1 (10μM), an NO donor. In the lower urinary tract mucosa, perivascular nitrergic nerves appear to counteract the sympathetic vasoconstriction to maintain the mucosal circulation. Bladder MM but not SMC-LP receive an inhibitory nitrergic innervation.

Mapping afferent and pelvic postganglionic neurons of the urethra from female rats: The L6 DRG is the major primary afferent supplier.

To map sensory and pelvic postganglionic neurons from three different regions of the female rat urethra. The neuronal tracer True Blue (TB) was injected into the pre-pelvic, pelvic, and clitoral regions of the urethra from female Wistar rats. Seven days after TB injection, TB+ cells from the dorsal root ganglia (DRGs) and the major pelvic ganglion (MPG) were examined. The number and morphometry of TB+ cells were determined. TB+ cells were mainly distributed in lumbar 1 (L1), lumbar 2 (L2), lumbar 6 (L6), and sacral 1 (S1) DRGs, and in the MPG. The mean number of sensory neurons was 1200 ± 143. TB injection in pre-pelvic and pelvic urethra labeled neurons in L1, L2, L6, and S1 DRGs. TB injection in clitoral urethra labeled neurons in L6 and S1 DRGs. L6 DRG contained >50% of the total urethral TB+ neurons, and ~80% of the clitoral region. The mean value of the total number of MPG TB+ neurons was 1217 ± 72. DRG and MPG neurons projecting to the urethra presented a somatotopic distribution. The results demonstrated that L6 DRG is the major supplier of afferent innervation to the urethra, and that the distal urethral region is exclusively innervated by lower lumbosacral DRGs. Considering that electrical stimulation of sensory pudendal nerve improves overactive bladder, and that most of the sensory neurons in the distal urethra are from L6 DRG, electrical stimulation of this ganglion may be an innovative and effective neuromodulation therapy for neurogenic urinary dysfunctions.

Regulation of Systemic Metabolism by Autonomic Nerve-Mediated Inter-Organ Networks

Autonomic nerves, including sympathetic nerves and parasympathetic nerves, innervate organs and modulate those function, thereby regulating systemic metabolism. Autonomic nerve bundles contain both afferent and efferent nerve fibers, and both fibers play important roles in regulating systemic metabolism for maintenance of homeostasis at the whole-body level. Furthermore, recently-obtained evidence unraveled the metabolic regulatory systems through autonomic nerve-mediated inter-organ networks. In these systems, afferent innervations of autonomic nerves transmit metabolic information from peripheral organs to the central nervous system (CNS), and the CNS regulates organ functions based on the transmitted metabolic information through efferent innervations of autonomic nerves. In this review, autonomic nerve-mediated inter-organ networks that are involved in systemic metabolism are introduced, especially focusing on the liver-brain-pancreatic β-cell inter-organ network.

Retroperitoneal adipose tissue denervation improves cardiometabolic and autonomic dysfunction in a high fat diet model

Sympathetic vasomotor overactivity is a major feature leading to the cardiovascular dysfunction related to obesity. Considering that the retroperitoneal white adipose tissue (rWAT) is an important fat visceral depot and receives intense sympathetic and afferent innervations, the present study aimed to evaluate the effects evoked by bilateral rWAT denervation in obese rats. Male Wistar rats were fed with HFD for 8 consecutive weeks and rWAT denervation was performed at the 6th week. Arterial pressure, splanchnic and renal sympathetic vasomotor nerve activities were assessed and inflammation and the components of the renin -angiotensin system were evaluated in different white adipose tissue depots. HFD animals presented higher serum levels of leptin and glucose, an increase in arterial pressure and splanchnic sympathetic nerve activity; rWAT denervation, normalized these parameters. Pro-inflammatory cytokines levels were significantly increased, as well as RAAS gene expression in WAT of HFD animals; rWAT denervation significantly attenuated these changes. In conclusion, HFD promotes vasomotor sympathetic overactivation and inflammation with repercussions on the cardiovascular system. In conclusion, the neural communication between WAT and the brain is fundamental to trigger sympathetic vasomotor activation and this pathway is a possible new therapeutic target to treat obesity-associated cardiovascular dysfunction.

Rehabilitation methods for patients with severe extragenital pathology after reconstructive plastic surgery for various types of urinary incontinence

In recent years, the frequency of operations for genital prolapse and urinary incontinence has been steadily increasing. Neurogenic disorders of urination can be the first manifestations of the disease of extragenital pathology. Neurogenic bladder is bladder dysfunction (lethargy or spasticity) caused by neurogenic damage. Any disease in which the afferent or efferent innervation of the bladder is damaged can lead to a neurogenic bladder.Purpose. To study the features of urinary disorders in women with severe extragenital diseases and to improve the methods of rehabilitation of patients after reconstructive plastic surgery for various types of urinary incontinence.Materials and methods. 153 patients aged 50-70 years (mean age 55.1 ± 6.3 years) and duration of postmenopause from 2 to 5 years (7.6 ± 4.1 years) were examined at the outpatient department of the of Moscow Regional Research Institute of Obstetrics and Gynecology, Russian Federation, who applied for various manifestations of urination disorders. All patients were offered the method of biofeedback in combination with electrical stimulation of the pelvic floor muscles as a treatment. When overactive detrusor therapy was detected, therapy was combined with medicamentous (solifenacin 5 mg [Vesicar] or myrobegron 50 mg [Betmiga] in the morning) in combination with estriol (cream or suppositories) 0.5 mg intravaginally 2 times a week. In the presence of symptoms of climacteric syndrome in the absence of contraindications, menopausal hormonal therapy was prescribed.Results. Subjectively, 150 (98.1 %) patients noted an improvement in their condition, 3 (1.9 %) patients did not notice the effect of treatment. The results showed a significant improvement in all OABSS and bladder diary scores, including frequency of urination during the day and at night, urgency and number of urge incontinence episodes, and urine volume. Analysis of the -hour pad test showed that the volume of urine lost, which averaged 16.5 g before treatment, was negative after treatment in patients who noted the effect. In 2 patients who did not notice the effect, no changes were found. Investigation of the intraurethral pressure profile in 23 (17.6 %) women before treatment revealed insufficiency of the internal sphincter of the urethra, leading to urinary incontinence during stress. After treatment, in 19 (82.6 %) patients, the insufficiency of the internal sphincter was not determined. In 3 (13.0 %) patients, intraurethral pressure remained in the range of 60 to 80 cm of water column and did not lead to urinary incontinence during stress. In 1 (4.3 %) patient, the insufficiency of the urethral closure persisted, which required repeated surgery.Conclusions. In patients with severe extragenital diseases against the background of vulvovaginal atrophy, an overactive bladder and a mixed form of urinary incontinence prevail. Extragenital pathology of various origins, especially concerning various parts of the central nervous system, obesity and diabetes significantly worsens the course of urination disorders in both conservative and surgical and combined treatment and requires additional treatment methods: pelvic floor muscle training, biofeedback therapy in combination with electrical stimulation of the pelvic floor muscles, local hormonal therapy, the use of M-anticholinergics, B-adrenomimetics.

Regulation of systemic metabolism by the autonomic nervous system consisting of afferent and efferent innervation.

Autonomic nerves, sympathetic and parasympathetic, innervate organs and modulate their functions. It has become evident that afferent and efferent signals of the autonomic nervous system play important roles in regulating systemic metabolism, thereby maintaining homeostasis at the whole-body level. Vagal afferent nerves receive signals, such as nutrients and hormones, from the peripheral organs/tissues including the gastrointestinal tract and adipose tissue then transmit these signals to the hypothalamus, thereby regulating feeding behavior. In addition to roles in controlling appetite, areas in the hypothalamus serve as regulatory centers of both sympathetic and parasympathetic efferent fibers. These efferent innervations regulate the functions of peripheral organs/tissues, such as pancreatic islets, adipose tissues and the liver, which play roles in metabolic regulation. Furthermore, recent evidence has unraveled the metabolic regulatory systems governed by autonomic nerve circuits. In these systems, afferent nerves transmit metabolic information from peripheral organs to the central nervous system (CNS) and the CNS thereby regulates the organ functions through the efferent fibers of autonomic nerves. Thus, the autonomic nervous system regulates the homeostasis of systemic metabolism, and both afferent and efferent fibers play critical roles in its regulation. In addition, several lines of evidence demonstrate the roles of the autonomic nervous system in regulating and dysregulating the immune system. This review introduces variety of neuron-mediated inter-organ cross-talk systems and organizes the current knowledge of autonomic control/coordination of systemic metabolism, focusing especially on a liver-brain-pancreatic β-cell autonomic nerve circuit, as well as highlighting the potential importance of connections with the neuronal and immune systems.

Esophageal afferent innervation and its role in gastro-esophageal reflux disease symptoms

Despite the wide prevalence of gastro-esophageal reflux disease (GERD), the neurophysiological mechanisms underlying heartburn perception in the esophagus of patients with GERD remains incompletely understood. Recent studies have highlighted the potential influence sensory afferent nerves innervating the oesophageal epithelium may have on heartburn pathogenesis. The purpose of this review is to consider the current understanding of esophageal afferent neuronal innervation, including the nociceptive role of acid-sensing receptors expressed on these sensory nerves, in relation to pain perception in the esophagus of GERD patients. Central and peripheral pathways of sensitization following noxious stimulation of nociceptive receptors expressed on afferent nerves can regulate the strength of sensory nerve activation in the esophagus, which can result in the amplification or suppression of afferent signal transmission. The localization and characterization of mucosal sensory afferent nerves vary between GERD phenotypes and may explain the heterogeneity of symptom perception in patients with apparently similar levels of reflux. In this review, we discuss the relevance of afferent esophageal innervation in heartburn perception, with a particular focus on the pathways of reflux-induced activation of nociceptive nerves.

Selective Denervation of the Facial Dermato-Muscular Complex in the Rat: Experimental Model and Anatomical Basis.

The facial dermato-muscular system consists of highly specialized muscles tightly adhering to the overlaying skin and thus form a complex morphological conglomerate. This is the anatomical and functional basis for versatile facial expressions, which are essential for human social interaction. The neural innervation of the facial skin and muscles occurs via branches of the trigeminal and facial nerves. These are also the most commonly pathologically affected cranial nerves, often requiring surgical treatment. Hence, experimental models for researching these nerves and their pathologies are highly relevant to study pathophysiology and nerve regeneration. Experimental models for the distinctive investigation of the complex afferent and efferent interplay within facial structures are scarce. In this study, we established a robust surgical model for distinctive exploration of facial structures after complete elimination of afferent or efferent innervation in the rat. Animals were allocated into two groups according to the surgical procedure. In the first group, the facial nerve and in the second all distal cutaneous branches of the trigeminal nerve were transected unilaterally. All animals survived and no higher burden was caused by the procedures. Whisker pad movements were documented with video recordings 4 weeks after surgery and showed successful denervation. Whole-mount immunofluorescent staining of facial muscles was performed to visualize the innervation pattern of the neuromuscular junctions. Comprehensive quantitative analysis revealed large differences in afferent axon counts in the cutaneous branches of the trigeminal nerve. Axon number was the highest in the infraorbital nerve (28,625 ± 2,519), followed by the supraorbital nerve (2,131 ± 413), the mental nerve (3,062 ± 341), and the cutaneous branch of the mylohyoid nerve (343 ± 78). Overall, this surgical model is robust and reliable for distinctive surgical deafferentation or deefferentation of the face. It may be used for investigating cortical plasticity, the neurobiological mechanisms behind various clinically relevant conditions like facial paralysis or trigeminal neuralgia as well as local anesthesia in the face and oral cavity.

Relevance of differential control of sympathorespiratory response magnitudes in clinical assessments.

Relevance of differential control of sympathorespiratory response magnitudes in clinical assessments.

Heartburn sensation in nonerosive reflux disease: pattern of superficial sensory nerves expressing TRPV1 and epithelial cells expressing ASIC3 receptors.

The underlying causes of heartburn, characteristic symptom of gastroesophageal reflux disease (GERD), remain incompletely understood. Superficial afferent innervation of the esophageal mucosa in nonerosive reflux disease (NERD) may drive nociceptive reflux perception, but its acid-sensing role has not yet been established. Transient receptor potential vanilloid subfamily member-1 (TRPV1), transient receptor potential melastatin 8 (TRPM8), and acid-sensing ion channel 3 (ASIC3) are regulators of sensory nerve activity and could be important reflux-sensing receptors within the esophageal mucosa. We characterized TRPV1, TRPM8, and ASIC3 expression in esophageal mucosa of patients with GERD. We studied 10 patients with NERD, 10 with erosive reflux disease (ERD), 7 with functional heartburn (FH), and 8 with Barrett's esophagus (BE). Biopsies obtained from the distal esophageal mucosa were costained with TRPV1, TRPM8, or ASIC3, and CGRP, CD45, or E-cadherin. RNA expression of TRPV1, TRPM8, and ASIC3 was assessed using qPCR. Patients with NERD had significantly increased expression of TRPV1 on superficial sensory nerves compared with ERD (P = 0.028) or BE (P = 0.017). Deep intrapapillary nerve endings did not express TRPV1 in all phenotypes studied. ASIC3 was exclusively expressed on epithelial cells most significantly in patients with NERD and ERD (P ≤0.0001). TRPM8 was expressed on submucosal CD45+ leukocytes. Superficial localization of TRPV1-immunoreactive nerves in NERD, and increased ASIC3 coexpression on epithelial cells in NERD and ERD, suggests a mechanism for heartburn sensation. Esophageal epithelial cells may play a sensory role in acid reflux perception and act interdependently with TRPV1-expressing mucosal nerves to augment hypersensitivity in patients with NERD, raising the enticing possibility of topical antagonists for these ion channels as a therapeutic option.NEW & NOTEWORTHY We demonstrate for the first time that increased pain perception in patients with nonerosive reflux disease likely results from expression of acid-sensitive channels on superficial mucosal afferents and esophageal epithelial cells, raising the potential for topical therapy.

NRG/ErbB signaling regulates neonatal muscle growth but not neuromuscular contractures in neonatal brachial plexus injury.

Neonatal brachial plexus injury (NBPI) causes disabling and incurable muscle contractures that are driven by impaired growth of denervated muscles. A rare form of NBPI, which maintains afferent muscle innervation despite motor denervation, does not cause contractures. As afferent innervation regulates various aspects of skeletal muscle homeostasis through NRG/ErbB signaling, our current study investigated the role of this pathway in modulating contracture development. Through pharmacologic modification with an ErbB antagonist and NRG1 isoforms, we discovered that NRG/ErbB signaling does not modulate the development of contractures in neonatal mice. Instead, ErbB inhibition impeded growth in nondenervated skeletal muscles, whereas increased ErbB activation exacerbated denervation‐induced skeletal muscle atrophy. This potential regulatory effect of NRG/ErbB signaling on neonatal muscle growth warrants deeper investigation.

Electron Microscopic Reconstruction of Neural Circuitry in the Cochlea

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.

Structure of the pecten neuropil pathway and its innervation by bimodal peg afferents in two scorpion species.

The pectines of scorpions are comb-like structures, located ventrally behind the fourth walking legs and consisting of variable numbers of teeth, or pegs, which contain thousands of bimodal peg sensillae. The associated neuropils are situated ventrally in the synganglion, extending between the second and fourth walking leg neuromeres. While the general morphology is consistent among scorpions, taxon-specific differences in pecten and neuropil structure remain elusive but are crucial for a better understanding of chemosensory processing. We analysed two scorpion species (Mesobuthus eupeus and Heterometrus petersii) regarding their pecten neuropil anatomy and the respective peg afferent innervation with anterograde and lipophilic tracing experiments, combined with immunohistochemistry and confocal laser-scanning microscopy. The pecten neuropils consisted of three subcompartments: a posterior pecten neuropil, an anterior pecten neuropil and a hitherto unknown accessory pecten neuropil. These subregions exhibited taxon-specific variations with regard to compartmentalisation and structure. Most notable were structural differences in the anterior pecten neuropils that ranged from ovoid shape and strong fragmentation in Heterometrus petersii to elongated shape with little compartmentalisation in Mesobuthus eupeus. Labelling the afferents of distinct pegs revealed a topographic organisation of the bimodal projections along a medio-lateral axis. At the same time, all subregions along the posterior-anterior axis were innervated by a single peg’s afferents. The somatotopic projection pattern of bimodal sensillae appears to be common among arachnids, including scorpions. This includes the structure and organisation of the respective neuropils and the somatotopic projection patterns of chemosensory afferents. Nonetheless, the scorpion pecten pathway exhibits unique features, e.g. glomerular compartmentalisation superimposed on somatotopy, that are assumed to allow high resolution of substrate-borne chemical gradients.