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

在高度重复性轻度创伤性脑损伤的啮齿动物模型中探究情境恐惧条件性遗忘背后的突触机制

• 批准号: 10557805
• 负责人: Daniel Chapman
• 金额: $ 5.27万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2024-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10557805
• 关键词: Accounting; Acute; Affect; Amnesia; Architecture; Athletic Injuries; Behavior; Bilateral; Brain; Burn injury; Cells; Cellular Morphology; Chemicals; Chronic; Cognition; Cognitive; Cognitive deficits; Data; Electrophysiology (science); Episodic memory; Exposure to; Freezing; Frequencies; Functional disorder; Glutamate Receptor; Goals; Grant; Hippocampal Formation; Hippocampus; Human; Immediate-Early Genes; Immunohistochemistry; Impaired cognition; Implant; Injury; Label; Learning; Memory; Memory impairment; Modeling; Modification; Mus; N-Methylaspartate; Neurobehavioral Manifestations; Neurologist; Neurons; Parahippocampal Gyrus; Patients; Persons; Physicians; Physiological; Physiology; Population; Preparation; Property; Research; Retrograde amnesia; Rodent; Rodent Model; Scientist; Services; Severities; Signal Transduction; Slice; Source; Sports; Structure; Synapses; Techniques; Technology; Testing; Time; Training; Transgenic Organisms; Traumatic Brain Injury; Vertebral column; common symptom; conditioned fear; contact sports; dentate gyrus; experience; fear memory; forgetting; head impact; hippocampal pyramidal neuron; in vivo; memory recall; mild traumatic brain injury; military service; mouse model; nervous system disorder; neural; neuronal excitability; neuropsychiatry; novel; optogenetics; pharmacologic; pre-clinical; receptor function; response; selective expression; skills; subconcussion; synaptic function; transcriptome sequencing; transcriptomics

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.

抽象的 创伤性脑损伤是最常见的神经系统疾病，80%为轻度创伤性脑损伤 （mTBI）。额外的重复 mTBI (rmTBI) 会增加认知症状的严重性和持续性。 Burns 实验室开发的高频头部撞击 (HF-HI) 小鼠模型显示 rmTBI 减少 与突触信号传导相关的转录组谱的学习和变化伴随可塑性下降 CA1 锥体神经元的突触变化。这表明突触修饰是 rmTBI 后的顺行性认知症状。目前尚不清楚 rmTBI 如何直接影响已经 已建立的记忆。印迹被定义为神经元中持久的物理或化学变化，是神经元 情景记忆的基础。转基因啮齿类动物的研究使用早期基因和 药理学标记，可以在情境恐惧调节（CFC）范式中标记印迹细胞。随后的 海马结构中印迹的光遗传学重新激活足以引发大脑外的记忆回忆。 条件环境并复活失忆症模型中的恐惧记忆。初步数据显示， HF-HI 模型缩短了 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 印迹细胞探索重复头部撞击大脑中的结构或突触修饰。我也会用 体内光遗传学可恢复失忆记忆。这项研究将探讨突触修饰如何 与 rmTBI 和探查记忆回忆后的逆行认知缺陷有关，而不是记忆基质丧失，因为 逆行性遗忘症的机制。