Fear generalization after traumatic experience in the dentate gyrus

摘要 焦虑症的一个显著症状是恐惧泛化。被诊断为精神障碍的患者 这一群体的特征不仅是害怕刺激和危险或非常相似的情况 原始创伤发生的背景，但也害怕客观上的刺激和情况 安然无恙，或者说与最初的创伤背景有些相似。作为边缘系统的一部分，海马体接受 并集成空间和上下文信息以及内部状态。此外，海马体的一部分， 具体地说，齿状回(DG)既是抗抑郁药物作用的主要靶点之一，也是抗抑郁药物作用的主要靶点之一 抗焦虑药物，也在通过区分相似的 上下文，这一过程称为模式分离。这一计算被认为主要是由粒执行的 然而，最近的实验结果表明，苔藓细胞(MC)是第二种主要的细胞类型 副秘书长也可参与这一进程。因此，我们假设恐惧在压力中泛化 小鼠诱导恐惧学习模型反映为MCs的语境辨别功能受损。我们会 通过记录应激小鼠头部固定模式下体内MC的钙活性来验证这一假说 分离模式。 SSRI治疗作为诊断为焦虑症患者的一线药物被认为可以恢复 DG的5-羟色胺(5-HT)水平较低。尽管有这样的概念，但人们对实际活动的了解要少得多 在正常或病理条件下5-羟色胺轴突的模式，绝对没有关于 主细胞和5-羟色胺轴突的相关活动。MCS表达兴奋性5-HT2a受体， 提示MCs的活动可能受5-羟色胺的控制，事实上，慢性SSRI的治疗已经显示出来 以增强MC的活性。因此，我们推测应激时5-羟色胺轴突活性降低。 小鼠参与了DG中低水平的5-羟色胺，最终导致MCs和 打乱了模式分离。为了验证这一假说，我们首先将通过以下方式证实5-羟色胺对MC的兴奋作用 结合5-羟色胺轴突的光遗传操作和双光子成像，我们将记录钙离子 应激性恐惧后双色双光子显像同时检测5-羟色胺轴突和MC的活动 学习。综上所述，这项建议旨在更好地理解MC的作用，MC仍然是一种在 DG在恐惧的泛化中的作用，并为5-羟色胺系统在惊厥发病机制中的作用提供直接证据 焦虑症。此外，我们的实验还将为进一步的研究奠定基础 在微电路水平上了解神经调节的机制。

Abstract One of the hallmark symptoms of anxiety disorders is fear generalization. Patients diagnosed with a disorder form this group are characterized by not only fearing stimuli and situations that are dangerous or closely resemble to the context in which the original trauma occurred but also fearing stimuli and situations that are objectively safe or just faintly resemble the original trauma context. Hippocampus as the part of the limbic system receives and integrates spatial and contextual information and internal states. Moreover, parts of the hippocampus, specifically the dentate gyrus (DG) are both one of the major targets of the effects of antidepressants and anxiolytics, and also play a role in encoding information about the environment by distinguishing between similar contexts, a process called pattern separation. This computation was thought to mostly performed by granule cells however recent experimental results suggest that mossy cells (MCs) the second major principal cell type of the DG may also participate in this process. Therefore, we hypothesized that fear generalization in a stress induced fear learning mouse model is reflected by impaired contextual discrimination function of MCs. We will test this hypothesis by recording the calcium activity of MCs in vivo in stressed mice during a head fixed pattern separation paradigm. SSRI treatment, as the first line of medication for patients diagnosed with anxiety disorders is thought to restore the low serotonin (5-HT) levels in the DG. Despite this notion there is much less known about the actual activity pattern of 5-HT axons under normal or pathological conditions and there is absolutely no data about the correlated activity of the principal cells and 5-HT axons. MCs express the excitatory 5-HT2A receptors which suggests that the activity of MCs may be controlled by 5-HT and indeed, chronic SSRI treatment has been shown to enhance the activity of MCs. Therefore, we hypothesized that decreased activity of 5-HT axons in stressed mice contributes to low levels of 5-HT in the DG which eventually leads to suppressed activity of MCs and disrupted patter separation. To test this hypothesis, first we will confirm the excitatory effect of 5-HT on MCs by combining optogenetical manipulation of 5-HT axons with two-photon imaging, then we will record the calcium activity of 5-HT axons and MCs simultaneously with dual color two-photon imaging following stress induced fear learning. Altogether, this proposal aims to better understand the role of MCs, a still “enigmatic” cell type in the DG in fear generalization and to provide direct evidence for the role of the 5-HT system in the pathogenesis of anxiety disorders. Furthermore, our experiments will lay the foundation for further studies aiming at understanding the mechanism of neuromodulation at the microcircuit level.