Characterizing Sleep Disruption as a Post-Injury Immune Stressor

项目摘要/摘要 越来越多的证据表明，创伤性脑损伤(TBI)损害了脑内稳态的恢复能力 对应激源的反应，反映了下丘脑-垂体-肾上腺(HPA)轴的失调。结果, 正常的日常应激源会对身体造成强烈的“磨损”或“不平衡负荷”，实质上 影响脑损伤后的预后。总的假设是，日常睡眠中断是一种生理上的 颅脑损伤后直接接触HPA轴的相关应激源，以及调节失调的应激反应 促进神经炎症、神经病理和行为障碍的增加。公布的数据显示， 脑外伤后小胶质细胞被“激活”，并对二次免疫挑战产生高反应性。 导致神经病理和行为障碍加重。因为反应性小胶质细胞可以驱动神经元 损伤和进行性神经退行性变通过大脑传播，初步数据表明 它们是损伤后睡眠加重神经炎症和病理的主要效应细胞。 颠覆。三个特定的目标将检验以下假设：(目标1)脑损伤减少皮质酮 (CORT)介导的神经内分泌反应导致睡眠中断导致神经病理恶化和 恢复；(目标2)脑外伤小鼠表现出糖皮质激素负反馈敏感性增加和恢复 CORT对睡眠中断的反应将减少神经炎症和神经病理；(目标3)脑损伤后 睡眠障碍将加强由脑外伤引起的tau病理和行为障碍，这两者都将是 改进了药物去除小胶质细胞的方法。归根结底，睡眠中断可以被认为是 挑战HPA轴并介导损伤后神经炎症增加的创伤后应激源 通过糖皮质激素受体。去除小胶质细胞以改善术后预后的治疗潜力 受伤后的睡眠中断也将得到证实。这项拟议的研究具有创新性，因为第一次 提供的时间数据表明，睡眠中断可能是一种病理性应激源，会加剧 颅脑损伤后的神经炎症、神经病理和行为障碍。这些研究可以促使 开发不需要药物开发的治疗干预措施。例如，特定的 可以实施指导方针，以减少医院和护理机构的夜间唤醒。终极的 这项提案的目标是强调损伤后睡眠中断对神经内分泌的影响，并确定关键 促进脑外伤后慢性神经炎症和神经变性的分子途径。

Project Summary/Abstract Accumulating evidence shows that traumatic brain injury (TBI) impairs the ability to restore homeostasis in response to a stressor, reflecting dysregulation of the hypothalamic-pituitary-adrenal (HPA)-axis. As a result, normal everyday stressors elicit intense “wear and tear” or “allostatic load” on the body and substantially influence outcome after brain injury. The overall hypothesis is that daily sleep disruption is a physiologically relevant stressor that directly engages the HPA-axis after TBI, and upon a dysregulated stress response promotes increased neuroinflammation, neuropathology, and behavioral impairment. Published data show that microglia are “primed” after TBI and become hyper-reactive in response to secondary immune challenge resulting in increased neuropathology and behavioral impairment. Since reactive microglia can drive neuronal injury and the spreading of progressive neurodegeneration through the brain, preliminary data suggest that they are the primary effector cells that exacerbate neuroinflammation and pathology after post-injury sleep disruption. Three specific aims will test the following hypotheses: (Aim 1) TBI reduces the corticosterone (CORT)-mediated neuroendocrine response to sleep disruption resulting in worsened neuropathology and recovery; (Aim 2) TBI mice demonstrate increased glucocorticoid negative-feedback sensitivity and restoration of the CORT response to sleep disruption will reduce neuroinflammation and neuropathology; (Aim 3) Post-TBI sleep disruption will enhance tau pathology and behavioral impairments caused by TBI, which will both be improved upon pharmacological removal of microglia. Upon conclusion, sleep disruption can be considered a post-injury stressor that challenges the HPA-axis and mediates increased post-injury neuroinflammation through glucocorticoid receptors. The therapeutic potential of removing microglia to improve outcome following post-injury sleep disruption will also be confirmed. The proposed research is innovative because, for the first time data are provided to show that sleep disruption can serve as a pathological stressor that exacerbates neuroinflammation, neuropathology, and behavioral impairment after TBI. These studies can prompt the development of therapeutic interventions that do not require drug development. For example, specific guidelines can be implemented to reduce nighttime awakenings in hospitals and care facilities. The ultimate goal of this proposal is to highlight the neuroendocrine effects of post-injury sleep disruption and identify key molecular pathways that promote chronic neuroinflammation and neurodegeneration after TBI.