Characterizing Sleep Disruption as a Post-Injury Immune Stressor

将睡眠中断描述为损伤后免疫应激源

• 批准号: 10633060
• 负责人: Olga Nicole Kokiko-Cochran
• 金额: $ 33.05万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10633060
• 关键词: Acute; Adrenal Glands; Anti-Inflammatory Agents; Antiinflammatory Effect; Attention; Behavior; Brain; Brain Injuries; Brain Pathology; CCL2 gene; CSF1R gene; Cells; Central Nervous System; Chronic; Corticosterone; Custom; Data; Development; Dexamethasone; Disease; Drowsiness; Effector Cell; Electroencephalography; Environmental Risk Factor; Event; Excision; Exhibits; Exposure to; Feedback; Glucocorticoid Receptor; Glucocorticoids; Goals; Guidelines; Health care facility; Homeostasis; Hormones; Hospitals; Hour; Housing; Human; Hypothalamic structure; Immune; Impairment; Individual; Inflammation; Inflammatory; Injury; Interleukin-1 beta; Intervention; Leukocytes; Light; Macrophage; Mechanics; Mediating; Microglia; Mifepristone; Molecular; Morphology; Mus; Nerve Degeneration; Neuronal Injury; Neurons; Neurosecretory Systems; Outcome; Pathologic; Pathology; Pathway interactions; Physiological; Pituitary Gland; Plasma; Population; Production; Publishing; Recovery; Recurrence; Research; Rodent; Role; Secondary to; Signal Pathway; Signal Transduction; Sleep; Sleep Wake Cycle; Sleep disturbances; Stimulus; Stress; TNF gene; Testing; Therapeutic; Therapeutic Intervention; Time; Transcriptional Regulation; Traumatic Brain Injury; Traumatic Brain Injury recovery; allostasis; allostatic load; analog; antagonist; behavioral impairment; biological adaptation to stress; cytokine; drug development; experimental study; hypothalamic-pituitary-adrenal axis; improved; improved outcome; indexing; injured; injury stressor; innovation; mechanical stimulus; neuroinflammation; neuropathology; neuropsychiatry; neurotransmission; pharmacologic; progressive neurodegeneration; receptor-mediated signaling; recruit; response; restoration; sleep behavior; stressor; suprachiasmatic nucleus; tau Proteins; tau-1; therapeutic development

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.

项目总结/摘要 越来越多的证据表明，创伤性脑损伤（TBI）损害了恢复体内平衡的能力， 应激反应，反映下丘脑-垂体-肾上腺（HPA）轴失调。因此，在本发明中， 正常的日常应激源引起身体上强烈的“磨损”或“非稳态负荷”， 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 TBI后直接参与HPA轴的相关应激源，以及失调的应激反应 促进神经炎症、神经病理学和行为障碍的增加。公布的数据显示， 小胶质细胞在TBI后被“启动”，并在响应二次免疫攻击时变得高度反应性 导致神经病理学和行为损伤增加。由于反应性小胶质细胞可以驱动神经元 损伤和进行性神经变性在大脑中的扩散，初步数据表明， 它们是主要的效应细胞，在损伤后的睡眠后， 破坏三个具体目标将测试以下假设：（目标1）TBI降低皮质酮 （CORT）介导的对睡眠中断的神经内分泌反应导致神经病理学恶化， （目的2）TBI小鼠表现出增加的糖皮质激素负反馈敏感性和恢复 CORT对睡眠中断的反应将减少神经炎症和神经病理学;（目的3）TBI后 睡眠中断将增强由TBI引起的tau病理学和行为障碍，这两者都将是 在药理学去除小胶质细胞方面有所改善。结论是，睡眠中断可以被认为是一种 损伤后应激源，挑战HPA轴并介导损伤后神经炎症增加 通过糖皮质激素受体。去除小胶质细胞以改善以下结果的治疗潜力 受伤后的睡眠中断也将得到证实。这项研究是创新的，因为首先， 提供时间数据以显示睡眠中断可作为病理性应激源， TBI后的神经炎症、神经病理学和行为障碍。这些研究可以促进 开发不需要药物开发的治疗干预措施。例如特定 可以实施指南以减少医院和护理设施中的夜间觉醒。最终 这项提案的目的是强调损伤后睡眠中断的神经内分泌影响，并确定关键的 TBI后促进慢性神经炎症和神经变性的分子途径。