DESCRIPTION (provided by applicant): Depression phenomenology is different in adolescents, and many antidepressants do not work in adolescents. But the reasons for this are not known. One possible explanation is differences in the pathophysiology of depression. The long-term goal of our research is to determine how abnormalities of the amygdala contribute to symptoms of affective disorders. The short-term goal of these experiments is to test whether differences in specific amygdala output pathways underlie differences between adolescent and adult affective behavior. The basolateral amygdala (BLA) guides anxiety behavior and many appetitive behaviors via outputs to different neural regions. A balance between these BLA outputs balances anxiety and appetitive behavior. This project will test the hypothesis that the balance between major BLA output pathways is different in adolescents, and this leads to a shift towards 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. The Aims of this project are to determine the balance between two major BLA output paths in adolescents, to determine if repeated stress exerts opposite actions on two major BLA output paths, and to determine if targeting BLA paths selectively reverses behavioral effects of stress. This study will compare the age- dependent mechanisms for the effects of repeated stress. 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 novel targetable mechanisms for the impact of stress on emergence of psychiatric symptoms in adolescents. These experiments are innovative because they will test amygdala function in the context of its place in behaviorally important circuits. This approach will yield exciting new information about subsets of BLA circuits. This project will lead to novel insight about how a deficit in the BLA can
lead to abnormalities that comprise a psychiatric syndrome, and is expected to uncover a new avenue in the development of an alternative pharmacological approach to treat depression in adolescents.