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。这些通常具有显著的恐惧成分，有时被称为“恐惧/焦虑”障碍。例子包括创伤后应激障碍（PTSD）和简单的恐惧症。因为只有少数人暴露于压力或创伤的可比水平发展这些疾病，受影响的个人必须拥有一些先天的遗传或表观遗传的脆弱性。识别这种脆弱性是生物精神病学的主要目标，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，以及关于恐惧/焦虑障碍可能改变的基本生物学机制的知识，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，这些回路在恐惧反应的获取、储存、表达和调节中起着作用。这些研究大多集中在随机动物种群的恐惧机制上。然而，由于大多数患有恐惧/焦虑症的人被认为代表了潜在脆弱性程度的极端，因此在随机动物群体中进行的研究可能不适合确定这些脆弱性。一个更有希望的选择是使用表达极端恐惧表型的动物。 一种流行的观点是，在特定的个体中，创伤暴露后易患恐惧/焦虑症的脆弱性可能至少部分涉及对创伤的过度恐惧学习/记忆和/或创伤停止后无法恢复。为了捕获这些生物表型，我们建议鉴定具有（1）极端恐惧反应行为（即，表现出最高的 和最低水平的条件恐惧反应）和（2）极端恐惧消退行为（即，表现出最慢和最快的恐惧记忆消退）以及动物， 表现出中等水平的恐惧反应性和恐惧消退，因此代表平均（“正常”）个体。使用我们实验室开发的恐惧条件反射范例，将表现出极端恐惧反应性、极端恐惧消退和中间表型的动物从远系繁殖大鼠群体中分离出来。 接下来，使用最先进的技术[全转录组测序（RNA-Seq）]和加权基因共表达网络分析，我们将研究最高，中间和最低恐惧反应表型之间以及最慢，中间和最快恐惧消退表型之间杏仁核特定核的基因表达差异。确定的差异将有助于确定具有高或低恐惧/焦虑障碍倾向的个体以及对这些疾病具有抵抗力的个体的基因和途径。这些全面的研究将为未来与恐惧相关的行为和疾病的重点研究确定特定的分子靶点。 公共卫生相关性：在过去的二十年里，恐惧的神经基础的关键方面已经通过巴甫洛夫恐惧条件反射的研究得到了阐明，这些研究主要是在随机的动物群体中进行的。然而，由于大多数患有恐惧/焦虑症的人（例如，戏剧性压力后障碍）被认为代表潜在脆弱性程度的极端，但对随机动物种群的研究可能不适合确定这些脆弱性。为了查明表征患有恐惧/焦虑症的个体的分子网络，在本提案中，我们将重点关注代表大鼠极端恐惧相关行为的行为识别表型。

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. PUBLIC HEALTH RELEVANCE: Over the past two decades, key aspects of the neural basis of fear have been elucidated through studies of Pavlovian fear conditioning, which have been mostly performed in random populations of animals. However, because most humans with fear/anxiety disorders (e.g., post dramatic stress disorder) 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. To pinpoint molecular networks that characterize individuals with high or low liability to fear/anxiety disorders, in the present proposal we will focus on behaviorally identified phenotypes that represent extremes of fear-related behaviors in rats.