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

描述（由申请人提供）：这是一项研究的资金申请，该研究旨在研究恐惧和焦虑的神经生物学，特别强调突触的作用。2-含有GABAA受体和突触外？5-含有GABAA受体。的？2-含有GABAA受体的神经元将分别从海马CA 1、CA 3和DG亚区的主要神经元中删除，所述GABAA受体已显示在焦虑的行为学测试中介导地西泮的抗焦虑样作用，并从基底外侧杏仁核使用cre-loxP介导的重组，以阐明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）参与焦虑的调节。虽然在学习和记忆任务中定义的海马子区域中的神经元的功能已经被广泛研究，但是这些神经元在情绪调节中的功能仍然是未知的。初步结果表明，突触外？5-含有GABAA受体的条件性恐惧的消退，并基于这一观察，我们提出了实验，旨在发展一种新的治疗策略，以促进灭绝，这是一个主要目标，在治疗创伤后应激障碍。焦虑症是社区中最常见的精神疾病类型，影响约10%-15%的人口。本研究将探讨GABAA受体亚型在海马和杏仁核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-还有5-含有GABAA受体作为单独的分子靶标，用于治疗不同的焦虑症，例如广泛性焦虑症和创伤后应激障碍。

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.