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Science Advances Jan 2022Myocardial ischemia is spontaneous, frequently asymptomatic, and contributes to fatal cardiovascular consequences. Importantly, myocardial sensory networks cannot...
Myocardial ischemia is spontaneous, frequently asymptomatic, and contributes to fatal cardiovascular consequences. Importantly, myocardial sensory networks cannot reliably detect and correct myocardial ischemia on their own. Here, we demonstrate an artificially intelligent and responsive bioelectronic medicine, where an artificial neural network (ANN) supplements myocardial sensory networks, enabling reliable detection and correction of myocardial ischemia. ANNs were first trained to decode spontaneous cardiovascular stress and myocardial ischemia with an overall accuracy of ~92%. ANN-controlled vagus nerve stimulation (VNS) significantly mitigated major physiological features of myocardial ischemia, including ST depression and arrhythmias. In contrast, open-loop VNS or ANN-controlled VNS following a caudal vagotomy essentially failed to reverse cardiovascular pathophysiology. Last, variants of ANNs were used to meet clinically relevant needs, including interpretable visualizations and unsupervised detection of emerging cardiovascular stress. Overall, these preclinical results suggest that ANNs can potentially supplement deficient myocardial sensory networks via an artificially intelligent bioelectronic medicine system.
PubMed: 34985951
DOI: 10.1126/sciadv.abj5473 -
Clinical Psychopharmacology and... May 2022Gut-microbiota-brain axis plays a role in the pathogenesis of Parkinson's disease (PD). The subdiaphragmatic vagus nerve serves as a major modulatory pathway between the...
OBJECTIVE
Gut-microbiota-brain axis plays a role in the pathogenesis of Parkinson's disease (PD). The subdiaphragmatic vagus nerve serves as a major modulatory pathway between the gut microbiota and the brain. However, the role of subdiaphragmatic vagus nerve in PD pathogenesis are unknown. Here, we investigated the effects of subdiaphragmatic vagotomy (SDV) on the neurotoxicity in the mouse striatum and colon after administration of 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP).
METHODS
Sham or SVD was performed. Subsequently, saline or MPTP (10 mg/kg × 3, 2-hour interval) was administered to mice. Western blot analysis of tyrosine hydroxylase (TH) and dopamine transporter (DAT) in the striatum and phosphorylated α-synuclein (p-α-Syn) in the colon was performed.
RESULTS
Repeated administration of MPTP significantly caused reduction of TH and DAT in the striatum and increase of p-α-Syn in the colon of mice. However, SDV did not affect the reduction of TH and DAT in the striatum and increases in p-α-Syn in the colon after repeated MPTP administration.
CONCLUSION
These data suggest that subdiaphragmatic vagus nerve doses not play a role in the MPTP-induced neurotoxicity in the brain and colon.
PubMed: 35466109
DOI: 10.9758/cpn.2022.20.2.389 -
PloS One 2020Lung volume is modulated by sensory afferent feedback via vagal and spinal pathways. The purpose of this study was to systematically alter afferent feedback with and...
Lung volume is modulated by sensory afferent feedback via vagal and spinal pathways. The purpose of this study was to systematically alter afferent feedback with and without a mechanical challenge (chest compression). We hypothesized that manipulation of afferent feedback by nebulization of lidocaine, extra-thoracic vagotomy, or lidocaine administration to the pleural space would produce differential effects on the motor pattern of breathing during chest compression in sodium pentobarbital anesthetized rats (N = 43). Our results suggest that: 1) pulmonary stretch receptors are not the sole contributor to breathing feedback in adult male and female rats; 2) of our manipulations, chest compression had the largest effect on early expiratory diaphragm activity ("yield"); 3) reduction of spinally-mediated afferent feedback modulates breathing patterns most likely via inhibition; and 4) breathing parameters demonstrate large sex differences. Compared to males, female animals had lower respiratory rates (RR), which were further depressed by vagotomy, while chest compression increased RR in males, and decreased yield in females without changing RR. Collectively, our results suggest that balance between tonic vagal inhibition and spinal afferent feedback maintains breathing characteristics, and that it is important to specifically evaluate sex differences when studying control of breathing.
Topics: Afferent Pathways; Animals; Cardiopulmonary Resuscitation; Female; Lidocaine; Male; Nebulizers and Vaporizers; Rats, Sprague-Dawley; Respiration; Sex Factors; Vagotomy; Vagus Nerve
PubMed: 32555612
DOI: 10.1371/journal.pone.0234193 -
World Journal of Surgical Oncology Jul 2023The interplay between the nervous system and cancer plays an important role in the initiation and progression of gastric cancer. Few studies have presented evidence that...
BACKGROUND
The interplay between the nervous system and cancer plays an important role in the initiation and progression of gastric cancer. Few studies have presented evidence that the sympathetic nervous system inhibits the occurrence and development of gastric cancer while the parasympathetic nervous system promotes the growth of gastric cancer. To investigate the effect of vagotomy, which is the resection of a parasympathetic nerve innervating the stomach, on the progression of gastric cancer, a retrospective study was conducted comparing the prognosis of simple palliative gastrojejunostomy (PGJ) and palliative gastrojejunostomy with vagotomy (PGJV).
METHODS
From January 01, 2000, to December 31, 2021, the medical records of patients who underwent PGJ or PGJV because of gastric outlet obstruction due to incurable advanced gastric cancer at the Yeungnam University Medical Center were retrospectively reviewed. Patients were divided into two groups: locally unresectable gastric cancer (LUGC) or gastric cancer with distant metastasis (GCDM), according to the reason for gastrojejunostomy, and factors affecting overall survival (OS) were analyzed.
RESULTS
There was no significant difference in surgical outcomes and postoperative complications between the patients with PGJV and patients with PGJ. In univariate analysis, vagotomy was not a significant factor for OS in the GCDM group (HR 1.14, CI 0.67-1.94, p value 0.642), while vagotomy was a significant factor for OS in the LUGC group (HR 0.38, CI 0.15-0.98, p value 0.045). In multivariate analysis, when vagotomy is performed together with PGJ for LUGC, the OS can be significantly extended (HR 0.25, CI 0.09-0.068, p value 0.007).
CONCLUSIONS
When PGJ for LUGC was performed with vagotomy, additional survival benefits could be achieved with low complication risk. However, to confirm the effect of vagotomy on the growth of gastric cancer, further prospective studies using large sample sizes are essential.
Topics: Humans; Retrospective Studies; Stomach Neoplasms; Case-Control Studies; Palliative Care; Prospective Studies; Vagotomy; Gastric Outlet Obstruction
PubMed: 37480111
DOI: 10.1186/s12957-023-03111-9 -
Molecular Medicine (Cambridge, Mass.) Dec 2020Increasing number of studies provide evidence that the vagus nerve stimulation (VNS) dampens inflammation in peripheral visceral organs. However, the effects of afferent...
BACKGROUND
Increasing number of studies provide evidence that the vagus nerve stimulation (VNS) dampens inflammation in peripheral visceral organs. However, the effects of afferent fibers of the vagus nerve (AFVN) on anti-inflammation have not been clearly defined. Here, we investigate whether AFVN are involved in VNS-mediated regulation of hepatic production of proinflammatory cytokines.
METHODS
An animal model of hepatitis was generated by intraperitoneal (i.p.) injection of concanavalin A (ConA) into rats, and electrical stimulation was given to the hepatic branch of the vagus nerve. AFVN activity was regulated by administration of capsaicin (CAP) or AP-5/CNQX and the vagotomy at the hepatic branch of the vagus nerve (hVNX). mRNA and protein expression in target tissues was analyzed by RT-PCR, real-time PCR, western blotting and immunofluorescence staining. Hepatic immune cells were analyzed by flow cytometry.
RESULTS
TNF-α, IL-1β, and IL-6 mRNAs and proteins that were induced by ConA in the liver macrophages were significantly reduced by the electrical stimulation of the hepatic branch of the vagus nerve (hVNS). Alanine transaminase (ALT) and aspartate transaminase (AST) levels in serum and the number of hepatic CD4 and CD8 T cells were increased by ConA injection and downregulated by hVNS. CAP treatment deteriorated transient receptor potential vanilloid 1 (TRPV1)-positive neurons and increased caspase-3 signals in nodose ganglion (NG) neurons. Concomitantly, CAP suppressed choline acetyltransferase (ChAT) expression that was induced by hVNS in DMV neurons of ConA-injected animals. Furthermore, hVNS-mediated downregulation of TNF-α, IL-1β, and IL-6 expression was hampered by CAP treatment and similarly regulated by hVNX and AP-5/CNQX inhibition of vagal feedback loop pathway in the brainstem. hVNS elevated the levels of α7 nicotinic acetylcholine receptors (α7 nAChR) and phospho-STAT3 (Tyr705; pY-STAT3) in the liver, and inhibition of AFVN activity by CAP, AP-5/CNQX and hVNX or the pharmacological blockade of hepatic α7 nAChR decreased STAT3 phosphorylation.
CONCLUSIONS
Our data indicate that the activity of AFVN contributes to hepatic anti-inflammatory responses mediated by hVNS in ConA model of hepatitis in rats.
Topics: Animals; Biomarkers; Chemotaxis, Leukocyte; Concanavalin A; Cytokines; Disease Models, Animal; Disease Susceptibility; Gene Expression; Hepatitis; Immunohistochemistry; Inflammation Mediators; Male; Neurons; Rats; STAT3 Transcription Factor; Vagotomy; Vagus Nerve; Vagus Nerve Stimulation; alpha7 Nicotinic Acetylcholine Receptor
PubMed: 33272194
DOI: 10.1186/s10020-020-00247-2 -
Frontiers in Neuroscience 2021The lateral habenula (LHb) plays essential roles in behavioral responses to stressful events. Stress is tightly linked to autonomic responses such as cardiovascular...
The lateral habenula (LHb) plays essential roles in behavioral responses to stressful events. Stress is tightly linked to autonomic responses such as cardiovascular responses, yet how the LHb regulates these responses is not well understood. To address this issue, we electrically stimulated the LHb in rats, measured its effects on heart rate (HR) and mean arterial pressure (MAP), and investigated the neural circuits that mediate these LHb-induced cardiovascular responses the autonomic nervous system. We observed that stimulation of the LHb induced bradycardia and pressor responses, whereas stimulation of the adjacent areas changed neither the HR nor the MAP. Bilateral vagotomy and administration of a muscarinic receptor antagonist suppressed the LHb stimulation effect on the HR but not on the MAP, whereas administration of a β-adrenoceptor antagonist partly attenuated the effect on the MAP but not on the HR. Thus, the LHb-induced cardiovascular responses of the HR and the MAP were likely caused by activations of the cardiac parasympathetic nerves and the cardiovascular sympathetic nerves, respectively. Furthermore, administration of a non-selective 5-HT receptor antagonist significantly attenuated the LHb stimulation effects on both the MAP and the HR. A 5-HT receptor antagonist also attenuated the LHb stimulation effects. A low dose of a 5-HT receptor antagonist enhanced the LHb stimulation effects, but a high dose of the drug attenuated them. 5-HT and 5-HT receptor antagonists as well as a 5-HT receptor antagonist did not affect the LHb stimulation effects. Taken together, our findings suggest that the LHb regulates autonomic cardiovascular responses at least partly through the serotonergic system, particularly the 5-HT and 5-HT receptors.
PubMed: 33854416
DOI: 10.3389/fnins.2021.655617 -
Scientific Reports Jul 2021Reflex cardiorespiratory alterations elicited after instillation of nociceptive agents intra-arterially (i.a) are termed as 'vasosensory reflex responses'. The present...
Reflex cardiorespiratory alterations elicited after instillation of nociceptive agents intra-arterially (i.a) are termed as 'vasosensory reflex responses'. The present study was designed to evaluate such responses produced after i.a. instillation of histamine (1 mM; 10 mM; 100 mM) and to delineate the pathways i.e. the afferents and efferents mediating these responses. Blood pressure, electrocardiogram and respiratory excursions were recorded before and after injecting saline/histamine, in a local segment of femoral artery in urethane anesthetized rats. Paw edema and latencies of responses were also estimated. Separate groups of experiments were conducted to demonstrate the involvement of somatic nerves in mediating histamine-induced responses after ipsilateral femoral and sciatic nerve sectioning (+NX) and lignocaine pre-treatment (+Ligno). In addition, another set of experiments was performed after bilateral vagotomy (+VagX) and the responses after histamine instillation were studied. Histamine produced concentration-dependent hypotensive, bradycardiac, tachypnoeic and hyperventilatory responses of shorter latencies (2-7 s) favouring the neural mechanisms in eliciting the responses. Instillation of saline (time matched control) in a similar fashion produced no response, excluding the possibilities of ischemic/stretch effects. Paw edema was absent in both hind limbs indicating that the histamine did not reach the paws and did not spill out into the systemic circulation. +NX, +VagX, +Ligno attenuated histamine-induced cardiorespiratory responses significantly. These observations conclude that instillation of 10 mM of histamine produces optimal vasosensory reflex responses originating from the local vascular bed; afferents and efferents of which are mostly located in ipsilateral somatic and vagus nerves respectively.
Topics: Afferent Pathways; Animals; Blood Pressure; Bradycardia; Endothelium, Vascular; Heart Rate; Histamine; Hyperventilation; Male; Peripheral Nervous System; Rats; Reflex; Tachypnea; Vagus Nerve; Vasodilation
PubMed: 34282171
DOI: 10.1038/s41598-021-94110-x -
Biomedicine & Pharmacotherapy =... Apr 2024The induction of intestinal inflammation as a result of abdominal surgery is an essential factor in postoperative ileus (POI) development. Electroacupuncture (EA) at...
BACKGROUND
The induction of intestinal inflammation as a result of abdominal surgery is an essential factor in postoperative ileus (POI) development. Electroacupuncture (EA) at ST36 has been demonstrated to relieve intestinal inflammation and restore gastrointestinal dysmotility in POI. This study aims to elucidate the neuroimmune pathway involved in the anti-inflammatory properties of EA in POI.
METHODS
After intestinal manipulation (IM) was performed to induce POI, intestinal inflammation and motility were assessed 24 h post-IM, by evaluating gastrointestinal transit (GIT), cytokines expression, and leukocyte infiltration. Experimental surgery, pharmacological intervention, and genetic knockout mice were used to elucidate the neuroimmune mechanisms of EA.
RESULTS
EA at ST36 significantly improved GIT and reduced the expression of pro-inflammatory cytokines and leukocyte infiltration in the intestinal muscularis following IM in mice. The anti-inflammatory effectiveness of EA treatment was abolished by sub-diaphragmatic vagotomy, whereas splenectomy did not hinder the anti-inflammatory benefits of EA treatment. The hexamethonium chloride (HEX) administration contributes to a notable reduction in the EA capacity to suppress inflammation and enhance motility dysfunction, and EA is ineffective in α7 nicotinic acetylcholine receptor (α7nAChR) knockout mice.
CONCLUSIONS
EA at ST36 prevents intestinal inflammation and dysmotility through a neural circuit that requires vagal innervation but is independent of the spleen. Further findings revealed that the process involves enteric neurons mediating the vagal signal and requires the presence of α7nAChR. These findings suggest that utilizing EA at ST36 may represent a possible therapeutic approach for POI and other immune-related gastrointestinal diseases.
Topics: Mice; Animals; alpha7 Nicotinic Acetylcholine Receptor; Electroacupuncture; Ileus; Inflammation; Cytokines; Signal Transduction; Anti-Inflammatory Agents; Mice, Knockout; Postoperative Complications
PubMed: 38471276
DOI: 10.1016/j.biopha.2024.116387 -
American Journal of Physiology.... Sep 2019An esophago-esophageal contractile reflex (EECR) of the cervical esophagus has been identified in humans. The aim of this study was to characterize and determine the...
An esophago-esophageal contractile reflex (EECR) of the cervical esophagus has been identified in humans. The aim of this study was to characterize and determine the mechanisms of the EECR. Cats ( = 35) were decerebrated, electrodes were placed on pharynx and cervical esophagus, and esophageal motility was recorded using manometry. All areas of esophagus were distended to locate and quantify the EECR. The effects of esophageal perfusion of NaCl or HCl, vagus nerve or pharyngoesophageal nerve (PEN) transection, or hexamethonium administration (5 mg/kg iv) were determined. We found that distension of the esophagus at all locations activated EECR rostral to stimulus only. EECR response was greatest when the esophagus 2.5-11.5 cm from cricopharyngeus (CP) was distended. HCl perfusion activated repetitively an EECR-like response of the proximal esophagus only within 2 min, and after ~20 min EECR was inhibited. Transection of PEN blocked or inhibited EECR 1-7 cm from CP, and vagotomy blocked EECR at all locations. Hexamethonium blocked EECR at 13 and 16 cm from CP but sensitized its activation at 1-7 cm from CP. EECR of the entire esophagus exists, which is directed in the orad direction only. EECR of striated muscle esophagus is mediated by vagus nerve and PEN and inhibited by mechanoreceptors of smooth muscle esophagus. EECR of smooth muscle esophagus is mediated by enteric nervous system and vagus nerve. Activation of EECR of the striated muscle esophagus is initially sensitized by HCl exposure, which may have a role in prevention of supraesophageal reflux. An esophago-esophageal contractile reflex (EECR) exists, which is directed in the orad direction only. EECR of the proximal esophagus can appear similar to and be mistaken for secondary peristalsis. The EECR of the striated muscle is mediated by the vagus nerve and pharyngoesophageal nerve and inhibited by mechanoreceptor input from the smooth muscle esophagus. HCl perfusion initially sensitizes activation of the EECR of the striated muscle esophagus, which may participate in prevention of supraesophageal reflux.
Topics: Animals; Cats; Deglutition; Esophagus; Female; Hexamethonium; Male; Muscle Contraction; Muscle, Skeletal; Muscle, Smooth; Muscle, Striated; Peristalsis; Reflex; Vagus Nerve
PubMed: 31268772
DOI: 10.1152/ajpgi.00138.2019 -
Journal of Neuroinflammation Jul 2019Determining the etiology and possible treatment strategies for numerous diseases requires a comprehensive understanding of compensatory mechanisms in physiological...
BACKGROUND
Determining the etiology and possible treatment strategies for numerous diseases requires a comprehensive understanding of compensatory mechanisms in physiological systems. The vagus nerve acts as a key interface between the brain and the peripheral internal organs. We set out to identify mechanisms compensating for a lack of neuronal communication between the immune and the central nervous system (CNS) during infection.
METHODS
We assessed biochemical and central neurotransmitter changes resulting from subdiaphragmatic vagotomy and whether they are modulated by intraperitoneal infection. We performed a series of subdiaphragmatic vagotomy or sham operations on male Wistar rats. Next, after full, 30-day recovery period, they were randomly assigned to receive an injection of Escherichia coli lipopolysaccharide or saline. Two hours later, animal were euthanized and we measured the plasma concentration of prostaglandin E2 (with HPLC-MS), interleukin-6 (ELISA), and corticosterone (RIA). We also had measured the concentration of monoaminergic neurotransmitters and their metabolites in the amygdala, brainstem, hippocampus, hypothalamus, motor cortex, periaqueductal gray, and prefrontal medial cortex using RP-HPLC-ED. A subset of the animals was evaluated in the elevated plus maze test immediately before euthanization.
RESULTS
The lack of immunosensory signaling of the vagus nerve stimulated increased activity of discrete inflammatory marker signals, which we confirmed by quantifying biochemical changes in blood plasma. Behavioral results, although preliminary, support the observed biochemical alterations. Many of the neurotransmitter changes observed after vagotomy indicated that the vagus nerve influences the activity of many brain areas involved in control of immune response and sickness behavior. Our studies show that these changes are largely eliminated during experimental infection.
CONCLUSIONS
Our results suggest that in vagotomized animals with blocked CNS, communication may transmit via a pathway independent of the vagus nerve to permit restoration of CNS activity for peripheral inflammation control.
Topics: Animals; Brain; Inflammation; Lipopolysaccharides; Male; Neuroimmunomodulation; Rats; Rats, Wistar; Vagotomy; Vagus Nerve
PubMed: 31324250
DOI: 10.1186/s12974-019-1544-y