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

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This high-impact Center revised renewal proposal integrates 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. It posits that unpredictable, fragmented sensory signals to the developing brain (FRAG), constitute a previously unrecognized indicator of early-life adversity that impacts brain circuit maturation across species, provoking anhedonia and vulnerability to psychopathology. The overarching goal of the Imaging Core is to enable the Center to use imaging tools to address the as yet unknown mechanistic pathways by which FRAG may lead to anhedonia and other vulnerabilities to psychopathology. The Core will work with Projects 1-4 to conduct translational neuroimaging across species and cohorts, and with the BCDM core it will develop computational and statistical models to provide novel insights into circuit mechanisms that underlie the impact of FRAG on the developing brain. The core will: 1. Acquire, process, analyze, store, and make available all high-resolution structural, functional, and diffusion MRI data on human and rodent cohorts, in support of Projects 1-4 and to address imaging-related hypotheses. 2. Identify aberrant and sex-specific patterns and trajectories in structure, function, and connectivity of pleasure/reward circuitry that link early life FRAG to anhedonia and risk for psychopathology, using innovative multimodal MRI approaches across cohorts, projects, and species. 3. Develop a rich dataset of whole-brain-derived imaging metrics using network connectomics and, working with the BCDM Core, integrate these metrics in statistical models that predict anhedonia and psychopathology from FRAG-associated aberrations in brain circuitry. Whole brain functional and structural connectomes will be created using diffusion and resting state fMRI data to assess dynamic and stable reorganization of circuits as a function of FRAG. Network approaches such as graph theory based on structural and functional connectomes will be used to quantify overall shifts in brain circuits (e.g. rich club and small world networks). The BCDM and Imaging cores, guided by expertise of Center consultant, Prof. Olaf Sporns, will collaborate on employing these methods for integration into models that take into account all other data types to predict anhedonia and psychopathology from FRAG and the associated brain circuitry alterations. These data-driven approaches will additionally allow us to examine alternative and secondary hypotheses.