Adults in the United States today are consuming ~300-500 kcal per day more compared to adults in 1980 20,21, a phenomenon underlying the fact that obesity prevalence in the United States has increased by 75% in the past 30 years 18,19. The development of more effective pharmacological treatments for obesity requires a better understanding of the neurobiological systems controlling the excessive food seeking and consumption that is triggered by exposure to environmental stimuli associated with palatable, easily accessible foods (e.g., those high % fat content and simple sugars). Research in the present proposal is distinct from, yet thematically linked to the applicant's K01 award and is designed to deepen understanding of the functional neural circuitry underlying cue-potentiated hyperphagia of palatable Western foods. Experiments build directly on recent published work from the applicant and from unpublished pilot data recently collected during his K01 award to explore the hypothesis that the gut-derived hunger hormone ghrelin signals on receptors in the ventral hippocampal formation (vHPF) to control cue-potentiated hyperphagia via neural communication to neurons in the lateral hypothalamic area (LHA) that produce the neuropeptide orexin-A. This hypothesis will be assessed by, 1) determining whether neural communication from the vHPF to the LHA is required for the hyperphagia induced by vHPF ghrelin signaling (using a neuronal disconnection approach), and by 2) examining whether vHPF neurons that are activated by ghrelin project to orexin-producing neurons in the LHA (using tract tracing and immunohistochemical strategies), and 3) by examining whether vHPC -> LHA projecting neurons synapse on LHA neurons that produce the food intake stimulating neuropeptide, orexin-A. A second set of experiments will examine the ascending pathways from LHA orexin A-producing neurons that control excessive food seeking and hyperphagia in response to environmental food cues. Preliminary data collected during the applicant's K01 award demonstrate that LHA orexin-producing neurons project to the medial prefrontal cortex (mPFC), and that the orexin-1 receptor (ORX1-R) signaling in the mPFC increases food intake in rats. Experiments will build on these findings using behavioral and genetic (viral vector-mediated RNA-interference) methodologies to determine whether mPFC ORX1-R signaling is physiologically relevant for food-seeking and excessive consumption of food in response to environmental food-related stimuli. These experiments directly complement those of the applicant's K01 award that focus on how the adipose-derived hormone leptin acts in the vHPF to influence food-motivated behaviors. Results from the experiments in this R03 proposal, combined with results from the applicant's K01 award will: 1) substantially bolster the development of a successful independent research program for the applicant that will be competitive for NIH R01 funding in the near future, and 2) deepen understanding of the neuropeptidergic systems controlling excessive food intake.