Effects of chronic stress on amygdala physiology

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 DESCRIPTION (provided by applicant): There is an urgent need for new antidepressants that work in adolescents. Depression phenomenology is different in adolescents, but the reasons for this are not known. One possible explanation for lack of efficacy of many antidepressants and different phenomenology is that there is a difference in the pathophysiology of depression in adolescents. The long-term goal of our research is to determine how pathophysiology of the amygdala contributes to symptoms of depressive disorders. The short-term goal of these experiments is to test whether differences in specific amygdala output pathways underlie differences between adolescent and adult depressive behavior. The basolateral amygdala (BLA) guides many anxiety and appetitive behaviors via outputs to different neural regions. The relative activity between these BLA outputs balances anxiety and appetitive behavior. This project will test the hypothesis that the activity of major BLA output pathways is different in adolescents, and this leads to a favoring of appetitive behaviors. Repeated stress mimics several symptoms of depression, including anhedonia and anxiety. This project will also test the hypothesis that repeated stress shifts the balance of major BLA outputs towards those involved with anxiety and away from those that guide hedonic behaviors, but via different mechanisms in adults and adolescents. Using electrophysiological, behavioral and genetic approaches, this project aims to determine the relative activity of BLA outputs in adolescents and adults, to determine if repeated stress exerts age-dependent actions on two major BLA outputs, and to determine their contribution to behavioral effects of stress. Furthermore, this study will directly compare the mechanisms for the effects of repeated stress in adults and adolescents. This project is significant because it can demonstrate a novel neurobiological mechanism for differences in the balance of anxiety and hedonic behaviors across age, and provide novel targetable mechanisms for the development of new antidepressants for adolescents. These experiments are innovative because they will test the function of specific BLA neuronal populations in the context of their place in behaviorally important circuits across age. This approach will yield exciting new information about the behavioral importance of BLA circuits and novel insight into the formation of a psychiatric syndrome via an imbalance in the activity of BLA outputs. Understanding of the mechanism that underlies this imbalance in adolescents is expected to uncover alternative pharmacological approaches to treat depression in adolescents.