Melanocortin-3 receptor in feeding and anxiety neural circuits

PROJECT SUMMARY (See instructions): Neural circuits modulating feeding, stress 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 metabolic disorders. Despite an increasing prevalence of both metabolic and psychological 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 stress/anxiety circuits. Importantly, MC3R neurons bidirectionally regulate both feeding and anxiety, and deletion of MC3R produces multiple forms of sexually dimorphic alterations in feeding, including anxiety-related hypophagia. While it is evident MC3R impacts feeding and stress/anxiety circuitry in both male and female mice, the 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 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, stress and anxiety-like behaviors. Intriguingly, this crucial integrative hub also seems to be highly susceptible to developmental perturbations that can have lasting health consequences. The K99 phase revealed the structure and function of the mature BSTMC3R circuitry. The R00 phase will focus on determining how dietary and stressful perturbations during critical periods of development may permanently alter the structure and function of BSTMC3R circuitry. The overall hypothesis of this application is dietary and stressful perturbations during critical periods of development will disrupt BSTMC3R neural circuitry, culminating in lasting consequences in feeding behavior and responses to stress.