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.