Noradrenergic circuit mechanisms of persistent fear

描述（由申请人提供）：学习重组大脑活动，以编码情感事件的持久记忆。这些记忆通过指导适应性行为（如追求食物和避免威胁）来增强生存能力。然而，在6.8%的美国人和高达14-16%的美国军人中，创伤的经历会导致严重和反复出现的焦虑和恐惧，并因创伤事件的提醒而加剧。这种综合征被称为创伤后应激障碍（PTSD），与恐慌和恐惧症等与恐惧有关的疾病有共同之处，其特征是持续重新体验创伤情绪。目前对PTSD的治疗可以缓解一些症状，但对某些人不起作用，并且随着时间的推移，由于复发而经常变得无效。情绪反应的获得和衰减可以在实验室中通过巴甫洛夫恐惧条件反射和消退来建模。这些研究表明，阻碍PTSD恢复的一个因素可能是暴露于与压力相关的神经递质。这项研究的目的是确定哪些细胞和大脑通路介导神经递质去甲肾上腺素的不良反应。在初步实验中，我们确定去甲肾上腺素信号通过α 1肾上腺素受体亚型激活抑制性神经元，并增加其在杏仁核，恐惧条件反射的关键大脑区域和创伤后应激障碍的异常活动的网站的传输。 此外，我们发现这些受体促进了恐惧记忆的形成，这些记忆是抵抗灭绝的，这是一个抑制恐惧的过程，类似于基于焦虑的情绪疗法。这个建议的目的是定义特定的电路机制，当被去甲肾上腺素激活时，阻止灭绝。我们的具体目标是1。为了确定特定抑制性细胞类型在去甲肾上腺素依赖性回路修饰中的作用，2。测试这些抑制性神经元对行为灵活性的影响; 3.建立灭绝成功和失败的电路决定因素。我们将依靠转基因小鼠、膜片钳电生理学、光遗传学和化学遗传学来实现这些目标。这些实验的结果将确定细胞类型以及突触通路，从而可以指导用于减弱情绪的改进疗法。

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.