Genetic Mapping of Neuronal Circuits Involved in Regulation of Anxiety and Fear

描述（由申请人提供）：这是一份研究恐惧和焦虑的神经生物学研究的申请，特别强调突触的作用？2-含GABAA受体和突触外？5-含GABAA受体。的吗?在焦虑的行为学测试中，含有2的GABAA受体已被证明可以介导地西平的抗焦虑样作用，这些受体将分别从海马CA1、CA3和DG亚区主要神经元中删除，并通过cre- loxp介导的重组从基底外侧杏仁核中删除，以阐明参与焦虑调节的亚区域特异性功能和神经元回路（例如海马三突触和单突触通路）。虽然海马亚区神经元在学习和记忆任务中的功能已经被广泛研究，但这些神经元在情绪调节中的功能仍然未知。初步结果表明突触外？在此基础上，我们提出了一种新的促进消退的治疗策略，这是创伤后应激障碍治疗的一个主要目标。焦虑症是社区中最普遍的精神障碍类型，影响了大约10%-15%的人口。本研究将探讨GABAA受体亚型在海马和杏仁核特定神经元回路中的功能作用，以调节焦虑相关行为。预计拟议的研究将确定？2-和？5-含GABAA受体作为单独的分子靶点治疗不同的焦虑障碍，如广泛性焦虑障碍和创伤后应激障碍。

DESCRIPTION (provided by applicant): This is an application for funding of a study examining the neurobiology of fear and anxiety with a special emphasis on the role of synaptic ?2-containing GABAA receptors and extrasynaptic ?5- containing GABAA receptors. The ?2-containing GABAA receptors, which have been shown to mediate the anxiolytic-like action of diazepam in ethological tests of anxiety will be deleted from hippocampal principal neurons in the CA1, CA3, and DG subregions, respectively, and from the basolateral amygdala using cre- loxP-mediated recombination to elucidate subregion-specific functions and neuronal circuits (e.g. hippocampal trisynaptic and monosynaptic pathways) involved in modulation of anxiety. While the function of neurons in defined hippocampal subregions in learning and memory tasks has been extensively studied, the functions of these neurons in the regulation of emotions is still unknown. Preliminary results indicate a role for extrasynaptic ?5-containing GABAA receptors in extinction of conditioned fear, and based on this observation we propose experiments directed towards the development of a novel therapeutic strategy to promote extinction, which is a major goal in the treatment of posttraumatic stress disorder. Anxiety disorders are the most prevalent type of psychiatric disorders in the community, affecting approximately 10%-15% of the population. This proposal will investigate the functional role of GABAA receptor subtypes in defined neuronal circuits in the hippocampus and the amygdala for the modulation of anxiety-related behaviors. It is expected that the proposed research will identify the ?2- and the ?5- containing GABAA receptors as separate molecular targets for the treatment of distinct anxiety disorders, e.g. generalized anxiety disorder and posttraumatic stress disorder.