PROJECT SUMMARY Early exposure to social disadvantage, specifically family and neighborhood financial disadvantage in utero and through the first 3 years of life, is a powerful and potentially modifiable environmental determinant of risk for childhood psychopathology. The ongoing Early Life Adversity and Biological Embedding (eLABE) study launched in 2017 has aimed to elucidate mechanisms of this risk trajectory and guide preventive interventions. To date, eLABE has detected powerful associations between prenatal social disadvantage and structural and functional brain development at birth which are mediated through elevations in maternal cytokines and alterations in the gut microbiome. These neonatal neurodevelopmental variations have been linked to elevations in markers of psychopathology risk at age 2 years. Further, decreased caregiver nurturance mediated some aspects of this relationship, with supportive caregiving mitigating child psychopathology risk. Our central hypothesis is that pro- inflammatory immune and gut microbiome profiles evident in children exposed to prenatal and early life social disadvantage induce neuronal effects that negatively impact structural and functional brain development leading to increased risk for psychopathology. This renewal proposes to build upon the existing data to continue following our unique and well-characterized sample of 377 children for whom we have assembled a rich, unparalleled repository including comprehensive measures of social disadvantage (in utero and ages 1, 2, and 3 years) with early life measures of inflammation, the gut microbiome, and brain development (structural, microstructural, and functional MRI at birth and ages 2 and 3). In the next phase of eLABE, we propose to follow this sample into school entry (age 6) and middle childhood (age 8), adding assessments of social disadvantage, developmental/behavioral, inflammatory marker, multimodal MRI, and caregiver and social support measures at both timepoints and one additional wave of the gut microbiome at age 6. We will utilize these data to test specific hypotheses about mechanistic pathways to mental disorders that begin to clearly emerge in early childhood and school age, and will utilize novel brain metrics to more directly examine the roles of neuroinflammation and plasticity in this risk pathway. We will also examine the effects of caregiver and family, peer, and school supports on this risk trajectory, including their role as possible resilience factors, and explore whether there are sensitive periods for these effects. The results will provide the first systematic and intensive prospective examination of the relationship of social disadvantage to chronic systemic inflammation, the gut microbiome, and their links to brain development and behavior related to risk for clinical mental disorders. Critically, by targeting caregiving, inflammation, and the gut microbiome as key mechanistic pathways, these data will also have tremendous c...