Cellular substrates of early life trauma

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Most psychiatric conditions have their highest incidence of onset in early life, and it is currently estimated that one in five adolescents will develop such a condition that persists into adulthood. A major risk factor for such disorders is the experience of childhood trauma. Among the brain regions most highly implicated in these conditions is the medial prefrontal cortex (mPFC), which forms a synaptic network that plays important roles in emotional regulation. During a developmental stage equivalent of human adolescence, rodents exhibit heightened susceptibility to stress-induced behavioral phenotypes that resemble human conditions like anxiety and depression, and that are accompanied by long-term changes in the structure and function of mPFC in adulthood. However, it remains unclear whether unique mechanisms confer susceptibility to stress in immature animals, or what processes immediately ensue upon exposure to stress in adults versus mice. The long-term goal of this project is to reveal how trauma impacts directly on mPFC neurons, delineate substrates and mechanisms in these effects, and understand the abnormal functional properties that result. In particular, our preliminary data suggest that early adolescence is a sensitive period for noradrenaline-dependent suppression of mPFC activity and excitability, and that engagement of this process during traumatic stress leads to a long- lasting increase in threat avoidance, a potential correlate of human anxiety. We will make unprecedented use of longitudinal calcium imaging in freely behaving mice to measure these physiological effects as well as changes in mPFC activity that signal abnormal avoidance behaviors. Cellular and synaptic mechanisms for hypoexcitability will be elucidated by electrophysiological recordings. Finally, we will use temporally specific optogenetic manipulations to test whether recovering mPFC activity within specific projection pathways is sufficient to reverse trauma-related phenotypes. We hope that be establishing this comprehensive paradigm of stress susceptibility, we can shed light on biological factors that potentially contribute to a high rate of childhood onset for psychiatric disorders.