Recovering amnestic memories from the repeat head impact brain

从重复头部撞击大脑中恢复失忆记忆

• 批准号: 10184658
• 负责人: MARK P BURNS
• 金额: $ 104万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10184658
• 关键词: Affect; Alzheimer' s Disease; Athletic; Axon; Behavior Control; Behavioral; Bilateral; Brain; Brain Injuries; Case Study; Cells; Chronic; Cognitive; Cognitive deficits; Data; Disease; Electrophysiology (science); Excitatory Synapse; Exposure to; FOS gene; Frequencies; Functional disorder; Genetic; Hippocampus (Brain); Impaired cognition; Impairment; Implant; Individual; Learning; Link; Memory; Memory impairment; Mus; N-Methylaspartate; Nature; Neurodegenerative Disorders; Neurons; Parahippocampal Gyrus; Pathology; Physiological; Potassium; Proteins; Proteome; Proteomics; Synapses; Synaptic Transmission; TBI Patients; Techniques; Technology; Testing; Time; Traumatic Brain Injury; axon injury; brain dysfunction; career; cognitive function; common symptom; conditioned fear; controlled cortical impact; cost; dementia risk; dentate gyrus; experimental study; head impact; memory recall; new therapeutic target; novel; optogenetics; patch clamp; response; selective expression; transcriptome; transcriptomics

PROJECT SUMMARY (ABSTRACT) An athletic career filled with head impacts (HI) predisposes athletes to memory impairments and is a risk factor for dementias including Alzheimer’s disease. While proteinopathy is clearly linked to brain dysfunction in the late stages of these disease, memory problems are also a common symptom in reported cases with early-stage disease – and even those cases with no neurodegenerative disease pathology. To understand the nature of the chronic memory impairments caused by HI, we are focused on the physiological changes that occur in the brain after exposure to a high frequency of non-damaging HI (HFHI), and comparing our results to a single severe single TBI. Our preliminary data shows that exposing mice to HFHI causes an adaptive response in excitatory synapses. These adaptations occur at the cost of normal brain function, with widespread and prolonged impairments in learning and memory. This synaptic dampening is permanent, and does not spontaneously reverse. In this proposal we aim to determine if we can reverse chronic synaptic dysfunction in the injured brain, and recall a forgotten memory. In this proposal we will test the hypothesis that HFHI disrupts synaptic transmission within the memory circuits of the hippocampus, and that activation of engram neurons can override these cognitive deficits and reanimate a forgotten memory. These data will allow us to test if it will be possible to treat cognitive impairments by targeting the synapse in different types of TBI. This will have profound implications for the millions of people living with cognitive and behavioral dysfunction after head impact, and could be harnessed to reduce the number of TBI patients that progress to develop Alzheimer’s disease each year.

项目摘要（摘要） 一个充满头部影响（HI）的运动职业使运动员易于记忆力障碍，这是一个 痴呆症的危险因素，包括阿尔茨海默氏病。而蛋白质病显然与大脑有关 在这些疾病的后期功能障碍，记忆问题也是常见的症状 报道了早期疾病的病例，甚至没有神经退行性疾病的病例 病理。要了解由HI造成的慢性记忆障碍的性质，我们专注于 暴露于高频无损后，大脑发生的身体变化 HI（HFHI），并将我们的结果与单个严重的单个TBI进行比较。我们的初步数据表明 将小鼠暴露于HFHI会引起兴奋性突触的自适应反应。这些适应发生 以正常的大脑功能为代价，在学习和 记忆。这种合成抑制是永久性的，并且不会逆转。在此提案中 我们旨在确定是否可以逆转受伤的大脑中的慢性突触功能障碍，并回忆起 被遗忘的记忆。 在此提案中，我们将检验以下假设：HFHI破坏了综合传播 海马的记忆电路和发动机神经元的激活可以覆盖这些 认知定义并复活了被遗忘的记忆。 这些数据将使我们能够测试是否可以通过针对 在不同类型的TBI中突触。这将对数百万生活的人产生深远的影响 具有头部影响后的认知和行为功能障碍，可以利用以减少 每年发展为发展阿尔茨海默氏病的TBI患者人数。