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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 -
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 -
Reproductive Biology and Endocrinology... Jun 2022Women with endometriosis have been shown to have a reduced vagal tone as compared with controls and vagotomy promoted while vagus nerve stimulation (VNS) decelerated the...
BACKGROUND
Women with endometriosis have been shown to have a reduced vagal tone as compared with controls and vagotomy promoted while vagus nerve stimulation (VNS) decelerated the progression of endometriosis in mice. Extensive research also has shown that the activation of the cholinergic anti-inflammatory pathway by VNS activates α7 nicotinic acetylcholine receptor (α7nAChR), potently reducing inflammation. Yet whether α7nAChR plays any role in endometriosis is unknown. We evaluated its expression in normal endometrium, ovarian and deep endometriotic lesions, and evaluated its role in the development of endometriosis.
METHODS
Immunohistochemistry analyses of α7nAChR in endometriotic lesions as well as control endometrium, and quantification of tissue fibrosis by Masson trichrome staining were performed. Mouse experiments were conducted to evaluate the impact of α7nAChR activation or suppression on lesional progression and possible therapeutic effect. Finally, in vitro experiments were conducted to evaluate the effect of activation of α7nAChR on epithelial-mesenchymal transition (EMT), fibroblast-to-myofibroblast transdifferentiation (FMT), smooth muscle metaplasia (SMM) and fibrogenesis in an endometriotic epithelial cell line and primary endometriotic stromal cells derived from ovarian endometrioma tissue samples.
RESULTS
Immunostaining of α7nAChR was significantly reduced in human endometriotic epithelial cells as compared with their counterpart in normal endometrium. Lesional α7nAChR staining levels correlated negatively with lesional fibrosis and the severity of dysmenorrhea. The α7nAChR agonist significantly impeded the development of endometriotic lesions in mouse models possibly through hindrance of EMT and FMT. It also demonstrated therapeutic effects in mice with induced deep endometriosis. Treatment of endometriotic epithelial and stromal cells with an α7nAChR agonist significantly abrogated platelet-induced EMT, FMT and SMM, and suppressed cellular contractility and collagen production.
CONCLUSIONS
α7nAChR is suppressed in endometriotic lesions, and its activation by pharmacological means can impede EMT, FMT, SMM, and fibrogenesis of endometriotic lesions. As such, α7nAChR can be rightfully viewed as a potential target for therapeutic invention.
TRIAL REGISTRATION
Not applicable.
Topics: Animals; Cell Transdifferentiation; Endometriosis; Female; Fibrosis; Humans; Mice; Myofibroblasts; alpha7 Nicotinic Acetylcholine Receptor
PubMed: 35658970
DOI: 10.1186/s12958-022-00955-w -
Clinical & Translational Oncology :... Apr 2021The nervous system plays an important role in cancer initiation and progression. Accumulated evidences clearly show that the sympathetic nervous system exerts... (Review)
Review
The nervous system plays an important role in cancer initiation and progression. Accumulated evidences clearly show that the sympathetic nervous system exerts stimulatory effects on carcinogenesis and cancer growth. However, the role of the parasympathetic nervous system in cancer has been much less elucidated. Whereas retrospective studies in vagotomized patients and experiments employing vagotomized animals indicate the parasympathetic nervous system has an inhibitory effect on cancer, clinical studies in patients with prostate cancer indicate it has stimulatory effects. Therefore, the aim of this paper is a critical evaluation of the available data related to the role of the parasympathetic nervous system in cancer.
Topics: Animals; Cholinergic Neurons; Disease Progression; Dogs; Heart Rate; Humans; Male; Mice; Neoplasms; Parasympathetic Nervous System; Prostatic Neoplasms; Rats; Retrospective Studies; Sympathetic Nervous System; Vagotomy; Vagus Nerve
PubMed: 32770391
DOI: 10.1007/s12094-020-02465-w -
American Journal of Physiology.... Mar 2023The Bezold-Jarisch reflex is a powerful inhibitory reflex initiated by activation of cardiopulmonary vagal nerves during myocardial ischemia, hemorrhage, and orthostatic...
The Bezold-Jarisch reflex is a powerful inhibitory reflex initiated by activation of cardiopulmonary vagal nerves during myocardial ischemia, hemorrhage, and orthostatic stress leading to bradycardia, vasodilation, hypotension, and vasovagal syncope. This clinically relevant reflex has been studied by measuring heart rate (HR) and mean arterial pressure (MAP) responses to injections of a variety of chemical compounds. We hypothesized that reflex responses to different compounds vary due to differential activation of vagal afferent subtypes and/or variable coactivation of excitatory afferents. HR and MAP responses to intravenous injections of the transient receptor potential vanilloid-1 (TRPV1) agonist capsaicin and the serotonin 5-HT receptor agonist phenylbiguanide (PBG) were measured in anesthetized C57BL/6 mice before and after bilateral cervical vagotomy. Capsaicin and PBG evoked rapid dose-dependent decreases in HR and MAP followed by increases in HR and MAP above baseline. Bezold-Jarisch reflex responses were abolished after vagotomy, whereas the delayed tachycardic and pressor responses to capsaicin and PBG were differentially enhanced. The relative magnitude of bradycardic versus depressor responses (↓HR/↓MAP) in vagus-intact mice was greater with capsaicin. In contrast, after vagotomy, the magnitude of excitatory tachycardic versus pressor responses (↑HR/↑MAP) was greater with PBG. Although capsaicin-induced increases in MAP and HR postvagotomy were strongly attenuated or abolished after administration of the ganglionic blocker hexamethonium, PBG-induced increases in MAP and HR were mildly attenuated and unchanged, respectively. We conclude that responses to capsaicin and PBG differ in mice, with implications for delineating the role of endogenous agonists of TRPV1 and 5-HT receptors in evoking cardiopulmonary reflexes in pathophysiological states.
Topics: Mice; Animals; Capsaicin; Serotonin; Mice, Inbred C57BL; Bradycardia; Heart Rate; Reflex; Blood Pressure
PubMed: 36622083
DOI: 10.1152/ajpregu.00102.2022 -
Journal of Affective Disorders Jan 2024Depression is a frequent symptom in patients with chronic liver disease; however, the mechanisms underlying this association remain unclear. Dysbiosis of gut microbiota...
Depression is a frequent symptom in patients with chronic liver disease; however, the mechanisms underlying this association remain unclear. Dysbiosis of gut microbiota plays a critical role in depression through the gut-brain axis via the vagus nerve. In this study, we investigated whether the gut-microbiota-liver-brain axis plays a role in depression-like phenotypes in mice with hepatic ischemia/reperfusion (HI/R) injury via the vagus nerve. Behavioral tests for depression-like behaviors were performed 7 days after sham or HI/R injury surgery. Mice with HI/R injury exhibited splenomegaly, systemic inflammation, depression-like behaviors, reduced expression of synaptic proteins in the prefrontal cortex (PFC), abnormal composition of gut microbiota, and altered blood metabolites and lipids. Furthermore, there were positive or negative correlations between the relative abundance of microbiome and behavioral data or blood metabolites (or lipids). Moreover, subdiaphragmatic vagotomy significantly blocked these changes in mice with HI/R injury. Notably, depression-like phenotypes in mice with HI/R injury were ameliorated after subsequent single injection of the new antidepressant arketamine. The current findings suggest that HI/R injury induces depression-like phenotypes in mice through the gut-microbiota-liver-brain axis via the subdiaphragmatic vagus nerve. Furthermore, arketamine may have therapeutic potential in the treatment of depression in patients with chronic liver disease.
Topics: Humans; Mice; Animals; Depression; Brain-Gut Axis; Microbiota; Vagus Nerve; Phenotype; Prefrontal Cortex; Liver Diseases; Reperfusion Injury; Ischemia; Lipids
PubMed: 37879416
DOI: 10.1016/j.jad.2023.10.142 -
American Journal of Physiology.... Apr 2021Impaired cardiac preload secondary to umbilical cord occlusion (UCO) has been hypothesized to contribute to intrapartum decelerations, brief falls in fetal heart rate...
Impaired cardiac preload secondary to umbilical cord occlusion (UCO) has been hypothesized to contribute to intrapartum decelerations, brief falls in fetal heart rate (FHR), through activation of the Bezold-Jarisch reflex. This cardioprotective reflex increases parasympathetic and inhibits sympathetic outflows triggering hypotension, bradycardia, and peripheral vasodilation, but its potential to contribute to intrapartum decelerations has never been systematically examined. In this study, we performed bilateral cervical vagotomy to remove the afferent arm and the efferent parasympathetic arm of the Bezold-Jarisch reflex. Twenty-two chronically instrumented fetal sheep at 0.85 of gestation received vagotomy ( = 7) or sham vagotomy (control, = 15), followed by three 1-min complete UCOs separated by 4-min reperfusion periods. UCOs in control fetuses were associated with a rapid fall in FHR and reduced femoral blood flow mediated by intense femoral vasoconstriction, leading to hypertension. Vagotomy abolished the rapid fall in FHR ( < 0.001) and, despite reduced diastolic filling time, increased both carotid ( < 0.001) and femoral ( < 0.05) blood flow during UCOs, secondary to carotid vasodilation ( < 0.01) and delayed femoral vasoconstriction ( < 0.05). Finally, vagotomy was associated with an attenuated rise in cortical impedance during UCOs ( < 0.05), consistent with improved cerebral substrate supply. In conclusion, increased carotid and femoral blood flows after vagotomy are consistent with increased left and right ventricular output, which is incompatible with the hypothesis that labor-like UCOs impair ventricular filling. Overall, the cardiovascular responses to vagotomy do not support the hypothesis that the Bezold-Jarisch reflex is activated by UCO. The Bezold-Jarisch reflex is therefore mechanistically unable to contribute to intrapartum decelerations.
Topics: Animals; Autonomic Nervous System; Blood Flow Velocity; Blood Pressure; Carotid Arteries; Constriction; Femoral Artery; Fetal Heart; Heart Rate, Fetal; Hemodynamics; Reflex; Sheep, Domestic; Time Factors; Umbilical Cord; Uterine Contraction; Vagotomy; Ventricular Function
PubMed: 33533313
DOI: 10.1152/ajpregu.00357.2020 -
BMC Cardiovascular Disorders Jul 2020The activity of autonomic nervous system and its association with organ damage have not been entirely elucidated in hemorrhagic shock. The aim of this study was to...
BACKGROUND
The activity of autonomic nervous system and its association with organ damage have not been entirely elucidated in hemorrhagic shock. The aim of this study was to investigate heart rate variability (HRV) and pulmonary gas exchange in hemorrhagic shock during unilateral subdiaphragmatic vagotomy.
METHODS
Male Sprague Dawley rats were randomly assigned into groups of Sham, vagotomized (Vag), hemorrhagic shock (HS) and Vag + HS. HS was induced in conscious animals by blood withdrawal until reaching to mean arterial blood pressure (MAP) of 40 ± 5 mmHg. Then, it was allowed to MAP returning toward the basal values. MAP and heart rate (HR) were recorded throughout the experiments, HRV components of low (LF, sympathetic index), high (LH, parasympathetic index), and very low (VLF, injury index) frequencies and the LF/HF ratio calculated, and the lung histological and blood gas parameters assessed.
RESULTS
In the initial phases of HS, the increase in HR with no change in MAP were observed in both HS and Vag + HS groups, while LF increased only in the HS group. In the second phase, HR and MAP decreased sharply in the HS group, whereas, only MAP decreased in the Vag + HS group. Meanwhile, LF and HF increased relative to their baselines in the HS and Vag + HS groups, even though the values were much pronounced in the HS group. In the third phase, HR, MAP, LF, HF, and the LF/HF ratio were returned back to their baselines in both HS and Vag + HS groups. In the Vag + HS group, the VLF was lower and HR was higher than those in the other groups. Furthermore, blood gas parameters and lung histology indicated the impairment of gas exchange in the Vag + HS group.
CONCLUSIONS
The sympathetic activity is predominant in the first phase, whereas the parasympathetic activity is dominant in the second and third phases of hemorrhagic shock. There is an inverse relationship between the level of VLF and lung injury in vagotomized animals subjected to hemorrhagic shock.
Topics: Animals; Arterial Pressure; Disease Models, Animal; Heart; Heart Rate; Lung; Lung Injury; Male; Pulmonary Gas Exchange; Rats, Sprague-Dawley; Shock, Hemorrhagic; Sympathetic Nervous System; Time Factors; Vagotomy; Vagus Nerve
PubMed: 32652932
DOI: 10.1186/s12872-020-01606-x -
BMB Reports Mar 2024The stomach has emerged as a crucial endocrine organ in the regulation of feeding since the discovery of ghrelin. Gut-derived hormones, such as ghrelin and...
The stomach has emerged as a crucial endocrine organ in the regulation of feeding since the discovery of ghrelin. Gut-derived hormones, such as ghrelin and cholecystokinin, can act through the vagus nerve. We previously reported the satiety effect of hypothalamic clusterin, but the impact of peripheral clusterin remains unknown. In this study, we administered clusterin intraperitoneally to mice and observed its ability to suppress fasting-driven food intake. Interestingly, we found its synergism with cholecystokinin and antagonism with ghrelin. These effects were accompanied by increased c-fos immunoreactivity in nucleus tractus solitarius, area postrema, and hypothalamic paraventricular nucleus. Notably, truncal vagotomy abolished this response. The stomach expressed clusterin at high levels among the organs, and gastric clusterin was detected in specific enteroendocrine cells and the submucosal plexus. Gastric clusterin expression decreased after fasting but recovered after 2 hours of refeeding. Furthermore, we confirmed that stomachspecific overexpression of clusterin reduced food intake after overnight fasting. These results suggest that gastric clusterin may function as a gut-derived peptide involved in the regulation of feeding through the gut-brain axis. [BMB Reports 2024; 57(3): 149-154].
Topics: Mice; Animals; Ghrelin; Eating; Clusterin; Cholecystokinin; Stomach; Feeding Behavior
PubMed: 37817436
DOI: 10.5483/BMBRep.2023-0117 -
Neurobiology of Disease Jan 2023Multiple sclerosis (MS) is the most common demyelinating disease that attacks the central nervous system. Dietary intake of cuprizone (CPZ) produces demyelination...
Multiple sclerosis (MS) is the most common demyelinating disease that attacks the central nervous system. Dietary intake of cuprizone (CPZ) produces demyelination resembling that of patients with MS. Given the role of the vagus nerve in gut-microbiota-brain axis in development of MS, we performed this study to investigate whether subdiaphragmatic vagotomy (SDV) affects demyelination in CPZ-treated mice. SDV significantly ameliorated demyelination and microglial activation in the brain compared with sham-operated CPZ-treated mice. Furthermore, 16S ribosomal RNA analysis revealed that SDV significantly improved the abnormal gut microbiota composition of CPZ-treated mice. An untargeted metabolomic analysis demonstrated that SDV significantly improved abnormal blood levels of metabolites in CPZ-treated mice compared with sham-operated CPZ-treated mice. Notably, there were correlations between demyelination or microglial activation in the brain and the relative abundance of several microbiome populations, suggesting a link between gut microbiota and the brain. There were also correlations between demyelination or microglial activation in the brain and blood levels of metabolites. Together, these data suggest that CPZ produces demyelination in the brain through the gut-microbiota-brain axis via the subdiaphragmatic vagus nerve.
Topics: Animals; Mice; Brain; Cuprizone; Demyelinating Diseases; Disease Models, Animal; Mice, Inbred C57BL; Microbiota; Microglia; Multiple Sclerosis; Vagus Nerve
PubMed: 36493975
DOI: 10.1016/j.nbd.2022.105951