Prefrontal Mechanisms in Retention of Fear Extinction

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DESCRIPTION (provided by applicant): Fear extinction is the decrease of conditioned fear responses that normally occurs when a conditioned stimulus (CS) is repeatedly presented in the absence of the aversive unconditioned stimulus (US). Extinction does not erase the initial CS-US association, but rather forms a new memory. Thus, after extinction training, the recall of extinction memory becomes critical to compete with and inhibit the conditioning memory, thereby controlling inappropriate fear. In rats, the infralimbic region (IL, area 25) of the medial prefrontal cortex (PFC) has been shown to play a critical role in the retention and expression of extinction memory; recently additional PFC areas have also been implicated. In humans, while converging evidence suggests that extinction circuitry may be compromised in post-traumatic stress disorder (PTSD), little is known about the mediating anatomy of fear extinction retention in health or disease. The overall aim of this application is to delineate the homologous prefrontal areas in rats and humans that mediate fear extinction recall, and then test the functional integrity of these prefrontal areas in PTSD patients. In Aim 1 rat experiments will examine the role of specified prefrontal areas in fear extinction recall, using pharmacological inactivation, single-unit recording, and brain microstimulation. In Aim 2 we will map PFC areas involved in fear extinction recall using functional MRI and healthy human subjects. In Aim 3 we will test for PFC dysfunction during fear extinction recall in subjects with PTSD vs. trauma-exposed normal controls. This translational series of experiments promises to advance knowledge regarding the neural mechanisms underlying extinction retention and recall across species. In humans, such knowledge may be critical for elucidating the pathophysiology of anxiety disorders and developing improved extinction-based treatments.