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.

项目概要（摘要） 充满头部撞击 (HI) 的运动生涯使运动员容易出现记忆障碍，并且 包括阿尔茨海默病在内的痴呆症的危险因素，而蛋白质病显然与大脑有关。 这些疾病晚期出现功能障碍，记忆力问题也是常见症状 报告的早期疾病病例，甚至是那些没有神经退行性疾病的病例 为了了解 HI 引起的慢性记忆障碍的本质，我们重点关注。 暴露于高频非损伤性环境后大脑发生的生理变化 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 会导致兴奋性突触产生适应性反应。 以正常大脑功能为代价，学习和学习能力受到广泛而长期的损害 这种突触抑制是永久性的，并且不会自发逆转。 我们的目标是确定是否可以逆转受损大脑中的慢性突触功能障碍，并回忆起 被遗忘的记忆。 在本提案中，我们将测试 HFHI 破坏神经元内突触传递的假设。 海马体的记忆回路，印迹神经元的激活可以覆盖这些 认知缺陷并唤醒被遗忘的记忆。 这些数据将使我们能够测试是否有可能通过靶向治疗认知障碍 不同类型 TBI 中的突触这将对数百万人产生深远的影响。 头部撞击后认知和行为功能障碍，可以用来减少 每年有多少 TBI 患者进展为阿尔茨海默病。