Molecular Genetic Study of Fear and Anxiety

描述(由申请者提供)：在这个项目中，我们提出了一种识别精神障碍重要基因的新策略。这些研究的目标是人类焦虑的正常和病理性表达，并特别关注小鼠的后天恐惧和先天恐惧。因为恐惧是一种普遍的影响，在整个进化过程中都是保守的，所以有可能在老鼠身上建立恐惧的模型--一种既适用于生理分析又适用于基因分析的有机体。恐惧条件反射是一种衡量有机体了解新的危险或威胁刺激或环境并做出适当反应的基本能力的指标。恐惧条件作用的研究为分子遗传学分析提供了两个非常显著的优势：行为模式可以在人类受试者中非常接近地模拟，而支撑这些行为的神经回路和相关的信息处理系统在脊椎动物中相对容易理解，并且高度保守。由于在最普遍的意义上，焦虑症代表了神经机制中的一种故障，这种机制可以检测危险并动员对危险的适应性反应，因此我们提出，含有后天或先天形式的恐惧的遗传决定因素的基因子集也将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翻译研究，它结合了对小鼠习得性和先天形式的恐惧的直接分子遗传学研究，以及对人类焦虑相关行为、特征和障碍的遗传分析。该方案项目由五个独立项目和一个培训部分组成。1.小鼠恐惧状态的遗传和行为模型--1A。习得恐惧(Kandel)2A.天生恐惧(母鸡)。2.从老鼠到人类恐惧和焦虑的翻译：遗传和基因组方法(乔里安)。3.人类恐惧和焦虑的临床研究(Fyer)。4.人类焦虑障碍的临床研究(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).