Studies of Brainstem Control of Vagal Outflow to the Stomach

The vagus nerve is a vital component of the brain-gut axis by which the activity of the gastrointestinal tract, particularly the stomach is modulated by the CNS. Through two distinct sphincters, the lower esophageal sphincter (LES) and the pylorus, it regulates the entry of food into the stomach and the exit of chyme, as an end product out of it. The neural mechanisms underlying these activities are well established for the LES and to a lesser extent for the stomach. However, for the pylorus, little is known about the central neural processes that regulate its activity. The objectives of my thesis project were first to determine this by identifying the brain nuclei that make up the neural pathway, which innervates the pyloric sphincter. Second, to establish if stimulating one of the nuclei of this pathway, the dorsal motor nucleus of the vagus (DMV) would influence its activity in a site-specific manner, similar to that seen with LES. In addition, the identity of the neurotransmitters employed by this neural pathway to influence pyloric activity was also examined.;Besides the anatomical and functional studies of the pyloric sphincter, my thesis project also attempted to understand the impact of melanocortin receptors on gastric tone and motility in the brainstem nuclei, DMV and medial subnucleus of the solitary tract (mNTS). These receptors are densely distributed in these nuclei and have been shown to modulate food intake and body weight.;To accomplish my thesis aims, two techniques were employed: (1) neuroanatomical tract-tracing using a transneuronal tracer, pseudorabies virus (PRV), that was injected into the pylorus, antrum and fundus to identify neural circuitries associated with these gastric regions, and (2) microinjection of L-Glutamate and various drugs within the rostrocaudal extent of the DMV and the NTS, while recording pyloric/gastric tone and motility.;My results show that PRV injected into the pylorus, antrum and fundus labels higher order nuclei throughout the hindbrain and the forebrain that have distinct differences in transneuronal labeling. They also provide evidence that the DMV can differentially influence the activity of the pyloric sphincter. Thus, stimulation of the rostral part of the DMV results in pyloric contractions that are blocked by both ipsilateral vagotomy and intravenous administration of atropine methyl bromide. In contrast, stimulation of the caudal DMV produces a significant decrease in pyloric tone and inhibits phasic contractions, which are blocked by ipsilateral vagotomy but not by intravenous administration of L-NAME, suramin, or atropine methyl bromide.;My studies also present data showing a functional role for brainstem melanocortin receptors in gastric tone and motility. In particular, activation of these receptors in the DMV by the endogenous melanocortin agonist &agr;-MSH produces a short-lasting increase in the frequency and amplitude of gastric phasic contractions. Stimulation of the mNTS by the same agonist produces a decrease in both gastric tone and motility that is similarly of brief duration. The DMV-mediated excitatory responses are blocked by ipsilateral vagotomy and the MC4R antagonist SHU9119, whereas, the mNTS-mediated inhibitory responses are blocked by SHU9119 and the glutamate antagonist, kynurenic acid.;In comparison to the endogenous agonist, the selective MC4R agonist MT-II causes a long-lasting effect on the amplitude of gastric contractions in both the DMV and the NTS. However, unlike the endogenous agonist, microinjection of this synthetic analog in the DMV inhibits the amplitude of phasic contractions. In both nuclei, the effects of MT-II are blocked by vagotomy and SHU9119, but are not affected by intravenous administration of L-NAME.;Together, my thesis studies provide: (1) a neuroanatomical map of brain nuclei that comprise the neural circuitry by which the CNS may selectively control the activity of the pyloric sphincter. (2) Evidence that the activity of the pylorus can be differentially activated from the DMV in a site-specific manner; a rostral excitatory cholinergic-cholinergic pathway and a caudal inhibitory pathway whose neurotransmitter is yet to be established. (3) Novel findings that melanocortin receptors in the brainstem influence the activity of the stomach that is vagally mediated.