Prefrontal circuits underlying the maturation of learned avoidance

PROJECT SUMMARY The medial prefrontal cortex (mPFC) makes essential contributions to learning, mood, and decision making, including evaluating and responding to threats. Compared to other circuits, mPFC circuits undergo prolonged maturation that is likely necessary in order to support complex behaviors. Yet how the development of prefrontal circuits enables the maturation of adaptive behaviors is poorly understood. Moreover, its extended development renders mPFC circuits highly vulnerable to disruption by environmental insults such as early life adversity (ELA). Even after adverse environmental conditions improve, ELA can produce lasting alterations in cognitive and emotional processing that put individuals at risk for many psychiatric disorders including anxiety disorders and depression. Although mPFC circuits are clear therapeutic targets for psychiatric disorders, substantial gaps in our understanding of typical mPFC circuit development and how this maturation enables emergence of complex cognitive and emotional behaviors prevent us from designing effective interventions. Our research will fill this knowledge gap by combining threat avoidance behavioral assays with projection-specific optogenetic manipulations, activity monitoring, and a model of ELA to test the hypothesis that precisely timed maturation of PL-BLA and PL-NAc circuits determines age-specific avoidance behaviors, and by altering the trajectory of circuit development, ELA leads to age-specific alterations in learned avoidance. In Aim 1, we will use optogenetics to test the hypothesis that the behavioral contribtions of specific mPFC circuits change over development. In Aim 2, we will use fiber photometry to expose circuit and region-specific activity patterns during learned avoidance across development. Finally, in Aim 3, we will apply the aforementioned approaches to a model of early life adversity to understand how chronic early stress impacts the trajectory of threat avoidance circuit development. This proposal directly addresses a pressing need to understand the complex relationships between early adversity, mPFC circuit development, and adaptive threat resposnes. Our research can inform individualized mental health treatments that exploit a variety of developmental opportunities, depending on the stage at which symptoms emerge.