Neural mechanisms of extinction generalization in human

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PROJECT SUMMARY/ABSTRACT Post-Traumatic Stress Disorder (PTSD) is a serious detriment to mental health in the United States, with a lifetime prevalence of 6.8%. The most commonly used clinical technique in the treatment of PTSD is exposure therapy, however this strategy is imperfect, and the results obtained during exposure therapy in a clinical setting repeatedly fail to generalize to novel real-world situations. The Aims of this application are to characterize the neural mechanisms of the return of fear and to test a novel strategy to prevent this return. Pavlovian fear conditioning and extinction serve as useful laboratory models of PTSD and exposure therapy respectively. The observed lapses in exposure therapy can be explained by the role of context in fear and extinction learning and recall. Extinction is expressed in a contextually specific manner, while fear readily generalizes to new contexts in a phenomenon called renewal. The renewal of fear and the specificity of extinction explain why many treatments fail to produce lasting benefits. In laboratory settings, context is often defined as physical space, but advancements in episodic memory research have shown that mental context plays a significant role in the learning and recall of memories in humans. It is currently unknown how a mental context framework can be applied to enhance understanding of the neural and cognitive mechanisms of emotional learning and memory. In line with NIMH Strategic Objective 1 to define the mechanism of complex behaviors, Aim 1 of this proposal will investigate the neural mechanisms of fear and extinction mental context reinstatement in both healthy participants and patients with PTSD. Advanced fMRI neuroimaging techniques will be used to quantify the reactivation of mental contexts during a renewal test. Previous attempts to overcome the contextual specificity of extinction focus on contextual manipulations such as extinguishing in multiple contexts, cue reminders, or pharmacologically inhibiting contextual processing. These techniques have been implemented to mixed success, and in the case of pharmacological treatments are not always practical solutions. Accordingly, Aim 2 will test a novel behavioral strategy designed to diminish contextual processing during extinction learning, safely facilitating extinction generalization. This simple manipulation, known as directed forgetting, has previously been shown to diminish hippocampal activity. Healthy subjects will engage in directed forgetting during extinction learning. We will then test if extinction learning augmented with directed forgetting results in extinction generalization to new contexts. This Aim supports NIMH Strategic Objective 3 to develop new treatments through advancements in neuroscience and behavioral sciences. The combined Aims laid out in this proposal will significantly bolster current knowledge of the neural and cognitive mechanisms of successful extinction following fear learning and will test a novel behavioral strategy to increase extinction generalization. Completion of these Aims will advance knowledge of neuroscience of emotional learning and memory and contribute to the future treatments of PTSD.