Vagal Afferent Signaling Research Articles

Multi-organ Coordination of Lipoprotein Secretion by Hormones, Nutrients and Neural Networks.

Plasma triglyceride-rich lipoproteins (TRL), particularly atherogenic remnant lipoproteins, contribute to atherosclerotic cardiovascular disease. Hypertriglyceridemia may arise in part from hypersecretion of TRLs by the liver and intestine. Here we focus on the complex network of hormonal, nutritional, and neuronal interorgan communication that regulates secretion of TRLs and provide our perspective on the relative importance of these factors. Hormones and peptides originating from the pancreas (insulin, glucagon), gut [glucagon-like peptide 1 (GLP-1) and 2 (GLP-2), ghrelin, cholecystokinin (CCK), peptide YY], adipose tissue (leptin, adiponectin) and brain (GLP-1) modulate TRL secretion by receptor-mediated responses and indirectly via neural networks. In addition, the gut microbiome and bile acids influence lipoprotein secretion in humans and animal models. Several nutritional factors modulate hepatic lipoprotein secretion through effects on the central nervous system. Vagal afferent signaling from the gut to the brain and efferent signals from the brain to the liver and gut are modulated by hormonal and nutritional factors to influence TRL secretion. Some of these factors have been extensively studied and shown to have robust regulatory effects whereas others are "emerging" regulators, whose significance remains to be determined. The quantitative importance of these factors relative to one another and relative to the key regulatory role of lipid availability remains largely unknown. Our understanding of the complex interorgan regulation of TRL secretion is rapidly evolving to appreciate the extensive hormonal, nutritional, and neural signals emanating not only from gut and liver but also from the brain, pancreas, and adipose tissue.

TRPM3 expression and control of glutamate release from primary vagal afferent neurons

Vagal afferent fibers contact neurons in the nucleus of the solitary tract (NTS) and release glutamate via three distinct release pathways: synchronous, asynchronous, and spontaneous. The presence of TRPV1 in vagal afferents is predictive of activity-dependent asynchronous glutamate release along with temperature-sensitive spontaneous vesicle fusion. However, pharmacological blockade or genetic deletion of TRPV1 does not eliminate the asynchronous profile and only attenuates the temperature-dependent spontaneous release at high temperatures (>40°C), indicating additional temperature-sensitive calcium conductance(s) contributing to these release pathways. The transient receptor potential cation channel melastatin subtype 3 (TRPM3) is a calcium-selective channel that functions as a thermosensor (30-37°C) in somatic primary afferent neurons. We predict that TRPM3 is expressed in vagal afferent neurons and contributes to asynchronous and spontaneous glutamate release pathways. We investigated these hypotheses via measurements on cultured nodose neurons and in brainstem slice preparations containing vagal afferent to NTS synaptic contacts. We found histological and genetic evidence that TRPM3 is highly expressed in vagal afferent neurons. The TRPM3-selective agonist, pregnenolone sulfate, rapidly and reversibly activated the majority (∼70%) of nodose neurons; most of which also contained TRPV1. We confirmed the role of TRPM3 with pharmacological blockade and genetic deletion. In the brain, TRPM3 signaling strongly controlled both basal and temperature-driven spontaneous glutamate release. Surprisingly, genetic deletion of TRPM3 did not alter synchronous or asynchronous glutamate release. These results provide convergent evidence that vagal afferents express functional TRPM3 that serves as an additional temperature-sensitive calcium conductance involved in controlling spontaneous glutamate release onto neurons in the NTS.NEW & NOTEWORTHY Vagal afferent signaling coordinates autonomic reflex function and informs associated behaviors. Thermosensitive transient receptor potential (TRP) channels detect temperature and nociceptive stimuli in somatosensory afferent neurons, however their role in vagal signaling remains less well understood. We report that the TRPM3 ion channel provides a major thermosensitive point of control over vagal signaling and synaptic transmission. We conclude that TRPM3 translates physiological changes in temperature to neurophysiological outputs and can serve as a cellular integrator in vagal afferent signaling.

Pregnancy-related plasticity of gastric vagal afferent signals in mice.

Gastric vagal afferents (GVAs) sense food-related mechanical stimuli and signal to the central nervous system, to integrate control of meal termination. Pregnancy is characterized by increased maternal food intake, which is essential for normal fetal growth and to maximize progeny survival and health. However, it is unknown whether GVA function is altered during pregnancy to promote food intake. This study aimed to determine the mechanosensitivity of GVAs and food intake during early, mid-, and late stages of pregnancy in mice. Pregnant mice consumed more food compared with nonpregnant mice, notably in the light phase during mid- and late pregnancy. The increased food intake was predominantly due to light-phase increases in meal size across all stages of pregnancy. The sensitivity of GVA tension receptors to gastric distension was significantly attenuated in mid- and late pregnancy, whereas the sensitivity of GVA mucosal receptors to mucosal stroking was unchanged during pregnancy. To determine whether pregnancy-associated hormonal changes drive these adaptations, the effects of estradiol, progesterone, prolactin, and growth hormone on GVA tension receptor mechanosensitivity were determined in nonpregnant female mice. The sensitivity of GVA tension receptors to gastric distension was augmented by estradiol, attenuated by growth hormone, and unaffected by progesterone or prolactin. Together, the data indicate that the sensitivity of GVA tension receptors to tension is reduced during pregnancy, which may attenuate the perception of gastric fullness and explain increased food intake. Further, these adaptations may be driven by increases in maternal circulating growth hormone levels during pregnancy.NEW & NOTEWORTHY This study provides first evidence that gastric vagal afferent signaling is attenuated during pregnancy and inversely associated with meal size. Growth hormone attenuated mechanosensitivity of gastric vagal afferents, adding support that increases in maternal growth hormone may mediate adaptations in gastric vagal afferent signaling during pregnancy. These findings have important implications for the peripheral control of food intake during pregnancy.

High fat diet induced obesity alters endocannabinoid and ghrelin mediated regulation of components of the endocannabinoid system in nodose ganglia

BackgroundGhrelin and anandamide (AEA) can regulate the sensitivity of gastric vagal afferents to stretch, an effect mediated via the transient receptor potential vanilloid 1 (TPRV1) channel. High fat diet (HFD)-induced obesity alters the modulatory effects of ghrelin and AEA on gastric vagal afferent sensitivity. This may be a result of altered gastric levels of these hormones and subsequent changes in the expression of their receptors. Therefore, the current study aimed to determine the effects of ghrelin and AEA on vagal afferent cell body mRNA content of cannabinoid 1 receptor (CB1), ghrelin receptor (GHSR), TRPV1, and the enzyme responsible for the breakdown of AEA, fatty acid amide hydrolase (FAAH). MethodsMice were fed a standard laboratory diet (SLD) or HFD for 12wks. Nodose ganglia were removed and cultured for 14 h in the absence or presence of ghrelin or methAEA (mAEA; stable analogue of AEA). Relative mRNA content of CB1, GHSR, TRPV1, and FAAH were measured. ResultsIn nodose cells from SLD-mice, mAEA increased TRPV1 and FAAH mRNA content, and decreased CB1 and GHSR mRNA content. Ghrelin decreased TRPV1, CB1, and GHSR mRNA content.In nodose cells from HFD-mice, mAEA had no effect on TRPV1 mRNA content, and increased CB1, GHSR, and FAAH mRNA content. Ghrelin decreased TRPV1 mRNA content and increased CB1 and GHSR mRNA content. ConclusionsAEA and ghrelin modulate receptors and breakdown enzymes involved in the mAEA-vagal afferent satiety signalling pathways. This was disrupted in HFD-mice, which may contribute to the altered vagal afferent signalling in obesity.

Modulatory effect of methanandamide on gastric vagal afferent satiety signals depends on nutritional status.

Gastric vagal afferent responses to tension are dampened in high fat diet-induced obesity. Endocannabinoids are known to dose-dependently inhibit and excite gastric vagal afferents but their effect on gastric vagal afferents in diet-induced obesity are unknown. In individual gastric vagal afferent neurons of diet-induced obese mice the co-expression of components of the endocannabinoid system, including CB1, GHSR, TRPV1 and FAAH, was increased compared with lean mice. In high fat diet-induced obese mice, methanandamide only inhibited gastric vagal afferent responses to tension, possibly due to the observed change in the balance of receptors, hormones and breakdown enzymes in this system. Collectively, these data suggest that endocannabinoid signalling, by gastric vagal afferents, is altered in diet-induced obesity which may impact satiety and gastrointestinal function. Gastric vagal afferents (GVAs) play a role in appetite regulation. The endocannabinoid anandamide (AEA) dose-dependently inhibits and excites tension-sensitive GVAs. However, it is also known that high fat diet (HFD) feeding alters GVA responses to stretch. The aim of this study was to determine the role of AEA in GVA signalling in lean and HFD-induced obese mice. Male C57BL/6 mice were fed (12weeks) a standard laboratory diet (SLD) or HFD. Protein and mRNA expression of components of the cannabinoid system was determined in individual GVA cell bodies and the gastric mucosa. An in vitro GVA preparation was used to assess the effect of methanandamide (mAEA) on tension-sensitive GVAs and the second messenger pathways involved. In individual GVA cell bodies, cannabinoid 1 (CB1) and ghrelin (GHSR) receptor mRNA was higher in HFD mice than SLD mice. Conversely, gastric mucosal AEA and ghrelin protein levels were lower in HFD mice than SLD mice. In SLD mice, mAEA exerted dose-dependent inhibitory and excitatory effects on tension-sensitive GVAs. Only an inhibitory effect of mAEA was observed in HFD mice. The excitatory effect of mAEA was dependent on CB1, transient receptor potential vanilloid 1 (TRPV1) and the protein kinase C. Conversely, the inhibitory effect was dependent on CB1, growth hormone secretagogue receptor, TRPV1 and the protein kinase A. Endocannabinoids, acting through CB1 and TRPV1, have a pivotal role in modulating GVA satiety signals depending on the second messenger pathway utilised. In HFD mice only an inhibitory effect was observed. These changes may contribute to the development and/or maintenance of obesity.

Sub‐diaphragmatic vagal nerve stimulation alleviates rodent hypertension associated with gut dysbiosis and reduced serotonergic vagal afferent signaling

IntroductionThe gut‐brain vagal axis, of which serotonin (5HT) is an important mediator, can be altered by the gut microbiota. Low vagal tone and autonomic imbalance is present in conditions marked by gut dysbiosis including in hypertension (HTN); however, the effect of gut dysbiosis on vagal sensory/afferent function in HTN is unknown. We hypothesized that HTN‐associated gut dysbiosis will decrease serotonergic vagal afferent signaling from the gut and cause autonomic imbalance leading to increased blood pressure (BP). Moreover, we propose that restoring the vagal gut‐brain axis by chronic vagal stimulation will alleviate HTN.MethodsFecal matter transplant (FMT) was performed from either the spontaneously hypertensive (SHR) or Wistar‐Kyoto rats (WKY) to control WKY. BP and autonomic variables were recorded using radiotelemetry. Colonic 5HT, expression of 5HT3a receptors (5HT3aR) along the vagal gut‐brain axis, and cardiovascular responses to systemic 5HT3aR agonist injection were determined in the FMT rats, WKY and SHR. In vivo Ca2+ imaging was performed in gCAMP‐labeled nodose ganglia (NG) neurons in response to 5HT3aR agonist in WKY and SHR. Lastly, SHR were implanted with cuff electrodes on the sub‐diaphragmatic ventral vagal trunk for chronic vagal stimulation (sVNS) while measuring BP and autonomic variables using radiotelemetry. Endpoint bacterial 16s sequencing determined the effects of sVNS on SHR gut dysbiosis.ResultsFMT from SHR but not WKY significantly increased BP (P<0.05 vs baseline) and resulted in autonomic imbalance (P<0.05 vs baseline) in control WKY. This was associated with reduced colonic 5HT levels (P<0.01 vs FMT from WKY), as well as reduced 5HT3aR gene expression in vagal sensory (NG) neurons (p<0.05 vs FMT from WKY) and the brainstem region receiving vagal sensory projections (P<0.01 vs FMT from WKY). Furthermore, NG neuronal firing in response to 5HT3aR agonist corresponded with a time‐locked reduction in the HR in WKY, but both 5HT3aR agonist‐induced NG firing rates and HR responses were significantly blunted in the SHR (P<0.05). In addition, 5HT3aR agonist‐dependent HR responses were also reduced in the WKY following FMT from SHR (P<0.05 vs FMT from WKY). Crucially, chronic sVNS alleviated SHR HTN over eight weeks (P<0.05 vs SHAM SHR), without reversing gut dysbiosis, suggesting that the observed BP effect may primarily be due to restoration of the vagal afferent gut‐brain signaling.ConclusionsHTN‐associated gut dysbiosis reduces serotonergic gut‐brain vagal signaling and increases BP. Restoring vagal afferent tone is effective in alleviating HTN in the SHR.

Galanin suppresses visceral afferent responses to noxious mechanical and inflammatory stimuli.

Galanin is a neuropeptide expressed by sensory neurones innervating the gastrointestinal (GI) tract. Galanin displays inhibitory effects on vagal afferent signaling within the upper GI tract, and the goal of this study was to determine the actions of galanin on colonic spinal afferent function. Specifically, we sought to evaluate the effect of galanin on lumbar splanchnic nerve (LSN) mechanosensitivity to noxious distending pressures and the development of hypersensitivity in the presence of inflammatory stimuli and colitis. Using ex vivo electrophysiological recordings we show that galanin produces a dose‐dependent suppression of colonic LSN responses to mechanical stimuli and prevents the development of hypersensitivity to acutely administered inflammatory mediators. Using galanin receptor (GalR) agonists, we show that GalR1 activation, but not GalR2/3 activation, suppresses mechanosensitivity. The effect of galanin on colonic afferent activity was not observed in tissue from mice with dextran sodium sulfate‐induced colitis. We conclude that galanin has a marked suppressive effect on colonic mechanosensitivity at noxious distending pressures and prevents the acute development of mechanical hypersensitivity to inflammatory mediators, an effect not seen in the inflamed colon. These actions highlight a potential role for galanin in the regulation of mechanical nociception in the bowel and the therapeutic potential of targeting galaninergic signaling to treat visceral hypersensitivity.

Relieving tension: effects of cannabinoids on vagal afferent sensitivity.

Endocannabinoids are produced within the gastrointestinal (GI) tract and modulate energy homeostasis and food intake, at least in part, via vagally-dependent actions. The recent paper by Christie etal., [Christie, etal. J Physiol, 2019] demonstrate, for the first time, that cannabinoids exert biphasic effects on the mechanosensitivity of tension-sensitive gastric vagal afferents. At higher concentrations, anandamide increased vagal afferent sensitivity in a CB1 and TRPV1 receptor dependent manner. At lower concentrations, however, anandamide decreased afferent mechanosensitivity; while this was also dependent upon CB1 and TRPV1 receptors, it also appeared dependent upon signaling via the potent orexigenic neurohormone, ghrelin. These results provide further evidence to support the remarkable degree of neuroplasticity within vagal afferent signaling, and suggest that untangling the complex interactions of cannabinoid effects on food intake and energy homeostasis will require careful physiological and pharmacological investigations. This article is protected by copyright. All rights reserved.

Optimal Criteria for the Selection of Probiotics, Based on their Mode of Action

Abstract The objective of this review was to discuss some of the criteria which influence the selection of microorganisms with probiotic properties based on their mode of action. The most common bacteria that belong to the “group” probiotics are the Lactobacillus and Bifidobacterium species/strains. Probiotics have benefits and effects by their mechanism of action in different axial locations such as: producing substances, influencing immune function and response, modification as well as maintenance of a healthy population of microorganisms in the intestinal environment. Probiotics have demonstrated significant potential as therapeutic options for a variety of diseases Potential peripheral pathways that link probiotic ingestion in the brain function are focused on the role of the vagal afferent nerve signalling and changes in the cerebral levels of neuromodulators. The application of probiotic microorganisms represents a way to effectively influence the composition of the intestinal microbiome and the immune system of the host, as well as they can be considered as a suitable alternative to influence a healthy quality of life.

Biphasic effects of methanandamide on murine gastric vagal afferent mechanosensitivity.

The fine control of food intake is important for the maintenance of a healthy metabolic state. Gastric vagal afferents (GVAs) are involved in the peripheral regulation of food intake via signalling the degree of distension of the stomach which ultimately leads to feelings of fullness and satiety. This study provides evidence that endocannabinoids such as anandamide are capable of regulating GVA sensitivity in a concentration-dependent biphasic manner. This biphasic effect is dependent upon interactions between the CB1, TRPV1 and GHSR receptors. These data have important implications for the peripheral control of food intake. Gastric vagal afferents (GVAs) signal to the hindbrain resulting in satiety. Endocannabinoids are endogenous ligands of cannabinoid 1 receptor (CB1) and transient receptor potential vanilloid-1 (TRPV1) channels. The endocannabinoid anandamide (AEA) is expressed in the stomach, and its receptor CB1 is expressed in ghrelin-positive gastric mucosal cells. Further, TRPV1, CB1 and growth hormone secretagogue receptor (ghrelin receptor, GHSR) are expressed in subpopulations of GVA neurons. This study aimed to determine the interaction between TRPV1, CB1, GHSR and endocannabinoids in the modulation of GVA signalling. An in vitro electrophysiology preparation was used to assess GVA mechanosensitivity in male C57BL/6 mice. Effects of methanandamide (mAEA; 1-100nm), on GVA responses to stretch were determined in the absence and presence of antagonists of CB1, TRPV1, GHSR, protein kinase-A (PKA), protein kinase-C (PKC) and G-protein subunits Gαi/o , or Gαq . Low doses (1-10nm) of mAEA reduced GVA responses to 3g stretch, whereas high doses (30-100nm) increased the response. The inhibitory and excitatory effects of mAEA (1-100nm) were reduced/lost in the presence of a CB1 and TRPV1 antagonist. PKA, Gαi/o or GHSR antagonists prevented the inhibitory effect of mAEA on GVA mechanosensitivity. Conversely, in the presence of a PKC or Gαq antagonist the excitatory effect of mAEA was reduced or lost, respectively. Activation of CB1, by mAEA, can activate or inhibit TRPV1 to increase or decrease GVA responses to stretch, depending on the pathway activated. These interactions could play an important role in the fine control of food intake.

Modulation of vagal afferent signalling by the amino acid metabolite sensor GPR35

Modulation of vagal afferent signalling by the amino acid metabolite sensor GPR35

Fatigue in Multiple Sclerosis is related to relapses, autonomic dysfunctions and introversion: A quasi-experimental study

BackgroundFatigue in Multiple Sclerosis (MS) might be partially due to inflammatory processes. If so, relapses should increase the fatigue level. MethodsTwo groups of MS patients participated in this study. One suffered from a relapse and was treated by Methylprednisolone. The other group experienced a deterioration of their neurological condition but no relapse and received neurological rehabilitation. We assessed fatigue before admission, at admission and after discharge (t1, t2, t3). Furthermore, autonomic dysfunctions, depressive mood, apathy and extraversion were assessed at admission. Changes in fatigue were analysed with ANCOVAs and fatigue levels were analysed with regression analyses using clinical data and scores for depressive mood, apathy, extraversion and autonomic dysfunctions. ResultsOnly patients suffering from a relapse showed a significant increment in fatigue from t1 to t2. Regression analyses revealed that autonomic dysfunctions and introversion best explained the fatigue level. ConclusionsThis study shows that a relapse is accompanied by an increase in MS-related fatigue. Moreover, autonomic dysfunctions and introversion, more than depression and apathy, play a major role in the explanation of MS-related fatigue. This finding represents additional evidence for the relationship between inflammation, vagal afferent signaling, autonomic dysfunctions, introversion and the feeling of MS-related fatigue.

Modulation of gastric vagal afferent satiety signalling by endocannabinoids

Modulation of gastric vagal afferent satiety signalling by endocannabinoids

175. Targeting the Gut-Brain Axis to Regulate Preference and Striatal Response to Fat

High fat diet (HFD) leads to disrupted striatal dopamine function and alterations in fat preference. One mechanism by which this occurs is depletion of gut lipid messengers, including oleoylethanolamine (OEA), which when replenished rescues dopamine response and increases preference for low fat emulsions via the generation of vagal afferent signals (Tellez et al., 2013). Using a supplement containing the OEA precurser N-oleyl-phosphatidylethanolamine and epigallocatechin-3-gallate (NOPE+EGCG), we tested whether this effect translates to humans and whether supplementation improves outcomes on a behavioral weight loss trial.

Abdominal vagal deafferentation alters affective behaviors in rats

BackgroundThere is growing evidence for a role of abnormal gut-brain signaling in disorders involving altered mood and affect, including depression. Studies using vagus nerve stimulation (VNS) suggest that the disruption of vagal afferent signaling may contribute to these abnormalities. To test this hypothesis, we used a rat model of subdiaphragmatic vagal deafferentation (SDA), the most complete and selective vagal deafferentation method existing to date, to study the consequences of complete disconnection of abdominal vagal afferents on affective behaviors. MethodsSDA- and Sham-operated male rats were subjected to several tests that are commonly used in preclinical rodent models to assess the presence of anhedonic behavior, namely the novel object-induced exploration test, the novelty-suppressed eating test, and the sucrose preference test. In addition, we compared SDA and Sham rats in a social interaction test and the forced swim test to assess sociability and behavioral despair, respectively. ResultsCompared to Sham controls, SDA rats consistently displayed signs of anhedonic behavior in all test settings used. SDA rats also showed increased immobility and reduced swimming in the forced swim test, whereas they did not differ from Sham controls with regards to social approach behavior. LimitationsThis study was conducted in male rats only. Hence, possible sex-specific effects of SDA on affective behaviors remained unexamined. ConclusionsOur findings demonstrate that hedonic behavior and behavioral despair are subject to visceral modulation through abdominal vagal afferents. These data are compatible with preclinical models and clinical trials showing beneficial effects of VNS on depression-like and affective behaviors.

Modeling experimental recordings of vagal afferent signaling of intestinal inflammation for neuromodulation

Objective. Artificial modulation of peripheral nerve signals (neuromodulation) by electrical stimulation is an innovation with potential to develop treatments that replace or supplement drugs. One function of the nervous system that can be exploited by neuromodulation is regulation of disease intensity. Optimal interfacing of devices with the nervous system requires suitable models of peripheral nerve systems so that closed-loop control can be utilized for therapeutic benefit. Approach. We use physiological data to model afferent signaling in the vagus nerve that carries information about inflammation in the small intestine to the brain. Main results. The vagal nerve signaling system is distributed and complex; however, we propose a class of reductive models using a state-space formalism that can be tuned in a patient-specific manner. Significance. These models provide excellent fits to a large range of nerve recording data but are computationally simple enough for feedback control in implantable neuromodulation devices.

The metabolic role of vagal afferent innervation.

The regulation of energy and glucose balance contributes to whole-body metabolic homeostasis, and such metabolic regulation is disrupted in obesity and diabetes. Metabolic homeostasis is orchestrated partly in response to nutrient and vagal-dependent gut-initiated functions. Specifically, the sensory and motor fibres of the vagus nerve transmit intestinal signals to the central nervous system and exert biological and physiological responses. In the past decade, the understanding of the regulation of vagal afferent signals and of the associated metabolic effect on whole-body energy and glucose balance has progressed. This Review highlights the contributions made to the understanding of the vagal afferent system and examines the integrative role of the vagal afferent in gastrointestinal regulation of appetite and glucose homeostasis. Investigating the integrative and metabolic role of vagal afferent signalling represents a potential strategy to discover novel therapeutic targets to restore energy and glucose balance in diabetes and obesity.

Involvement of TRPV1 Channels in Energy Homeostasis.

The ion channel TRPV1 is involved in a wide range of processes including nociception, thermosensation and, more recently discovered, energy homeostasis. Tightly controlling energy homeostasis is important to maintain a healthy body weight, or to aid in weight loss by expending more energy than energy intake. TRPV1 may be involved in energy homeostasis, both in the control of food intake and energy expenditure. In the periphery, it is possible that TRPV1 can impact on appetite through control of appetite hormone levels or via modulation of gastrointestinal vagal afferent signaling. Further, TRPV1 may increase energy expenditure via heat production. Dietary supplementation with TRPV1 agonists, such as capsaicin, has yielded conflicting results with some studies indicating a reduction in food intake and increase in energy expenditure, and other studies indicating the converse. Nonetheless, it is increasingly apparent that TRPV1 may be dysregulated in obesity and contributing to the development of this disease. The mechanisms behind this dysregulation are currently unknown but interactions with other systems, such as the endocannabinoid systems, could be altered and therefore play a role in this dysregulation. Further, TRPV1 channels appear to be involved in pancreatic insulin secretion. Therefore, given its plausible involvement in regulation of energy and glucose homeostasis and its dysregulation in obesity, TRPV1 may be a target for weight loss therapy and diabetes. However, further research is required too fully elucidate TRPV1s role in these processes. The review provides an overview of current knowledge in this field and potential areas for development.

Apelin modulates murine gastric vagal afferent mechanosensitivity.

Gastric vagal afferents play an important role in the peripheral control of food intake. Apelin, a central appetite regulating hormone, is also abundantly released from the stomach. Whether apelin modulates gastric vagal afferent signalling is unknown. We aimed to determine whether apelin modulates gastric vagal afferent signalling under different states of nutrition. Female C57BL/6 mice were fed either a standard laboratory diet (SLD) or a high fat diet (HFD) for 12 weeks. An in vitro gastric vagal afferent preparation was used to determine the effect of apelin on gastric vagal afferent mechanosensitivity in SLD mice, fed ad libitum or fasted overnight, and HFD mice. To determine the signalling pathway of apelin via gastric vagal afferents, we determined the expression of apelin receptor (APJ receptor) in the gastric mucosa, the whole nodose ganglion and in gastric vagal afferent neurons innervating the stomach using retrograde tracing and real-time quantitative reverse-transcription polymerase chain reaction (qRT-PCR). The location of apelin and APJ receptor within the gastric mucosa was determined by immunohistochemistry. Expression of apelin and APJ receptor mRNA in gastric mucosa was determined using qRT-PCR. Apelin inhibited the response of gastric mucosal vagal afferents to mucosal stroking in fasted SLD mice, but not in mice fed ad libitum a SLD or HFD. Apelin inhibited the response of gastric tension sensitive afferents to circular stretch in SLD mice fed ad libitum or fasted, an effect not observed in HFD mice. APJ receptor mRNA was detected in the gastric mucosa and whole nodose ganglion, but not specifically in gastric vagal afferents neurons. In the gastric mucosa, APJ receptor immunoreactive cells were co-localised or closely associated with apelin containing cells and co-localised with serotonin, gastrin, histamine and gastric intrinsic factor containing cells. In conclusion, apelin modulates gastric vagal afferent signalling in a nutritional status dependent manner. Further, apelin modulates gastric vagal afferents through an indirect pathway, possibly through the release of hormones/peptides from the gastric mucosa.

Development of an ex Vivo Method for Multi-unit Recording of Microbiota-Colonic-Neural Signaling in Real Time.

Background and Objectives: Bidirectional signaling between the gastrointestinal tract and the brain is vital for maintaining whole-body homeostasis. Moreover, emerging evidence implicates vagal afferent signaling in the modulation of host physiology by microbes, which are most abundant in the colon. This study aims to optimize and advance dissection and recording techniques to facilitate real-time recordings of afferent neural signals originating in the distal colon.New Protocol: This paper describes a dissection technique, which facilitates extracellular electrophysiological recordings from visceral pelvic, spinal and vagal afferent neurons in response to stimulation of the distal colon.Examples of Application: Focal application of 75 mM KCl to a section of distal colon with exposed submucosal or myenteric nerve cell bodies and sensory nerve endings evoked activity in the superior mesenteric plexus and the vagal nerve. Noradrenaline stimulated nerve activity in the superior mesenteric plexus, whereas application of carbachol stimulated vagal nerve activity. Exposure of an ex vivo section of distal colon with an intact colonic mucosa to peptidoglycan, but not lipopolysaccharide, evoked vagal nerve firing.Discussion: Previous studies have recorded vagal signaling evoked by bacteria in the small intestine. The technical advances of this dissection and recording technique facilitates recording of afferent nerve signals evoked in extrinsic sensory pathways by neuromodulatory reagents applied to the distal colon. Moreover, we have demonstrated vagal afferent activation evoked by bacterial products applied to the distal colonic mucosa. This protocol may contribute to our understanding of functional bowel disorders where gut-brain communication is dysfunctional, and facilitate real-time interrogation of microbiota-gut-brain signaling.