Role of hippocampal adult-born granule cells in TBI-induced dentate gyrus circuit pathology and pattern separation deficit

项目摘要 创伤性脑损伤（TBI）是一种非常普遍的健康问题，导致认知和心理缺陷 例如记忆障碍、抑郁、焦虑和癫痫。在啮齿动物模型中TBI后， 海马成体神经发生的快速和短暂增加。成人出生颗粒细胞（abGC）出生于 对皮质撞击损伤的反应表现出改变的形态和迁移模式，表明这些神经元 可能会在齿状回网络中产生异常连接通常，abGC成熟以形成功能性的 有丝分裂后8周，兴奋性突触连接到表达小清蛋白的中间神经元上，并起到抑制 通过激活抑制回路来增强齿状回的兴奋性。如果因损伤而产生的abGCs未能 整合到各自的抑制网络中，那么它们可能会导致功能失调的抑制， 过度兴奋和脑外伤后齿状回记忆处理改变。具体来说，模式 分离，一种依赖于牙齿的记忆功能，用于区分重叠的空间和物理 信息，依赖于神经发生和稀疏齿状活动水平。正常模式分离函数为 在很大程度上由abGC偶联到齿状回中的反馈抑制介导， TBI之后。我假设TBI诱导的abGC在与反馈抑制的耦合中功能失调， 并导致脑损伤后的模式分离缺陷。拟议的研究将使用流体冲击 TBI的损伤（FPI）模型诱导比皮质撞击更大的海马神经病理学，并检查 损伤后8周时TBI诱导的abGCs的形态、迁移和电生理特性 点将进行TBI诱导的abGC的体内和离体光遗传学操作，以分析它们的生物学特性。 分别对靶神经元上的网络兴奋性和功能性突触的贡献。TBI诱导的abGC 将通过在海马神经元中的光遗传学抑制来检查对模式分离缺陷的贡献。 牙齿特异性自发位置识别任务。这项研究的结果将解决有关 损伤诱导abGCs功能障碍在齿状回兴奋性和模式分离缺陷中的作用 受伤。

Project Summary Traumatic brain injury (TBI) is a highly prevalent health issue that results in cognitive and psychological deficits such as memory dysfunction, depression, anxiety, and epilepsy. Following TBI in rodent models, there is a robust and transient increase in hippocampal adult neurogenesis. Adult-born granule cells (abGCs) born in response to cortical impact injury exhibit altered morphology and migration patterns, suggesting these neurons may make aberrant connections within the dentate gyrus network. Normally, abGCs mature to form functional excitatory synapses onto parvalbumin expressing interneurons by 8 weeks post-mitosis and act to suppress the dentate gyrus excitability through activation of inhibitory circuits. If abGCs born in response to injury fail to integrate into their respective inhibitory networks, then they may contribute to dysfunctional inhibition, hyperexcitability, and altered memory processing in the dentate gyrus following TBI. Specifically, pattern separation, a dentate-dependent memory function necessary to distinguish overlapping spatial and physical information, relies on neurogenesis and sparse dentate activity levels. Normal pattern separation function is largely mediated by abGC coupling to feedback inhibition in the dentate gyrus and is drastically hindered following TBI. I hypothesize that TBI-induced abGCs are dysfunctional in their coupling to feedback inhibition and contribute to pattern separation deficits after brain injury. The proposed study will use the Fluid Percussion Injury (FPI) model of TBI which induces greater hippocampal neuropathology than cortical impact, and examine morphology, migration, and electrophysiological properties of TBI-induced abGCs at the 8 week post-injury time point. In-vivo and ex-vivo optogenetic manipulation of TBI-induced abGCs will be performed to analyze their contribution to network excitability and functional synapses onto target neurons respectively. TBI-induced abGC contribution to pattern separation deficit will be examined through optogenetic suppression during a hippocampal dentate-specific spontaneous location recognition task. The results of this study will resolve controversies about the role of injury-induced dysfunctional abGCs in dentate excitability and pattern separation deficits in response to injury.