PROJECT SUMMARY Altered connectivity between emotional (vmPFC/amyg) and cognitive (vlPFC/dACC/OFC) control areas are thought to underlie compulsive and persistent behaviors in OCD. Human brain imaging can be used to image circuits, but direct manipulation of circuits is needed to evaluate their role in behavior. Because amyg/vmPFC and striatal circuitry is largely conserved in rodents, the overall goal of P5 is to use anatomical and optogenetic methods to test the hypothesis that connections between emotional and cognitive areas regulate persistent avoidance responses. We hypothesize that inputs to the cingulate and prelimbic corticies (Cg/PL, a putative dACC homologue) drive appropriate decisions to avoid (or not avoid) a stimulus previously associated with danger. In Aim 1, we will identify connection nodes within Cg/PL based on sites of convergence of inputs from amyg, medial orbital cortex (MO, putative OFC homologue), and lateral orbital cortex (LO, putative vlPFC homologue). In Aim 2, we will use cFos to characterize the activity of these Cg/PL nodes in a conditioned avoidance task, in which rats learn to step onto a nearby platform to avoid a tone-signaled footshock. We hypothesize that persistent avoidance resulting from failed extinction of avoidance is due to excessive activity in the Cg/PL emotional node (inputs from MO, amyg), whereas persistent avoidance resulting from failed devaluation of avoidance is due to deficient activity in the Cg/PL decision node (inputs from LO, amyg). In Aim 3, we will use an optogenetic approach to activate or silence, respectively, inputs from LO or MO to these Cg/PL nodes, to reverse persistent avoidance. The manipulation of these nodes in our avoidance task allows for a direct test of the connectivity hypotheses in P1 and P2, and silencing of specific inputs will help target rTMS placements for treatment of OCD (P4).