PROJECT SUMMARY/ABSTRACT Autism spectrum disorder (ASD) is common (1 in 59 US children) and impairing. Yet, co-occurring psychiatric disorders—especially depression—in ASD remain understudied, hindering clinical care. This K23 seeks to address an important gap in knowledge about the neural mechanisms underlying depressive symptoms in ASD, which could ultimately provide a precision medicine-based approach to novel treatment development. Our central hypothesis is that depressive symptoms in adolescents with ASD will be associated with fronto-limbic, fronto-frontal and fronto-thalamic connectivity that, in turn, are related to underlying differences in white matter integrity and myelination. Our central methodology is to scan n=40 children (ages 12-16) with ASD and n=40 age-matched controls without ASD. The research goals of this K23 are to: (i) identify resting-state functional magnetic resonance imaging (rs-fMRI) correlates of depressive symptoms in ASD; (ii) investigate white matter microstructural alterations linked to depressive symptoms in ASD; (iii) utilize connectome-based approaches to explore the interaction between depressive symptoms across modalities. My career development goals are to gain expertise in: (i) rs-fMRI (and deeper understanding of promising circuit-based approaches to target engagement); (ii) diffusion spectrum imaging/myelin imaging; (iii) research- grade diagnostic evaluation of ASD; (iv) characterization of mood disorders in individuals with ASD; and (v) professional development to become an independent investigator. This proposal is significant because it will address NIMH Strategic Plan Objective 1.3 to characterize neural circuit mechanism disruption underlying depressive symptoms in ASD, using neuroimaging and detailed psychopathology phenotyping. This K23 is innovative because it will be the first to use multimodal imaging methods, including rs-fMRI, diffusion spectrum imaging, and myelin imaging, to define neural mechanisms of depressive symptoms in a sex-balanced sample of adolescents with ASD. Leveraging vital data and career development from this K23, I will submit future R01s as an independent investigator that focuses on: (i) deeper understanding of the neural mechanisms of co-occurring depressive disorders (including major depressive disorder, persistent depressive disorder) in individuals with ASD, and (ii) examination of how circuits change across development (expanding the age range to early childhood and young adulthood) in individuals with ASD with or without depressive disorders.