Cellular mechanisms mediating extinction of conditioned fear

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DESCRIPTION (provided by applicant): Anxiety disorders, which include panic, phobias, post-traumatic stress disorder, obsessive-compulsive disorder, and generalized anxiety, are among the most common forms of mental illness. It was suggested that at least some anxiety disorders involve the fear system of the brain. An individual can have very poor conscious memory of a certain traumatic event, but at the same time very strong unconscious emotional memories could be formed through fear conditioning mechanisms. These very resistant to extinction fears can become a source of intense anxiety. A complete understanding of etiology of such pathological conditions requires detailed information about the neuronal mechanisms of fear-related behaviors and, specifically, about the nature of plastic modifications that provide the neural substrate of fear extinction. This could be translated eventually to the clinical setting for the treatment of anxiety and therapy-resistant phobias. Fear conditioning training paradigm is well suited for the cellular and molecular studies of fear learning and fear extinction. Our studies, as well as previous findings from other laboratories, indicate that neuronal plasticity underlying learning can be directly determined in the slice preparation and then correlated to the behavioral status of the experimental animal. Here we propose a combined behavioral and electrophysiological study to address specific questions concerning the nature of plastic modifications in the neural circuitry underlying extinction of conditioned fear. In Aim 1, we will explore the changes in intrinsic excitability of neurons in the infralimbic division of the mPFC projecting to the lateral, basal and central nuclei of the amygdala associated with extinction of conditioned fear. Our approach will be to obtain whole-cell patch clamp recordings from retrogradely labeled neurons in the infralimbic division of the mPFC in brain slices at different time points after extinction training. In Aim 2, we will analyze the effects of fear extinction on GABAeric inhibitory neurotransmission and intrinsic excitability of interneurons in the lateral and basal nuclei of the amygdala in slices from fear conditioned and fear-extinguished rats. These experiments will elucidate the nature of plastic modifications which may provide a neural substrate of fear extinction. A better understanding of the cellular mechanisms of fear extinction will permit the rational development of novel therapeutic treatments for generalized anxiety and posttraumatic stress disorder (PTSD) or other illnesses implicating the fear system of the brain. PUBLIC HEALTH RELEVANCE : The proposed studies will improve our understanding of the cellular mechanisms underlying extinction of fear memory. A better knowledge of the cellular mechanisms of fear-related behavior will permit the rational development of novel therapeutic treatments for posttraumatic stress disorder (PTSD) and generalized anxiety.