Project Summary The development of therapeutic drugs to cure obesity has not been successful due to unwanted side effects and limited efficacy. My long term research goal is to delineate neural pathways responsible for body weight homeostasis, and provide a framework for effective and specific therapeutics against obesity. Despite exciting progress has been made in understanding feeding behavior regulated by melanocortin receptors 4 (Mc4Rs) and paraventricular hypothalamus, downstream neurons that mediate their action on feeding are not clear. Our preliminary data showed that PVH neurons sent abundant projections to the ventral part of lateral septum (LSv), where a subset of leptin receptor (LepR)-expressing neurons are located. In vivo optogenetic stimulation of channelrhodopsin 2 (ChR2)-expressing PVH→LSv fibers potently inhibited feeding, suggesting a previously unappreciated role for LSv neurons in mediating the PVH action on feeding. Importantly, LSv local administration of glutamate receptor antagonists increased feeding, suggesting an ongoing tonic glutamatergic action in LSV on feeding inhibition. Based on our strong preliminary data and the established role for PVH Mc4R neurons in feeding, we hypothesize that monosynaptic PVH Mc4R→LSv glutamatergic projections regulate feeding through controlling LSv LepR neuron activity. Aim 1 will test the effects on inhibiting PVH Mc4R-LSv firers on anxiety and anxiety related hypophagia. Aim 2 will determine the role of Mc4Rs and glutamate release from LSv-projecting PVH neurons in body weight regulation. Aim 3 will determine whether the role of PVH direct downstream neurons the LSv in body weight regulation. This proposal utilizes a combination of optogenetics and mouse genetics to reveal a previously unknown PVH→LSV neural pathway in feeding regulation and will establish LepR neurons in LSV as a novel direct downstream target of PVH for feeding regulation. This novel circuit will potentially bridge hypothalamic feeding regulation with functions associated with limbic LSV regions such as stress and anxiety, representing a significant step in understanding the complex feeding behavior with more relevance to human obesity associated with anxiety-related overeating.