Search

Exercise intolerance and exertional dyspnoea are hallmarks of fibrosing interstitial lung disease (FILD) and are associated with worse prognosis and quality of life. Activation of pulmonary vagal afferents influences the ventilatory pattern and contributes to the sensation of dyspnoea. We tested the hypothesis that nebulized fentanyl, which might attenuate aberrant pulmonary afferent activity in FILD, reduces ventilation and dyspnoea while extending exercise endurance time (EET). In this randomized, single‐blind, placebo‐controlled study, eight FILD patients (two males, 71 ± 6 years of age) performed incremental cardiopulmonary cycle exercise tests following nebulization of either fentanyl citrate (100 µg) or 0.9% saline. Previous work indicated that this dose was unlikely to produce central effects. Comparisons between treatment conditions at rest were undertaken using Student's paired t‐test, and exercise data were evaluated with two‐way ANOVA with repeated measures. Dyspnoea was assessed using the Borg dyspnoea scale. Resting respiratory variables were not different following treatment with fentanyl and saline; however, resting heart rate was lower following fentanyl (P = 0.002) and remained lower throughout exercise compared with placebo (P = 0.008). Fentanyl did not increase EET (placebo 334 ± 117 s vs. fentanyl 348 ± 126 s, P = 0.250) although overall minute ventilation was reduced slightly (mean difference: −0.97 L/min, P = 0.022). There were no differences in ratings of dyspnoea intensity or unpleasantness between the conditions either at rest or at end‐exercise. Nebulized fentanyl did not improve EET or exercise dyspnoea but did decrease minute ventilation during exercise, although the extent of this reduction appears clinically insignificant. These findings suggest that nebulized fentanyl is unlikely to offer significant benefits for enhancing exercise capacity in FILD. [ABSTRACT FROM AUTHOR]

The article describes the results of studies on the impulse activity of various groups of afferent fibers and EMG patterns of lower leg antagonist muscles when walking without, during, and after transcutaneous electrical stimulation of the dorsal roots of the lower thoracic spinal cord of a person. Using a mathematical model based on the prediction of the triggering of muscle spindles, variability in the manifestation of impulse activity of various afferents of the tibialis anterior (TA) and gastrocnemius medialis (GM) muscle when walking under different experimental conditions is shown. It was found that walking on a movable treadmill tape in the absence of spinal cord stimulation was accompanied by strong impulse activity of afferents of I (Ia and Ib) and II groups of GM and increased excitability of its motorneuron pool and weakening of afferent activity and excitability of TA. On the contrary, electrical stimulation of the spinal cord during walking caused strong impulsive activity of group II of TA afferents and moderate in GM, while the activity of Ia fibers in TA and GM decreased to moderate impulsivity, Ib afferents of the same muscles had the weakest activity, and the excitability of the GM motor neuron pool was greater than TA. During the postactivation period, walking was accompanied by increased impulses of afferent fibers of group Ib and II of GM, weakening of afferent flows of Ib of TA and Ia afferents of GM, but along with this, afferent signals of group Ia and II to the motor neuron nucleus of TA decreased to moderate impulses, and excitability of the motor neuron pool of GM was higher than TA. The supposed reflex mechanisms of locomotion regulation are discussed on the basis of well-known phenomena associated with the interaction of various afferent inputs to the spinal cord neuronal apparatus in the system of lower leg antagonist muscles. [ABSTRACT FROM AUTHOR]

Background. Transarterial chemoembolization (TACE) with drug-eluting beads has been used in the treatment of tumors of the female reproductive system complicated by bleeding. However, questions arise: how to integrate the method into the treatment regimen and at what stage should it be applied?Aim. To evaluate the effectiveness of TACE in tumors of the female reproductive system complicated by bleeding at different stages of the disease.Materials and methods. A retrospective analysis of 80 women with primary (group 1) and 20 with recurrent tumors (group 2) of the reproductive system, who underwent 110 TACE with drug-eluting beads “Sphere-Spectrum” (100 primary, 10 repeated), is presented. Mostly used drug-eluting beads “Sphere-Spectrum”. The indication for TACE was tumor bleeding. For dynamic control, magnetic resonance imaging of the small pelvis was performed no later than 14 days before, 14–21 days and 1–3 months after TACE.Results. Hemostasis after TACE in all cases was achieved by the end of 1 day. There was no progression of the tumor process in any case. In group 1, 56 women (70 %) after TACE were operated on (stages 1B–2A), although according to preoperative magnetic resonance imaging staging, only 34 women (43 %) were subject to surgical treatment; 3 women underwent radiation therapy, 23 – chemoradiotherapy, systemic chemotherapy and immunotherapy in accordance with the stage of the disease. In group 2, 3 women were operated on after correction of their somatic condition and tumor reduction, 3 women underwent chemoradiotherapy, 14 women continued systemic chemotherapy.Conclusion. TACE has shown high efficiency as a hemostatic and antitumor therapy. It should be included in the treatment regimen for women with bleeding from tumors of the reproductive system at any stage of the disease, which allows expanding the available options for antitumor therapy for this category of patients; at the same time, the use of TACE as a monomethod requires further study.

There is clinical and physiological evidence that presynaptic inhibition and sensory afferent pathways have an effect on what is considered a primarily upper motor neurone problem. This could redefine spasticity and the need to refocus assessment and management of spasticity is proposed with an emphasis on functional assessment and treatments which modulate sensory afferent thresholds in order to improve the precision of skilled movements.

Recent studies using a novel method for targeted ablation of afferent renal nerves have demonstrated their importance in the development and maintenance of some animal models of hypertension. However, relatively little is known about the anatomy of renal afferent nerves distal to the renal pelvis. Here, we investigated the anatomical relationship between renal glomeruli and afferent axons identified based on transient receptor potential vanilloid 1 channel (TRPV1) lineage or calcitonin gene related peptide (CGRP) immunolabeling. Analysis of over 6,000 (10,000 was accurate prior to the removal of the TH data during the review process) glomeruli from wildtype C57BL/6J mice and transgenic mice expressing tdTomato in TRPV1 lineage cells indicated that approximately half of all glomeruli sampled were closely apposed to tdTomato+ or CGRP+ afferent axons. Glomeruli were categorized as superficial, midcortical, or juxtamedullary based on their depth within the cortex. Juxtamedullary glomeruli were more likely to be closely apposed by afferent axon subtypes than more superficial glomeruli. High-resolution imaging of thick, cleared renal slices and subsequent distance transformations revealed that CGRP+ axons closely apposed to glomeruli were often found within 2 microns of nephrin+ labeling of glomerular podocytes. Furthermore, imaging of thick slices suggested that CGRP+ axon bundles can closely appose multiple glomeruli that share the same interlobular artery. Based on their expression of CGRP or tdTomato, prevalence near glomeruli, proximity to glomerular structures, and close apposition to multiple glomeruli within a module, we hypothesize that periglomerular afferent axons may function as mechanoreceptors monitoring glomerular pressure. These anatomical findings highlight the importance of further studies investigating the physiological role of periglomerular afferent axons in neural control of renal function in health and disease. [ABSTRACT FROM AUTHOR]

Recent studies using a novel method for targeted ablation of afferent renal nerves have demonstrated their importance in the development and maintenance of some animal models of hypertension. However, relatively little is known about the anatomy of renal afferent nerves distal to the renal pelvis. Here, we investigated the anatomical relationship between renal glomeruli and afferent axons identified based on transient receptor potential vanilloid 1 channel (TRPV1) lineage or calcitonin gene related peptide (CGRP) immunolabeling. Analysis of over 6,000 (10,000 was accurate prior to the removal of the TH data during the review process) glomeruli from wildtype C57BL/6J mice and transgenic mice expressing tdTomato in TRPV1 lineage cells indicated that approximately half of all glomeruli sampled were closely apposed to tdTomato+ or CGRP+ afferent axons. Glomeruli were categorized as superficial, midcortical, or juxtamedullary based on their depth within the cortex. Juxtamedullary glomeruli were more likely to be closely apposed by afferent axon subtypes than more superficial glomeruli. High-resolution imaging of thick, cleared renal slices and subsequent distance transformations revealed that CGRP+ axons closely apposed to glomeruli were often found within 2 microns of nephrin+ labeling of glomerular podocytes. Furthermore, imaging of thick slices suggested that CGRP+ axon bundles can closely appose multiple glomeruli that share the same interlobular artery. Based on their expression of CGRP or tdTomato, prevalence near glomeruli, proximity to glomerular structures, and close apposition to multiple glomeruli within a module, we hypothesize that periglomerular afferent axons may function as mechanoreceptors monitoring glomerular pressure. These anatomical findings highlight the importance of further studies investigating the physiological role of periglomerular afferent axons in neural control of renal function in health and disease.

Background: Studies have examined the influence of postexercise blood flow restriction as a mechanism to activate muscle afferents and assess nonlocal muscle fatigue. Although these studies have assessed fatigue during maximal contractions, less is known about how these afferents may impact submaximal local muscle endurance, which was the purpose of the present study. Methods: Individuals completed two testing visits which involved completing a set of elbow flexion exercises to volitional failure on the nondominant followed by the dominant arm. During both trials, a pneumatic cuff was placed at the top of the nondominant arm before exercise. This cuff was inflated to either 0% (control) or 70% (experimental) of the individual's arterial occlusion pressure immediately after the set was completed. We then evaluated how this impacted local muscle endurance of the dominant arm using a Bayesian paired samples t‐test with an uninformed prior width of 0.707 centred on 0. Results: A total of 36 individuals completed the study (18 females). There was a greater discomfort present in the experimental trial when compared to the control trial (control: 4.5 standard deviation [SD]: 2.4); experimental: 5.8 [SD: 1.9]; BF10 = 61.46), but there were no differences in repetitions completed on the dominant arm (control: 43 [SD: 9], experimental: 43 [SD: 10]; BF10 = 0.179). Conclusion: Applying blood flow restriction postexercise induced sensations of discomfort but did not alter the local muscle endurance of the contralateral limb. These results suggest that increasing the activation of muscle afferents does not appear to alter the submaximal muscle endurance of a remote limb. [ABSTRACT FROM AUTHOR]

The effect of 20-minute transcutaneous electrical spinal cord stimulation (tESCS) on the severity of nonreciprocal and recurrent inhibition of spinal α-motoneurons in humans at rest and during a weak muscular effort was studied. It was found that during the entire time of exposure to tESCS at rest, the nonreciprocal and recurrent inhibition of the α-motoneurons of the synergist muscle (m. soleus) weakened, inverting to nonreciprocal and recurrent facilitation. Nonreciprocal facilitation of the soleus α-motorneurons was maintained throughout the entire after effect and recurrent facilitation was inverted to recurrent inhibition, which increased up to 20 min after the end of stimulation. The retention of a weak muscular effort during spinal cord stimulation was accompanied by an increase in nonreciprocal and recurrent inhibition of α-motoneurons of the synergist muscle. This post-activation effect lasted up to 20 min after electrical stimulation of the spinal cord. The activity of recurrent inhibition was more pronounced during spinal cord stimulation when performing a weak voluntary effort, and the post-activation effect was manifested by similar changes in the severity of recurrent and nonreciprocal inhibition: their enhancement occurred within 10 min and weakening at 20 min after the end of stimulation to background values. The reflex mechanisms of descending supraspinal and ascending peripheral influences on the functional activity of nonreciprocal and recurrent inhibition in the system of lower leg synergistic muscles in humans based on the effects of tESCS are discussed. [ABSTRACT FROM AUTHOR]

Irritable bowel syndrome (IBS) is a chronic gastrointestinal disorder characterized by abdominal pain and altered bowel habit that affects ~11% of the global population. Over the past decade, preclinical and clinical studies have revealed a variety of novel mechanisms relating to the visceral analgesic effects of guanylate cyclase-C (GC-C) agonists. Here we discuss the mechanisms by which GC-C agonists target the GC-C/cyclic guanosine-3′,5′-monophosphate (cGMP) pathway, resulting in visceral analgesia as well as clinically relevant relief of abdominal pain and other sensations in IBS patients. Due to the preponderance of evidence we focus on linaclotide, a 14-amino acid GC-C agonist with very low oral bioavailability that acts within the gut. Collectively, the weight of experimental and clinical evidence supports the concept that GC-C agonists act as peripherally acting visceral analgesics. Linaclotide and plecanatide are synthetic peptide agonists of guanylate cyclase-C (GC-C), a transmembrane receptor that is predominantly located on intestinal epithelial cells. These medications have very low oral bioavailability, which, when combined with the expression profile of GC-C, provides a mechanism of action 'targeted to the gut'. Linaclotide has been shown to inhibit colonic nociceptors and reduce peripheral drive from the colon, resulting in reduced numbers of activated dorsal horn neurons within the spinal cord and reduced pain responses to noxious colorectal distension. These effects are greatest in animal models of chronic visceral hypersensitivity that drive the 'bottom-up' and/or 'top-down' sensitization relevant to irritable bowel syndrome (IBS). Activation of GC-C results in the generation and release of cyclic guanosine-3′,5′-monophosphate (cGMP) from intestinal epithelial cells. When released into the submucosal space through the basolateral membrane, extracellular cGMP acts as a neuromodulator to inhibit pain-sensing nerve fibers innervating the colon. cGMP has also been demonstrated to inhibit pain-sensing nerves from human donors. In all human Phase III clinical studies conducted to date in patients with irritable bowel syndrome with constipation (IBS-C) or chronic idiopathic constipation (CIC), linaclotide significantly improved abdominal pain, discomfort, and bloating. Recent preclinical studies also provide the prospect that linaclotide may offer a novel therapeutic option, not only for the treatment of chronic abdominal pain in IBS-C, but also comorbid bladder dysfunction and endometriosis-associated pain. [ABSTRACT FROM AUTHOR]

Muscle spindles are sensory organs that detect and mediate both static and dynamic muscle stretch and monitor muscle position, through a specialised cell population, termed intrafusal fibres. It is these fibres that provide a key contribution to proprioception and muscle spindle dysfunction is associated with multiple neuromuscular diseases, aging and nerve injuries. To date, there are few publications focussed on de novo generation and characterisation of intrafusal muscle fibres in vitro. To this end, current models of skeletal muscle focus on extrafusal fibres and lack an appreciation for the afferent functions of the muscle spindle. The goal of this study was to produce and define intrafusal bag and chain myotubes from differentiated C2C12 myoblasts, utilising the addition of the developmentally associated protein, Neuregulin 1 (Nrg-1). Intrafusal bag myotubes have a fusiform shape and were assigned using statistical morphological parameters. The model was further validated using immunofluorescent microscopy and western blot analysis, directed against an extensive list of putative intrafusal specific markers, as identified in vivo. The addition of Nrg-1 treatment resulted in a 5-fold increase in intrafusal bag myotubes (as assessed by morphology) and increased protein and gene expression of the intrafusal specific transcription factor, Egr3. Surprisingly, Nrg-1 treated myotubes had significantly reduced gene and protein expression of many intrafusal specific markers and showed no specificity towards intrafusal bag morphology. Another novel finding highlights a proliferative effect for Nrg-1 during the serum starvation-initiated differentiation phase, leading to increased nuclei counts, paired with less myotube area per myonuclei. Therefore, despite no clear collective evidence for specific intrafusal development, Nrg-1 treated myotubes share two inherent characteristics of intrafusal fibres, which contain increased satellite cell numbers and smaller myonuclear domains compared with their extrafusal neighbours. This research represents a minimalistic, monocellular C2C12 model for progression towards de novo intrafusal skeletal muscle generation, with the most extensive characterisation to date. Integration of intrafusal myotubes, characteristic of native, in vivo intrafusal skeletal muscle into future biomimetic tissue engineered models could provide platforms for developmental or disease state studies, pre-clinical screening, or clinical applications.

Objectives The aim of this study was to investigate whether the restriction in neck rotation and increased neck muscle tension could be causally related to vertigo and dizziness. Material and Methods Seventy-one patients reporting vertigo and/or imbalance were divided into 2 groups: 45 subjects with unilateral restriction (R+) and 26 without restriction (R–) of cervical rotation and muscle tension in the clinical flexion-rotation test. The normal caloric test was the inclusion criterion. The control group comprised 36 healthy volunteers with no history of vertigo. The vestibulo-ocular reflex (VOR) and the cervico-occular reflex (COR) were measured through the videonystagmography (VNG) sinusoidal pendular kinetic test in the conditions of not inactivated head and immobilized head, respectively. The VNG-head torsion test (VNG-HTT) nystagmus was recorded. Results Among the reported complaints, neck stiffness, headaches and blurred vision were more frequent in the R+ group than in both the R– group and the control group. VNG revealed an increased COR gain and the presence of VNG-HTT nystagmus in the R+ group only. Similarly, only in the R+ group a positive relationship between COR and VOR was observed. Conclusions Patients with asymmetric restriction in neck rotation and increased neck muscle tension reveal the tendency to have an increased response of the vestibular system, along with co-existing COR upregulation. Further research is needed to investigate the relationships between the activation of cervical mechanoreceptors and dizziness pathomechanisms. Int J Occup Med Environ Health. 2019;32(5):723–33

The ability to sense visceral pain during appendicitis is diminished with age leading to delay in seeking health care and poorer clinical outcomes. To understand the mechanistic basis of this phenomenon, we examined visceral nociception in aged mouse and human tissue. Inflamed and noninflamed appendixes were collected from consenting patients undergoing surgery for the treatment of appendicitis or bowel cancer. Supernatants were generated by incubating samples in buffer and used to stimulate multiunit activity in intestinal preparations, or single-unit activity from teased fibres in colonic preparations, of young and old mice. Changes in afferent innervation with age were determined by measuring the density of calcitonin gene-related peptide-positive afferent fibres and by counting dorsal root ganglia back-labelled by injection of tracer dye into the wall of the colon. Finally, the effect of age on nociceptor function was studied in mouse and human colon. Afferent responses to appendicitis supernatants were greatly impaired in old mice. Further investigation revealed this was due to a marked reduction in the afferent innervation of the bowel and a substantial impairment in the ability of the remaining afferent fibres to transduce noxious stimuli. Translational studies in human tissue demonstrated a significant reduction in the multiunit but not the single-unit colonic mesenteric nerve response to capsaicin with age, indicative of a loss of nociceptor innervation. Our data demonstrate that anatomical and functional deficits in nociception occur with age, underpinning the atypical or silent presentation of appendicitis in the elderly. [ABSTRACT FROM AUTHOR]

Jingbo Zhao,1 Jian Yang,1 Donghua Liao,1 Hans Gregersen2 1Giome Academia, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; 2Giome Center, Department of Surgery, Chinese University of Hong Kong and Prince of Wales Hospital, Shatin, Hong Kong Background: Gastrointestinal disorders are very common in diabetic patients, but the pathogenesis is still not well understood. Peripheral afferent nerves may be involved due to the complex regulation of gastrointestinal function by the enteric nervous system. Objective: We aimed to characterize the stimulus–response function of afferent fibers innervating the jejunum in the Goto-Kakizaki (GK) type 2 diabetic rat model. A key question is whether changes in afferent firing arise from remodeled tissue or from adaptive afferent processes. Design: Seven 32-week-old male GK rats and seven age-matched normal Wistar rats were studied. Firing from mesenteric afferent nerves was recorded in excised jejunal segments of seven GK rats and seven normal Wistar rats during ramp test, stress relaxation test, and creep test. The circumferential stress–strain, spike rate increase ratio (SRIR), and single unit firing rates were calculated for evaluation of interdependency of the mechanical stimulations and the afferent nerve discharge. Results: Elevated sensitivity to mechanical stimuli was found for diabetic nerve bundles and single unit activity (P

The cerebellum is involved in some forms of motor coordination and learning, and in cognitive and emotional functions. To elucidate the functions of the cerebellum, it is important to unravel the detailed connections of the cerebellar neurons. Although the cerebellar neural circuit structure is generally conserved among vertebrates, it is not clear whether the cerebellum receives and processes the same or similar information in different vertebrate species. Here, we performed monosynaptic retrograde tracing with recombinant rabies viruses (RV) to identify the afferent connections of the zebrafish cerebellar neurons. We used a G-deleted RV that expressed GFP. The virus was also pseudotyped with EnvA, an envelope protein of avian sarcoma and leucosis virus (ALSV-A). For the specific infection of cerebellar neurons, we expressed the RV glycoprotein (G) gene and the envelope protein TVA, which is the receptor for EnvA, in Purkinje cells (PCs) or granule cells (GCs), using the promoter for aldolase Ca (aldoca) or cerebellin 12 (cbln12), respectively. When the virus infected PCs in the aldoca line, GFP was detected in the PCs’ presynaptic neurons, including GCs and neurons in the inferior olivary nuclei (IOs), which send climbing fibers (CFs). These observations validated the RV tracing method in zebrafish. When the virus infected GCs in the cbln12 line, GFP was again detected in their presynaptic neurons, including neurons in the pretectal nuclei, the nucleus lateralis valvulae (NLV), the central gray (CG), the medial octavolateralis nucleus (MON), and the descending octaval nucleus (DON). GFP was not observed in these neurons when the virus infected PCs in the aldoca line. These precerebellar neurons generally agree with those reported for other teleost species and are at least partly conserved with those in mammals. Our results demonstrate that the RV system can be used for connectome analyses in zebrafish, and provide fundamental information about the cerebellar neural circuits, which will be valuable for elucidating the functions of cerebellar neural circuits in zebrafish.

Objectives: The aim of this study was to investigate whether the restriction in neck rotation and increased neck muscle tension could be causally related to vertigo and dizziness.Material and Methods: Seventy-one patients reporting vertigo and/or imbalance were divided into 2 groups: 45 subjects with unilateral restriction (R+) and 26 without restriction (R-) of cervical rotation and muscle tension in the clinical flexion-rotation test. The normal caloric test was the inclusion criterion. The control group comprised 36 healthy volunteers with no history of vertigo. The vestibulo-ocular reflex (VOR) and the cervico-occular reflex (COR) were measured through the videonystagmography (VNG) sinusoidal pendular kinetic test in the conditions of not inactivated head and immobilized head, respectively. The VNG-head torsion test (VNG-HTT) nystagmus was recorded.Results: Among the reported complaints, neck stiffness, headaches and blurred vision were more frequent in the R+ group than in both the R- group and the control group. VNG revealed an increased COR gain and the presence of VNG-HTT nystagmus in the R+ group only. Similarly, only in the R+ group a positive relationship between COR and VOR was observed.Conclusions: Patients with asymmetric restriction in neck rotation and increased neck muscle tension reveal the tendency to have an increased response of the vestibular system, along with co-existing COR upregulation. Further research is needed to investigate the relationships between the activation of cervical mechanoreceptors and dizziness pathomechanisms. Int J Occup Med Environ Health. 2019;32(5):723-33. [ABSTRACT FROM AUTHOR]

The cerebellum is involved in some forms of motor coordination and learning, and in cognitive and emotional functions. To elucidate the functions of the cerebellum, it is important to unravel the detailed connections of the cerebellar neurons. Although the cerebellar neural circuit structure is generally conserved among vertebrates, it is not clear whether the cerebellum receives and processes the same or similar information in different vertebrate species. Here, we performed monosynaptic retrograde tracing with recombinant rabies viruses (RV) to identify the afferent connections of the zebrafish cerebellar neurons. We used a G-deleted RV that expressed GFP. The virus was also pseudotyped with EnvA, an envelope protein of avian sarcoma and leucosis virus (ALSV-A). For the specific infection of cerebellar neurons, we expressed the RV glycoprotein (G) gene and the envelope protein TVA, which is the receptor for EnvA, in Purkinje cells (PCs) or granule cells (GCs), using the promoter for aldolase Ca (aldoca) or cerebellin 12 (cbln12), respectively. When the virus infected PCs in the aldoca line, GFP was detected in the PCs' presynaptic neurons, including GCs and neurons in the inferior olivary nuclei (IOs), which send climbing fibers (CFs). These observations validated the RV tracing method in zebrafish. When the virus infected GCs in the cbln12 line, GFP was again detected in their presynaptic neurons, including neurons in the pretectal nuclei, the nucleus lateralis valvulae (NLV), the central gray (CG), the medial octavolateralis nucleus (MON), and the descending octaval nucleus (DON). GFP was not observed in these neurons when the virus infected PCs in the aldoca line. These precerebellar neurons generally agree with those reported for other teleost species and are at least partly conserved with those in mammals. Our results demonstrate that the RV system can be used for connectome analyses in zebrafish, and provide fundamental information about the cerebellar neural circuits, which will be valuable for elucidating the functions of cerebellar neural circuits in zebrafish. [ABSTRACT FROM AUTHOR]

Most of us live blissfully unaware of the orchestrated function that our internal organs conduct. When this peace is interrupted, it is often by routine sensations of hunger and urge. However, for >20% of the global population, chronic visceral pain is an unpleasant and often excruciating reminder of the existence of our internal organs. In many cases, there is no obvious underlying pathological cause of the pain. Accordingly, chronic visceral pain is debilitating, reduces the quality of life of sufferers, and has large concomitant socioeconomic costs. In this review, we highlight key mechanisms underlying chronic abdominal and pelvic pain associated with functional and inflammatory disorders of the gastrointestinal and urinary tracts. This includes how the colon and bladder are innervated by specialized subclasses of spinal afferents, how these afferents become sensitized in highly dynamic signaling environments, and the subsequent development of neuroplasticity within visceral pain pathways. We also highlight key contributing factors, including alterations in commensal bacteria, altered mucosal permeability, epithelial interactions with afferent nerves, alterations in immune or stress responses, and cross talk between these two adjacent organs. [ABSTRACT FROM AUTHOR]

Gravity has remained constant during animal evolution and the neural sensory systems detecting acceleration forces have remained remarkably conserved among vertebrates. The utricular organ senses the sum of inertial force due to head translation and head tilt relative to gravitational vertical. Change in gravitational force would be expected to have profound effects on how an organism maintains equilibrium. We characterize the physiology of utricular afferents to applied accelerations in the oyster toadfish, Opsanus tau, in normal 1 g to establish benchmarks, after 1–32-day exposures to 2.24 g (resultant) via centrifugation (hypergravity, HG), after 4- and 16-day exposures to 1.12 g (resultant), and following 1–8 days recovery to HG exposures to study re-adaptation to 1 g. Afferents were also examined during activation of efferent vestibular pathway. Centrifugation at 2.24 g included 228°/s constant angular velocity component, and thus horizontal canal afferent responses to yaw rotation were recorded as an internal control in each fish. Afferents studied after 228°/s rotation for 4 and 16 days without centripetal acceleration, called On-Center-Control, were indistinguishable from their control counterparts. Principal response to HG was an adjustment of afferent sensitivity as a function of magnitude and duration of exposure: an initial robust increase at 3–4 days followed by a significant decrease from 16 to 32 days. Initial increase observed after 4 days of HG took >4 days in 1 g to recover, and the decrease observed after 16 days of HG took >2 days to readapt to 1 g. Hair cells in striola and medial extrastriola macula regions were serially reconstructed in 3D from thin sections using transmission electron microscopy in control fish and fish exposed to 4 and 16 days of HG. Despite the highly significant differences in afferent physiology, synaptic body counts quantified in the same fish were equivalent in their inter-animal variability and averages. No clear role of the efferent pathway as a feedback mechanism regulating afferent behavior to HG was found. Transfer from 1 g to HG imparts profound effects on gravitational sensitivity of utricular afferents and the accompanying transfer from the HG back to the 1 g resembles in part (as an analog) the transfer from 1 g to the micrograms.

Gravity has remained constant during animal evolution and the neural sensory systems detecting acceleration forces have remained remarkably conserved among vertebrates. The utricular organ senses the sum of inertial force due to head translation and head tilt relative to gravitational vertical. Change in gravitational force would be expected to have profound effects on how an organism maintains equilibrium. We characterize the physiology of utricular afferents to applied accelerations in the oyster toadfish, Opsanus tau , in normal 1 g to establish benchmarks, after 1–32-day exposures to 2.24 g (resultant) via centrifugation (hypergravity, HG), after 4- and 16-day exposures to 1.12 g (resultant), and following 1–8 days recovery to HG exposures to study re-adaptation to 1 g. Afferents were also examined during activation of efferent vestibular pathway. Centrifugation at 2.24 g included 228°/s constant angular velocity component, and thus horizontal canal afferent responses to yaw rotation were recorded as an internal control in each fish. Afferents studied after 228°/s rotation for 4 and 16 days without centripetal acceleration, called On-Center-Control, were indistinguishable from their control counterparts. Principal response to HG was an adjustment of afferent sensitivity as a function of magnitude and duration of exposure: an initial robust increase at 3–4 days followed by a significant decrease from 16 to 32 days. Initial increase observed after 4 days of HG took >4 days in 1 g to recover, and the decrease observed after 16 days of HG took >2 days to readapt to 1 g. Hair cells in striola and medial extrastriola macula regions were serially reconstructed in 3D from thin sections using transmission electron microscopy in control fish and fish exposed to 4 and 16 days of HG. Despite the highly significant differences in afferent physiology, synaptic body counts quantified in the same fish were equivalent in their inter-animal variability and averages. No clear role of the efferent pathway as a feedback mechanism regulating afferent behavior to HG was found. Transfer from 1 g to HG imparts profound effects on gravitational sensitivity of utricular afferents and the accompanying transfer from the HG back to the 1 g resembles in part (as an analog) the transfer from 1 g to the micrograms. [ABSTRACT FROM AUTHOR]

Abstract Like several other arthropod species, stick insects use their antennae for tactile exploration of the near-range environment and for spatial localisation of touched objects. More specifically, Carausius morosus continuously moves its antennae during locomotion and reliably responds to antennal contact events with directed movements of a front leg. Here we investigate the afferent projection patterns of antennal hair fields (aHF), proprioceptors known to encode antennal posture and movement, and to be involved in antennal movement control. We show that afferents of all seven aHF of C. morosus have terminal arborisations in the dorsal lobe (DL) of the cerebral (=supraoesophageal) ganglion, and descending collaterals that terminate in a characteristic part of the gnathal (=suboesophageal) ganglion. Despite differences of functional roles among aHF, terminal arborisation patterns show no topological arrangement according to segment specificity or direction of movement. In the DL, antennal motoneuron neurites show arborizations in proximity to aHF afferent terminals. Despite the morphological similarity of single mechanoreceptors of aHF and adjacent tactile hairs on the pedicel and flagellum, we find a clear separation of proprioceptive and exteroceptive mechanosensory neuropils in the cerebral ganglion. Moreover, we also find this functional separation in the gnathal ganglion. Highlights • Afferents of all seven antennal hair fields of stick insects have similar projection patterns in the cerebral ganglion and gnathal ganglion. • Hair field projections show no clear topological arrangement. • Hair field afferents are in proximity to antennal motoneuron projections in the dorsal lobe. • Antennal proprioceptive and exteroceptive mechanosensory neuropils are functionally separated in the cerebral ganglion and gnathal ganglion. [ABSTRACT FROM AUTHOR]

Irritable bowel syndrome and inflammatory bowel disease are major forms of chronic visceral pain, which affect over 15% of the global population. In order to identify new therapies, it is important to understand the underlying causes of chronic visceral pain. This review provides recent evidence demonstrating that inflammation or infection of the gastrointestinal tract triggers specific changes in the neuronal excitability of sensory pathways responsible for the transmission of nociceptive information from the periphery to the central nervous system. Specific changes in the expression and function of a variety of ion channels and receptors have been documented in inflammatory and chronic visceral pain conditions relevant to irritable bowel syndrome and inflammatory bowel disease. An increase in pro-nociceptive mechanisms enhances peripheral drive from the viscera and provides an underlying basis for enhanced nociceptive signalling during chronic visceral pain states. Recent evidence also highlights increases in anti-nociceptive mechanisms in models of chronic visceral pain, which present novel targets for pharmacological treatment of this condition. [ABSTRACT FROM AUTHOR]

Background: Gastrointestinal disorders are very common in diabetic patients, but the pathogenesis is still not well understood. Peripheral afferent nerves may be involved due to the complex regulation of gastrointestinal function by the enteric nervous system. Objective: We aimed to characterize the stimulus-response function of afferent fibers innervating the jejunum in the Goto-Kakizaki (GK) type 2 diabetic rat model. A key question is whether changes in afferent firing arise from remodeled tissue or from adaptive afferent processes. Design: Seven 32-week-old male GK rats and seven age-matched normal Wistar rats were studied. Firing from mesenteric afferent nerves was recorded in excised jejunal segments of seven GK rats and seven normal Wistar rats during ramp test, stress relaxation test, and creep test. The circumferential stress-strain, spike rate increase ratio (SRIR), and single unit firing rates were calculated for evaluation of interdependency of the mechanical stimulations and the afferent nerve discharge. Results: Elevated sensitivity to mechanical stimuli was found for diabetic nerve bundles and single unit activity (P<0.05). The stress relaxed less in the diabetic intestinal segment (P<0.05). Linear association between SRIR and the thickness of circumferential muscle layer was found at high stress levels as well as for SRIR and the glucose level. Conclusion: Altered viscoelastic properties and elevated mechanosensitivity were found in the GK rat intestine. The altered nerve signaling is related to muscle layer remodeling and glucose levels and may contribute to gastrointestinal symptoms experienced by diabetic patients. [ABSTRACT FROM AUTHOR]

Key points Pairing motor cortex stimulation and spinal cord epidural stimulation produced large augmentation in motor cortex evoked potentials if they were timed to converge in the spinal cord., The modulation of cortical evoked potentials by spinal cord stimulation was largest when the spinal electrodes were placed over the dorsal root entry zone., Repeated pairing of motor cortex and spinal cord stimulation caused lasting increases in evoked potentials from both sites, but only if the time between the stimuli was optimal., Both immediate and lasting effects of paired stimulation are likely mediated by convergence of descending motor circuits and large diameter afferents onto common interneurons in the cervical spinal cord., Abstract Convergent activity in neural circuits can generate changes at their intersection. The rules of paired electrical stimulation are best understood for protocols that stimulate input circuits and their targets. We took a different approach by targeting the interaction of descending motor pathways and large diameter afferents in the spinal cord. We hypothesized that pairing stimulation of motor cortex and cervical spinal cord would strengthen motor responses through their convergence. We placed epidural electrodes over motor cortex and the dorsal cervical spinal cord in rats; motor evoked potentials (MEPs) were measured from biceps. MEPs evoked from motor cortex were robustly augmented with spinal epidural stimulation delivered at an intensity below the threshold for provoking an MEP. Augmentation was critically dependent on the timing and position of spinal stimulation. When the spinal stimulation was timed to coincide with the descending volley from motor cortex stimulation, MEPs were more than doubled. We then tested the effect of repeated pairing of motor cortex and spinal stimulation. Repetitive pairing caused strong augmentation of cortical MEPs and spinal excitability that lasted up to an hour after just 5 min of pairing. Additional physiology experiments support the hypothesis that paired stimulation is mediated by convergence of descending motor circuits and large diameter afferents in the spinal cord. The large effect size of this protocol and the conservation of the circuits being manipulated between rats and humans makes it worth pursuing for recovery of sensorimotor function after injury to the central nervous system. [ABSTRACT FROM AUTHOR]

Background One aspect of rehabilitation in swallowing disorders is to change liquid properties. The objective of our study was to test how liquid properties could improve oropharyngeal dysphagia and swallowing and ventilation coordination in an animal model. Methods Forty-two healthy male rats were distributed in six groups, including a control group. Rats were deprived of water for 24 h and then each group was administered liquid with different properties: tap water, sugar water, sparkling water, salt water, cold water, and acidic water. Rats were studied without and with oropharyngeal dysphagia achieved by unilateral section of the hypoglossal nerve. Swallowing and ventilation were analyzed by barometric plethysmograph. Key Results In healthy rats, swallowing occurred during expiratory time for all liquid properties. Most deglutitions were during expiratory time for all liquid properties (88±12%) and were not modified. There was an increase in VT/ TI during swallowing with sparkling water and cold water ( P<.05). In the operated groups, rats had significantly fewer swallows with tap water ( P<.05) and significantly more swallows with sparkling water ( P<.001), sugar water ( P<.001) and cold water ( P<.001) during expiratory time. The mean inspiratory volume ( VT/ TI) increased with sparkling water ( P<.05). Conclusion and Inferences Sparkling water seemed to improve swallowing and ventilation coordination in an animal model, to be confirmed in a study including patients with oropharyngeal dysphagia. [ABSTRACT FROM AUTHOR]

Optimization of gait rehabilitation using split-belt treadmills critically depends on our understanding of the roles of somatosensory perception and sensorimotor recalibration in perceiving gait asymmetry and adapting to split-belt walking. Recent evidence justifies the hypothesis that perception of gait asymmetry is based mainly on detection of temporal mismatches between afferent inputs at the spinal level. [ABSTRACT FROM AUTHOR]

The habenulae are bilateral nuclei located in the dorsal diencephalon that are conserved across vertebrates.Here we describe the main afferents to the habenulae in larval and adult zebrafish.We observe afferents from the subpallium, nucleus rostrolateralis,posterior tuberculum, posterior hypothalamic lobe, median raphe, olfactory bulb to the right habenula and from the parapineal to the lefthabenula.In addition,we find afferents from a ventrolateral telencephalic nucleus that neurochemical and hodological data identify as the ventral entopeduncular nucleus(vENT),confirming and extending observations of Amo et al.(2014).Fate map and marker studies suggest that vENT originates from the diencephalic prethalamic eminence and extends into the lateral telencephalon from 48 to 120 hpf.No afferents to the habenula were observed from the dorsal entopeduncular nucleus(dENT).Consequently,we confirm that the vENT(and not the dENT) should be considered as the entopeduncular nucleus proper in zebrafish.Furthermore,comparison with data in other vertebrates suggests that the vENT is a conserved basal ganglia nucleus,being homologous to the entopeduncular nucleus of mammals(internal segment of the globus pallidus of primates) by both embryonic origin and projections,as previously suggested by Amo et al.(2014).Key words: habenula,connections,afferents,entopeduncular nucleus,posterior tuberculum,basal ganglia,zebrafish

Many airway sensory units respond to both lung inflation and deflation. Whether those responses to opposite stimuli come from one sensor (one-sensor theory) or more than one sensor (multiple-sensor theory) is debatable. One-sensor theory is commonly presumed in the literature. This article proposes a multiple-sensor theory in which a sensory unit contains different sensors for sensing different forces. Two major types of mechanical sensors operate in the lung: inflation- and deflation-activated receptors (DARs). Inflation-activated sensors can be further divided into slowly adapting receptors (SARs) and rapidly adapting receptors (RARs). Many SAR and RAR units also respond to lung deflation because they contain DARs. Pure DARs, which respond to lung deflation only, are rare in large animals but are easily identified in small animals. Lung deflation-induced reflex effects previously attributed to RARs should be assigned to DARs (including pure DARs and DARs associated with SARs and RARs) if the multiple-sensor theory is accepted. Thus, based on the information, it is proposed that activation of DARs can attenuate lung deflation, shorten expiratory time, increase respiratory rate, evoke inspiration, and cause airway secretion and dyspnea. [ABSTRACT FROM AUTHOR]

The habenulae are bilateral nuclei located in the dorsal diencephalon that are conserved across vertebrates. Here we describe the main afferents to the habenulae in larval and adult zebrafish. We observe afferents from the subpallium, nucleus rostrolateralis, posterior tuberculum, posterior hypothalamic lobe, median raphe; we also see asymmetric afferents from olfactory bulb to the right habenula, and from the parapineal to the left habenula. In addition, we find afferents from a ventrolateral telencephalic nucleus that neurochemical and hodological data identify as the ventral entopeduncular nucleus (vENT), confirming and extending observations of Amo et al. (2014). Fate map and marker studies suggest that vENT originates from the diencephalic prethalamic eminence and extends into the lateral telencephalon from 48 to 120 hour post-fertilization (hpf). No afferents to the habenula were observed from the dorsal entopeduncular nucleus (dENT). Consequently, we confirm that the vENT (and not the dENT) should be considered as the entopeduncular nucleus "proper" in zebrafish. Furthermore, comparison with data in other vertebrates suggests that the vENT is a conserved basal ganglia nucleus, being homologous to the entopeduncular nucleus of mammals (internal segment of the globus pallidus of primates) by both embryonic origin and projections, as previously suggested by Amo et al. (2014). [ABSTRACT FROM AUTHOR]

The article discusses a study on the role of recurrent inhibition (RI) mediated by Renshaw cells in motor control. Topics include several research which examined the distribution of RI in motoneuron (MN) pools supplying various cats and human muscles, the multiple synaptic influences converging on MNs, and an illustration of the possible short-latency inhibition in the MN.

The lack of multi-scale empirical measurements (e.g. recording simultaneously from neurons, muscles, whole body, etc.) complicates understanding of sensorimotor function in humans. This is particularly true for the understanding of development during childhood, which requires evaluation of measurements over many years. We have developed a synthetic platform for emulating multi-scale activity of the vertebrate sensorimotor system. Our design benefits from Very Large Scale Integrated-circuit (VLSI) technology to provide considerable scalability and high-speed, as much as 365x faster than real-time. An essential component of our design is the proprioceptive sensor, or muscle spindle. Here we demonstrate an accurate and extremely fast emulation of a muscle spindle and its spiking afferents, which are computationally expensive but fundamental for reflex functions. We implemented a well-known rate-based model of the spindle (Mileusnic et al., 2006) and a simplified spiking sensory neuron model using the Izhikevich approximation to the Hodgkin-Huxley model. The resulting behavior of our afferent sensory system is qualitatively compatible with classic cat soleus recording (Matthews, 1964; 1972; Crowe and Matthews, 1964b). Our results suggest that this simplified structure of the spindle and afferent neuron is sufficient to produce physiologically-realistic behavior. The VLSI technology allows us to accelerate this behavior beyond 365x real-time. Our goal is to use this testbed for predicting years of disease progression with only a few days of emulation. This is the first hardware emulation of the spindle afferent system, and it may have application not only for emulation of human health and disease, but also for the construction of compliant neuromorphic robotic systems.

ABSTRACT The anatomical organization of the lateral prefrontal cortex (LPFC) afferents to the anterior part of the temporal lobe (ATL) remains to be clarified. The LPFC has two subdivisions, dorsal (dLPFC) and ventral (vLPFC), which have been linked to cognitive processes. The ATL includes several different cortical areas, namely, the temporal polar cortex and rostral parts of the perirhinal, inferotemporal, and anterior tip of the superior temporal gyrus cortices. Multiple sensory modalities converge in the ATL. All of them (except the rostral inferotemporal and superior temporal gyrus cortices) are components of the medial temporal lobe, which is critical for long-term memory processing. We studied the LPFC connections with the ATL by placing retrograde tracer injections into the ATL: the temporal polar ( n = 3), perirhinal (areas 35 and 36, n = 6), and inferotemporal cortices (area TE, n = 5), plus one additional deposit in the posterior parahippocampal cortex (area TF, n = 1). Anterograde tracer deposits into the dLPFC (A9 and A46, n = 2), the vLPFC (A46v, n = 2), and the orbitofrontal cortex (OF; n = 2) were placed for confirmation of those projections. The results showed that the vLPFC displays a moderate projection to rostral area TE and the dorsomedial portion of the temporal polar cortex; in contrast, the dLPFC connections with the ATL were weak. By comparison, the OFC and medial frontal cortices (MFC) showed dense connectivity with the ATL, namely, A13 with the temporopolar and perirhinal cortices. All areas of the MFC projected to the temporopolar cortex, albeit with a lower intensity. The functional significance of such paucity of LPFC afferents is unknown. J. Comp. Neurol. 523:2570-2598, 2015. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

The medical septal area (MSA) provides the major cholinergic projection to the hippocampus which is critical for function of the memory. Different brain areas through the MSA modulates septohippocampal functions. This study was designed to determin origins of inputs to this area. For this purpose, stereotaxic injections of one microliter HRP (25 percent, Sigma) by Hamilton syringe to the medical septal area were performed in 8 rats. Following brain tissue fixation, sectioning and enzyme histochemical reaction, the labeled neurons were detected microscopically. Retrogradely labeled perikarya observed ipsilaterally in diagonal band of Broca, lateral septum, hippocampus, subfornical area and ventral pallidum in the telencephalon, lateral preoptic area, lateral hipothalamicarea/tuber cinereum, posterior hypothalamus, submammillothalamic, supramammillary and lateral mammillary nuclei in the diencephalons, ventral tegmental area, interpeduncular nucleus, central grey area and locus coerruleus and also bilaterally in raphe nuclei of the brain stem regions. Based on this results, in addition to learning processes, MSA through its connections with subfornical and lateral hypothalamic area can also support the physiological mechanisms for dipsogenic, electrolytic, and pressor responses in living animals.

Age-related features of spinal inhibition were studied in males at relative muscle rest. Main developmental stages were identified for spinal inhibition, including the periods when the relevant processes grow weaker or more intense. Heterochrony was observed for the development of particular spinal inhibition types, i.e., their definitive developmental stages were achieved at different ages: 9-12 years of age for presynaptic inhibition of heteronymous I a afferents and reciprocal inhibition of homonymous α motoneurons, 17-18 years of age for recurrent inhibition of heteronymous α motoneurons, and 14-15 years of age for nonreciprocal inhibition of heteronymous and homonymous α motoneurons. Teenage age was identified as a critical period in the development of presynaptic inhibition of heteronymous and homonymous Ia afferents and recurrent inhibition of α motoneurons. The physiological mechanisms underlying the above age-related regularities are discussed. [ABSTRACT FROM AUTHOR]

Single i.m. doses of amitriptyline (10-30 mg/kg) induced a mild antidepressant effect in rats, decreasing immobility in the Porsolt test by factors of no more than 1.3-1.7. These doses of amitriptyline had significant sedative effects, as they decreased horizontal activity in the open field by factors of 3-6 and reduced vertical activity by factors of 2-2.5. Combined single i.m. administration of a low dose of amitriptyline (3 mg/kg) or a high dose of amitriptyline (30 mg/kg) combined with Mesaton (phenylephrine) at a threshold dose of 0.02 mg/kg (ineffective when given alone), induced a maximum antidepressant effect, decreasing immobility in the Porsolt test by factors of 3 and 4.6 respectively, but had no sedative side effect in the open field. The mechanism of potentiation of the antidepressant effect and elimination of the sedative effect of amitriptyline appears to be based on stimulation of gastric mucosal afferents by Mesaton. [ABSTRACT FROM AUTHOR]

Chronic oral sodium valproate given at high doses (100-200 mg/kg) suppressed the development of generalized clonic-tonic corasol (pentylenetetrazole) kindled convulsions in 100% of rats but prevented local clonic kindled convulsions in only 33-57%. At these doses, sodium valproate induced strong sedation. Combined chronic oral administration of Mesaton at the threshold dose of 0.2 mg/kg, inactive when give alone, and sodium valproate at the high doses of 100 and 200 mg/kg potentiated the anticonvulsant action of sodium valproate and prevented not only clonic-tonic kindled convulsions in 100% of rats, but also clonic kindled convulsions in 86-100% of rats, and also increased the anticonvulsant activity of valproate by factors of 1.7-1.9. These combinations of sodium valproate with Mesaton did not induce any sedative side effect. The mechanism of potentiation of the anticonvulsant effect and elimination of the sedative side effect of high-dose sodium valproate is based on stimulation of gastric mucosal afferents by Mesaton. [ABSTRACT FROM AUTHOR]

Background The complex pathophysiology of heart failure (HF) creates a challenging paradigm to differentiate the role of central and peripheral hemodynamic dysfunction during conventional exercise. Adopting a novel reductionist approach with potential clinical relevance, we studied the central and peripheral contributors to both continuous and single passive leg movement (PLM)-induced hyperemia in 14 HF patients with reduced ejection fraction (HFrEF) and 13 controls. Methods Heart rate (HR), stroke volume (SV), cardiac output (CO), mean arterial pressure (MAP), and femoral artery blood flow (FBF) were recorded during PLM. Results The FBF response (area under the curve; AUC) to 60 s of continuous PLM was attenuated in the HFrEF (25 ± 15 ml AUC) compared to controls (199 ± 34 ml AUC) as were peak changes from baseline for FBF, leg vascular conductance (LVC), CO, and HR. During single PLM, increases in CO and HR were smaller and no longer different between groups, supporting the use of this modality to assess groups with disparate central hemodynamics. Interestingly, single PLM-induced hyperemia, likely predominantly driven by flow-mediated vasodilation due to minimal vessel deformation, was essentially nonexistent in the HFrEF (- 9 ± 10 ml AUC) in contrast to the controls (43 ± 25 ml AUC). Conclusions These data fail to support a HFrEF-associated exaggeration in the mechanoreceptor driven component of the exercise pressor response. In fact, by exhibiting limited central hemodynamic responses compared to the controls, the observed attenuation in movement-induced FBF in HFrEF appears largely due to peripheral vascular dysfunction, particularly flow-mediated vasodilation. [ABSTRACT FROM AUTHOR]

High doses of phenylephrine and diazepam (1 and 10 mg/kg, respectively) suppressed the development of generalized tonic-clonic pentylenetetrazole-induced convulsions in 86-100% rats, but did not prevent local clonic pentylenetetrazole-induced convulsions. Diazepam in the specified dose produced strong sedation, while phenylephrine had no sedative effect in the open-field test. Combined intragastric administration of phenylephrine in a medium and individually ineffective dose (0.3 mg/kg) and diazepam in a high dose (10 mg/kg) potentiated the anticonvulsant effect of diazepam: it prevented not only tonic-clonic, but also clonic pentylenetetrazole-induced convulsions in 100% rats and 2.6-fold increased anticonvulsant activity of diazepam. The specified combination of diazepam and phenylephrine had no sedative effect. The mechanism of potentiation of the anticonvulsive effect and elimination of the sedative side effect is based on stimulation of gastric mucosa afferents by phenylephrine. [ABSTRACT FROM AUTHOR]

The lack of multi-scale empirical measurements (e.g., recording simultaneously from neurons, muscles, whole body, etc.) complicates understanding of sensorimotor function in humans. This is particularly true for the understanding of development during childhood, which requires evaluation of measurements over many years. We have developed a synthetic platform for emulating multi-scale activity of the vertebrate sensorimotor system. Our design benefits from Very Large Scale Integrated-circuit (VLSI) technology to provide considerable scalability and high-speed, as much as 365× faster than real-time. An essential component of our design is the proprioceptive sensor, or muscle spindle. Here we demonstrate an accurate and extremely fast emulation of a muscle spindle and its spiking afferents, which are computationally expensive but fundamental for reflex functions. We implemented a well-known rate-based model of the spindle (Mileusnic et al., 2006) and a simplified spiking sensory neuron model using the Izhikevich approximation to the Hodgkin–Huxley model. The resulting behavior of our afferent sensory system is qualitatively compatible with classic cat soleus recording (Crowe and Matthews, 1964b; Matthews, 1964, 1972). Our results suggest that this simplified structure of the spindle and afferent neuron is sufficient to produce physiologically-realistic behavior. The VLSI technology allows us to accelerate this behavior beyond 365× real-time. Our goal is to use this testbed for predicting years of disease progression with only a few days of emulation. This is the first hardware emulation of the spindle afferent system, and it may have application not only for emulation of human health and disease, but also for the construction of compliant neuromorphic robotic systems. [ABSTRACT FROM AUTHOR]

A harmonized interplay between the central nervous system and the five peripheral end organs is how the vestibular system helps organisms feel a sense of balance and motion in three-dimensional space. The receptor cells of this system, much like their cochlear equivalents, are the specialized hair cells. However, research over the years has shown that the vestibular end organs and hair cells evolved very differently from their cochlear counterparts. The structurally unique calyceal synapse, which appeared much later in the evolutionary time scale, and continues to intrigue researchers, is now known to support several forms of synaptic neurotransmission. The conventional quantal transmission is believed to employ the ribbon structures, which carry several tethered vesicles filled with neurotransmitters. However, the field of vestibular hair cell synaptic molecular anatomy is still at a nascent stage and needs further work. In this review, we will touch upon the basic structure and function of the peripheral vestibular system, with the focus on the various modes of neurotransmission at the type I vestibular hair cells. We will also shed light on the current knowledge about the molecular anatomy of the vestibular hair cell synapses and vestibular synaptopathy. • In the vestibular endorgans of amniotes, different types of hair cells and afferents form complex synaptic connections to support transmission of transient/sustained signals. • The calyceal synaptic terminal that enwraps type I hair cells supports quantal and nonquantal transmission. • The nonquantal transmission may be exceptionally fast, essentially driving some of the fastest reflexes in the body. • Such speed is likely enabled by the architecture of the calyceal synapse and the ion channel composition. This is adapted to support ultrafast signalling. • Evidence for quantal transmission in both types of vestibular hair cells has been obtained, however, the molecular (quantal) synaptic machinery remains relatively unknown. • Vestibular hair cell ribbons show adaptations upon changes in gravity and display vulnerability upon aging, the effects of which remain largely unexplored. [ABSTRACT FROM AUTHOR]