PROJECT SUMMARY Neural circuits modulating feeding and anxiety must communicate with each other to maintain homeostasis. Failure to appropriately respond to certain stressors can promote the development of maladaptive feeding behaviors observed with obesity and eating disorders. Despite an increasing prevalence of both eating and anxiety disorders, our understanding of the key inputs linking these behavioral states remains rudimentary. Melanocortin-3 receptor (MC3R) is ideally positioned, both anatomically and functionally, to mediate direct communication between feeding and anxiety circuits. MC3R is a part of the central melanocortin system and is implicated in the bidirectional control of responses to homeostatic challenges, providing rheostatic control on energy storage. Importantly, MC3R neurons bidirectionally regulate both feeding and anxiety, and deletion of MC3R produces multiple forms of sexually dimorphic disordered eating, including anxiety-related hypophagia. While it is evident MC3R impacts feeding and anxiety circuitry in both male and female mice, the sexually dimorphic sites driving these behaviors remain unknown. The bed nucleus of the stria terminalis (BST) is a highly differentiated nuclear complex whereby autonomic, emotional and neuroendocrine signals are integrated and subsequently relayed to hypothalamic and brainstem regions to regulate the expression of motivated behaviors, including feeding and defensive actions. The BST is centrally involved in stress-related psychopathologies, such as pathological and adaptive anxiety and also modulates food intake and energy balance with both anorexic and binge-like eating effects. The BST is also one of the most sexually dimorphic areas in the brain and thus may regulate sex differences observed in numerous eating and stress-related clinical disorders. MC3R neurons and terminals are abundantly expressed in the BST, and therefore BSTMC3R circuitry may function as an integration hub for information driving feeding and anxiety-like behaviors. The overall hypothesis of this application is MC3R neurons in the BST provide a neurological substrate mediating communication between feeding and anxiety circuits and may do so differently in males and females. As a first step in testing this hypothesis, the following two specific aims will be pursued: 1) Define the molecular phenotype and map the organization of neural inputs and outputs of BSTMC3R neurons and 2) Characterize the activity of BSTMC3R neurons in feeding and anxiety paradigms and determine if activity is sexually dimorphic. Completion of these aims will advance our understanding of the role of MC3R in the coordination of feeding and anxiety, identify important differences between males and females and serve as a crucial step in discerning the complex feeding behavior associated with obesity and eating disorders.