Deregulation of Sleep/Wake Homeostasis by Binge Alcohol Use Following Traumatic Brain Injury

摘要 睡眠/醒来周期由大脑的主生物钟调节。睡眠障碍 在普通人群中常见，在神经病理疾病患者中突出。 值得注意的是，酗酒(BAU)和创伤性脑损伤(TBI)是最严重的两种 神经功能障碍的环境风险因素。虽然认知缺陷仍然是 BAU/TBI病理的基本表现，非认知性体内平衡异常是一种 是疾病不可分割的一部分。TBI和BAU的常见症状是睡眠/觉醒障碍， 尤其是在晚年，通常在认知衰退之前驱动病理，并对 到认知功能障碍。因此，睡眠/清醒动态平衡既可能是罪魁祸首，也可能是 治疗干预，但不仅仅是在基础研究方面，这是一个重大错失的机会 也可用于临床实践。这是由于对两者之间的因果关系的认识有限。 慢性颅脑损伤/BAU病理和昼夜节律/睡眠障碍。最近的研究(包括我们自己的) 表明促炎因子-kB途径，炎症的关键驱动因素，直接相互作用 与核心时钟组件BMAL1结合，并干扰细胞和组织的时钟功能 运动类型和运动活动节律。此外，核因子-kB的激活也改变了睡眠时间和 质量。这些发现，再加上公认的睡眠-神经免疫相互作用， 支持我们的中心假设，即TBI/BAU并存的神经炎症和神经病理 造成昼夜节律和睡眠紊乱。这项拟议的研究将首次确定 TBI/BAU神经病理和睡眠障碍的终生时间表(急性、亚急性、慢性)， 这将使我们能够确定发病机制和睡眠/觉醒的关键时间窗口 表型。为此，我们将神经病理分析与无创纵向分析相结合。 睡眠测试。本研究将为今后的分子和基因组研究奠定基础。 TBI和BAU如何诱导神经炎症以及神经炎症如何影响昼夜节律和 睡眠动态平衡。这项研究将对许多神经病理学产生广泛的影响。 有炎症性成分的情况。

SUMMARY The sleep/wake cycle is regulated by the brain’s master circadian clock. Sleep disturbance is common in the general population and prominent in patients of neuropathological diseases. Notably, binge alcohol use (BAU) and traumatic brain injury (TBI) represent two of the strongest environmental risk factors for neurological disabilities. While cognitive deficits remain the cardinal manifestation of BAU/TBI pathology, non-cognitive homeostatic abnormalities are an integral part of the disease. A common symptom in TBI and BAU is sleep/wake disturbance, especially later in life, which often precedes cognitive decline to drive pathology and contributes to cognitive dysfunction. Thus, sleep/wake homeostasis can be both a culprit and target for therapeutic intervention, but represents a major missed opportunity not only in basic research but also for clinical practice. This is due to the limited understanding of the cause-effect between chronic TBI/ BAU pathology and circadian/sleep dysfunction. Recent studies (including our own) show that the proinflammatory NF-kB pathway, a key driver of inflammation, directly interacts with the core clock component BMAL1 and interferes with clock function across cell and tissue types and in locomotor activity rhythms. Further, NF-kB activation also alters sleep quantity and quality. These findings, together with the well-recognized sleep-neuroimmune interactions, support our central hypothesis that TBI/BAU comorbid neuroinflammation and neuropathology cause circadian and sleep disruption. The proposed research will determine for the first time the lifelong timeline (acute, subacute, chronic) of TBI/BAU neuropathology and sleep dysfunction, which will allow us to identify the key time windows of pathogenesis and sleep/wake phenotypes. For this, we will combine neuropathological analysis with non-invasive longitudinal sleep assays. This study will lay the groundwork for future molecular and genomic studies on how TBI and BAU induce neuroinflammation and how neuroinflammation impacts circadian and sleep homeostasis. This research will have broad implications in a number of neuropathological conditions that have an inflammatory component.