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: 9762268
• 负责人: Olga Nicole Kokiko-Cochran
• 金额: $ 29.78万
• 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/9762268
• 关键词: Acute; Adrenal Glands; Anti-inflammatory; Antiinflammatory Effect; Attention; Behavior; Brain; Brain Injuries; Brain Pathology; CCL2 gene; CSF1R gene; Cells; Chronic; Corticosterone; Custom; Data; Development; Dexamethasone; Disease; 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; Mechanics; Mediating; Microglia; Mifepristone; Molecular; Morphology; Mus; Nerve Degeneration; Neuraxis; Neuronal Injury; Neurons; Neurosecretory Systems; Outcome; Pathologic; Pathology; Pathway interactions; Pharmacology; Physiological; Pituitary Gland; Plasma; 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; behavioral impairment; biological adaptation to stress; cytokine; drug development; experimental study; hypothalamic-pituitary-adrenal axis; improved; improved outcome; indexing; injured; injury stressor; innovation; macrophage; neuroinflammation; neuropathology; neuropsychiatry; progressive neurodegeneration; receptor-mediated signaling; recruit; response; restoration; sleep behavior; stressor; suprachiasmatic nucleus; tau Proteins; tau phosphorylation; 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.

项目摘要/摘要 积累的证据表明，创伤性脑损伤（TBI）会损害恢复体内平衡的能力 对应激源的反应，反映了下丘脑 - 垂体 - 肾上腺（HPA）轴的失调。因此， 正常的每天压力源会在体内引起强烈的“磨损”或“同层负荷”，并且大大引起 影响脑损伤后的结果。总体假设是每天睡眠中断是一种身体 相关的压力源，在TBI之后直接接合HPA轴并且在压力反应失调下 促进神经炎症，神经病理学和行为障碍的增加。已发布的数据显示 小胶质细胞在TBI之后“底漆”，并因次要免疫挑战而变得过度反应 导致神经病理学和行为障碍增加。由于反应性小胶质细胞可以驱动神经元 损伤和进行性神经退行性通过大脑的传播，初步数据表明 它们是加剧伤害后睡眠后神经炎症和病理的主要效应细胞 破坏。三个具体目标将检验以下假设：（目标1）TBI降低了皮质酮 （Cort）介导的神经内分泌对睡眠破坏的反应，导致神经病理恶化和 恢复; （AIM 2）TBI小鼠表明糖皮质激素负反馈灵敏度和恢复性增加 Cort对睡眠破坏的反应将减少神经炎症和神经病理学； （AIM 3）TBI 睡眠中断将增强TAU病理学和由TBI造成的行为障碍，这两者都将是 小胶质细胞的药理去除后改善。总结一下，睡眠中断可以视为 伤害后压力源，挑战HPA轴并进行介导增加后伤害后神经炎症 通过糖皮质激素受体。去除小胶质细胞以改善预后的理论潜力 伤害后睡眠中断也将得到确认。拟议的研究具有创新性，因为第一个 提供时间数据以表明睡眠破坏可以作为病理压力源，使averbates恶化 TBI后神经炎症，神经病理学和行为障碍。这些研究可以促使 不需要药物开发的理论干预措施的发展。例如，具体 可以实施指南，以减少医院和护理设施中的夜间觉醒。最终 该提案的目标是突出伤害后睡眠中断的神经内分泌作用并确定关键 TBI后促进慢性神经炎症和神经退行性的分子途径。