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Chronic wasting disease (CWD) is a transmissible and fatal prion disease that affects cervids. While both oral and nasal routes of exposure to prions cause disease, the spatial and temporal details of how prions enter the central nervous system (CNS) are unknown. Carotid bodies (CBs) are structures that are exposed to blood-borne prions and are densely innervated by nerves that are directly connected to brainstem nuclei, known to be early sites of prion neuroinvasion. All CBs examined contained mast cells expressing the prion protein which is consistent with these cells playing a role in neuroinvasion following prionemia.

Some recent publications have used the term "vagal–adrenal axis" to account for mechanisms involved in the regulation of inflammation by electroacupuncture. This concept proposes that efferent parasympathetic nerve fibers in the vagus directly innervate the adrenal glands to influence catecholamine secretion. Here, we discuss evidence for anatomical and functional links between the vagi and adrenal glands that may be relevant in the context of inflammation and its neural control by factors, including acupuncture. First, we find that evidence for any direct vagal parasympathetic efferent innervation of the adrenal glands is weak and likely artifactual. Second, we find good evidence that vagal afferent fibers directly innervate the adrenal gland, although their function is uncertain. Third, we highlight a wealth of evidence for indirect pathways, whereby vagal afferent signals act via the central nervous system to modify adrenal‐dependent anti‐inflammatory responses. Vagal afferents, not efferents, are thus the likely key to these phenomena. [ABSTRACT FROM AUTHOR]

Sensory neurons cooperate with barrier tissues and resident immune cells to form a significant aspect of defensive strategies in concert with the immune system. This assembly of neuroimmune cellular units is exemplified across evolution from early metazoans to mammalian life. As such, sensory neurons possess the capability to detect pathogenic infiltrates at barrier surfaces. This capacity relies on mechanisms that unleash specific cell signaling, trafficking and defensive reflexes. These pathways exploit mechanisms to amplify and enhance the alerting response should pathogenic infiltration seep into other tissue compartments and/or systemic circulation. Here we explore two hypotheses: 1) that sensory neurons' potential cellular signaling pathways require the interaction of pathogen recognition receptors and ion channels specific to sensory neurons and; 2) mechanisms which amplify these sensing pathways require activation of multiple sensory neuron sites. Where possible, we provide references to other apt reviews which provide the reader more detail on specific aspects of the perspectives provided here.

Maintaining blood glucose at an appropriate physiological level requires precise coordination of multiple organs and tissues. The vagus nerve bidirectionally connects the central nervous system with peripheral organs crucial to glucose mobilization, nutrient storage, and food absorption, thereby presenting a key pathway for the central control of blood glucose levels. However, the precise mechanisms by which vagal populations that target discrete tissues participate in glucoregulation are much less clear. Here we review recent advances unraveling the cellular identity, neuroanatomical organization, and functional contributions of both vagal efferents and vagal afferents in the control of systemic glucose metabolism. We focus on their involvement in relaying glucoregulatory cues from the brain to peripheral tissues, particularly the pancreatic islet, and by sensing and transmitting incoming signals from ingested food to the brain. These recent findings - largely driven by advances in viral approaches, RNA sequencing, and cell-type selective manipulations and tracings - have begun to clarify the precise vagal neuron populations involved in the central coordination of glucose levels, and raise interesting new possibilities for the treatment of glucose metabolism disorders such as diabetes. [ABSTRACT FROM AUTHOR]

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Purpose: Although recent literature provides increasing evidence concerning urinary bladder innervation by vagal afferents, the functional aspects and the conditions at which these afferents are recruited are still unclear. Methods: In the present study, the neuronal responses of nodose ganglion following cystometry, under different models of rat's urinary bladder irritation, cyclophosphamide (CYP), cyclophosphamide with cervical vagotomy (Vx), chronic HCl, and acute HCl, were investigated using c-fos immunohistochemistry. Results: The c-fos expression in the nodose ganglion, following cystometry, was increased significantly in the CYP and chronic-HCl groups compared to the intact, Vx, and acute-HCl groups. In addition, the acute-HCl group showed a significant increase compared to intact animals. Following cervical vagotomy, the expression in the Vx group decreased significantly compared to the CYP group, but was significantly higher than that in the intact group. Conclusion: The results of this study demonstrate the innervation of the vagus afferents to the urinary bladder. This innervation is activated under urinary bladder irritation conditions, which may indicate a possible role of the vagus nerve during urinary bladder pathology. [ABSTRACT FROM AUTHOR]

Cisplatin is a platinum-based chemotherapeutic agent widely used to treat various cancers. However, several side effects have been reported in treated patients. Among these, acute anorexia is one of the most severe secondary effects. In this study, a single oral administration of 100 or 500 mg/kg ginger extract (GE) significantly alleviated the cisplatin-induced decrease in food intake in rats. However, these body weight and water intake decreases were reversed in the 100 mg/kg group rats. To elucidate the underlying mechanism of action, serotonin (5-HT) and 5-HT2C, 3A, and 4 receptors in the nodose ganglion of the vagus nerve were investigated. The results showed that cisplatin-induced increases in serotonin levels in both the blood and nodose ganglion tissues were significantly decreased by100 and 500 mg/kg of GE administration. On 5-HT receptors, 5-HT3A and 4, but not 2C receptors, were affected by cisplatin, and GE 100 and 500 mg/kg succeeded in downregulating the evoked upregulated gene of these receptors. Protein expression of 5-HT3A and 4 receptors were also reduced in the 100 mg/kg group. Furthermore, the injection of 5-HT3A, and 4 receptors antagonists (palonostron, 0.1 mg/kg, i.p.; piboserod, 1 mg/kg, i.p., respectively) in cisplatin treated rats prevented the decrease in food intake. Using high-performance liquid chromatography (HPLC) analysis, [6]-gingerol and [6]-shogaol were identified and quantified as the major components of GE, comprising 4.12% and 2.15% of the GE, respectively. Although [6]-gingerol or [6]-shogaol alone failed to alleviate the evoked anorexia, when treated together, the effect was significant on the cisplatin-induced decrease in food intake. These results show that GE can be considered a treatment option to alleviate cisplatin-induced anorexia. [ABSTRACT FROM AUTHOR]

Obesity has become a worldwide disease, posing a rapidly increasing challenge to the global healthcare system. The primary reason for obesity is that food intake exceeds the body’s needs. The central nervous system monitors the body’s energy status by continuously receiving peripheral gut-derived signals and functions as a master regulator in controlling feeding behaviors. Vagal afferents transmit gut-derived consumption signals from the periphery to the hindbrain (e.g., the nucleus of the solitary tract (NTS)). In contrast, vagal efferent nerves send commands to regulate peripheral organ activities. However, the precise role of the gut–vagus–NTS pathway and the gut–brain axis in regulating food intake is not yet fully understood. This review highlights the key roles of the NTS, vagal sensory neurons, and the gastrointestinal system in regulating feeding behaviors.

The gut-brain axis has received increasing attention recently due to evidence that colonic microbes can affect brain function and behavior. However, little is known about the innervation of the colon by a major component of the gut-brain axis, vagal afferent neurons. Furthermore, it is currently unknown whether individual NG neurons or DRG neurons innervate both the proximal and distal colon. We aimed to quantify the number of vagal and spinal afferent neurons that innervate the colon; and determine whether these individual neurons simultaneously innervate the mouse proximal and distal colon. C57Bl/6 mice received injections of a combination of retrograde tracers that were either injected into the muscularis externa of the proximal or the distal colon: fast blue, DiI and DiO. Five to seven percent of lumbosacral and thoracolumbar spinal afferent neurons, and 25% of vagal afferent neurons were labelled by injections of DiI and DiO into the colon. We also found that approximately 8% of NG neurons innervate the distal colon. Ten percent of labeled thoracolumbar and 15% of labeled lumbosacral DRG neurons innervate both the distal and proximal colon. Eighteen percent of labeled NG neurons innervated both the distal and proximal colon. In conclusion, vagal afferent innervation of the distal colon is less extensive than the proximal colon, whereas a similar gradient was not observed for the spinal afferent innervation. Furthermore, overlap appears to exist between the receptive fields of vagal and spinal afferent neurons that innervate the proximal and distal colon. [ABSTRACT FROM AUTHOR]

Transient receptor potential vanilloid type 2 (TRPV2) and type 1 (TRPV1) are originally identified as heat-sensitive TRP channels. We compared the expression patterns of TRPV2 and TRPV1 in the rat distal colon and extrinsic primary afferent neurons, and investigated their roles in visceral hypersensitivity in 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis rats. Both TRPV2 and TRPV1 expressions in the colon, dorsal root ganglion (DRG), and nodose ganglion (NG) were significantly upregulated in the TNBS-induced colitis model. TRPV2 cell bodies co-localized with the intrinsic primary afferent marker NeuN and the inhibitory motor neuronal marker nNOS in the myenteric plexus. TRPV2 expressions were further detected in the resident macrophage marker ED2 in the mucosa. In contrast, no TRPV1-expressing cell bodies were detected in the myenteric plexus. Both TRPV2- and TRPV1-positive cell bodies in the DRG and NG were double-labeled with the neuronal retrograde tracer fluorescent fluorogold. Large- and medium-sized TRPV2-positive neurons were labeled with the A-fiber marker NF200, calcitonin gene-related peptide (CGRP), and substance P (SP) in the DRG while small-sized TRPV1-positive neurons were labeled with the C-fiber markers IB4, CGRP, and SP. TRPV2- and TRPV1-positive NG neurons were labeled with NF200 and IB4. TNBS treatment increased p-ERK1/2-positive cells in TRPV2 and TRPV1 neurons but did not affect the TRPV2 and TRPV1 subpopulations in the DRG and NG. Both TRPV2 and TRPV1 antagonists significantly alleviated visceral hypersensitivity in TNBS-induced colitis model rats. These findings suggest that intrinsic/extrinsic TRPV2- and extrinsic TRPV1-neurons contribute to visceral hypersensitivity in an experimental colitis model. [ABSTRACT FROM AUTHOR]

Ghrelin is a stomach-derived peptide hormone that acts via the growth hormone secretagogue receptor (GHSR) and displays a plethora of neuroendocrine, metabolic, autonomic and behavioral actions. It has been proposed that some actions of ghrelin are exerted via the vagus nerve, which provides a bidirectional communication between the central nervous system and peripheral systems. The vagus nerve comprises sensory fibers, which originate from neurons of the nodose and jugular ganglia, and motor fibers, which originate from neurons of the medulla. Many anatomical studies have mapped GHSR expression in vagal sensory or motor neurons. Also, numerous functional studies investigated the role of the vagus nerve mediating specific actions of ghrelin. Here, we critically review the topic and discuss the available evidence supporting, or not, a role for the vagus nerve mediating some specific actions of ghrelin. We conclude that studies using rats have provided the most congruent evidence indicating that the vagus nerve mediates some actions of ghrelin on the digestive and cardiovascular systems, whereas studies in mice resulted in conflicting observations. Even considering exclusively studies performed in rats, the putative role of the vagus nerve in mediating the orexigenic and growth hormone (GH) secretagogue properties of ghrelin remains debated. In humans, studies are still insufficient to draw definitive conclusions regarding the role of the vagus nerve mediating most of the actions of ghrelin. Thus, the extent to which the vagus nerve mediates ghrelin actions, particularly in humans, is still uncertain and likely one of the most intriguing unsolved aspects of the field.

Excessive inflammation has been implicated in autism spectrum disorder (ASD), but the underlying mechanisms have not been fully studied. SHANK3 is a synaptic scaffolding protein and mutations of SHANK3 are involved in ASD. Shank3 expression in dorsal root ganglion sensory neurons also regulates heat pain and touch. However, the role of Shank3 in the vagus system remains unknown. We induced systemic inflammation by lipopolysaccharide (LPS) and measured body temperature and serum IL-6 levels in mice. We found that homozygous and heterozygous Shank3 deficiency, but not Shank2 and Trpv1 deficiency, aggravates hypothermia, systemic inflammation (serum IL-6 levels), and sepsis mortality in mice, induced by lipopolysaccharide (LPS). Furthermore, these deficits can be recapitulated by specific deletion of Shank3 in Nav1.8-expressing sensory neurons in conditional knockout (CKO) mice or by selective knockdown of Shank3 or Trpm2 in vagal sensory neurons in nodose ganglion (NG). Mice with Shank3 deficiency have normal basal core temperature but fail to adjust body temperature after perturbations with lower or higher body temperatures or auricular vagus nerve stimulation. In situ hybridization with RNAscope revealed that Shank3 is broadly expressed by vagal sensory neurons and this expression was largely lost in Shank3 cKO mice. Mechanistically, Shank3 regulates the expression of Trpm2 in NG, as Trpm2 but not Trpv1 mRNA levels in NG were significantly reduced in Shank3 KO mice. Our findings demonstrated a novel molecular mechanism by which Shank3 in vagal sensory neurons regulates body temperature, inflammation, and sepsis. We also provided new insights into inflammation dysregulation in ASD.

Chronic wasting disease (CWD) is a transmissible and fatal prion disease that affects cervids. While both oral and nasal routes of exposure to prions cause disease, the spatial and temporal details of how prions enter the central nervous system (CNS) are unknown. Carotid bodies (CBs) are structures that are exposed to blood-borne prions and are densely innervated by nerves that are directly connected to brainstem nuclei, known to be early sites of prion neuroinvasion. All CBs examined contained mast cells expressing the prion protein which is consistent with these cells playing a role in neuroinvasion following prionemia.

Background/Objective: GLP-1R agonists have been shown to reduce fasting and postprandial plasma lipids, both of which are independent risk factors for the development of cardiovascular disease. However, how endogenous GLP-1 – which is rapidly degraded – modulates intestinal and hepatic lipid metabolism is less clear. A vagal gut-brain-axis originating in the portal vein has been proposed as a possible mechanism for GLP-1’s anti-lipemic effects. Here we sought to examine the relationship between vagal GLP-1 signalling and intestinal lipid absorption and lipoprotein production. Methods: Syrian golden hamsters or C57BL/6 mice received portal vein injections of GLP-1(7-36), and postprandial and fasting plasma TG, TRL TG, or VLDL TG were examined. These experiments were repeated during sympathetic blockade, and under a variety of pharmacological or surgical deafferentation techniques. In addition, hamsters received nodose ganglia injections of a GLP-1R agonist or antagonist to further probe the vagal pathway. Peripheral studies were repeated in a novel GLP-1R KO hamster model and in our diet-induced hamster models of insulin resistance. Results: GLP-1(7-36) site-specifically reduced postprandial and fasting plasma lipids in both hamsters and mice. These inhibitory effects of GLP-1 were investigated via pharmacological and surgical denervation experiments and found to be dependent on intact afferent vagal signalling cascades and efferent changes in sympathetic tone. Furthermore, GLP-1R agonism in the nodose ganglia resulted in markedly reduced postprandial plasma TG and TRL TG, and fasting VLDL TG and this nodose GLP-1R activity was essential for portal GLP-1s effect. Notably, portal and nodose ganglia GLP-1 effects were lost in GLP-1R KO hamsters and following diet-induced insulin resistance. Conclusion: Our data demonstrates for the first time that portal GLP-1 modulates postprandial and fasting lipids via a complex vagal gut–brain–liver axis. Importantly, loss or interference with this signalling axis via surgical, pharmacological, or dietary intervention resulted in the loss of portal GLP-1s anti-lipemic effects. This supports emerging evidence that native GLP-1 works primarily through a vagal neuroendocrine mechanism.

Vagal afferents regulate numerous physiological functions including arterial blood pressure, heart rate, breathing, and nociception. Cell bodies of vagal afferents reside in the inferior vagal (nodose) ganglia and their stimulation by various means is being considered as a way to regulate cardiorespiratory responses and control pain sensations. Stimulation of the nodose by exposure to infrared light is recently being considered as a precise way to elicit responses. These responses would likely involve the activity of temperature‐sensitive membrane‐bound channels. While papers have been published to track the expression of these transient receptor potential ion channels (TRPs), further studies are warranted to determine the in situ expression of the endogenous TRP proteins in the nodose ganglia to fully understand their pattern of expression, subcellular locations, and functions in this animal model. TRP ion channels are a superfamily of Na+/Ca2+‐channels whose members are temperature‐ and/or mechano‐sensitive and therefore represent a potential set of proteins that will be activated directly or indirectly by infrared light. Here, we report the spatial localization of six TRP channels, TRPV1, TRPV4, TRPM3, TRPM8, TRPA1, and TRPC1, from nodose ganglia taken from juvenile male Sprague–Dawley rats. The channels were detected using immunohistology with fluorescent tags on cryosections and imaged using confocal microscopy. All six TRP channels were detected with different levels of intensity in neuronal cell bodies and some were also detected in axonal fibers and blood vessels. The TRP receptors differed in their prevalence, in their patterns of expression, and in subcellular expression/localization. More specifically, TRPV1, TRPV4, TRPA1, TRPM8, TRPC1, and TRPM3 were found in vagal afferent cell bodies with a wide range of immunostaining intensity from neuron to neuron. Immunostaining for TRPV1, TRPV4, and TRPA1 appeared as fine particles scattered throughout the cytoplasm of the cell body. Intense TRPV1 immunostaining was also evident in a subset of axonal fibers. TRPM8 and TRPC1 were expressed in courser particles suggesting different subcellular compartments than for TRPV1. The localization of TRPM3 differed markedly from the other TRP channels with an immunostaining pattern that was localized to the periphery of a subset of cell bodies, whereas a scattering or no immunostaining was detected within the bulk of the cytoplasm. TRPV4 and TRPC1 were also expressed on the walls of blood vessels. The finding that all six TRP channels (representing four subfamilies) were present in the nodose ganglia provides the basis for studies designed to understand the roles of these channels in sensory transmission within vagal afferent fibers and in the responses elicited by exposure of nodose ganglia to infrared light and other stimuli. Depending on the location and functionality of the TRP channels, they may regulate the flux of Na+/Ca2+‐across the membranes of cell bodies and axons of sensory afferents, efferent (motor) fibers coursing through the ganglia, and in vascular smooth muscle. [ABSTRACT FROM AUTHOR]

Gamma-aminobutyric acid (GABA) is present in the mammalian brain as the main inhibitory neurotransmitter and in foods. It is widely used as a supplement that regulates brain function through stress-reducing and sleep-enhancing effects. However, its underlying mechanisms remain poorly understood, as it is reportedly unable to cross the blood–brain barrier. Here, we explored whether a single peroral administration of GABA affects feeding behavior as an evaluation of brain function and the involvement of vagal afferent nerves. Peroral GABA at 20 and 200 mg/kg immediately before refeeding suppressed short-term food intake without aversive behaviors in mice. However, GABA administration 30 min before refeeding demonstrated no effects. A rise in circulating GABA concentrations by the peroral administration of 200 mg/kg GABA was similar to that by the intraperitoneal injection of 20 mg/kg GABA, which did not alter feeding. The feeding suppression by peroral GABA was blunted by the denervation of vagal afferents. Unexpectedly, peroral GABA alone did not alter vagal afferent activities histologically. The coadministration of a liquid diet and GABA potentiated the postprandial activation of vagal afferents, thereby enhancing postprandial satiation. In conclusion, dietary GABA activates vagal afferents in collaboration with meals or meal-evoked factors and regulates brain function including feeding behavior. [ABSTRACT FROM AUTHOR]

Enteroendocrine cells (EECs) are the primary sensory cells that sense the gut luminal environment and secret hormones to regulate organ function. Recent studies revealed that vagal afferent neurons are connected to EECs and relay sensory information from EECs to the brain stem. To date, however, the identity of vagal afferent neurons connected to a given EEC subtype and the mode of their gene responses to its intestinal hormone have remained unknown. Hypothesizing that EEC-associated vagal afferent neurons change their gene expression in response to the microbiota-related extracellular stimuli, we conducted comparative gene expression analyses of the nodose-petrosal ganglion complex (NPG) using specific pathogen-free (SPF) and germ-free (GF) mice. We report here that the Uts2b gene, which encodes a functionally unknown neuropeptide, urotensin 2B (UTS2B), is expressed in a microbiota-dependent manner in NPG neurons. In cultured NPG neurons, expression of Uts2b was induced by AR420626, the selective agonist for FFAR3. Moreover, distinct gastrointestinal hormones exerted differential effects on Uts2b expression in NPG neurons, where cholecystokinin (CCK) significantly increased its expression. The majority of Uts2b -expressing NPG neurons expressed CCK-A, the receptor for CCK, which comprised approximately 25% of all CCK-A-expressing NPG neurons. Selective fluorescent labeling of Uts2b -expressing NPG neurons revealed a direct contact of their nerve fibers to CCK-expressing EECs. This study identifies the Uts2b as a microbiota-regulated gene, demonstrates that Uts2b -expressing vagal afferent neurons transduce sensory information from CCK-expressing EECs to the brain, and suggests potential involvement of UTS2B in a modality of CCK actions. • Vagal afferent neurons communicating with CCK-enteroendocrine cells identified. • Bacterial metabolites induce expression of Uts2b in vagal afferent neurons. • CCK induces expression of Uts2b in vagal afferent neurons. • Uts2b-expressing vagal afferent nerves contact CCK-enteroendocrine cells. [ABSTRACT FROM AUTHOR]

This study determined the presence of nitric oxide synthesis isoforms (nNOS, iNOS, and eNOS) in thoracic spinal cord segments and nodose ganglia of rats with gamma-irradiated livers.

Homeostatic reflexes are crucial for life, but the subpopulations of sensory neurons that stimulate these reflexes are largely unknown. A recent paper from Lovelace, Ma, and colleagues identified a population of sensory neurons in the cardiac ventricle that underlies the Bezold-Jarisch reflex and triggers syncope (fainting). [ABSTRACT FROM AUTHOR]

Internal human body normal temperature fluctuates between 36.5 and 37.5°C and it is generally measured in the oral cavity. Interestingly, most electrophysiological studies on the functioning of ion channels and their role in neuronal behavior are carried out at room temperature, which usually oscillates between 22 and 24°C, even when thermosensitive channels are studied. We very often forget that if the core of the body reached that temperature, the probability of death from cardiorespiratory arrest would be extremely high. Does this mean that we are studying ion channels in dying neurons? Thousands of electrophysiological experiments carried out at these low temperatures suggest that most neurons tolerate this aggression quite well, at least for the duration of the experiments. This also seems to happen with ion channels, although studies at different temperatures indicate large changes in both, neuron and channel behavior. It is known that many chemical, physical and therefore physiological processes, depend to a great extent on body temperature. Temperature clearly affects the kinetics of numerous events such as chemical reactions or conformational changes in proteins but, what if these proteins constitute ion channels and these channels are specifically designed to detect changes in temperature? In this review, we discuss the importance of the potassium channels of the TREK subfamily, belonging to the recently discovered family of two-pore domain channels, in the transduction of thermal sensitivity in different cell types. [ABSTRACT FROM AUTHOR]

Bacterially derived factors are implicated in the causation and persistence of obesity. Ingestion of a high fat diet in rodents and obesity in human subjects is associated with chronic elevation of low plasma levels of lipopolysaccharide (LPS), a breakdown product of Gram-negative bacteria. The terminals of vagal afferent neurons are positioned within the gut mucosa to convey information from the gut to the brain to regulate food intake and are responsive to LPS. We hypothesized that chronic elevation of LPS could alter vagal afferent signaling. We surgically implanted osmotic mini-pumps that delivered a constant, low-dose of LPS into the intraperitoneal cavity of rats (12.5 μg/kg/hr for 6 weeks). LPS-treated rats developed hyperphagia and showed marked changes in vagal afferent neuron function. Chronic LPS treatment reduced vagal afferent leptin signaling, characterized by a decrease in leptin-induced STAT3 phosphorylation. In addition, LPS treatment decreased cholecystokinin-induced satiety. There was no alteration in leptin signaling in the hypothalamus. These findings offer a mechanism by which a change in gut microflora can promote hyperphagia, possibly leading to obesity.

Internal human body normal temperature fluctuates between 36.5 and 37.5°C and it is generally measured in the oral cavity. Interestingly, most electrophysiological studies on the functioning of ion channels and their role in neuronal behavior are carried out at room temperature, which usually oscillates between 22 and 24°C, even when thermosensitive channels are studied. We very often forget that if the core of the body reached that temperature, the probability of death from cardiorespiratory arrest would be extremely high. Does this mean that we are studying ion channels in dying neurons? Thousands of electrophysiological experiments carried out at these low temperatures suggest that most neurons tolerate this aggression quite well, at least for the duration of the experiments. This also seems to happen with ion channels, although studies at different temperatures indicate large changes in both, neuron and channel behavior. It is known that many chemical, physical and therefore physiological processes, depend to a great extent on body temperature. Temperature clearly affects the kinetics of numerous events such as chemical reactions or conformational changes in proteins but, what if these proteins constitute ion channels and these channels are specifically designed to detect changes in temperature? In this review, we discuss the importance of the potassium channels of the TREK subfamily, belonging to the recently discovered family of two-pore domain channels, in the transduction of thermal sensitivity in different cell types.

Circulating factors access cell bodies of vagal afferents in nodose ganglia (NG) via the occipital artery (OA). Constrictor responses of OA segments closer in origin from the external carotid artery (ECA) differ from segments closer to NG. Our objective was to determine the role of endothelium in this differential vasoreactivity in rat OA segments. Vasoreactivity of OA segments (proximal segments closer to ECA, distal segments closer to NG) was examined in wire myographs. We evaluated 1) vasoconstrictor effects of 5-hydroxytryptamine (5-HT) in intact and endothelium-denuded OA segments in absence/presence of soluble guanylate cyclase (SGC) inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), 2) vasodilator responses elicited by the endothelium dependent vasodilator, acetylcholine (ACh), in intact or endothelium-denuded OA segments in absence/presence of ODQ, and 3) vasodilator responses elicited by NO-donor MAHMA NONOate, in intact OA segments in absence/presence of ODQ. Intact distal OA responded more to 5-HT than intact proximal OA. Endothelium denudation increased 5-HT potency in both OA segments, especially proximal OA. ODQ increased maximal responses of 5-HT in both segments, particularly proximal OA. ACh similarly relaxed both OA segments, effects abolished by endothelial denudation and attenuated by ODQ. MAHMA NONOate elicited transient vasodilation in both segments. Effects of ODQ against ACh were segment dependent whereas those against MAHMA NONOate were not. The endothelium regulates OA responsiveness in a segment-dependent fashion. Endothelial cells at the OA-ECA junction more strongly influence vascular tone than those closer to NG. Differential endothelial regulation of OA tone may play a role in controlling blood flow and access of circulating factors to NG. [ABSTRACT FROM AUTHOR]

UnlabelledGut-derived glucagon like peptide-1 (GLP-1) acts in the postprandial period to stimulate insulin secretion and inhibit gastrointestinal motor and secretory function; whether endogenous peripheral GLP-1 inhibits food intake is less clear. We hypothesized that GLP-1 inhibits food intake in the fed, but not fasted, state. There is evidence that GLP-1 acts via stimulation of vagal afferent neurons (VAN); we further hypothesized that the satiating effects of endogenous GLP-1 in the postprandial period is determined either by a change in GLP-1 receptor (GLP-1R) expression or localization to different cellular compartments in VAN.MethodsFood intake was recorded following administration of GLP-1 (50μg/kg or 100μg/kg) or saline (IP) in Wistar rats fasted for 18h or fasted then re-fed with 3g chow. GLP-1R protein expression and localization on VAN were determined by immunocytochemistry and immunoblots in animals fasted for 18h or fasted then re-fed for 40min. GLP-1R mRNA level was detected in animals fasted for 18h or fasted and re-fed ad libitum for 2h.ResultsGLP-1 (100μg/kg) significantly reduced 40min food intake by 38% in re-fed but not fasted rats (p

Neuronal nitric oxide synthase (nNOS)‐derived nitric oxide (NO) plays a major role in the neural control of circulation and in many cardiovascular diseases. However, the exact mechanism of how NO regulates these processes is still not fully understood. This study was designed to determine the possible sources of nitrergic nerve fibres supplying the heart attempting to imply their role in the cardiac neural control. Sections of medulla oblongata, vagal nerve, its rootlets and nodose ganglia, vagal cardiac branches, Th1‐Th5 spinal cord segments, dorsal root ganglia of C8‐Th5 spinal nerves, and stellate ganglia from 28 Wistar rats were examined applying double immunohistochemical staining for nNOS combined with choline acetyltransferase (ChAT), peripherin, substance P, calcitonin gene‐related peptide, tyrosine hydroxylase or myelin basic protein. Our findings show that the most abundant population of purely nNOS‐immunoreactive (IR) neuronal somata (NS) was observed in the nodose ganglia (37.4 ± 1.3%). A high number of nitrergic NFs spread along the vagal nerve and entered its cardiac branches. All nitrergic neuronal somata (NS) in the nucleus ambiguus were simultaneously immunoreactive (IR) to ChAT and composed only a small subset of neurons (6%). In the dorsal nucleus of vagal nerve, biphenotypic nNOS‐IR/ChAT‐IR neurons composed 7.0 ± 1.0%, while small purely nNOS‐IR neurons were scarce. Nitrergic NS were plentifully distributed within the nuclei of solitary tract. In the examined dorsal root and stellate ganglia, a few nitrergic NS were sporadically present. The majority of sympathetic NS in the intermediolateral nucleus were simultaneously immunoreactive for nNOS and ChAT. In conclusion, an abundant population of nitrergic NS in the nodose ganglion implies that neuronal NO is involved in afferent cardiac innervation. Nevertheless, nNOS‐IR neurons identified within vagal nuclei may play a role in the transmission of preganglionic parasympathetic nerve impulses. [ABSTRACT FROM AUTHOR]

Objective: The vagal, stellate, and cardiac ganglia cells changes following subarachnoid hemorrhage (SAH) may occur. This study aimed to investigate if there is any relation between vagal network/stellate ganglion and intrinsic cardiac ganglia insult following SAH., Materials and Methods: Twenty-six rabbits were used in this study. Animals were randomly divided as control (GI, n  = 5); SHAM 0.75 cc of saline-injected ( n  = 5) and study with autologous 1.5 cc blood injection into their cisterna magna(GIII, n  = 15). All animals were followed for three weeks and then decapitated. Their motor vagal nucleus, nodose, stellate, and intracardiac ganglion cells were estimated by stereological methods and compared statistically., Results: Numerical documents of heart-respiratory rates, vagal nerve- ICG, and stellate neuron densities as follows: 276 ± 32/min-22 ± 3/min-10.643 ± 1.129/mm 3 -4 ± 1/mm 3 -12 ± 3/mm 3 and 2 ± 1/cm 3 in the control group; 221 ± 22/min-16 ± 4/min-8.699 ± 976/mm 3 -24 ± 9/mm 3 -103 ± 32/mm 3 and 11 ± 3/cm 3 in the SHAM group; and 191 ± 23/min-17 ± 4/min-9.719 ± 932/mm 3 -124 ± 31/mm 3 -1.542 ± 162/mm 3 and 32 ± 9/cm 3 in the SAH (study) group. The animals with burned neuro-cardiac web had more neurons of stellate ganglia and a less normal neuron density of nodose ganglia ( p  < 0.005)., Conclusion: Sypathico-parasympathetic imbalance induced vagal nerve-ICG disruption following SAH could be named as Burned Neurocardiac Web syndrome in contrast to broken heart because ICG/parasympathetic network degeneration could not be detected in classic broken heart syndrome. It was noted that cardiac ganglion degeneration is more prominent in animals' severe degenerated neuron density of nodose ganglia. We concluded that the cardiac ganglia network knitted with vagal-sympathetic-somatosensitive fibers has an important in heart function following SAH. The neurodegeneration of the cardiac may occur in SAH, and cause sudden death.Graphical abstract[Formula: see text].

In this study, several properties of modulation of P2X3 currents by an endogenous opioid, leu-enkephalin (LEK), in neurons of the dorsal root and nodose ganglia (DRGs and NGs, respectively) were compared. P2X3-mediated currents were recorded using a patch-clamp technique in the whole-cell configuration. P2X3 receptors in DRG neurons were found to be more sensitive to LEK application compared to NG neurons; complete suppression of the corresponding currents required lower concentrations of LEK and rose more quickly. Short-term preapplication of naloxone (a nonselective opioid receptor antagonist) on NG neurons did not alter the effect of the tested opioid on P2X3 currents, while it dramatically enhanced LEK-induced inhibition in DRG neurons. This fact may be indicative of the existence of specific intracellular pathways involved in opioid-induced modulation of P2X3 receptors of different peripheral ganglia in vertebrates. [ABSTRACT FROM AUTHOR]

Objective and methods: Metabolic viscera and their vasculature are richly innervated by peripheral sensory neurons. Here, we examined the metabolic and inflammatory profiles of mice with selective ablation of all Nav1.8-expressing primary afferent neurons. Results: While mice lacking sensory neurons displayed no differences in body weight, food intake, energy expenditure, or body composition compared to controls on chow diet, ablated mice developed an exaggerated inflammatory response to high-fat feeding characterized by bouts of weight loss, splenomegaly, elevated circulating interleukin-6 and hepatic serum amyloid A expression. This phenotype appeared to be directly mediated by the ingestion of saturated lipids. Conclusions: These data demonstrate that the Nav1.8-expressing afferent neurons are not essential for energy balance but are required for limiting the acute phase response caused by an obesogenic diet.

Stress responses are coordinated by widespread neural circuits. Homeostatic and psychogenic stressors activate preproglucagon (PPG) neurons in the caudal nucleus of the solitary tract (cNTS) that produce glucagon-like peptide-1; published work in rodents indicates that these neurons play a crucial role in stress responses. While the axonal targets of PPG neurons are well established, their afferent inputs are unknown. Here we use retrograde tracing with cholera toxin subunit b to show that the cNTS in male and female mice receives axonal inputs similar to those reported in rats. Monosynaptic and polysynaptic inputs specific to cNTS PPG neurons were revealed using Cre-conditional pseudorabies and rabies viruses. The most prominent sources of PPG monosynaptic input include the lateral (LH) and paraventricular (PVN) nuclei of the hypothalamus, parasubthalamic nucleus, lateral division of the central amygdala, and Barrington's nucleus (Bar). Additionally, PPG neurons receive monosynaptic vagal sensory input from the nodose ganglia and spinal sensory input from the dorsal horn. Sources of polysynaptic input to cNTS PPG neurons include the hippocampal formation, paraventricular thalamus, and prefrontal cortex. Finally, cNTS-projecting neurons within PVN, LH, and Bar express the activation marker cFOS in mice after restraint stress, identifying them as potential sources of neurogenic stress-induced recruitment of PPG neurons. In summary, cNTS PPG neurons in mice receive widespread monosynaptic and polysynaptic input from brain regions implicated in coordinating behavioral and physiological stress responses, as well as from vagal and spinal sensory neurons. Thus, PPG neurons are optimally positioned to integrate signals of homeostatic and psychogenic stress. [ABSTRACT FROM AUTHOR]

The nodose ganglion (NG) is the main parasympathetic ganglion conveying sensory signals to the CNS from numerous visceral organs including digestive signals such as gastric distension or the release the gastrointestinal peptides. The response characteristics of NG neurons to ATP and ADP and pharmacological interrogation of purinergic receptor subtypes have been previously investigated but often in NG cells of undetermined visceral origin. In this study, we confirmed the presence of P2X3 and P2Y1 receptors and characterized P2X and P2Y responses in gastric-innervating NG neurons. Application of ATP-evoked large inward currents and cytosolic Ca2+ increases in gastric-innervating NG neurons. Despite the expression of P2Y1 receptors, ADP elicited only minor modulation of voltage-gated Ca2+ channels. Considering the sensitivity of NG neurons to comorbidities associated with disease or neural injury, purinergic modulation of gastric NG neurons in disease- or injury-states is worthy of further investigation. [ABSTRACT FROM AUTHOR]

Cisplatin is a platinum-based chemotherapeutic agent widely used to treat various cancers. However, several side effects have been reported in treated patients. Among these, acute anorexia is one of the most severe secondary effects. In this study, a single oral administration of 100 or 500 mg/kg ginger extract (GE) significantly alleviated the cisplatin-induced decrease in food intake in rats. However, these body weight and water intake decreases were reversed in the 100 mg/kg group rats. To elucidate the underlying mechanism of action, serotonin (5-HT) and 5-HT 2C , 3A, and 4 receptors in the nodose ganglion of the vagus nerve were investigated. The results showed that cisplatin-induced increases in serotonin levels in both the blood and nodose ganglion tissues were significantly decreased by100 and 500 mg/kg of GE administration. On 5-HT receptors, 5-HT 3A and 4 , but not 2C receptors, were affected by cisplatin, and GE 100 and 500 mg/kg succeeded in downregulating the evoked upregulated gene of these receptors. Protein expression of 5-HT 3A and 4 receptors were also reduced in the 100 mg/kg group. Furthermore, the injection of 5-HT 3A, and 4 receptors antagonists (palonostron, 0.1 mg/kg, i.p.; piboserod, 1 mg/kg, i.p., respectively) in cisplatin treated rats prevented the decrease in food intake. Using high-performance liquid chromatography (HPLC) analysis, [6]-gingerol and [6]-shogaol were identified and quantified as the major components of GE, comprising 4.12% and 2.15% of the GE, respectively. Although [6]-gingerol or [6]-shogaol alone failed to alleviate the evoked anorexia, when treated together, the effect was significant on the cisplatin-induced decrease in food intake. These results show that GE can be considered a treatment option to alleviate cisplatin-induced anorexia., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Kim, Park, Jo, Shin, Chung, Ko, Jin and Kim.)

The vagus nerve connects peripheral organs to the central nervous system (CNS), and gastrointestinal hormones transmit their signals to the CNS via the vagal afferent nerve. Ghrelin, a gastric-derived orexigenic peptide, stimulates food intake by transmitting starvation signals via the vagus nerve. To understand peripheral ghrelin signaling via the vagus nerve, we investigated the ghrelin receptor (GHSR)-null mouse. For this purpose, we tried to produce mice in which GHSR was selectively expressed in the hindbrain and vagus nerve. GHSR was expressed in some nodose ganglion neurons in these mice, but GHSR-expressing neurons were less abundant than in wild-type mice. Intraperitoneal administration of ghrelin did not induce food intake or growth hormone release, but did increase blood glucose levels. Our findings suggest that the abundance of GHSR-expressing neurons in the nodose ganglion is critical for peripheral administration of ghrelin-induced food intake and growth hormone release via the vagus nerve. [ABSTRACT FROM AUTHOR]

Fermentable carbohydrates including dietary fibers and resistant starch produce short-chain fatty acids (SCFAs), including acetate, propionate and butyrate, through microbial fermentation in the intestine of rodents and humans. Consumption of fermentable carbohydrate and SCFAs suppress food intake, an effect involving the brain. However, their signaling pathway to the brain remains unclear. Vagal afferents serve to link intestinal information to the brain. In the present study, we explored possible role of vagal afferents in the anorexigenic effect of SCFAs. Intraperitoneal (ip) injection of three SCFA molecules (6 mmol/kg) suppressed food intake in fasted mice with the rank order of butyrate > propionate > acetate. The suppressions of feeding by butyrate, propionate and acetate were attenuated by vagotomy of hepatic branch and blunted by systemic treatment with capsaicin that denervates capsaicin-sensitive sensory nerves including vagal afferents. Ip injection of butyrate induced significant phosphorylation of extracellular-signal-regulated kinase 1/2, cellular activation markers, in nodose ganglia and their projection site, medial nucleus tractus solitaries. Moreover, butyrate directly interacted with single neurons isolated from nodose ganglia and induced intracellular Ca2+ signaling. The present results identify the vagal afferent as the novel pathway through which exogenous SCFAs execute the remote control of feeding behavior and possibly other brain functions. Vagal afferents might participate in suppression of feeding by intestine-born SCFAs. [ABSTRACT FROM AUTHOR]