Role of hydrogen sulfide within the dorsal motor nucleus of the vagus in the control of gastric function in rats

Previous studies have demonstrated the efficacy of electroacupuncture at ST36 for patients with gastrointestinal motility disorders. While several lines of evidence suggest that the effect may involve vagal reflex, the precise molecular mechanism underlying this process still remains unclear. Here we report that the intragastric pressure increase induced by low frequency electric stimulation at ST36 was blocked by AP-5, an antagonist of N-methyl-D-aspartate receptors (NMDARs). Indeed, stimulating ST36 enhanced NMDAR-mediated, but not 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl)propanoic-acid-(AMPA-) receptor-(AMPAR-) mediated synaptic transmission in gastric-projecting neurons of the dorsal motor nucleus of the vagus (DMV). We also identified that suppression of presynapticμ-opioid receptors may contribute to upregulation of NMDAR-mediated synaptic transmission induced by electroacupuncture at ST36. Furthermore, we determined that the glutamate-receptor-2a-(NR2A-) containing NMDARs are essential for NMDAR-mediated enhancement of gastric motility caused by stimulating ST36. Taken together, our results reveal an important role of NMDA receptors in mediating enhancement of gastric motility induced by stimulating ST36.

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NMDA Receptors of Gastric-Projecting Neurons in the Dorsal Motor Nucleus of the Vagus Mediate the Regulation of Gastric Emptying by EA at Weishu (BL21)

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2012/583479 ◽

2012 ◽

Vol 2012 ◽

pp. 1-7 ◽

Cited By ~ 4

Author(s):

Xin Zhang ◽

Bin Cheng ◽

Xianghong Jing ◽

Yongfa Qiao ◽

Xinyan Gao ◽

...

Keyword(s):

Gastric Emptying ◽

Nmda Receptor ◽

Ampa Receptor ◽

Gastrointestinal Motility ◽

Kynurenic Acid ◽

Basic Mechanism ◽

Motor Nucleus ◽

Dorsal Motor Nucleus ◽

Lines Of Evidence

A large number of studies have been conducted to explore the efficacy of electroacupuncture (EA) for the treatment of gastrointestinal motility. While several lines of evidence addressed the basic mechanism of EA on gastrointestinal motility regarding effects of limb and abdomen points, the mechanism for effects of the back points on gastric motility still remains unclear. Here we report that the NMDA receptor (NMDAR) antagonist kynurenic acid inhibited the gastric emptying increase induced by high-intensity EA at BL21 and agonist NMDA enhanced the effect of the same treatment. EA at BL21 enhanced NMDAR, but not AMPA receptor (AMPAR) component of miniature excitatory postsynaptic current (mEPSC) in gastric-projecting neurons of the dorsal motor nucleus of the vagus (DMV). In sum, our data demonstrate an important role of NMDAR-mediated synaptic transmission of gastric-projecting DMV neurons in mediating EA at BL21-induced enhancement of gastric emptying.

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Glutamatergic plasticity within neurocircuits of the dorsal vagal complex and the regulation of gastric functions

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00014.2021 ◽

2021 ◽

Author(s):

Courtney Clyburn ◽

Kirsteen N Browning

Keyword(s):

Food Intake ◽

Energy Homeostasis ◽

Intestinal Secretion ◽

Motor Nucleus ◽

Glutamatergic Transmission ◽

Gi Tract ◽

Dorsal Motor Nucleus ◽

Efferent Neurons ◽

Rapid Transmission

The meticulous regulation of the gastrointestinal (GI) tract is required for the co-ordination of gastric motility and emptying, intestinal secretion, absorption, and transit as well as for the overarching management of food intake and energy homeostasis. Disruption of GI functions is associated with the development of severe GI disorders as well as the alteration of food intake and caloric balance. Functional GI disorders as well as the dysregulation of energy balance and food intake are frequently associated with, or result from, alterations in the central regulation of GI control. The faithful and rapid transmission of information from the stomach and upper GI tract to second order neurons of the nucleus of the tractus solitarius (NTS) relies on the delicate modulation of excitatory glutamatergic transmission, as does the relay of integrated signals from the NTS to parasympathetic efferent neurons of the dorsal motor nucleus of the vagus (DMV). Many studies have focused on understanding the physiological and pathophysiological modulation of these glutamatergic synapses, although their role in the control and regulation of GI functions has lagged behind that of cardiovascular and respiratory functions. The purpose of this review is to examine the current literature exploring the role of glutamatergic transmission in the DVC in the regulation of Gl functions.

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GABAA receptor currents in the dorsal motor nucleus of the vagus in females: influence of ovarian cycle and 5α-reductase inhibition

Journal of Neurophysiology ◽

10.1152/jn.00039.2019 ◽

2019 ◽

Vol 122 (5) ◽

pp. 2130-2141

Author(s):

Erica L. Littlejohn ◽

Liliana Espinoza ◽

Monica M. Lopez ◽

Bret N. Smith ◽

Carie R. Boychuk

Keyword(s):

Sex Differences ◽

Motor Neurons ◽

Ovarian Cycle ◽

Receptor Activity ◽

Motor Nucleus ◽

Gabaergic Neurotransmission ◽

Physiological Processes ◽

Dorsal Motor Nucleus

The dorsal motor nucleus of the vagus (DMV) contains the preganglionic motor neurons important in the regulation of glucose homeostasis and gastrointestinal function. Despite the role of sex in the regulation of these processes, few studies examine the role of sex and/or ovarian cycle in the regulation of synaptic neurotransmission to the DMV. Since GABAergic neurotransmission is critical to normal DMV function, the present study used in vitro whole cell patch-clamping to investigate whether sex differences exist in GABAergic neurotransmission to DMV neurons. It additionally investigated whether the ovarian cycle plays a role in those sex differences. The frequency of phasic GABAA receptor-mediated inhibitory postsynaptic currents in DMV neurons from females was lower compared with males, and this effect was TTX sensitive and abolished by ovariectomy (OVX). Amplitudes of GABAergic currents (both phasic and tonic) were not different. However, females demonstrated significantly more variability in the amplitude of both phasic and tonic GABAA receptor currents. This difference was eliminated by OVX in females, suggesting that these differences were related to reproductive hormone levels. This was confirmed for GABAergic tonic currents by comparing females in two ovarian stages, estrus versus diestrus. Female mice in diestrus had larger tonic current amplitudes compared with those in estrus, and this increase was abolished after administration of a 5α-reductase inhibitor but not modulation of estrogen. Taken together, these findings demonstrate that DMV neurons undergo GABAA receptor activity plasticity as a function of sex and/or sex steroids. NEW & NOTEWORTHY Results show that GABAergic signaling in dorsal vagal motor neurons (DMV) demonstrates sex differences and fluctuates across the ovarian cycle in females. These findings are the first to demonstrate that female GABAA receptor activity in this brain region is modulated by 5α-reductase-dependent hormones. Since DMV activity is critical to both glucose and gastrointestinal homeostasis, these results suggest that sex hormones, including those synthesized by 5α-reductase, contribute to visceral, autonomic function related to these physiological processes.

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Oral-pharyngeal-esophageal and gastric cues contribute to meal-induced c-fos expression

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1995.268.1.r223 ◽

1995 ◽

Vol 268 (1) ◽

pp. R223-R230 ◽

Cited By ~ 16

Author(s):

K. A. Fraser ◽

E. Raizada ◽

J. S. Davison

Keyword(s):

Area Postrema ◽

Receptor Activation ◽

Gastric Distension ◽

Motor Nucleus ◽

Gastric Fistula ◽

Gastric Balloon ◽

Sham Feeding ◽

Dorsal Motor Nucleus ◽

Caudal Level

We recently demonstrated that a meal induces c-fos immunoreactivity in the dorsal motor nucleus of the vagus (DMV), the nucleus of the tractus solitarius (NTS), and the area postrema (AP) of the rat brain stem. This response was not eliminated by the cholecystokinin A (CCK-A) antagonist L-364,718, a finding suggesting that feeding induces c-fos immunoreactivity by a pathway that is largely independent of CCK-A receptor activation. Consequently, the role of alternative gastrointestinal cues in the induction of c-fos was investigated. The induction of c-fos after oral-pharyngeal and esophageal stimuli was examined by use of a sham-feeding procedure via a gastric fistula. Gastric fistula-closed and fed rats displayed c-fos immunoreactivity similar to that of meal-fed rats seen previously. Fistula-open and fed rats showed the same degree of staining in the more rostral section of NTS examined as fistula-closed and fed rats, but fewer c-fos-positive nuclei in the more caudal level of the NTS. The potential for gastric distension to induce c-fos was assessed after the inflation of a gastric balloon. Physiological inflation of the balloon produced marked c-fos induction primarily in the medial NTS.

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Central Neurocircuits Regulating Food Intake in Response to Gut Inputs—Preclinical Evidence

Nutrients ◽

10.3390/nu13030908 ◽

2021 ◽

Vol 13 (3) ◽

pp. 908

Author(s):

Kirsteen N. Browning ◽

Kaitlin E. Carson

Keyword(s):

Food Intake ◽

Vagus Nerve ◽

Sensory Information ◽

Specific Reference ◽

Motor Nucleus ◽

Dorsal Motor Nucleus ◽

The Central Nervous System ◽

Complex Integration ◽

The Many

The regulation of energy balance requires the complex integration of homeostatic and hedonic pathways, but sensory inputs from the gastrointestinal (GI) tract are increasingly recognized as playing critical roles. The stomach and small intestine relay sensory information to the central nervous system (CNS) via the sensory afferent vagus nerve. This vast volume of complex sensory information is received by neurons of the nucleus of the tractus solitarius (NTS) and is integrated with responses to circulating factors as well as descending inputs from the brainstem, midbrain, and forebrain nuclei involved in autonomic regulation. The integrated signal is relayed to the adjacent dorsal motor nucleus of the vagus (DMV), which supplies the motor output response via the efferent vagus nerve to regulate and modulate gastric motility, tone, secretion, and emptying, as well as intestinal motility and transit; the precise coordination of these responses is essential for the control of meal size, meal termination, and nutrient absorption. The interconnectivity of the NTS implies that many other CNS areas are capable of modulating vagal efferent output, emphasized by the many CNS disorders associated with dysregulated GI functions including feeding. This review will summarize the role of major CNS centers to gut-related inputs in the regulation of gastric function with specific reference to the regulation of food intake.

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α-Synuclein pathology in Parkinson disease activates homeostatic NRF2 anti-oxidant response

10.1101/2021.04.15.439988 ◽

2021 ◽

Author(s):

Alberto Delaidelli ◽

Mette Richner ◽

Lixiang Jiang ◽

Amelia van der Laan ◽

Ida Bergholdt Jul Christiansen ◽

...

Keyword(s):

Nervous System ◽

Parkinson Disease ◽

Redox Homeostasis ◽

Alpha Synuclein ◽

Experimental Models ◽

Motor Nucleus ◽

Related Factor ◽

Dorsal Motor Nucleus ◽

Anti Oxidant

Circumstantial evidence points to a pathological role of alpha-synuclein (aSyn; gene symbol SNCA), conferred by aSyn misfolding and aggregation, in Parkinson disease (PD) and related synucleionpathies. Several findings in experimental models implicate perturbations in the tissue homeostatic mechanisms triggered by pathological aSyn accumulation, including impaired redox homeostasis, as significant contributors in the pathogenesis of PD. The nuclear factor erythroid 2-related factor (NRF2) is recognized as the master regulator of cellular anti-oxidant response, both under physiological as well as in pathological conditions. Using immunohistochemical analyses, we show a robust nuclear NRF2 accumulation in post-mortem PD midbrain, detected by NRF2 phosphorylation on serine residue 40 (nuclear active p-NRF2, S40). Curated gene expression analyses of four independent publicly available microarray datasets revealed considerable alterations in NRF2-responsive genes in the disease affected regions in PD, including substantia nigra, dorsal motor nucleus of vagus, locus coeruleus and globus pallidus. To further examine the putative role of pathological aSyn accumulation on nuclear NRF2 response, we employed a transgenic mouse model of synucleionopathy (M83 line, Prnp-SNCA*Ala53Thr), which manifest widespread aSyn pathology (phosphorylated aSyn; S129) in the nervous system following intramuscular inoculation of exogenous fibrillar aSyn. We observed strong immunodetection of nuclear NRF2 in neuronal populations harboring p-aSyn (S129), and found an aberrant anti-oxidant and inflammatory gene response in the affected neuraxis. Taken together, our data support the notion that pathological aSyn accumulation impairs the redox homeostasis in nervous system, and boosting neuronal anti-oxidant response is potentially a promising approach to mitigate neurodegeneration in PD and related diseases.

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The Role of the Dorsal Vagal Complex and the Vagus Nerve in Feeding Effects of Melanocortin-3/4 Receptor Stimulation*

Endocrinology ◽

10.1210/endo.141.4.7410 ◽

2000 ◽

Vol 141 (4) ◽

pp. 1332-1337 ◽

Cited By ~ 89

Author(s):

Diana L. Williams ◽

Joel M. Kaplan ◽

Harvey J. Grill

Keyword(s):

Food Intake ◽

Vagus Nerve ◽

Messenger Rna ◽

Motor Nucleus ◽

Dorsal Vagal Complex ◽

Dorsal Motor Nucleus ◽

Ventricular Response ◽

Feeding Effects ◽

Diet Intake

Abstract Fourth intracerebroventricular (4th-icv) administration of the melanocortin-3/4 receptor (MC3/4-R) agonist, MTII, reduces food intake; the antagonist, SHU9119, increases feeding. The dorsal motor nucleus of the vagus nerve (DMX) contains the highest density of MC4-R messenger RNA in the brain. To explore the possibility that the DMX contributes to 4th-icv MC4-R effects, we delivered doses of MTII and SHU9119 that are subthreshold for ventricular response unilaterally through a cannula centered above the DMX. MTII markedly suppressed 2-h (50%), 4-h (50%), and 24-h (33%) intake. Feeding was significantly increased 4 h (50%) and 24 h (20%) after SHU9119 injections. These results suggest that receptors in the DMX, or the dorsal vagal complex more generally, underlie effects obtained with 4th-icv administration of these ligands. We investigated possible vagal mediation of 4th-icv MTII effects by giving the agonist to rats with subdiaphragmatic vagotomy. MTII suppressed 2-, 4-, and 24-h liquid diet intake (∼80%) to the same extent in vagotomized and surgical control rats. We conclude that stimulation or antagonism of MC3/4-Rs in the dorsal vagal complex yields effects on food intake that do not require an intact vagus nerve.

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