Project Summary/Abstract. Stress and a parental history of Major Depressive Disorder (MDD) are among the most potent risk factors for future MDD development. Evidence suggests that the offspring of parents with MDD are especially vulnerable to the development of maladaptive responses to stress. Early adolescence is a critical window for studying MDD risk, as this developmental stage is just prior to the peak period of initial MDD onsets and a time of enhanced stress sensitivity, especially among females. Despite the importance of stress in MDD onset, the neural mechanisms underlying stress responses in female adolescents at high familial risk for MDD remain unclear. Furthermore, little is known about how stress-induced brain network changes may be linked to physiological and behavioral responses to stress and be predictive of future MDD onset. In this R01 resubmission, we aim to test a model in which having a parental history of MDD increases the risk for dysfunctional dynamic default mode network (DMN) – Central Executive Network (CEN) stress responses, two networks consistently linked to MDD pathophysiology and stress responsivity, prior to the onset of depression. Specifically, we expect that adolescents with versus without a parental MDD history will spend more time and persist longer in a DMN-CEN co-activated pattern in response to stress. We further hypothesize that this maladaptive DMN-CEN pattern will predict maladaptive psychophysiological and behavioral responses seen in the adolescents’ natural environment. Together, we expect that this stress sensitive profile of dysfunctional dynamic DMN-CEN, psychophysiological, and behavioral responses will predict future depression onset. We focus on DMN-CEN dynamics given accumulating evidence showing that, relative to static network properties, brain network dynamic properties may be more robustly associated with MDD pathophysiology as well as the behavioral and psychophysiological processes impacted by stress and