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Scientific Reports Jun 2020Vagus nerve stimulation (VNS) is a bioelectronic therapy for disorders of the brain and peripheral organs, and a tool to study the physiology of autonomic circuits....
Vagus nerve stimulation (VNS) is a bioelectronic therapy for disorders of the brain and peripheral organs, and a tool to study the physiology of autonomic circuits. Selective activation of afferent or efferent vagal fibers can maximize efficacy and minimize off-target effects of VNS. Anodal block (ABL) has been used to achieve directional fiber activation in nerve stimulation. However, evidence for directional VNS with ABL has been scarce and inconsistent, and it is unknown whether ABL permits directional fiber activation with respect to functional effects of VNS. Through a series of vagotomies, we established physiological markers for afferent and efferent fiber activation by VNS: stimulus-elicited change in breathing rate (ΔBR) and heart rate (ΔHR), respectively. Bipolar VNS trains of both polarities elicited mixed ΔHR and ΔBR responses. Cathode cephalad polarity caused an afferent pattern of responses (relatively stronger ΔBR) whereas cathode caudad caused an efferent pattern (stronger ΔHR). Additionally, left VNS elicited a greater afferent and right VNS a greater efferent response. By analyzing stimulus-evoked compound nerve potentials, we confirmed that such polarity differences in functional responses to VNS can be explained by ABL of A- and B-fiber activation. We conclude that ABL is a mechanism that can be leveraged for directional VNS.
Topics: Action Potentials; Animals; Electrocardiography; Electrodes, Implanted; Heart Rate; Male; Rats; Rats, Sprague-Dawley; Respiratory Rate; Vagus Nerve; Vagus Nerve Stimulation
PubMed: 32513973
DOI: 10.1038/s41598-020-66332-y -
PloS One 2019GPR40/FFAR1 is a Gq protein-coupled receptor expressed in pancreatic β cells and enteroendocrine cells, and mediates insulin and incretin secretion to regulate feeding...
GPR40/FFAR1 is a Gq protein-coupled receptor expressed in pancreatic β cells and enteroendocrine cells, and mediates insulin and incretin secretion to regulate feeding behavior. Several GPR40 full agonists have been reported to reduce food intake in rodents by regulating gut hormone secretion in addition to their potent glucose-lowering effects; however, detailed mechanisms of feeding suppression are still unknown. In the present study, we characterized T-3601386, a novel compound with potent full agonistic activity for GPR40, by using in vitro Ca2+ mobilization assay in Chinese hamster ovary (CHO) cells expressing FFAR1 and in vivo hormone secretion assay. We also evaluated feeding suppression and weight loss after the administration of T-3601386 and investigated the involvement of the vagal nerve in these effects. T-3601386, but not a partial agonist fasiglifam, increased intracellular Ca2+ levels in CHO cells with low FFAR1 expression, and single dosing of T-3601386 in diet-induced obese (DIO) rats elevated plasma incretin levels, suggesting full agonistic properties of T-3601386 against GPR40. Multiple doses of T-3601386, but not fasiglifam, in DIO rats showed dose-dependent weight loss accompanied by feeding suppression and durable glucagon-like peptide-1 elevation, all of which were completely abolished in Ffar1-/- mice. Immunohistochemical analysis in the nuclei of the solitary tract demonstrated that T-3601386 increased the number of c-Fos positive cells, which also disappeared in Ffar1-/- mice. Surgical vagotomy and drug-induced deafferentation counteracted the feeding suppression and weight loss induced by the administration of T-3601386. These results suggest that T-3601386 exerts incretin release and weight loss in a GPR40-dependent manner, and that afferent vagal nerves are important for the feeding suppression induced by GPR40 full agonism. Our novel findings raise the possibility that GPR40 full agonist can induce periphery-derived weight reduction, which may provide benefits such as less adverse effects in central nervous system compared to centrally-acting anti-obesity drugs.
Topics: Animals; Blood Glucose; CHO Cells; Calcium; Cell Line; Cricetulus; Enteroendocrine Cells; Female; Glucagon-Like Peptide 1; Insulin; Insulin-Secreting Cells; Islets of Langerhans; Male; Mice; Obesity; Rats; Rats, Inbred F344; Rats, Sprague-Dawley; Rats, Wistar; Receptors, G-Protein-Coupled; Signal Transduction; Vagus Nerve; Weight Loss
PubMed: 31525244
DOI: 10.1371/journal.pone.0222653 -
Acta Neurobiologiae Experimentalis 2023In the central nervous system, long‑term effects of a vagotomy include disturbance of monoaminergic activity of the limbic system. Since low vagal activity is observed...
In the central nervous system, long‑term effects of a vagotomy include disturbance of monoaminergic activity of the limbic system. Since low vagal activity is observed in major depression and autism spectrum disorder, the study aimed to determine whether animals fully recovered after subdiaphragmatic vagotomy demonstrates neurochemical indicators of altered well‑being and social component of sickness behavior. Bilateral vagotomy or sham surgery was performed in adult rats. After one month of recovery, rats were challenged with lipopolysaccharide or vehicle to determine the role of central signaling upon sickness. Striatal monoamines and met‑enkephalin concentrations were evaluated using HPLC and RIA methods. We also defined a concentration of immune‑derived plasma met‑enkephalin to establish a long‑term effect of vagotomy on peripheral analgesic mechanisms. The data indicate that 30 days after vagotomy procedure, striatal dopaminergic, serotoninergic, and enkephalinergic neurochemistry was altered, both under physiological and inflammatory conditions. Vagotomy prevented inflammation‑induced increases of plasma met‑enkephalin - an opioid analgesic. Our data suggest that in a long perspective, vagotomized rats may be more sensitive to pain and social stimuli during peripheral inflammation.
Topics: Rats; Animals; Enkephalin, Methionine; Autism Spectrum Disorder; Vagotomy; Vagus Nerve; Inflammation; Amines
PubMed: 37078817
DOI: 10.55782/ane-2023-009 -
Biomedicines Apr 2023GLP-1 is a gastro-intestinal hormone acting within the gut/brain axis for energy balance regulation. We aimed to evaluate the role of the vagus nerve in whole-body...
GLP-1 is a gastro-intestinal hormone acting within the gut/brain axis for energy balance regulation. We aimed to evaluate the role of the vagus nerve in whole-body energy homeostasis and in mediating GLP-1 effects. For this, rats submitted to truncal vagotomy and sham-operated controls underwent a comprehensive evaluation, including eating behavior, body weight, percentage of white (WAT) and brown adipose tissue (BAT), resting energy expenditure (REE) and acute response to GLP-1. Truncal vagotomized rats had significantly lower food intake, body weight, body weight gain, WAT and BAT, with a higher BAT/WAT ratio, but no significant difference in REE when compared to controls. Vagotomized rats also had significantly higher fasting ghrelin and lower glucose and insulin levels. After GLP-1 administration, vagotomized rats depicted a blunted anorexigenic response and higher plasma leptin levels, as compared to controls. However, in vitro stimulation of VAT explants with GLP-1 resulted in no significant changes in leptin secretion. In conclusion, the vagus nerve influences whole-body energy homeostasis by modifying food intake, body weight and body composition and by mediating the GLP-1 anorectic response. The higher leptin levels in response to acute GLP-1 administration observed after truncal vagotomy suggest the existence of a putative GLP-1-leptin axis that relies on the integrity of gut-brain vagal pathway.
PubMed: 37238993
DOI: 10.3390/biomedicines11051322 -
Virulence Dec 2021Abnormalities in CD4 T cell (Th cell) differentiation play an important role in the pathogenesis of viral myocarditis (VMC). Our previous studies demonstrated that...
Abnormalities in CD4 T cell (Th cell) differentiation play an important role in the pathogenesis of viral myocarditis (VMC). Our previous studies demonstrated that activation of the cholinergic anti-inflammatory pathway (CAP) alleviated the inflammatory response. In addition, we observed that right cervical vagotomy aggravates VMC by inhibiting CAP. However, the vagus nerve's effect on differentiation of CD4 T cells has not been studied in VMC mice to date. In this study, we investigated the effects of cervical vagotomy and the α7nAChR agonist pnu282987 on CD4 T cell differentiation in a murine myocarditis model (BALB/c) infected with coxsackievirus B3 (CVB3). Splenic CD4 T cells from CVB3-induced mice obtained and cultured to investigate the potential mechanism of CD4 T cell differentiation. Each Th cell subset was analyzed by flow cytometry. Our results showed that right cervical vagotomy increased proportions of Th1 and Th17 cells and decreased proportions of Th2 and Treg cells in the spleen. Vagotomy-induced upregulation of T-bet, Ror-γ, IFN-γ, and IL-17 expression while downregulating the expression of Gata3, Foxp3, and IL-4 in the heart. In addition, we observed upregulated levels of proinflammatory cytokines, aggravated myocardial lesions and cellular infiltration, and worsened cardiac function in VMC mice. Pnu282987 administration reversed these outcomes. Furthermore, vagotomy inhibited JAK2-STAT3 activation and enhanced NF-κB activation in splenic CD4 T cells. The CD4 T cell differentiation was related to JAK2-STAT3 and NF-κB signal pathways. In conclusion, vagus nerve modulates the inflammatory response by regulating CD4 T cell differentiation in response to VMC.
Topics: Acute Disease; Animals; CD4-Positive T-Lymphocytes; Cell Differentiation; Coxsackievirus Infections; Cytokines; Enterovirus B, Human; Male; Mice; Mice, Inbred BALB C; Myocarditis; Vagus Nerve
PubMed: 33380272
DOI: 10.1080/21505594.2020.1869384 -
Research Square Apr 2022Severe COVID-19 is characterized by pro-inflammatory cytokine release syndrome (cytokine storm) which causes high morbidity and mortality. Recent observational and...
Severe COVID-19 is characterized by pro-inflammatory cytokine release syndrome (cytokine storm) which causes high morbidity and mortality. Recent observational and clinical studies suggest famotidine, a histamine 2 receptor (H2R) antagonist widely used to treat gastroesophageal reflux disease , attenuates the clinical course of COVID-19. Because evidence is lacking for a direct antiviral activity of famotidine, a proposed mechanism of action is blocking the effects of histamine released by mast cells. Here we hypothesized that famotidine activates the inflammatory reflex, a brain-integrated vagus nerve mechanism which inhibits inflammation via alpha 7 nicotinic acetylcholine receptor ( α7nAChR ) signal transduction, to prevent cytokine storm. The potential anti-inflammatory effects of famotidine and other H2R antagonists was assessed in mice exposed to lipopolysaccharide (LPS)-induced cytokine storm. As the inflammatory reflex is integrated and can be stimulated in the brain, and H2R antagonists penetrate the blood brain barrier poorly, famotidine was administered by intracerebroventricular (ICV) or intraperitoneal (IP) routes. Famotidine administered IP significantly reduced serum and splenic LPS-stimulated tumor necrosis factor α and interleukin-6 concentrations, significantly improving survival. The effects of ICV famotidine were significantly more potent as compared to the peripheral route. Mice lacking mast cells by genetic deletion also responded to famotidine, indicating the anti-inflammatory effects are not mast cell dependent. Either bilateral sub-diaphragmatic vagotomy or genetic knock-out of α7nAChR abolished the anti-inflammatory effects of famotidine, indicating the inflammatory reflex as famotidine's mechanism of action. While the structurally similar H2R antagonist tiotidine displayed equivalent anti-inflammatory activity, the H2R antagonists cimetidine or ranitidine were ineffective even at very high dosages. These observations reveal a previously unidentified vagus nerve-dependent anti-inflammatory effect of famotidine in the setting of cytokine storm which is not replicated by high dosages of other H2R antagonists in clinical use. Because famotidine is more potent when administered intrathecally, these findings are also consistent with a primarily central nervous system mechanism of action.
PubMed: 35441176
DOI: 10.21203/rs.3.rs-1493296/v1 -
Neurogastroenterology and Motility Nov 2019We have shown previously that an attenuated rodent model of mild necrotizing enterocolitis (NEC) increases intestinal histopathological severity grade, prevents typical...
BACKGROUND
We have shown previously that an attenuated rodent model of mild necrotizing enterocolitis (NEC) increases intestinal histopathological severity grade, prevents typical developmental increases in the high-frequency spectrum of heart rate variability (HF-HRV), alters the nitrergic myenteric phenotype, and increases IL-6 and IL-1β when combined with anterior subdiaphragmatic vagotomy. The aims of the present study were to test the hypotheses that in mild NEC-induced pups, administration of the orexigenic hormone ghrelin (a) reduces the histopathological score, (b) increases the HF-HRV power, (c) improves the altered myenteric phenotype, and (d) subdiaphragmatic vagotomy prevents the effects of ghrelin.
METHODS
Newborn Sprague Dawley rats were subjected to seven days of brief periods of cold stress and hypoxia to induce mild NEC with or without anterior subdiaphragmatic vagotomy. HRV was measured at postnatal days one, five, and ten; intraperitoneal ghrelin (0.05 mg kg ) was administered postnatal days five through ten b.i.d. Pups were sacrificed at day 12, and whole brains, gastrointestinal tissues, and blood were collected for immunohistochemical, corticosterone, and cytokine analysis.
KEY RESULTS
Ghrelin treatment reduced the intestinal histopathological score, increased the HF-HRV power, improved the altered intestinal myenteric phenotype, and subdiaphragmatic vagotomy prevented the effects of ghrelin. There were no differences in serum cytokines or corticosterone between groups.
CONCLUSIONS AND INFERENCES
Our data suggest that ghrelin administration is able to recover the mild NEC-induced changes to the histology, HF-HRV, and myenteric phenotype in a vagally dependent manner.
Topics: Animals; Animals, Newborn; Enterocolitis, Necrotizing; Ghrelin; Heart Rate; Intestines; Myenteric Plexus; Phenotype; Rats; Rats, Sprague-Dawley
PubMed: 31386261
DOI: 10.1111/nmo.13682 -
Aging Nov 2020Light exerts critical non-visual effects on a multitude of physiological processes and behaviors, including sleep-wake behavior and cognitive function. In this study, we... (Comparative Study)
Comparative Study
Light exerts critical non-visual effects on a multitude of physiological processes and behaviors, including sleep-wake behavior and cognitive function. In this study, we investigated the effects of continued exposure to different colors of light on cognitive function after sepsis in old mice. We found that exposure to red light, but not green light, exaggerated learning impairments and anxiety-like behaviors after sepsis. Red light also induced remarkable splenomegaly and altered the diversity and composition of the fecal microbiota. Pseudo germ-free mice transplanted with fecal bacteria from septic mice exposed to red light developed the same behavioral defects and splenomegaly as their donors. Intriguingly, splenectomy and subdiaphragmatic vagotomy reversed the learning impairments and anxiety-like behaviors resulting from red light exposure after sepsis. After subdiaphragmatic vagotomy, no differences in behavior or spleen size were observed among pseudo germ-free mice transplanted with fecal bacteria from septic mice exposed to different colors of light. Our results suggested that red light exposure after sepsis in old mice causes gut microbiota dysfunction, thus stimulating signaling through the subdiaphragmatic vagus nerve that induces splenomegaly and aggravates learning impairments and anxiety-like behaviors.
Topics: Age Factors; Animals; Anxiety; Behavior, Animal; Disease Models, Animal; Dysbiosis; Feces; Gastrointestinal Microbiome; Intestines; Learning Disabilities; Light; Male; Maze Learning; Mice, Inbred C57BL; Open Field Test; Sepsis; Splenomegaly; Vagus Nerve
PubMed: 33197883
DOI: 10.18632/aging.103940 -
Journal of Neuroinflammation Jul 2023Inflammation is a fundamental biological response to injury and infection, which if unregulated can contribute to the pathophysiology of many diseases. The vagus nerve,...
BACKGROUND
Inflammation is a fundamental biological response to injury and infection, which if unregulated can contribute to the pathophysiology of many diseases. The vagus nerve, which primarily originates from the dorsal motor nucleus (DMN), plays an important role in rapidly dampening inflammation by regulating splenic function. However, direct vagal innervation of the spleen, which houses the majority of immune and inflammatory cells, has not been established. As an alternative to direct innervation, an anti-inflammatory reflex pathway has been proposed which involves the vagus nerve, the sympathetic celiac ganglion, and the neurotransmitter norepinephrine. Although sympathetic regulation of inflammation has been shown, the interaction of the vagus nerve and the celiac ganglia requires a unique interaction of parasympathetic and sympathetic inputs, making this putative mechanism of brain-spleen interaction controversial. BODY: As neuropeptides can be expressed at relatively high levels in neurons, we reasoned that DMN neuropeptide immunoreactivity could be used to determine their target innervation. Employing immunohistochemistry, subdiaphragmatic vagotomy, viral tract tracing, CRISPR-mediated knock-down, and functional assays, we show that cocaine and amphetamine-regulated transcript (CART) peptide-expressing projection neurons in the caudal DMN directly innervate the spleen. In response to lipopolysaccharide (LPS) stimulation, CART acts to reduce inflammation, an effect that can be augmented by intrasplenic administration of a synthetic CART peptide. These in vivo effects could be recapitulated in cultured splenocytes, suggesting that these cells express the as yet unidentified CART receptor(s).
CONCLUSION
Our results provide evidence for direct connections between the caudal DMN and spleen. In addition to acetylcholine, these neurons express the neuropeptide CART that, once released, acts to suppress inflammation by acting directly upon splenocytes.
Topics: Humans; Spleen; Neurons; Neuropeptides; Vagus Nerve; Inflammation
PubMed: 37403174
DOI: 10.1186/s12974-023-02838-2 -
Cureus Sep 2023Background The incidence of gastric stump carcinoma (GSC) is not declining because of the long latency period. The survival rate of treated gastric cancer patients has...
Background The incidence of gastric stump carcinoma (GSC) is not declining because of the long latency period. The survival rate of treated gastric cancer patients has increased due to early detection and improvements in surgical techniques and chemotherapy. Increased survival rates and improved surveillance following gastric surgery have increased the incidence of GSC. Aim The study aims to investigate the clinicopathological factors affecting the interval between index gastric surgery and the occurrence of GSC, and our experience in the management of GSC is presented. Methods A retrospective review of patients diagnosed with GSC in our institution was completed. Patient characteristics and clinicopathological outcomes were analyzed. Results A total of 28 patients were included in this cohort with 17 (60.71%) males and 11 (39.28%) females. The mean interval from index surgery to the incidence of GSC was 24.42 years for benign etiology and six years for malignant etiology. Index surgeries were truncal vagotomy with 14 gastrojejunostomies (50%) and 14 subtotal gastrectomies (50%). The interval between index surgery and the incidence of GSC is not statistically significant concerning the type of surgery (p: 0.661), pathological TNM (tumor, nodes, metastases) stage (p: 0.520), pathological differentiation (p: 0.828), lymphovascular invasion (p: 0.252), perineural invasion (p: 0.672), and adjuvant therapy (p: -0.655). Survival was significantly higher in those patients who received curative resection in comparison to a palliative procedure (p: 0.041). Conclusion Strict surveillance for at least 10 years after initial gastric surgery is of utmost importance as half of the patients fated to develop GSC will do so within this time. In those patients with early diagnosis, no evidence of metastasis, and good performance status, curative surgery is feasible with acceptable morbidity.
PubMed: 37809185
DOI: 10.7759/cureus.44798