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

University Of California-Irvine, Irvine CA

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Abstract

This is a resubmitted renewal proposal for a Conte Center focused on the contribution of early-life experiences, especially unpredictable and fragmented maternal and environmental signals, to adolescent vulnerabilities and adult mental illness via mechanisms involving disruption of the maturation of cognitive and emotional brain circuits. Complex behaviors involve coordinated activities of brain circuits. During development, environment- derived sensory signals influence circuit maturation (e.g., visual, auditory) and may drive aberrant circuit maturation that can promote emotional and cognitive problems. Yet the nature of the signals that contribute to vulnerabilities to mental illness, and how they disrupt brain circuit maturation is unclear. Among environmental influences, early-life adversity is an established risk factor for mental illness, and aspects of adversity (e.g., maternal depression, poverty) explain a significant portion of mental problems later in life. Yet there are serious gaps in our ability to identify early vulnerability to mental illness. Here, we posit that unpredictable, fragmented sensory signals (FRAG) from the mother and environment constitute a previously unrecognized indicator of early-life adversity. This hypothesis originated from mechanistic animal studies where consistent, predictable patterns of maternal-derived signals promote resilience by modulating excitatory synapse number and function of specific cell populations. By contrast, FRAG promotes aberrant maturation of brain circuits involved in emotion and cognition, with commensurate behavioral deficits. During the original award we focused on several cognitive and emotional vulnerabilities and these remain outcomes in this proposal. Additionally, we identified anhedonia as a robust direct consequence of early-life FRAG in experimental systems, associated with evidence of aberrant pleasure / reward circuit maturation. Anhedonia, a dimensional (RDoC) entity linked to multiple mental disorders, is a recently-identified core feature of PTSD. We emphasize anhedonia in the proposed renewal because we find that it follows FRAG in children, adolescents and young adults and predicts risk for post-combat mental illness in a vulnerable population of Marines. Thus, supported by compelling recently-published and preliminary data and guided by the reviews of the original renewal proposal, we test the Center?s overarching hypothesis: It states that, in concert with established types of early-life adversity, fragmented and unpredictable maternal and environmental signals contribute to vulnerabilities to mental illness via mechanisms involving disruption of the maturation of cognitive and emotional brain circuits. The proposed Center will aim to: 1) Test the relative contribution of FRAG, along with other early-life risk factors, to mental health outcomes including anhedonia, considering sex and using tools enabling assessments across diverse cohorts. 2) Test the mechanisms underlying the effects of FRAG on the developing brain, with sensitivity to age- and sex-specific vulnerabilities and age-appropriate assessment tools. We will employ imaging and computational models focusing on brain circuit disruption; we will employ molecular and viral-genetic tools and capitalize on experimental animal systems to identify the underlying neurobiological mechanisms. 3) Create behavioral and neuroimaging sex-specific developmental trajectories from infancy to adulthood using our 3 prospective, well-characterized cohorts and repeated intra-individual measurements; generate predictive models for risk of anhedonia and vulnerability to mental illness; supported by preliminary data, identify intra-individual epigenetic signatures of FRAG in children as potential biomarkers. 4) Serve as a training forum and a magnet for the study and improved understanding of how early life experiences influence emotional and cognitive outcomes. In summary, guided by the reviews of the original, this resubmitted renewal proposal identifies FRAG as a novel source of aberrant brain circuit development that portends vulnerability to mental illness; it integrates FRAG within existing frameworks and offers novel, age-and sex-specific predictive markers of vulnerability to mental illness, and hence experiment-based, transformative paths for preventative interventions.