Tau-independent effects of high frequency head impact on cognition and neurobehavior

项目摘要(摘要) 充满头部撞击(HI)的运动生涯使运动员容易遭受慢性创伤 脑病(CTE)是一种以行为障碍、认知障碍为特征的神经退行性疾病 大脑最易受压力影响的脑沟深处的损伤和p-tau病理 和紧张。CTE领域的一个亟待解决的问题是，p-tau在行为障碍中的作用：它 因果关系、顺流关系或偶然关系？在阿尔茨海默病和其他肌肉疾病中，相当大的p- 在检测到强烈的行为变化之前，需要tau的积累和神经元的死亡，以及 在第一阶段和第二阶段的CTE中发现的低水平的p-tau是否是导致 据报道，这些运动员的行为发生了变化。因此，探索行为的原因 蛋白质聚集谱以外的缺陷是必需的。 重复创伤性脑损伤(TBI)啮齿动物模型被广泛应用于CTE的研究。总体而言，这项工作 已经取得了部分成功-几乎所有的组都报告了慢性认知缺陷和神经行为 异常现象。相比之下，重述慢性神经病理学的难度仍然很大。 啮齿动物的CTE，其中一个主要原因是啮齿动物的左脑。颅脑损伤所致急性 P-tau和淀粉样蛋白-β的积聚是可能的，但这需要轴突损伤才能产生。 没有轴突损伤的重复HI模型确实存在，并且既没有急性也没有慢性增加 在p-tau或淀粉样蛋白β中。正是由于这些局限性，没有轴突损伤的重复HI小鼠 研究重复性损伤的tau非依赖性效应的优秀模型。在本提案中，我们使用HI 无结构性损伤的高频撞击小鼠模型(HI-HF) 视束外：无轴突损伤，无神经细胞死亡，无神经炎症，无 P-tau的积累。我们将重点研究海马神经元，以研究它们对 Hi-HF。这个项目的长期目标是了解重复缺氧是如何扰乱生理大脑的 功能，为什么这些变化在HI暴露停止后仍然存在，并识别分子靶标 来扭转这些变化。 在这项建议中，我们正在检验HI-HF导致慢性突触适应的假设。 这些适应的目的是减少对HI的反应而进入神经元的钙内流， 但其后果包括包括认知障碍在内的慢性行为缺陷。 好了！

PROJECT SUMMARY (ABSTRACT) An athletic career filled with head impacts (HI) predisposes athletes to chronic traumatic encephalopathy (CTE), a neurodegenerative disease characterized by behavioral deficits, cognitive impairment, and p-tau pathology in the sulcal depths where the brain is most susceptible to stress and strain. A burning question in the CTE field is to the role of p-tau in behavioral impairments: is it causative, downstream, or incidental? In Alzheimer's disease and other tauopathies considerable p- tau accumulation and neuronal death is required before strong behavioral changes are detected, and it remains debatable if the low levels of p-tau found in Stage I and II CTE are causative factors of the behavioral changes reported in these same athletes. As such, exploration of the causes of behavioral deficits beyond the protein aggregation spectrum is required. Repeat traumatic brain injury (TBI) rodent models are widely used to study CTE. Overall, this work has had partial success – almost all groups report chronic cognitive deficits and neurobehavioral abnormalities. In contrast, immense difficulty remains recapitulating the chronic neuropathology of CTE in rodents, with one major reason being the lisencephalic brain of the rodent. TBI-induced acute accumulations of p-tau and amyloid-β are possible, but these require axonal injury to generate. Repeat HI models without axonal injury do exist, and do not have either an acute or chronic increase in p-tau or amyloid-β. Precisely because of these limitations, repeat HI mice without axonal injury are excellent models to study the tau-independent effects of repetitive injury. In this proposal we use a HI mouse model with high frequency impacts (HI-HF) that does not present with structural damage outside of the optic tract: with no axonal injury, no neuronal cell death, no neuroinflammation, and no p-tau accumulation. We will focus on hippocampal neurons to study their physiological response to HI-HF. The long-term goal of this project is to understand how repeat HI disrupts physiological brain function, why these changes persist after HI exposure has stopped, and to identify molecular targets to reverse these changes. In this proposal we are testing the hypothesis that HI-HF causes chronic synaptic adaptation. The purpose of these adaptations is to reduce calcium influx into neurons in response to HI, but the consequences include chronic behavioral deficits including cognitive impairment. !