Duodenal acidification inhibits gastric antral contractions, promotes gastric fundic relaxation, and thereby protects the duodenum from excess acid exposure. Secretin plays an important role in this process, mediating duodenal acid-induced gastric relaxation by acting on vagal afferent neurons that activate vagal motor neurons, releasing VIP which then evokes gastric relaxation by way of prostaglandin pathways. The current proposal focuses on vagovagal circuits that are activated by secretin and duodenal acid. It is postulated that secretin activates vagal afferent fibers that release CGRP that then stimulates interneurons in the nucleus tractus solitarius. GABAergic neurons inhibit dorsal motor nucleus of the vagal cholinergic neurons which synapse with intragastric cholinergic neurons, while stimulation of glutaminergic neurons activate dorsal motor nucleus vagal neurons which synapse with intragastric VIP neurons. This provides a mechanism whereby single vagal afferents may concurrently excite and inhibit vagal efferent transmission producing dysfacilitation of cholinergic and activation of nonadrenergic and noncholinergic input to the stomach to optimize gastric relaxation. In the current proposal, the neurotransmitter coding utilized by vagal fibers possessing secretin receptors will be assessed by intracellular recording and labeling techniques. The intracellular mechanisms involved in secretin-stimulated release of CGRP from the nodose ganglia will be explored. Both morphologic and electrophysiologic characterization of duodenal acid and secretin-stimulated nucleus tractus solitarius neurons will be performed and their neurochemical phenotypes examined. In vivo, the secretin-induced release of glutamine and GABA will be quantified using radionucleotide tagging techniques. Finally, the dorsal motor neuron vagoneural circuits mediating the action of secretin and the roles of GABA and NMDA will be explored. This should provide a comprehensive characterization of the neural components of the vagovagal circuit activated by secretin to effect gastric relaxation.
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