PROJECT SUMMARY Obesity is a major risk factor for many chronic medical conditions, including diabetes, cardiovascular disease, depression, and cancer. Elucidating the neural networks that regulate feeding behavior and body weight control is critically needed towards the development of effective strategies to combat obesity and its co-morbidities. We recently found that the ventral subiculum (vSub), a component of the hippocampal formation, provides monosynaptic inputs to the ventromedial hypothalamus (VMH). We further revealed that these VMH-projecting vSub neurons are responsive to food, and chemogenetic activation of VMH-projecting vSub neurons suppresses food intake in mice. However, we noted that the vSub→VMH circuitry has robust collateral projections to two other brain regions, the lateral septum (LS) and the accumbens nucleus shell (AcbSh), which could also contribute to the anorexigenic effects. Thus, our first objective is to systematically dissect which of these vSub collaterals mediate anorexigenic action. Importantly, we will explore the physiological relevance of this circuit in chronic feeding and weight regulation by using a mouse model with these vSub neurons genetically ablated. We also found that cholinergic neurons in the diagonal band of Broca (DBBChAT neurons) provide extensive synaptic inputs onto vSub neurons. The second objective of this research is to examine the effects of the DBBChAT→vSub circuit on feeding, and to explore the physiological relevance of this upstream circuit in the chronic regulation of proper feeding behavior and body weight control. Further, we found that vSub neurons abundantly express the α7 subunit of nAChRs, and these cells can be activated by α7-nAChR agonists. Thus, the third objective of the proposed research is to generate mice lacking α7-nChAR from vSub neurons, and use this model to elucidate the physiological relevance of α7-nAChR within vSub circuitry towards feeding behavior and obesity development. Together, these studies will rigorously examine the functions of both the downstream outputs and upstream inputs of vSub neurons in feeding circuitry, and further identify the role of nAChR signaling in vSub neurons that suppresses feeding. Accomplishment of these studies will fill a critical gap in knowledge by identifying a novel neural circuit in the context of body weight regulation. Further, our results may provide needed framework to develop novel therapeutic strategies towards obesity treatment.