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

轻度创伤性脑损伤（TBI）或脑震荡在美国流行，影响至少50万人 青少年运动员每年现在人们越来越意识到长期神经系统疾病的可能性。 在大脑还在发育的时候，反复脑震荡的后果，包括 长期认知和其他神经功能缺陷的可能性。不幸的是，几乎没有人知道 反复轻度TBI后导致脑损伤的具体机制，除休息外无具体治疗 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一种重复性闭合性头部损伤（rCHI）模型， 生物力学力，轻度组织病理学，以及学习和记忆，大脑连接， 脑血管反应性以及对二氧化碳激发的呼吸和心率反应性。我们的目标是 探讨重复性损伤的易感期与脑损伤发生的关系， 神经和生理缺陷的青春期小鼠，使用功能磁共振成像和测试呼吸和心率 对二氧化碳挑战的反应性，以预测大脑对进一步损伤的脆弱期， 永久性神经功能缺损，并测试假设，内皮细胞白细胞介素-1信号转导机制， 部分介导rCHI模型的结果，具体目的如下：目的1：表征神经系统 使用已知脑回路的一组集中测试的rCHI缺陷;定义电生理学相关性 并进行轴突追踪和cFos免疫组化检查回路 在受伤的雄性和雌性小鼠的完整性。目的2：利用fMRI/BOLD技术，研究单次和三次打击对脑功能的影响 在急性和慢性时间点，每日一次（3 HD）与每周3次（3 HW）CHI对脑血管反应性（CVR）的影响 伤后描述呼吸和心率对吸入CO2的反应性，并检验以下假设： 脑血流和呼吸及心率的异常反应性是闭合性脑缺血的生理生物标志物。 头部损伤（CHI），可用于预测重复CHI之间的安全休息时间。目标3：测试 脑内皮细胞IL-1信号转导介导青少年小鼠损伤后认知缺陷的假说 遗传学和药理学工具。拟议的研究将为今后的工作奠定基础。 青少年反复脑震荡性脑外伤的机制/治疗研究。

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.