Molecular Determinants of Individual Differences in Fear Reactivity and Recovery

描述（由申请人提供）：焦虑症通常在暴露于压力或创伤后发展。这些通常有明显的恐惧成分，有时被称为“恐惧/焦虑”障碍。例如创伤后应激障碍（PTSD）和单纯的恐惧症。因为只有少数具有相当水平的压力或创伤暴露的人会患上这些疾病，受影响的个体必须具有某些先天的遗传或表观遗传脆弱性。识别这些弱点是生物精神病学的一个主要目标，也是我们研究的主要焦点。大多数关于恐惧的大脑机制的现有知识，以及关于可能在恐惧/焦虑障碍中改变的基本生物学机制，都是在恐惧条件反射的动物研究中获得的。这些研究已经确定了杏仁核中特定的回路与恐惧反应的获取、储存、表达和调节有关。这些研究大多集中在随机动物群体的恐惧机制上。然而，由于大多数患有恐惧/焦虑障碍的人被认为是潜在脆弱性程度的极端代表，因此在随机动物群体中进行研究可能不是确定这些脆弱性的理想方法。一个更有希望的替代方法是使用表达极端恐惧表型的动物。一种流行的观点是，尤其是个体，创伤暴露后易患恐惧/焦虑障碍，至少在一定程度上可能与创伤反应中夸大的恐惧学习/记忆和/或创伤停止后未能恢复有关。为了捕捉这些生物表型，我们建议识别具有(1)极端恐惧反应行为的动物（即表现出最高的恐惧反应行为）

DESCRIPTION (provided by applicant): Anxiety disorders often develop following exposure to stress or trauma. These frequently have a significant fear component and are sometimes called "fear/anxiety" disorders. Examples include post- traumatic stress disorder (PTSD) and simple phobias. Because only a minority of persons with comparable levels of exposure to stress or trauma develops these disorders, the affected individuals must possess some innate genetic or epigenetic vulnerability. The identification of such vulnerabilities is a major goal of biological psychiatry, and is the main focus of our studies. Most existing knowledge about the brain mechanisms of fear, and hence about the basic biological mechanisms that may be altered in fear/anxiety disorders has been obtained in animal studies of fear conditioning. These studies have pinpointed particular circuits in the amygdala in the acquisition, storage, expression, and regulation of fear responses. Most of these studies have focused on the mechanisms of fear in random populations of animals. However, because most humans with fear/anxiety disorders are believed to represent extremes in the degree of underlying vulnerability, studies in random populations of animals may not be ideal for determining these vulnerabilities. A more promising alternative is to use animals expressing extremes of fear phenotypes. One popular view is that, in particular individuals, vulnerability to the development of fear/anxiety disorders after trauma exposure may, at least in part, involve exaggerated fear learning/memory in response to trauma and/or failure to recover following trauma cessation. To capture these biological phenotypes, we propose to identify animals with (1) extreme fear reactivity behavior (i.e., exhibiting the highest and the lowest levels of conditioned fear responses) and (2) extreme fear extinction behavior (i.e., exhibiting the slowest and the fastestrate of fear memory extinction)as well as animals that exhibit the intermediate levels of fear reactivity and fear extinction, and thus represent average ("normal") individuals. Using fear conditioning paradigms developed in our laboratory, animals exhibiting extreme fear reactivity, extreme fear extinction, and intermediate phenotypes will be separated from within a population of outbred rats. Next, using state-of-the art technology [whole transcriptome sequencing (RNA-Seq)]and weighted gene co-expression network analysis, we will study gene expression differences in particular nuclei of the amygdala among the highest, the intermediate, and the lowest fear reactivity phenotypes as well as among the slowest, the intermediate, and the fastest fear extinction phenotypes. The identified differences will help to pinpoint genes and pathways that characterize individuals with high or low liability t fear/anxiety disorders as well as individuals who are resistant to these disorders. These comprehensive studies will determine specific molecular targets for future focused research of fear-related behaviors and illnesses.