Molecular Genetic Study of Fear and Anxiety

描述（由申请人提供）：在这个项目中，我们提出了一种新的策略，用于识别对精神疾病重要的基因。这些研究针对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性恐惧。由于恐惧是一种在整个胚胎发育过程中保守的普遍情感，因此有可能在小鼠中建立恐惧模型--一种既适合生理学分析又适合遗传学分析的生物体。恐惧条件反射是衡量生物体学习新的危险或威胁性刺激或环境的基本能力，并做出适当反应。恐惧条件反射的研究为分子遗传学分析提供了两个非常重要的优势：行为模式可以在人类受试者中被密切模仿，神经回路和相关的信息处理系统是这些行为的基础，相对较好地理解，并且在脊椎动物中高度保守。从最普遍的意义上讲，焦虑症代表了神经机制的一种功能障碍，这种神经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，一个包含后天或先天恐惧形式遗传决定因素的基因子集也会包含人类焦虑症的易感等位基因。因此，我们提出了一个翻译的恐惧和焦虑的研究，结合直接的分子遗传学研究学习和先天形式的恐惧在小鼠与遗传分析的焦虑相关的行为，特征和疾病在人类。 该计划项目包括五个独立的项目和一个培训部分。 1.小鼠恐惧状态的遗传和行为模型- 1A。学习恐惧（坎德尔）2A。天生恐惧（母鸡）。2.从小鼠到人类的恐惧和焦虑的翻译：遗传和基因组方法（Gilliam）。3.人类恐惧和焦虑的临床研究（传单）。4.人类焦虑症的临床研究（韦斯曼）。

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).