Molecular control of excitation-inhibition balance to encode ambiguous threats

兴奋抑制平衡的分子控制来编码模糊的威胁

• 批准号: 8748717
• 负责人: Amar Sahay
• 金额: $ 54.65万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8748717
• 关键词: Address; Adherens Junction; Adult; Anxiety Disorders; Behavior Control; Behavioral; Biological Assay; Brain; Cell Nucleus; Cells; Cellular Compartment Analysis; Cues; Cytoplasmic Granules; Development; Discrimination; Dose; Engineering; Environment; Equilibrium; Exhibits; Failure; Fluorescent in Situ Hybridization; Foundations; Fright; Gene Transfer; Generalized Anxiety Disorder; Genetic; Growth; Immediate-Early Genes; Interneurons; Knowledge; Life; Link; Maps; Mediating; Memory; Molecular; Neural Pathways; Neurobiology; Neurons; Panic Disorder; Pathway interactions; Pattern; Post-Traumatic Stress Disorders; Principal Investigator; Process; Recruitment Activity; Regulation; Research; Retrieval; Rodent; Role; Specificity; Testing; Therapeutic; Viral Genes; Work; base; cilium biogenesis; dentate gyrus; drug discovery; experience; feeding; improved; in vivo; insight; interdisciplinary approach; mossy fiber; neural circuit; neurobiological mechanism; neurogenesis; neuromechanism; optogenetics; programs; public health relevance; research study; response; scaffold; small molecule; young adult

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

项目负责人/主要研究者（最后，第一，中间）：Sahay，Amar 项目摘要 焦虑症，如广泛性焦虑症（GAD）和创伤后应激障碍（PTSD）， 以对模棱两可的威胁的高度恐惧反应为特点。这种对恐惧的过度概括可能会出现 由于对线索相关意外事件的错误评估或未能区分安全环境和危险环境， 以前经历过的厌恶性记忆，然后导致厌恶性记忆的不适当检索， 恐惧回路的激活由于齿状回（DG）-CA 3回路中的模式分离被认为是最小化 类似输入之间的干扰，它可以作为神经机制，模糊的威胁， 已处理。DG是啮齿动物和人类以及成年人一生中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 处理模棱两可的威胁。然而，成年人的局部回路机制和神经通路- 天生的神经元处理模棱两可的威胁是知之甚少。解决我们知识中的这一差距， 产生对恐惧泛化的神经生物学的基本见解，并为重新设计 DG-CA 3电路，以改善模糊威胁处理。在这里，我们将使用多学科方法 涉及逆转录病毒和慢病毒基因转导、基于光遗传学的神经通路操纵，以及 行为分析，以询问成年出生的神经元依赖性摄食调节之间的因果关系 前向兴奋-抑制平衡和DG-CA 3外部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，我们建议从基因上重新设计兴奋-抑制 DG-CA 3回路中的平衡，以增强对模糊威胁的处理，并开发假设驱动 药物发现方法来鉴定兴奋-抑制平衡的小分子调节剂， 因此，害怕泛化。总之，这些研究将为成年人的牙齿如何生长提供一个框架。 颗粒神经元支配恐惧泛化，并展示兴奋-抑制平衡的调节 可能被用于治疗焦虑症中的恐惧泛化。 OMB编号0925-0001/0002（2012年8月8日至2015年8月31日批准的修订版）页码简历格式页码