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，影响到至少50万人 每年都有青少年运动员参加。现在人们对长期神经性疾病的可能性有了更大的认识 在大脑仍在发育期间反复脑震荡的后果，包括 长期认知和其他神经缺陷的可能性。不幸的是，人们对此几乎一无所知 反复轻度颅脑损伤后脑损伤的具体机制，除休息外无特异性治疗 存在着减少长期认知和其他后遗症的作用。为了开始解决这些知识差距，我们 在青春期小鼠中建立了一种重复性闭合性头部损伤(RCHI)模型，该模型可产生亚震荡 生物力学力量，轻微的组织病理学，学习和记忆的长期缺陷，大脑连接， 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 目的：探讨反复损伤的易损伤期与慢性阻塞性肺疾病发展的关系 青春期小鼠的神经和生理缺陷，使用功能磁共振成像和呼吸和心率测试 对二氧化碳的反应性挑战预测大脑对进一步损伤的脆弱时期 永久性神经功能障碍，并测试内皮细胞白介素1信号机制在 部分调节rCHI模型的结果，具有以下特定目的：目标1：描述神经学特征 使用已知大脑回路的一组集中测试的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 受伤的雄性和雌性小鼠的完整性。目的2：使用fMRI/BOLD，表征单次击打和三次击打的效果 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。表征呼吸和心率对吸入二氧化碳的反应性，并检验假设 脑血流、呼吸和心率的异常反应性是闭合的生理生物标志物 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 脑内皮细胞IL-1信号介导青春期小鼠损伤后认知功能障碍的假说 遗传和药理工具。拟议的研究将为今后的工作奠定基础 青少年反复脑震荡脑损伤的机制/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.