The Role of Amygdala GABAergic Transmission in Fear and Anxiety

项目摘要 大量研究的结果表明，快速谷氨酸能传递的变化 杏仁核在神经过程中起着重要作用，这些神经过程参与了 条件性恐惧。然而，有一致的证据表明， γ-氨基丁酸(GABA)也可能参与这些过程。在人类中，参与 GABA能传递在调节恐惧和焦虑方面的突出表现是这样一个事实 患有焦虑症的患者通常通过给予 苯二氮类药物(BZS)，通过GABAA受体(GABAARs)介导其作用。杏仁核 尤其富含GAABAAR，这种已知与抗焦虑和致焦虑有关的物质 GABA激动剂和拮抗剂的作用。目前，这方面的研究还存在空白。 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，我们的实验室报告了与学习有关的 收购后杏仁核GABA相关基因和GABAAR水平的变化 巴甫洛夫式恐惧的消失，这是一种常用的恐惧和焦虑症的动物模型。我们的 研究结果表明，恐惧的习得导致与以下相关的遗传标记的下调 杏仁核GABA能功能降低；而恐惧消退的习得会产生UP 与增强的GABA能传递相关的GABA能标志物的调节。 这项研究提案将采用一种新颖而有力的方法来研究 杏仁核GABA能传递恐惧和对药物的行为反应。 具体地说，在这项建议的目标1中，我们建议审查收购和灭绝 杏仁核中2-GABAARs或GAD67基因表达下调的小鼠条件性恐惧 使用基于载体的RNA干扰(RNAi)策略局部诱导功能丧失。我们 假设GABA能功能的相关变化将降低相水平 抑制，导致更容易获得恐惧和钝化消除恐惧。在这个目标2中 建议，我们计划检测BZ给药对被击倒的小鼠的行为影响 2-GABAARs或GAD67在杏仁核中的表达我们假设相关的变化在 杏仁核GABA能功能会对BZ产生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.