The Role of Amygdala GABAergic Transmission in Fear and Anxiety

项目摘要 大量研究的结果表明，快速多巴胺能传递的变化 在杏仁核的神经过程中起着重要作用， 条件性恐惧然而，有证据表明， γ-氨基丁酸（GABA）也可能参与这些过程。在人类中， GABA能传输在调节恐惧和焦虑中的作用， 患有焦虑症的患者通常通过给药 苯二氮卓类（BZ），其通过GABAA受体（GABAAR）介导其作用。 特别富含GABAAR，已知GABAAR参与抗焦虑和致焦虑的作用。 GABA激动剂和拮抗剂的作用。目前，在研究方面存在空白 旨在研究杏仁核GABA能传递的变化如何影响情绪， 与焦虑和恐惧相关的记忆和行为。最近，我们的实验室报告说， 获得后杏仁核中GABA相关基因和GABAAR水平的变化 和消除巴甫洛夫恐惧，一种常用的恐惧和焦虑症的动物模型。我们 研究结果表明，恐惧的获得诱导了与以下相关的遗传标记的下调： 杏仁核GABA能功能下降;而获得恐惧消退产生了一个上升， 与增强的GABA能传递相关的GABA能标记物的调节。 这项研究计划将采用一种新颖而有力的方法来研究 杏仁核GABA能传递的恐惧和行为反应的药物制剂。 具体而言，在本建议的目标1中，我们建议研究 杏仁核中2-GABAARs或GAD 67表达敲低的小鼠的条件性恐惧 使用基于载体的RNA干扰（RNAi）策略来局部诱导功能丧失。我们 假设GABA能功能的相关变化将降低阶段性 抑制，导致容易获得的恐惧和钝化消除恐惧。目标2 我们计划研究BZ给药对敲除小鼠的行为影响， 杏仁核中2-GABAAR或GAD 67的表达。我们假设， 杏仁核GABA能功能将导致对BZ的钝化的焦虑样行为效应。

Project Summary The results of numerous studies have demonstrated that changes in fast glutamatergic tr ansmission in the amygdala play a major role in neural processes involved in the acquisition and extinction of conditioned fear. However, there are converging lines of evidence suggesting that changes in gamma-aminobutyric acid (GABA) may also be involved in these processes. In humans, involvement of GABAergic transmission in the regulation of fear and anxiety is highlighted by the fact that patients suffering from anxiety disorders are commonly treated by the administration of benzodiazepines (BZs), which mediate their actions via GABAA receptors (GABAARs).The amygdala is particularly rich in GABAARs which are known to be involved in the anxiolytic and anxiogenic effects of GABA agonists and antagonists, respectively. At present, there is a void in research designed to investigate how the changes in amygdala GABAergic transmission influences emotional memories and behaviors associated with anxiety and fear. Recently, our lab reported learningrelated changes in GABA-related genes and GABAAR levels in the amygdala after the acquisition and extinction of Pavlovian fear , a commonly used animal model of fear and anxiety disorders. Our findings showed that the acquisition of fear induced a down regulation of genetic markers related to decreased amygdala GABAergic function; whereas the acquisition of fear extinction produced an up regulation of GABAergic markers related to enhanced GABAergic transmission. This research proposal will employ a novel and powerful approach to investigating the role of amygdala GABAergic transmission in fear and behavioral responses to pharmacological agents. Specifically, in Aim 1 of this proposal, we propose to examine the acquisition and extinction of conditioned fear in mice with knocked down expression of 2-GABAARs or GAD67 in the amygdala using a vector-based RNA interference (RNAi) strategy to locally induce loss-of-function. We hypothesize that associated changes in GABAergic function will decrease the level of phasic inhibition, resulting in facilitated acquisition of fear and blunted extinction of fear. In Aim 2 of this proposal, we plan to examine the behavioral effects of BZ administration in mice with knocked down expression of 2-GABAARs or GAD67 in the amygdala. We hypothesize that associated changes in amygdala GABAergic function will result in blunted anxiety-like behavioral effects to BZ.