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

基本信息

批准号：
9237311
负责人：
Amar Sahay
金额：
$ 54.13万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9237311
关键词：
Address Adherens Junction Adult Anatomy Anxiety Disorders Behavioral Biography 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 Human Immediate-Early Genes Interneurons Knowledge Life Link Maps Mediating Memory Molecular Neural Pathways Neurobiology Neurons Panic Disorder Pathway interactions Pattern Pharmacology Post-Traumatic Stress Disorders Principal Investigator Process Recruitment Activity Regulation Research Retrieval Rodent Role Specificity Testing Therapeutic Transduction Gene Viral Genes Work base cilium biogenesis dentate gyrus drug discovery experience experimental study feeding improved in vivo insight interdisciplinary approach mossy fiber neural circuit neurobiological mechanism neurogenesis neuromechanism optogenetics programs public health relevance response scaffold small molecule young adult

项目摘要

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：焦虑症（例如普遍焦虑症（GAD）和创伤后应激障碍（PTSD））的特征是对歧义威胁的恐惧反应增加。恐惧的过度概括可能是由于对提示相关的偶然性的错误评估或未能将安全环境与以前经历的厌恶厌恶的环境区分开来引起，从而导致对厌恶记忆和激活恐惧回路的不适当检索。由于齿状回（DG）-CA3电路中的模式分离被认为可以最大程度地减少相似输入之间的干扰，因此它可以用作处理模棱两可威胁的神经机制。 DG在啮齿动物和人类和成年神经元中的整个生命中均宿主与模式分离有关，这表明这些细胞在处理模棱两可的威胁中的潜在作用。但是，对成年神经元进行歧义威胁的局部电路机制和神经途径知之甚少。在我们的知识中解决这一差距可能会产生对恐惧概括和燃料策略的神经生物学的基本见解，以重新设计DG-CA3电路，以改善模棱两可的威胁处理。在这里，我们将使用涉及复古和易发性基因转导，基于光遗传学的神经途径操纵和行为分析的多学科方法，以询问成人出生的神经元依赖的饲料前馈激发抑制平衡和DG-CA3之间的因果关系外部电路，调节对歧义威胁的恐惧反应。在概念研究证明中，我们建议在DG-CA3电路中遗传重新设计的激发抑制平衡，以增强对歧义威胁的处理，并开发出假设驱动的药物发现方法，以识别刺激性抑制平衡的小分子调节剂，因此，害怕普遍性。。这些研究将共同为成人出生的牙齿颗粒神经元如何决定恐惧的概括，并证明如何在焦虑症中恐惧概括来治疗恐惧的恐惧平衡。