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

基本信息

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
项目类别：
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&apos 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

Acute Aggressive behavior Alzheimer&apos 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

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项目摘要

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. !

项目摘要（摘要）运动生涯充满了头部影响（HI），使运动员易于慢性创伤脑病（CTE），一种以行为缺陷为特征的神经退行性疾病在大脑最容易受到压力的沟深度中的损伤和p-tau病理和应变。 CTE领域的一个燃烧问题是P-Tau在行为障碍中的作用：是因果，下游还是偶然？在阿尔茨海默氏病和其他tauopathies中相当大的p- 在检测到强烈的行为改变之前，需要tau积累和神经元死亡，并且如果在第I和II期中发现的低水平的P-TAU是严重因素，则仍然有争议这些运动员报告的行为变化。因此，探索行为原因需要超出蛋白质聚集光谱的缺陷。重复创伤性脑损伤（TBI）啮齿动物模型被广泛用于研究CTE。总体而言，这项工作已经取得了部分成功 - 几乎所有小组都报告了慢性认知缺陷和神经行为异常。相反，巨大的困难仍然概括了啮齿动物中的CTE，其中一个主要原因是啮齿动物的脑脑大脑。 TBI诱导的急性 P-TAU和淀粉样蛋白β的积累是可能的，但是这些需要轴突损伤才能产生。重复没有轴突损伤的模型确实存在，并且没有急性或慢性增加在p-tau或淀粉样蛋白β中。正是由于这些限制，重复没有轴突损伤的小鼠是研究重复损伤的非依赖性作用的出色模型。在此提案中，我们使用HI 具有高频冲击的小鼠模型（HI-HF），不会出现结构性损害在视线外：没有轴突损伤，没有神经元细胞死亡，没有神经炎症，没有 p-tau积累。我们将专注于海马神经元，以研究其对 hi-hf。该项目的长期目标是了解重复如何破坏身体大脑功能，为什么这些变化在HI暴露停止之后持续存在，并确定分子靶标扭转这些变化。在此提案中，我们正在测试HI-HF引起慢性突触适应的假设。这些适应的目的是减少响应于HI的钙对神经元的影响，但是后果包括慢性行为定义包括认知障碍。呢