Noradrenergic circuit mechanisms of persistent fear

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DESCRIPTION (provided by applicant): Learning reorganizes brain activity to encode long-lasting memories of emotional events. These memories enhance survival by guiding adaptive behaviors like pursuit of food and avoidance of threats. However, in 6.8% of Americans, and as high as 14-16% of U.S. military service members, the experience of trauma leads to severe and recurrent anxiety and fear, exacerbated by reminders of the traumatic event. This syndrome, known as post-traumatic stress disorder (PTSD), shares commonalities with fear-related disorders like panic and phobia, and is characterized by persistent re-experiencing of traumatic emotion. Current treatments for PTSD confer some remission of symptoms, but do not work in some individuals, and frequently become ineffective over time due to relapse. Acquisition and attenuation of emotional responses can be modeled in the laboratory by Pavlovian fear conditioning and extinction. These studies have suggested that one factor impeding recovery from PTSD may be exposure to stress-related neurotransmitters. The goal of this study is to define which cells and brain pathways mediate adverse effects of the neurotransmitter noradrenaline. In preliminary experiments, we determined that noradrenaline signals through the a1 adrenoreceptor subtype to activate inhibitory neurons and increase their transmission in the amygdala, a critical brain region in fear conditioning and a site of abnormal activity in PTSD. Furthermore, we show that these receptors promote formation of fear memories that are resistant to extinction, a process for inhibiting fear that is analogous to exposure-based emotional therapies. The objective of this proposal is to define the specific circuit mechanisms that, when activated by noradrenaline, impede extinction. Our specific aims are 1. To establish the role of specific inhibitory cell types in noradrenaline-dependent circuit modifications, 2. To test the impact of these inhibitory neurons on behavioral flexibility, and 3. To establish circuit determinants of extinction success and failure. We will rely on transgenic mice, patch-clamp electrophysiology, optogenetics and chemicogenetics to accomplish these goals. The results of these experiments will define cell types as well as synaptic pathways at which improved therapies for attenuating emotion can be directed.