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.

在美国，轻度创伤性脑损伤（TBI）或脑震荡是流行病，至少有50万每年的青少年运动员。现在人们对长期神经的可能性有了更高的认识在大脑仍在发展的时期，重复脑震荡的后果，包括长期认知和其他神经系统缺陷的可能性。不幸的是，几乎一无所知重复轻度TBI后导致脑损伤的具体机制，除了休息以外，没有其他特定的治疗存在以减少长期认知和其他后遗症。为了开始解决这些知识差距，我们在青少年小鼠中开发了重复的闭合头部损伤（RCHI）模型，产生亚困扰生物力学力，轻度组织病理学和学习和记忆中的长期缺陷，大脑连接性，脑血管反应性以及对二氧化碳挑战的呼吸和心率反应性。我们的目标是检查脆弱时期重复伤害和发展之间的关系青少年小鼠的神经和生理缺陷，使用fMRI和呼吸和心率测试对二氧化碳挑战的反应性，以预测大脑的脆弱时期，以进一步伤害永久神经缺陷，并检验了内皮白细胞介素-1信号传导机制的假设 RCHI模型中的零件中介结果，具有以下特定目的：目标1：表征神经系统 RCHI的缺陷，使用已知的脑电路的集合的测试电池；定义电生理相关神经功能障碍；并执行轴突跟踪和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。 AIM 2：使用fMRI/BOLD，表征单命中和3命中的效果每天（3HD）与3次每周（3HW）CHI在急性和慢性时间点上的脑血管反应性（CVR）受伤后。表征对吸入二氧化碳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性是封闭的生理生物标志物头部损伤（CHI）可用于预测重复的CHI之间的安全休息间隔。目标3：测试假设脑内皮内皮IL-1信号传导介导了青少年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脑震荡TBI的机理/治疗研究。