Molecular control of excitation-inhibition balance to encode ambiguous threats

项目主任/首席调查员(最后、第一、中间)：萨海，阿马尔 项目摘要 广泛性焦虑症(GAD)和创伤后应激障碍(PTSD)等焦虑症是 以对模棱两可的威胁的高度恐惧为特征。这种对恐惧的过度泛化可能会出现 由于对与提示相关的意外情况的错误评估或未能将安全环境与 先前经历的厌恶，这会导致厌恶记忆的不适当提取和 激活恐惧回路。由于齿状回(DG)-CA3回路中模式分离被认为是最小化 相似输入之间的干扰，它可以作为模糊威胁的神经机制 已处理。在啮齿动物、人类和成年动物的一生中，DG都是持续神经发生的宿主。 出生的神经元与模式分离有关，这表明这些细胞在 处理不明确的威胁。然而，成年人通过局部电路机制和神经通路- 天生的神经元处理模棱两可的威胁，人们对此知之甚少。解决我们知识中的这一差距可能会 对恐惧泛化的神经生物学产生基本的见解，并推动战略的重新设计 DG-CA3电路，改进模糊威胁处理。在这里，我们将使用多学科方法 包括逆转录病毒和Lenti病毒的基因转导，基于光遗传的神经通路操作，以及 用行为分析探讨成体神经元依赖饲料调节之间的因果联系 正向兴奋-抑制平衡和DG-CA3外在回路与恐惧反应的调制 模棱两可的威胁。在概念验证研究中，我们建议对兴奋抑制进行基因重组。 DG-CA3回路中的平衡，以增强对模糊威胁的处理并开发假设驱动 识别兴奋-抑制平衡小分子调节剂的药物发现方法 因此，害怕一概而论。总而言之，这些研究将为成年出生的齿状齿 颗粒神经元支配恐惧概括，并展示兴奋-抑制的调节如何平衡 可用于治疗焦虑症的恐惧泛化。 OMB编号0925-0001/0002(截至2015年8月31日批准的08/12修订版)页面传记素描格式页面

Program Director/Principal Investigator (Last, First, Middle): Sahay, Amar Project Summary Anxiety disorders such as generalized anxiety disorder (GAD) and post-traumatic stress disorder (PTSD) are characterized by heightened fear reactivity to ambiguous threats. This over generalization of fear may arise from erroneous assessment of cue-associated contingency or failure to distinguish a safe environment from a previously experienced aversive one, which then results in inappropriate retrieval of aversive memories and activation of fear circuits. Since pattern separation in dentate gyrus (DG)-CA3 circuit is thought to minimize interference between similar inputs, it may serve as neural mechanism by which ambiguous threats are processed. The DG is host to ongoing neurogenesis throughout life in both rodents and humans and adult- born neurons have been implicated in pattern separation, suggesting a potential role for these cells in processing of ambiguous threats. However, the local circuit mechanisms and neural pathways by which adult- born neurons process ambiguous threats are poorly understood. Addressing this gap in our knowledge may generate fundamental insights into the neurobiology of fear generalization and fuel strategies to reengineer the DG-CA3 circuit to improve ambiguous threat processing. Here, we will use a multidisciplinary approach involving retro-and lenti-viral gene transduction, optogenetic based neural pathway manipulations, and behavioral analysis to interrogate the causal links between adult-born neuron dependent regulation of feed forward excitation-inhibition balance and DG-CA3 extrinsic circuitry with modulation of fear responses to ambiguous threats. In proof of concept studies, we propose to genetically reengineer excitation-inhibition balance in the DG-CA3 circuit to enhance processing of ambiguous threats and develop a hypothesis driven drug discovery approach to identify small molecule modulators of excitation-inhibition balance and consequently, fear generalization. Together, these studies will generate a scaffold for how adult-born dentate granule neurons dictate fear generalization and demonstrate how modulation of excitation-inhibition balance may be harnessed for treatment of fear generalization in anxiety disorders. OMB No. 0925-0001/0002 (Rev. 08/12 Approved Through 8/31/2015) Page Biographical Sketch Format Page