Molecular Genetic Study of Fear and Anxiety

描述（由申请人提供）：在本项目中，我们提出了一种鉴定精神疾病重要基因的新策略。这些研究的目标是人类焦虑的正常和病理表达，并特别关注小鼠的习得性和先天恐惧。因为恐惧是一种普遍的情感，在整个系统发育过程中都是保守的，所以在老鼠身上建立恐惧模型是可能的——老鼠是一种适合于生理和基因分析的有机体。恐惧条件反射是衡量生物体了解新的危险或威胁性刺激或环境并作出适当反应的基本能力。恐惧条件反射的研究为分子遗传分析提供了两个非常重要的优势：行为范式可以在人类受试者中进行密切模仿，并且这些行为背后的神经回路和相关信息处理系统在脊椎动物中得到了相对较好的理解和高度保守。因为，从最普遍的意义上说，焦虑症代表了检测危险和调动对危险的适应性反应的神经机制的故障，我们提出，包含习得性或先天恐惧形式的遗传决定因素的基因子集也包含人类焦虑症的易感等位基因。因此，我们提出了一项关于恐惧和焦虑的转化研究，将对小鼠习得性和先天形式的恐惧的直接分子遗传学研究与对人类焦虑相关行为、特征和障碍的遗传分析结合起来。该项目由五个独立的项目和一个培训部分组成。小鼠恐惧状态的遗传和行为模型- 1A。习得性恐惧（坎德尔）天生的恐惧（母鸡）。2.翻译从老鼠到人类的恐惧和焦虑：遗传和基因组方法（吉利亚姆）。3. 人类恐惧和焦虑的临床研究（费尔）。4. 人类焦虑症的临床研究（Weissman）。

DESCRIPTION (provided by applicant): In this program project we present a novel strategy for the identification of genes important for psychiatric disorders. The studies are aimed at normal and pathological expressions of anxiety in humans, and focus specifically on learned and innate fear in mice. Because fear is a universal affect conserved throughout phylogeny, it is possible to model fear in mice - an organism that is suitable for both physiological and genetic analysis. Fear conditioning is a measure of an organism's basic ability to learn about new dangerous or threatening stimuli or environments, and to respond appropriately. The study of fear conditioning offers two very significant advantages for molecular genetic analysis: the behavioral paradigms can be closely mimicked in human subjects, and the neurocircuitry, and associated information processing systems that underlie these behaviors, are relatively well understood, and highly conserved among vertebrates. Since, in their most general sense, anxiety disorders represent a malfunction in the neural mechanisms that detect danger and mobilize adaptive responses to that danger, we propose that a subset of genes that harbor genetic determinants for learned or innate forms of fear will also harbor susceptibility alleles for human anxiety disorders. Thus, we propose a translational study of fear and anxiety that combines direct molecular genetic study of learned and innate forms of fear in mice with genetic analysis of anxiety related behaviors, traits, and disorders in humans. The Program Project consists of five independent Projects and a Training Component. 1. Genetic and Behavioral Models of Fear States in Mice- 1A. Learned Fear (Kandel) 2A. Innate Fear (Hen). 2.Translation from Mouse to Human Fear and Anxiety: Genetic and Genomic Approaches (Gilliam). 3. Clinical Studies of Human Fear and Anxiety (Fyer). 4. Clinical Studies of Human Anxiety Disorders (Weissman).