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

高频头部影响认知和神经行为的 Tau 独立效应

• 批准号: 10200916
• 负责人: MARK P BURNS
• 金额: $ 38.88万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10200916
• 关键词: Acute; Aggressive behavior; Alzheimer' s Disease; Amyloid beta-Protein; Anxiety; Athletic; Axon; Behavioral; Biochemical; Brain; Calcium; Cells; Chronic; Cognition; Cognitive deficits; Data; Discrimination; Electrophysiology (science); Exposure to; Frequencies; Glutamate Receptor; Glutamates; Goals; Head; Hippocampus (Brain); Image; Impaired cognition; Impairment; Injury; Long-Term Depression; Long-Term Potentiation; MK801; Manufactured football; Memantine; Memory; Mental Depression; Messenger RNA; Modality; Modeling; Molecular Target; Mus; Mutation; Neurodegenerative Disorders; Neurons; Odors; Optic tract structure; Output; Pathology; Pathway interactions; Persons; Physiological; Reporting; Rodent; Rodent Model; Role; Sensory; Slice; Stress; Structure; Synapses; Tauopathies; Testing; Traumatic Brain Injury; Work; axon injury; behavioral impairment; behavioral phenotyping; career; chronic traumatic encephalopathy; conditioned fear; head impact; morris water maze; mouse model; neurobehavior; neurobehavioral; neuroinflammation; neuron loss; neuropathology; novel; patch clamp; prevent; protein aggregation; response; success; synaptic function; tau Proteins; tau aggregation; tau-1; transcriptome; transcriptome sequencing; treatment strategy

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. !

项目概要（摘要） 充满头部撞击（HI）的运动生涯使运动员容易患慢性创伤性疾病。 脑病（CTE），一种以行为缺陷、认知缺陷、认知缺陷为特征的神经退行性疾病。 损伤和脑沟深处的p-tau病理学，其中大脑最容易受到压力的影响 和应变。CTE领域的一个紧迫问题是p-tau在行为障碍中的作用：它是 因果关系，下游，还是偶然？在阿尔茨海默病和其他tau蛋白病中， 在检测到强烈的行为变化之前需要tau积累和神经元死亡， 在I期和II期CTE中发现的低水平p-tau是否是CTE的致病因素仍然存在争议。 这些运动员的行为变化因此，探索行为的原因， 需要超出蛋白质聚集谱的缺陷。 重复创伤性脑损伤（TBI）啮齿动物模型被广泛用于研究CTE。总的来说，这项工作 已经取得了部分成功-几乎所有的群体报告慢性认知缺陷和神经行为 异常相比之下，要概括慢性神经病理学仍然存在巨大的困难， 啮齿类动物的CTE，一个主要原因是啮齿类动物的无脑脑。TBI诱导的急性 p-tau和淀粉样蛋白-β的积累是可能的，但这些需要轴突损伤来产生。 没有轴突损伤的重复HI模型确实存在，并且没有急性或慢性增加 在β-淀粉样蛋白中的作用。正是由于这些限制，没有轴突损伤的重复HI小鼠， 研究重复性损伤的tau独立效应的极好模型。在这个建议中，我们使用一个HI 不存在结构损伤的高频冲击（HI-HF）小鼠模型 视束外：无轴突损伤，无神经元细胞死亡，无神经炎症， p-tau积累。我们将重点研究海马神经元，以研究它们对 高频这个项目的长期目标是了解重复HI如何扰乱生理大脑 功能，为什么这些变化持续后HI暴露已经停止，并确定分子靶点 来扭转这些变化。 在这个提议中，我们正在测试HI-HF导致慢性突触适应的假设。 这些适应的目的是减少响应HI的钙流入神经元， 但后果包括慢性行为缺陷包括认知障碍。 !