PROJECT SUMMARY Memory of a meal provides a record of recent intake that outlasts most signals generated by the meal. Memory of a recent meal decreases intake in humans and interfering with meal-related memory encoding increases later intake. The brain regions that mediate the inhibitory effects of memory on future intake are not known. The long-term goal of this research is to elucidate the cognitive mnemonic mechanisms that control food intake. Dorsal hippocampus (dHC) is critical for memories of personal experiences and ventral hippocampus (vHC) is important for emotional memory. Both likely contribute to meal-related memory. dHC- and vHC-dependent memory typically require synaptic plasticity in glutamatergic (Glu) synapses; thus, dHC and vHC synaptic plasticity likely influences eating behavior. The melanocortin (MC) system is a strong candidate for providing meal-related signals because it integrates the actions of numerous food-related indicators and inhibits intake after ingestion. MC agonists and receptors (MCRs) are found in dHC CA1àCA3 synapses and promote Glu-dependent synaptic plasticity. The overarching hypothesis of this proposal is that eating and food-related signals mediated by MCs induce synaptic plasticity in dCA1 neurons necessary to inhibit subsequent intake, and that dHC neurons inhibit intake by activating vHC Glu neurons, which project to several brain areas critical for eating behavior. AIM 1 will determine whether dHC and vHC Glu neurons inhibit energy intake after ingestion and whether dHC Glu neurons inhibit intake by activating vHC Glu neurons. It is predicted that postmeal optical inhibition of dHC or vHC Glu neurons or dHCàvHC Glu projections will increase energy intake and that optical excitation will have the opposite effect. Inclusion of both sexes will show whether dHC and vHC control of energy intake is sex-dependent. AIM 2 will determine whether ingestion increases markers of synaptic plasticity in dHC or vHC neurons and whether synaptic plasticity is necessary for dHC and vHC inhibition of energy intake. It is predicted that ingestion will increase synaptic plasticity-associated protein activation and gene expression in dHC and vHC, optical inhibition of dHC Glu neurons will attenuate these increases in vHC, that pharmacological inhibition of synaptic plasticity will increase intake, and that long-term knock down of dHC or vHC synaptic plasticity- associated genes will increase intake, body mass and adiposity. AIM 3 will determine whether dHC MCs enhance meal-related synaptic plasticity and inhibit energy intake via Glu receptors (GluRs). It is expected that dCA1 infusions of MCR antagonists will attenuate eating-induced increases in genes and protein activation events necessary for synaptic plasticity and increase intake, body mass, and adiposity, that MCR agonists will have the opposite effect, and that pharmacological inhibition of dCA1 GluRs will interfere with the effects of MCR agonists. This project wi...