CONTROL OF FEEDING BEHAVIOR--HEPATIC AFFERENT SIGNALING

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DESCRIPTION (adapted from the application) The overall objective of the proposed research is to determine the properties of neural pathways from the liver to the brain that control feeding behavior and energy balance. This project will determine the hepatic metabolic stimuli that activate vagal afferent fibers and brainstem neurons. During the career award, the candidate will learn neurophysiological techniques to record from the nervous system of the anesthetized rat; this training will advance the candidate's career goal to become an independent research scientist. Dr. Gary Schwartz, Cornell University, will provide training in the recording of vagal afferent nerve activity; the instruction will focus on the isolation of single units and stimulation of the hepatic branch of the vagus. Dr. Ralph Norgren, Pennsylvania State University, will train the candidate to record single units from the nucleus of the solitary tract (NTS; brainstem sensory relay nucleus for the vagus). Experiments will be conducted at the Monell Chemical Senses Center (Philadelphia, PA) with Dr. Mark Friedman, an expert in the metabolic control of food intake, as the primary mentor. Previous research indicates that the vagus nerve is the route of passage for signals that arise from liver metabolism to affect feeding. 2,5-anhydro-D-mannitol (2,5-AM) and mercaptoacetate (MA), are two metabolic inhibitors with different actions that stimulate feeding behavior. The effects of these metabolic inhibitors on feeding are blocked by vagotomy, which suggests a peripheral site of action for these inhibitors on feeding. In the current project 2,5-AM and MA will be infused into the portal vein to isolate the treatments to the liver, while electrophysiological recordings are done from the vagus nerve and the NTS. The effects of 2,5-A.M and MA on single unit afferent activity will be compared to determine if these treatments activate the same population of hepatic afferent fibers (and if this population is distinct from glucose-sensitive fibers). A comparison between up-stream portal vein infusion and adjacent liver infusion will determine the site of action for the effects of 2,5 -AM and MA. on vagal afferent activity. Results from this project may contribute to a better understanding of metabolic stimuli that are sensed by the nervous system, and may elucidate neural controls that are involved in obesity, anorexia, and diabetes.