Project Summary Primary characteristics of posttraumatic stress disorder (PTSD) include persistent fears and excessive maladaptive avoidance behaviors. Preclinical models of PTSD have heavily investigated the brain mechanisms of fear inhibition and active avoidance learning. Significant progress has been made in translating fear conditioning and extinction data into the human brain and their implications have helped further our understanding of PTSD psychopathology. The mechanisms of active avoidance, however, have scarcely been examined in the human brain, especially within the context of maladaptive responses as in the case of PTSD. The studies proposed in this application are designed to begin to fill this scientific gap. We will use a novel conditioning and active avoidance paradigm (CAAP) to examine the neural correlates of active avoidance and fear extinction learning and explore how extinction modulates active avoidance responses in participants with and without a PTSD diagnosis using functional magnetic resonance imaging (fMRI). PTSD psychopathology involves dysfunctional limbic-frontal activity including the ventromedial prefrontal cortex (vmPFC), hippocampus (HPC), and amygdala. Studies of avoidance in rodents and a few fMRI studies in healthy humans suggest that the vmPFC and striatum mediate threat response by toggling the expression of fear vs. avoidance responses. Participants (healthy controls with trauma exposure, and patients diagnosed with PTSD) will undergo the novel (validated) two- day CAAP. On day 1, participants will undergo Pavlovian fear conditioning, immediately followed by an active avoidance conditioning phase. Avoidance is achieved by pressing a button to prevent a shock from occurring but will not terminate the conditioned stimulus (CS). Pavlovian fear extinction learning (button removed; no avoidance possible) will follow. On day 2, recall of extinction learning will be tested. Before the start of the recall test, participants will receive a small monetary endowment and will be told that this money could be used to pay for shock avoidance during the recall test. The first aim is to Identify neural correlates of active avoidance. The second aim is to study activations after the CS+ terminates that index the relief from the avoided shock. The third aim is to examine neural correlates of extinction-to-avoidance transfer. The proposed studies are expected to provide a more integrated mechanistic understanding of the psychopathology of PTSD and reduce the gap between the rodent literature and human neuroimaging in avoidance research.