Disorders of appetite and feeding (including anorexia nervosa and bulimia nervosa) can have a profound impact on the quality of life and may even contribute to or cause death. Recent data indicate that certain forebrain structures, such as the hypothalamus and amygdala, play a particularly important role in feeding behavior. Unfortunately, while it is clear that these forebrain regions are important in the regulation of feeding, we know very little about the mechanism(s) of this regulation. Our preliminary studies, however, indicate that the hypothalamus and the amygdala have the ability to dramatically modify the response properties of neurons in the dorsal vagal complex. Increased or decreased activity in these descending pathways to the dorsal vagal complex has the potential to alter ascending satiety signals, modulate the cephalic phase of feeding and affect the absorption of nutrients from the gastrointestinal tract. Our data suggest that most gut-sensitive neurons in the nucleus of the solitary tract (NST) are inhibited by electrical stimulation of the paraventricular nucleus of the hypothalamus (PVN). We postulate that the NST neurons that are inhibited by the PVN will exhibit this response when the PVN is injected with neuropeptide Y (NPY) and/or galanin (GAL), with this influence mediated by the release of GAL from GAL-positive PVN neurons that terminate in the NST. We propose that the subset of NST neurons that is excited by the PVN will exhibit this response when the PVN is injected with corticotropin releasing hormone (CRH) and/or glucagon-like peptide-1 (GLP-1) and hypothesize that the excitatory influence of the PVN on the NST is mediated by bombesin-like peptides (BN-LP). Our data indicate that most of the NST neurons that respond to stimulation of the central nucleus of the amygdala (Ce) are inhibited by this input and we propose that these NST neurons will exhibit this response when the Ce is injected with GAL. We will demonstrate whether the Ce's inhibition of the NST is mediated by gamma-aminobutyric acid (GABA) and/or endogenous opioids. Finally, we will examine the response properties of gastric- and intestine-sensitive DMNV neurons that are modulated by descending inputs from the PVN. Our preliminary data indicate that the PVN inputs to the DMNV are primarily excitatory. We postulate that the DMNV neurons that are excited by the PVN will exhibit this response when the PVN is injected with NPY and/or GAL, an effect that we believe is mediated by oxytocin (OT). We will test these hypotheses with three Specific Aims that will employ a combination of extracellular and intracellular recording, intracellular labeling, microinjection of four peptides into the forebrain and picospritzer injection of multiple receptor agonists and antagonists in the dorsal vagal complex. Our goal is to provide data that will contribute to our understanding of the mechanisms underlying feeding behavior as well as form a foundation for future behavioral and pharmacological studies designed to ameliorate the devastating effects of feeding disorders.
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