PROJECT SUMMARY/ABSTRACT Life often requires us to be proactive in the face of danger. When crossing the road, the adaptive response to the horn of an oncoming care is to cross to the other side as quickly as possible. Yet fear can have an immobilizing effect, creating a paradoxical situation in which a deeply engrained defense against danger must be suppressed in order to achieve safety. Thus, adaptive coping in a complex environment necessitates the ability to move past defensive reactions in favor of proactive, problem- solving behavioral strategies. Signaled active avoidance (SAA) is a behavioral conditioning paradigm that effectively models the process by which a learned, problem-solving action replaces the innate reactions elicited by a threatening cue. Past work suggests that the nucleus reuniens of the midline thalamus plays a crucial role in this process, acting to suppress immobilizing responses in favor of an adaptive behavioral strategy that prevents an aversive outcome. Work proposed here will extend this finding by using chemogenetic techniques to target the crucial outputs of the reuniens that function to suppress freezing and facilitate active avoidance. Our primary hypothesis is that projections from the nucleus reuniens engage feedforward inhibition by activating inhibitory interneurons in limbic regions, such as the ventral hippocampus and the basolateral amygdala, that mediate the expression of aversive associative memory and thus conditioned freezing. Successful execution of the proposed studies will establish an important neural mechanism that promotes behavioral flexibility and adaptive problem solving under threat. A proactive style of coping is associated with an internal locus of control and resilience, suggesting the mental health relevance of its underlying circuitry. By dissecting the function of this pathway, our goal is to generate preclinical data that hastens clinical advancement by providing targets for cutting-edge therapeutic innovations.