The goal of this Translational Research Center Development Grant application is to bring together preclinical and clinical investigators to explore procedures that will promote the process of extinction following fear conditioning. By exploring reactions to traumatic events and defining methods to alleviate the chronic effects of trauma, this work would inform the pathophysiology and treatment of trauma-related disorders such as posttraumatic stress disorder (PTSD). PTSD can be characterized as a failure of recovery caused, in part, by a failure of fear extinction following trauma. We propose a series of pilot projects to determine the optimal timing of extinction training and define specific interventions (e.g., pharmacological agents, presence of safety cues) that will enable conditioned stimulus presentation to decrease rather than enhance fear responses. Fear will be measured using fear potentiated startle in rats and humans, in conditioned defeat in hamsters, in human brain functioning through the use of fMRI, and in human fear reports and psychophysiological responses.
The specific aims of this project include: 1) to determine effective early interventions for fear extinction (behavioral, pharmacological, and their combination) as well as the optimal timing of such interventions; 2) to determine the best paradigms for treatment once chronic PTSD has developed; and 3) to develop methods to measure conditional discrimination of threat (conditioned fear) vs. safety cues (conditioned inhibition) in both rodents and humans and to determine how these interact with various pharmacological treatments. This project will provide a mechanism for investigators to meet regularly to exchange information, to have access to each other's data and results, and to develop methodologies to translate preclinical findings on extinction and safety cues in animals to preclinical studies in normal humans and, in selected instances, patients with PTSD. Because animal studies offer advantages of speed, cost and availability in a simpler model system, we will use them to determine optimal parameters for producing longterm extinction of conditioned fear. We will then apply the best parameters in healthy humans and patients with PTSD. It is the ultimate goal to develop interventions derived from preclinical work, based on extinction training, to treat recently traumatized individuals to prevent long-term disability. Currently, no such interventions with proven efficacy exist. ? ?
