Posttraumatic stress disorder (PTSD) is debilitating illness, impairing health, well-being, and productivity of 25-30% of combat veterans. Currently approved drug treatments are largely ineffective. Behavioral therapies, including exposure therapy, can be more effective for some, but efficacy is also limited by many factors, including the duration of treatment and the anxiety and distress it can produce, both of which contribute to a high rate of attrition. Many patients cease treatment before completing the full course of therapy, so anything that can enhance the effectiveness of exposure therapy and accelerate clinical improvement would be highly beneficial. Thus, there is a need to identify and investigate new adjunct treatments that can enhance the efficacy of exposure therapy. Exposure therapy is a form of extinction learning. To investigate the mechanisms underlying the beneficial effects of exposure therapy and identify potential entry points for intervention that may enhance it, we have developed extinction learning as a valid preclinical model of exposure therapy in rats. We showed that treating rats with extinction learning was effective in reversing several behaviors impaired by exposure to chronic unpredictable stress (CUS), that model key symptom dimensions of PTSD. However, our standard 16-trial extinction model was fully effective in restoring stress-impaired behaviors that resemble components of PTSD, which made it impossible to detect improvements in efficacy. Therefore, to be able to detect increased efficacy with adjunct treatment, we developed a sub-effective 8-trial extinction procedure, and validated its ability to detect improved efficacy with adjunct treatment. The first purpose of the current renewal is to now use this sub-effective extinction model to test transcranial direct current stimulation (tDCS), a non-invasive, painless, easily administered neuromodulatory treatment, as a potential adjunct strategy to enhance the plasticity induced by extinction in the infralimbic cortex (IL), a sub-region of ventral medial prefrontal cortex (mPFC) that has been implicated in PTSD. Aim 1 will test the hypotheses that tDCS will: a) enhance the efficacy of 8-tone extinction in restoring cognitive flexibility mediated in IL, and improve other PTSD-like behaviors mediated by sub-cortical targets of IL; b) enhance the rescue of afferent-evoked responses in mPFC that have been compromised by CUS; and c) enhance the activation by 8-tone extinction of mPFC and its downstream targets that mediate stress-compromised behaviors. We previously showed that activation of the projection from ventral hippocampus (vHipp) to mPFC is important for the therapeutic effects of extinction. In the last grant period, L-655,708, a negative allosteric modulator of a5-GABAA receptors expressed selectively in the hippocampus, was studied as a potential therapy for stress-impaired behaviors. Because a5 NAMs increase vHipp activity, in Aim 2 we will test TB2100...