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

基本信息

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
项目类别：
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

项目摘要

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 信号介导青少年小鼠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。