Duke Neurobiology Invited Seminar: Laura DeNardo: The development and function of prefrontal threat avoidance circuit

Active avoidance promotes survival by keeping animals safe from harm. However, maladaptive avoidance conflicts with other behaviors important for wellbeing and is a hallmark symptom of psychiatric disorders including anxiety, depression, phobias, and OCD. The medial prefrontal cortex (mPFC) coordinates activity of output circuits targeting basolateral amygdala (BLA) and nucleus accumbens (NAc) to determine whether animals approach or avoid threatening stimuli. mPFC neurons undergo a prolonged maturation that may be necessary to establish complex behaviors but extends the time that insults can perturb healthy circuit assembly. How mPFC circuits develop typically is poorly understood. Our study investigates the maturation of learned threat avoidance in mice and the contributions of mPFC output circuits over postnatal development. We modified a platform-mediated avoidance (PMA) assay for use in developing mice. In PMA, a conditioned tone prompts mice to navigate to a safety platform to avoid a mild foot shock. We tested mice in the juvenile (postnatal day; P23), adolescent (P35) and adult (P60+) periods. While mice at all ages were able to learn PMA, in a retrieval session the following day, P35 mice showed reduced avoidance compared to the other ages. We then used optogenetic techniques to either excite or inhibit mPFC-BLA or mPFC-NAc at each age. At P23, these manipulations had the opposite effect on PMA than in adulthood suggesting a critical period of circuit reorganization through which mPFC refines its control over avoidance. Results of optogenetic experiments at P35 suggest that mPFC-NAc neurons may be more active in adolescence promoting exploration over avoidance. In ongoing work, we are using fiber photometry to observe the activity of mPFC projections in mice performing PMA.