Mechanisms of Circadian and Synaptic Dysfunction After Repetitive Mild TBI

轻度创伤性脑损伤(MTBI)每年影响全球数亿年轻人。 然而，流行病学研究将重复性脑损伤与痴呆症和晚年神经退行性疾病联系起来。 致病机制仍不明确。昼夜节律的紊乱是 脑震荡后综合征，与阿尔茨海默氏样神经退行性变有关，但 MTBI、神经退行性变和昼夜节律的联系机制尚不清楚，突出了一个关键的未得到满足的需求 和一个未被探索的治疗机会。我们先前报道了IL-1受体-1信号转导是 MTBI模型中损伤后认知障碍所必需的，暗示炎症通路是关键致病因素 机械装置。我们假设生物钟之间存在直接的分子联系 和通过IL-1受体途径的神经免疫信号。我们的初步数据显示，重复的mTBI 诱导野生型小鼠关键生物钟蛋白BMAL1的磷酸化，但不能诱导IL-1R1缺陷小鼠的磷酸化 大脑。我们正在进行的工作已经确定了BMAL1磷酸化在组织中的关键功能 突触前功能和长时记忆。我们的结果导致了我们的假设，即重复的mTBI诱导 IL-1R1介导的BMAL1过度磷酸化导致的突触功能障碍和认知障碍。在目标1中，我们 将定义ILR1介导的pBMAL1信号如何响应mTBI破坏突触功能的时序 并损害突触的可塑性。在目标2中，我们将使用组合和互补的转基因方法 包括我们小组唯一可用的小鼠模型，以定义负责IL-1R介导的细胞类型 这一信号最终导致mTBI后的认知功能障碍。最后，Aim 3将定义一条新的信号通路 IL-1介导的mTBI后pBMAL1过度磷酸化导致KEY功能失调 突触和神经元激酶，如CaMKIIA，随后公布与tau相关的聚集和 突触可塑性受损。AIMS的成功完成有望提供细胞和分子上的 重复性mTBI所致认知功能障碍的基础和寻找新的治疗靶点以减轻后遗症 脑震荡和其他形式的重复性脑外伤。

Mild traumatic brain injury (mTBI) affects hundreds of millions of young people world-wide each year. Epidemiological studies link repetitive mTBI to dementia and neurodegenerative disease later in life, however causative mechanisms remain undefined. Disruption of circadian rhythms is a prominent manifestation of the post-concussive syndrome and has been associated with Alzheimer’s-like neurodegeneration but the mechanisms linking mTBI, neurodegeneration, and circadian rhythms is unknown, highlighting a key unmet need in mTBI and an unexplored therapeutic opportunity. We previously reported that IL-1 receptor-1 signaling is required for post-injury cognitive deficits in mTBI models, implicating inflammatory pathways as key pathogenic mechanisms. We hypothesized that there would be direct molecular connections between the circadian clock and neuroimmune signaling through the IL-1 receptor pathway. Our preliminary data show that repetitive mTBI induces phosphorylation of the key circadian clock protein BMAL1 in wild type but not IL-1R1-deficient mouse brain. Our ongoing work has identified a critical function for BMAL1 phosphorylation in the organization of presynaptic function and long-term memory. Our results lead to our hypothesis that repetitive mTBI induces synaptic dysfunction and cognitive deficits via IL-1R1-mediated hyperphosphorylation of BMAL1. In Aim 1, we will define how ILR1-mediated pBMAL1 signaling in response to mTBI corrupts the timing of synaptic function and impairs synaptic plasticity. In Aim 2, we will use combinatorial and complementary transgenic approaches including mouse models uniquely available to our groups, to define the cell types responsible for IL-1R-mediated signaling that culminate in cognitive dysfunction after mTBI. Finally, Aim 3 will define a novel signaling pathway by which IL-1-mediated hyperphosphorylation of pBMAL1 after mTBI results in dysfunctional regulation of key synaptic and neuronal kinases such as CaMKIIA with subsequent promulgation of tau-related aggregation and impaired synaptic plasticity. Successful completion of the Aims is expected to provide a cellular and molecular basis for repetitive mTBI-induced cognitive dysfunction and identify new therapeutic targets to alleviate sequelae of concussions and other forms of repetitive mTBI.