Interrogating Synaptic Mechanisms Underlying Contextual Fear Conditioning Amnesia in Rodent Model of Highly Repetitive Mild Traumatic Brain Injury

摘要 创伤性脑损伤是最常见的神经系统疾病，80%的创伤性脑损伤为轻度 （mTBI）。认知症状的严重程度和持续性随着额外的重复mTBI（rmTBI）而增加。 由Burns实验室开发的rmTBI的高频头部撞击（HF-HI）小鼠模型显示， 学习和与突触信号相关的转录组学谱的变化伴随着可塑性降低 和CA1锥体神经元的突触变化。这可能表明，突触修饰的基础， rmTBI后的顺行性认知症状。目前还不清楚rmTBI如何直接影响已经存在的 建立记忆。记忆痕迹，定义为神经元中持久的物理或化学变化，是神经元的神经功能。 情景记忆的基底转基因啮齿类动物的研究使用立即早期基因， 药理学标记，可以标记背景恐惧条件反射（CFC）范例中的记忆印迹细胞。后续 海马结构中的记忆印迹的光遗传学再激活足以引起海马结构外的记忆回忆。 条件情境和失忆症模型中的恐惧记忆。初步数据显示， HF-HI模型减少了CFC探针试验中的冷冻时间，并且可以标记表达Chr2-YFP的印迹细胞 在转基因印迹小鼠中。我建议询问免疫组织学和电生理学特性， 记忆细胞，以探索重复头部撞击大脑中的结构或突触修饰。我也会用 光遗传学在活体中复活遗忘记忆。这项研究将探索突触修饰如何 与rmTBI和探针记忆回忆后的逆行性认知缺陷有关，而不是记忆基质丢失， 逆行性失忆的机制

Abstract Traumatic brain injury is the most common neurological disorder and 80% consist of mild traumatic brain injury (mTBI). The severity and persistence of cognitive symptoms is increased with additional repeat mTBIs (rmTBI). A high frequency head impact (HF-HI) mouse model of rmTBI developed by the Burns lab displays decreased learning and changes in transcriptomic profiles related to synaptic signaling accompanied by decreased plasticity and synaptic changes in CA1 pyramidal neurons. This would suggest that synaptic modifications underly the anterograde cognitive symptoms following rmTBI. It is still unknown how rmTBI directly effects an already established memory. Engrams, defined as lasting physical or chemical changes in neurons, are the neural substrate underlying episodic memory. Studies in transgenic rodents use immediate early genes and pharmacological labeling, can tag engram cells in contextual fear conditioning (CFC) paradigms. Subsequent optogenetic reactivation of engrams in the hippocampal formation is sufficient to elicit memory recall outside the conditioned context and reanimate fear memories in models of amnesia. Preliminary data has shown that the HF-HI model reduces freezing time in CFC probe trials and engram cells expressing Chr2-YFP can be tagged in transgenic engram mice. I propose to interrogate immunohistological and electrophysiological properties of engram cells to explore architectural or synaptic modifications in the repeat head impact brain. I will also use optogenetics in vivo to reanimate amnestic memories. This research will explore how synaptic modification relates to retrograde cognitive deficits following rmTBI and probe memory recall, not memory substrate loss, as a mechanism for retrograde amnesia.