Mechanisms of cognitive dysfunction after repetitive closed head injury in adolescent mice

青春期小鼠重复闭合性颅脑损伤后认知功能障碍的机制

• 批准号: 9902566
• 负责人: MICHAEL J WHALEN
• 金额: $ 35.68万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 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 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9902566
• 关键词: Acceleration; Acute; Address; Adolescent; Adult; Affect; Anatomy; Attentional deficit; Awareness; Axon; BIRC4 gene; Behavior; Behavioral; Biochemical; Biological Markers; Biomechanics; Brain; Brain Concussion; Brain Injuries; Brain region; CASP1 gene; Carbon Dioxide; Cell Death; Cerebrovascular Circulation; Childhood; Chronic; Clinical Research; Closed head injuries; Cognitive; Cognitive deficits; Complement; Complex; Core-Binding Factor; Corpus striatum structure; Cross-Sectional Studies; Data; Development; Electrophysiology (science); Endothelial Cells; Endothelium; Epidemic; Female; Functional Magnetic Resonance Imaging; Functional disorder; Future; Gender; Genes; Genetic; Genetic Transcription; Goals; Heart Rate; Hippocampus (Brain); Histopathology; Hyperactive behavior; I Kappa B-Alpha; IRAK4 gene; Image; Immunohistochemistry; Immunoprecipitation; Impaired cognition; Impairment; Incidence; Inflammasome; Inhalation; Injury; Interleukin-1; Interleukin-1 Receptors; Interleukin-1 beta; Interleukin-18; Intravenous; Knock-out; Knockout Mice; Knowledge; Lead; Learning; Link; Long-Term Potentiation; MAP Kinase Gene; Manufactured football; Maps; Mediating; Memory; Microglia; Modeling; Molecular; Mus; Nerve Degeneration; Neurologic; Neurologic Deficit; Neurologic Dysfunctions; Neurological outcome; Outcome; PECAM1 gene; Pathologic; Pharmacology; Phosphorylation; Physiological; Play; Proteins; Public Health; Research Design; Rest; Risk; Signal Pathway; Signal Transduction; Sports; Structure; TRAF6 gene; Testing; Time; Tracer; Traumatic Brain Injury; United States; Viral Vector; Work; base; behavior test; brain circuitry; brain endothelial cell; cell type; cerebrovascular; chronic traumatic encephalopathy; clinically relevant; cognitive development; cohort; experimental study; head impact; injured; intravenous injection; male; mild traumatic brain injury; p38 Mitogen Activated Protein Kinase; p65; prevent; reconstitution; respiratory; therapy development; tool

Mild traumatic brain injury (TBI), or concussion, is epidemic in the United States affecting at least half a million adolescent athletes annually. There is now a greater awareness of the possibility of long term neurological consequences of repeated concussions suffered during a time when the brain is still developing, including the possibility of long term cognitive and other neurological deficits. Unfortunately, almost nothing is known about the specific mechanisms leading to brain injury after repeated mild TBI, and no specific therapy other than rest exists to reduce long-term cognitive and other sequelae. To begin to address these knowledge gaps, we developed a repetitive closed head injury (rCHI) model in adolescent mice that produces sub-concussive biomechanical forces, mild histopathology, and long-term deficits in learning and memory, brain connectivity, cerebrovascular reactivity, and respiratory and heart rate reactivity to carbon dioxide challenge. Our goals are to examine the relationship between the vulnerable period to repetitive injuries and development of neurological and physiological deficits in adolescent mice, use fMRI and tests of respiratory and heart rate reactivity to carbon dioxide challenge to predict the brain's vulnerable period to further injury resulting in permanent neurological deficits, and test the hypothesis that endothelial interleukin-1 signaling mechanisms in part mediate outcome in the rCHI model, with the following Specific Aims: Aim 1: Characterize the neurological deficits of rCHI using a focused battery of tests with known brain circuitry; define electrophysiological correlates of neurological dysfunction; and perform axon tracing and cFos immunohistochemistry to examine circuit integrity in injured male and female mice. Aim 2: Using fMRI/BOLD, characterize the effects of single and 3 hit daily (3HD) vs. 3 hit weekly (3HW) CHI on cerebrovascular reactivity (CVR) at acute and chronic time points after injury. Characterize respiratory and heart rate reactivity to inhaled CO2 and test the hypothesis that abnormal reactivity of cerebral blood flow and respiratory and heart rate are physiological biomarkers of closed head injury (CHI) that can be used to predict safe rest interval between repeated CHIs. Aim 3: Test the hypothesis that brain endothelial IL-1 signaling mediates postinjury cognitive deficits in adolescent mice using genetic and pharmacological tools. The proposed studies would lay the groundwork for future mechanistic/treatment studies of repetitive concussive TBI in adolescents.

轻度创伤性脑损伤 (TBI) 或脑震荡在美国很流行，影响了至少 50 万人 每年青少年运动员。现在人们越来越意识到长期神经系统疾病的可能性 在大脑仍在发育期间反复遭受脑震荡的后果，包括 长期认知和其他神经功能障碍的可能性。不幸的是，人们对此几乎一无所知 反复轻度TBI后导致脑损伤的具体机制，除了休息外没有特殊疗法 存在是为了减少长期认知和其他后遗症。为了开始解决这些知识差距，我们 在青春期小鼠中开发了一种重复性闭合性头部损伤（rCHI）模型，该模型会产生亚震荡 生物力学、轻度组织病理学以及学习和记忆、大脑连接的长期缺陷， 脑血管反应性、呼吸和心率对二氧化碳挑战的反应性。我们的目标是 研究重复性损伤的易感期与发展之间的关系 青春期小鼠的神经和生理缺陷，使用功能磁共振成像以及呼吸和心率测试 对二氧化碳挑战的反应性可预测大脑遭受进一步损伤的脆弱期 永久性神经功能缺陷，并检验内皮细胞白细胞介素 1 信号传导机制的假设 rCHI 模型中的部分介导结果，具有以下具体目标： 目标 1：表征神经系统 使用已知大脑回路进行一系列集中测试来发现 rCHI 缺陷；定义电生理相关性 神经功能障碍；并进行轴突追踪和 cFos 免疫组织化学检查电路 受伤的雄性和雌性小鼠的完整性。目标 2：使用 fMRI/BOLD 描述单次和 3 次命中的效果 每日 (3HD) 与每周 3 次 (3HW) CHI 对急性和慢性时间点脑血管反应性 (CVR) 的影响 受伤后。表征吸入 CO2 的呼吸和心率反应性并检验以下假设： 脑血流、呼吸和心率的异常反应是闭锁的生理生物标志物 头部损伤 (CHI)，可用于预测重复 CHI 之间的安全休息间隔。目标 3：测试 假设脑内皮 IL-1 信号传导介导青春期小鼠的损伤后认知缺陷 遗传和药理学工具。拟议的研究将为未来奠定基础 青少年重复性震荡 TBI 的机制/治疗研究。