Using Electrochemical Methods to Probe Neuronal Signaling in the GI Tract

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DESCRIPTION (provided by applicant): Electrochemical methods with diamond microelectrodes will be used to investigate neuronal signaling pathways in the gut wall. These methods provide a direct measure of local concentration changes of electroactive neurotransmitters near the sites of release and action with high temporal resolution. Enteric neurons contain and release many neurotransmitters and some of these can be detected by electrochemical methods, in particular, serotonin (5-HT) and nitric oxide (NO). The extension of these techniques to the study of the peripheral nervous system constitutes an interesting and significant development. Many functional GI disorders, such as disturbances in motility, absorption/secretion and sensation that do not have an identifiable pathophysiological basis, are thought to be related to dysfunction in neurogenic signaling mechanisms. The proposed research will improve our understanding of the normal motility and secretory activities of the GI tract during postnatal maturation of the intestine. These studies will lead to the discovery of age specific pathophysiologic changes in neuronal signaling responsible for functional gut disorders that lead to disease. To this end, we will apply electrochemical methods of analysis with a diamond microelectrode, to investigate two functional questions: (i) can the excitatory neurotransmitter serotonin (5-HT) and the inhibitory neurotransmitter nitric oxide (NO) be measured in the small intestine and colon of test animals and can the associated neuropharmacology controlling release and clearance be understood, and (ii) how do the 5-HT and NO signaling pathways change with postnatal maturation of the ENS? Our goal is to identify the mechanisms controlling release and clearance of 5-HT and NO in the gut wall. We will conduct these studies in vitro in the myenteric and submucosal plexuses of the small intestine (ileum and duodenum) and colon of guinea pigs and a new SERT-KO rat animal model. We also propose to expand the scope of the studies to include dopamine (DA) and norepinephrine (NE) released in the myenteric plexus. These studies, which have significant relevance for pediatric health, will be performed as a function of test animal (guinea pig) age in order to learn about the postnatal ENS development. A better understanding of neural signaling pathways in GI health and disease can be gained through measurements of local neurotransmitter concentrations in the gut wall with high spatial and temporal resolution. PUBLIC HEALTH RELEVANCE: The research will investigate the postnatal development of neuronal signaling in the gut wall that controls muscular function. This will be accomplished through in vitro electrochemical measurements of neurotransmitter concentration changes made near the sites of release and action. These studies will provide new insights into potential pathophysiological changes responsible for pediatric GI motility disturbances that would persist into adulthood and would be responsible for the prevalence of functional GI disorders in the United States.