Molecular control of excitation-inhibition balance to encode ambiguous threats

描述（由申请人提供）：焦虑症，如广泛性焦虑症（GAD）和创伤后应激障碍（PTSD），其特征是对模糊威胁的高度恐惧反应。这种对恐惧的过度概括可能是由于对线索相关的偶发事件的错误评估，或者无法区分安全环境和先前经历过的厌恶环境，从而导致对厌恶记忆的不适当检索和恐惧回路的激活。由于齿状回(DG)-CA3回路中的模式分离被认为可以最大限度地减少相似输入之间的干扰，因此它可能是处理模糊威胁的神经机制。在啮齿类动物和人类的整个生命过程中，DG都是持续神经发生的宿主，并且成年出生的神经元与模式分离有关，这表明这些细胞在处理模糊威胁方面具有潜在作用。然而，成人出生的神经元处理模糊威胁的局部电路机制和神经通路尚不清楚。解决我们知识上的这一差距可能会对恐惧泛化的神经生物学产生根本性的见解，并为重新设计DG-CA3电路以改善模糊威胁处理提供策略。在这里，我们将使用多学科方法，包括逆转录和慢病毒基因转导，基于光遗传学的神经通路操作和行为分析，来询问成年出生的神经元依赖前馈兴奋-抑制平衡调节和DG-CA3外源性回路与对模糊威胁的恐惧反应调节之间的因果关系。在概念验证研究中，我们建议基因重组DG-CA3电路中的兴奋-抑制平衡，以增强对模糊威胁的处理，并开发一种假设驱动的药物发现方法，以识别兴奋-抑制平衡的小分子调节剂，从而识别恐惧泛化。总之，这些研究将为成年出生的齿状颗粒神经元如何支配恐惧泛化提供一个框架，并证明如何利用兴奋-抑制平衡的调节来治疗焦虑障碍中的恐惧泛化。

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.