PROJECT SUMMARY/ABSTRACT Adolescent depression and cannabis use are concurrent major public health concerns, and this comorbidity has been associated with long-term cognitive and behavioral consequences. However, there has been sparse research in this area, as most neuroimaging studies in adolescent depression exclude cannabis users. We seek to address this gap based on converging evidence that: 1) Reward dysfunction contributes to maintenance and progression of depression in adolescents; 2) Reward dysfunction is a heterogenous construct involving deficits in diverse cognitive processes, including reward anticipation, attainment, and prediction error; 3) These deficits entail distinct neural mechanisms that can be studied by functional magnetic resonance imaging (fMRI); 4) The major psychoactive agent in cannabis, Δ9-tetrahydrocannabinol (THC), exerts its effects through modulation of the cortico-striatal reward system; and 5) Cannabis use may result in temporary relief of mood and anxiety symptoms while inducing potentially deleterious long-term neural reward alterations. We documented that anhedonia–a core symptom of depression reflecting reward deficits–was associated with worse depression outcomes, including chronicity and suicidality, in adolescents. Similarly, using resting-state fMRI, we found that altered striatal intrinsic functional connectivity (iFC) with the prefrontal cortex was associated with anhedonia severity in depressed adolescents. Further, using the reward flanker task (RFT), we found that adolescents with diverse mood and anxiety symptoms showed weaker striatal activation during reward anticipation than healthy controls, while stronger activation in the anterior cingulate cortex predicted worse higher levels of anhedonia at two-year follow-up. We therefore propose a 2×2 cross-sectional study to test the overall hypothesis that comorbid cannabis use in adolescent depression is associated with more severe neural reward deficits and clinical symptoms. Participants will comprise 30 depressed cannabis users, 30 depressed cannabis non-users, 30 non- depressed cannabis users, and 30 healthy controls, all ages 14-18 (Tanner stage ≥ 4) and psychotropic- medication-free. Using resting-state and RFT task fMRI, we predict that comorbid cannabis use and depression will be associated with more pronounced deficits in reward anticipation (Aim 1) and alterations in cortico-striatal iFC (Aim 2) than depression alone. Further analyses (Exploratory Aims) will assess the relationships between cannabis use frequency and activation during reward anticipation, cortico-striatal iFC, and symptom severity.