Fragmented early-life experiences, aberrant circuit maturation, emotional vulnerabilities

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This trans-disciplinary Center renewal proposal addresses early environmental signals that influence cognitive and emotional outcomes and the mechanisms by which these signals modulate the development of brain circuits underlying emotion and cognition. We have identified that patterns of maternal signals profoundly influence cognitive and emotional development: Specifically, unpredictable and fragmented patterns of maternal mood and behavior (FRAG) beginning in the fetal period increase the risk for internalizing symptoms that presage anhedonia and cognitive impairments in infancy through adolescence. Importantly, the effects of FRAG are additional to those of previously identified influences (e.g. maternal depression, anxiety, sensitivity). In this revised renewal application we benefit from Reviewer suggestions and capitalize on a cohort of children developed during the original award period for whom we have an unprecedented pre and postnatal exposure history, to test the hypothesis that FRAG is a novel form of adversity that influences mental health outcomes via aberrant maturation of brain circuits. Extending our existing cognitive and emotional assessments and considering sex and ages at exposure and assessment as important variables, we will emphasize anhedonia, a novel FRAG outcome identified across species with emerging significance as an important transdiagnostic dimensional entity in mental illness. We will examine the early manifestation of anhedonia in 3-6 year old children using a dimensional RDoC approach, determine novel maternal signals that increase risk for its expression, and identify mechanisms and biomarkers focusing, respectively, on disruption of normal brain circuit development and epigenetic signatures. Thus, we shall capitalize on our cutting edge neuroimaging, intra-individual methylomics and novel assessment tools to test the following hypotheses: (1) that early life exposure to fragmented and unpredictable maternal signals increases risk for anhedonia in 3 to 6-year-old children. (2) that exposure to a fragmented and unpredictable early life home environment increases the risk of anhedonia in 3 to 6-year-old children. (3) that early life exposure to fragmented and unpredictable maternal and environmental signals increases risk for anhedonia in early childhood through the disruption of pleasure/reward brain circuits and that methylome changes (signatures) in two paired samples from the same infant will provide predictive biomarkers of this risk.