Project Summary/Abstract Depression is a common, serious form of psychopathology that is associated with suffering, disability, and suicide. Young people who identify as sexual or gender minority (SGM) are at strikingly high risk for experiencing depression, putatively because of their experience of SGM-specific stress. Yet the mechanisms of the association between stress and depression in SGM youth have been relatively neglected, with studies to date limited by cross-sectional designs and a lack of focus on clinical neuroscience. Depression is characterized by disrupted reward function and typically begins during adolescence, a key developmental period for change in neurobehavioral systems supporting reward. The dopamine (DA) neuromodulatory system is consistently associated with depression, considered a mediator of stress-depression associations through the influence of inflammation, and thought to be specifically influential for anhedonia, a cardinal symptom of depression that involves difficulty with motivation for or enjoyment of pleasant experiences. Understanding the role of DA in depression requires examining reward function over time and across domains, including frontostriatal reward circuitry, dopamine availability, reward-driven behavior, and reward-focused experiences in real-life settings. The proposed supplement activities will contribute to the parent R01 by examining associations of SGM identity and related stress with (1) depression/anhedonia and (2) reward function (e.g., DA availability, frontostriatal circuitry, behavior, real-life experience, and phone sensor-based movement). Exploratory work will investigate the exacerbating or buffering role, respectively, of SGM-related stress and protective factors. This work will contribute to the aims of the current, R01-funded DRIVE Study (MH127014), which uses a translational clinical neuroscience approach to examine associations between depression and DA. In addition to enrolling a new sample of 35 SGM youth with depression and varying in SGM-specific stress, the proposed activities include adding rigorous measures of SGM identity and related stressors and protective factors to the original R01 and administering DRIVE procedures and a 6-month follow-up visit to new SGM participants. Methods include magnetic resonance imaging (MRI) to assess DA function (striatal tissue iron, brainstem neuromelanin) and frontostriatal circuit function; ecological momentary assessment of reward processing and reward-seeking behavior; smartphone-based passive sensing of motor activity; behavioral reward tasks; self- report of depression, anhedonia, and reward function; and blood draw and assay for measurement of circulating inflammatory markers (e.g., CRP, IL-6). Findings will have relevance to the course and treatment of depression and will increase the impact of the parent R01 while elucidating a pathway toward disparities.