UCLA

Threat avoidance is a key survival behavior that keeps animals away from harm. However, threat avoidance must be balanced with other behaviors important for survival and well-being, including feeding and social interaction. Excessive avoidance, especially in the absence of threat, is a hallmark symptom of numerous psychiatric disorders including OCD, depression, phobias, and anxiety disorders. Many of these disorders arise early in life. Understanding the neural circuit basis of threat avoidance across development and in adulthood is necessary to understand how these circuits may be perturbed to contribute to psychiatric disease. Output circuits from the medial prefrontal cortex (mPFC) control both innate and learned threat avoidance behaviors. Two unique features of mPFC – its prolonged development and intricate connectivity – may make it particularly well suited to regulate adaptive responses to a dynamic environment. Compared to other brain regions, mPFC undergoes an extended maturation that lasts into early adulthood. The demands for threat avoidance change with developmental stage and the prolonged maturation of mPFC may support dynamic circuit changes that contribute to age-specific avoidance strategies. However, we do not understand how the mPFC circuits underlying threat avoidance mature and contribute to behavior in early life. Second, mPFC output circuits are anatomically complex and display a high degree of collateralization. Collateralization of mPFC projections may be a mechanism to precisely coordinate activity in multiple downstream regions to produce behavior, however, complex connectivity patterns have yet to be linked with the behavioral contributions of mPFC circuits. This thesis elucidates how the circuit maturation and connectivity of mPFC shapes threat avoidance behavior. Using optogenetics, fiber photometry, viral circuit mapping, and slice electrophysiology, this thesis provides convergent evidence that prefrontal projections to the basolateral amygdala and nucleus accumbens change their function throughout early life to shape age-specific avoidance phenotypes. This thesis also reveals the brain wide connectivity patterns of mPFC neurons defined by their projections to the ventral tegmental area, nucleus accumbens, and contralateral mPFC in adult mice. Differential roles of each of these projection classes in learned and innate avoidance were also discovered. Finally, this thesis presents two new user-friendly analysis pipelines to quantify brain wide axonal projections and labelled cell bodies allowing others to continue to probe circuit function together with complex anatomy. The circuits and maturational processes uncovered may be key sites of disruption that lead to psychiatric disease and potential targets for therapeutic intervention.