The overall aim of this investigation is to understand how the CNS uses afferent input from the upper GI tract to regulate energy balance and body weight. The working hypothesis is that the normal internal signal for termination of food ingestion involves integration of multiple negative feedback signals produced by the presence of food in the upper GI tract, well before digestive absorption of metabolic fuels. The proposal outlines a series of neurophysiological experiments to elucidate the neuro-humoral basis of energy balance. These experiments will: 1) identify and characterize short term meal-related gut neurophysiological signals, 2) determine their representation and integration at peripheral vagal and central brainstem nervous system sites, and 3) evaluate how they are interpreted in the context of the neuro-humoral signals related to the long-term control and mobilization of stored fuels. Focusing on the sensory vagus nerve and its CNS projections as the main neuroanatomical pathway linking the upper gastrointestinal sites exposed to nutrients during a meal and the CNS sites mediating the control of food intake, experiments will characterize vagal afferent responses arising from nutrient contact with the duodenum. Further experiments will determine the extent to which these responses are secondary to and/or modulated by exogenous administration of gut-brain peptides normally released by the duodenal presence of nutrients. Specific chemical blockade of macro nutrient absorption will evaluate the degree to which vagal afferent transduction of duodenal nutrient chemosensitivity is mediated by the absorptive process. Single unit extracellular neurophysiological recordings will assess the neural brainstem representation of signals arising from individual and combined meal-related stimulation of multiple alimentary tract compartments, including stomach and duodenum. Central administration of putative long-term energy balance peptides modifies meal-related brainstem neurophysiological signals from the gut.
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