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

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The overall Center will integrate a multidisciplinary group of scientists to investigate the developmental origins of vulnerability to mental illness, with a focus on perturbed environmental / sensory signals impacting brain circuits during sensitive developmental periods. Guided by the constructive suggestions of the Reviewers, Project 1 will exploit rat and mouse systems to directly test our overarching hypothesis that fragmented and unpredictable early-life sensory signals (FRAG) promote functional deficits in pleasure and reward-seeking behaviors by disrupting normal maturation of the underlying brain circuits. The studies using experimental animals will enable addressing the hypothesis at molecular, cellular and circuit levels of analysis that are not possible in humans. Coupled with the use of structural and functional neuroimaging approaches, our experimental studies will overlap and integrate with human subject studies aimed at modeling network trajectories, allowing inferences of processes and mechanisms across species. Synergizing with Projects 2-4 and the Imaging and BCDM cores, Project 1 defines trajectories considering sex-dependent differences, truly bridging across species. Importantly, rodent experiments enable direct testing of causality of correlative observations made across species and provide mechanistic insight via intervention studies that target candidate mechanisms. These approaches further capitalize on species-unique opportunities including short life span, access to brain tissue and controlled interventions, utilizing the latest Neuroscience techniques. The goals of Project 1 are: (a) To test the hypothesis that aberrant maturation of pleasure and reward circuits underlies FRAG-evoked anhedonia, using state-of-the-art structural and functional (resting state fMRI) imaging and mechanistic interventions; (b) Test the hypothesis that aberrant function of pleasure and reward circuits is a mechanism for FRAG-evoked anhedonia, using cutting-edge viral-genetic technologies; (c) Test if early-life FRAG creates ‘epigenetic signatures’ using novel within subject analyses, and if these provide predictive markers for emotional vulnerabilities in children.