Genetically Dissecting Cholinergic Signaling in Body Weight Control

Abstract / Project Summary Obesity-associated diseases such as diabetes and cardiovascular disease together account for the leading cause of death in the United States. Roughly one-third of the U.S. population is obese, and it is estimated that nearly half of the population will be obese within the next two decades. To date, studies investigating the neural contribution to body weight control have focused largely on neuropeptidergic signaling in the hypothalamus, a key brain region involved in feeding behavior. However, signaling from extra-hypothalamic brain regions has also been implicated in regulating nutrient metabolism, appetite, and satiety. We have recently uncovered a novel mechanism by which cholinergic signaling in the basal forebrain strongly influences feeding and body weight control. This discovery provides intriguing evidence that cholinergic circuits in the brain critically regulate feeding behavior and body weight homeostasis. To elucidate the mechanisms by which forebrain cholinergic signaling influences body weight management, feeding behaviors, and metabolism, we will test the hypothesis that downstream basolateral amygdalar (BLA) neurons and their projections to the nucleus of accumbens (NAc) and ventromedial hypothalamus (VMH) mediate forebrain cholinergic action on body weight regulation. Using a combination conditional genetic targeting, optogenetic manipulations, electrophysiology, and behavioral analysis, we will set out to determine the role for direct downstream BLA neurons that project to the NAc or VMH in mediating obesity induced by loss of forebrain cholinergic action. The results from the proposed series of experiments using animal models with precisely targeted manipulations of neuron activity will elucidate roles of specific cholinergic basal forebrain to BLA circuits that differentially regulate the NAc and VMH in feeding and body weight control, providing needed insight into the central mechanisms underlying appetite and body weight regulation.