The ability of nutrients in the intestinal lumen to exert negative feedback control over proximal gastrointestinal function is well recognized, yet the control mechanisms are poorly defined. Extrinsic sensory pathways from the intestine and CCK are required for this regulatory process. The interaction between CCK and activation of intestinal sensory neurons is the focus of this proposal, which addresses the fundamental mechanism by which lumenal events are signalled to extrinsic sensory nerves. The hypothesis to be tested is that nutrients in the intestinal lumen stimulate from endocrine cells release of CCK that acts locally to stimulate intestinal sensory terminals resulting in reflex changes in gastric function. To test this hypothesis, studies with the following specific aims are proposed: (1) to determine that increased discharge in afferents in response to intestinal nutrients is dependent on CCK A receptor activation; (2) to determine that the functional response (inhibition of gastric motor function) to intestinal nutrients is dependent on a post-absorptive signal; and (3) to determine that activation of sensory pathways by intestinal nutrients alters gastric function via vagal and spinal reflex pathways. A combined experimental approach using electrophysiological recording of vagal afferent fiber discharge, in vivo physiology and functional anatomy of reflex pathways using Fos protein immunoreactivity as a marker for cell activation will be used to address these specific aims. The proposal is focused on determining a fundamental mechanism by which changes in lumenal content are signalled to afferent terminals located in the mucosal epithelium. This process is important in the regulation of normal digestive function. In addition, these mechanism may be disturbed in clinical condiitons were feedback from the intestine may be altered such as following abdominal surgery, alterations in feeding behaviors, such as obesity, anorexia and bulimia, and in functional bowel disease.
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