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

总结 睡眠/觉醒周期由大脑的主生物钟调节。睡眠障碍 在一般人群中很常见，在神经病理疾病患者中很突出。 值得注意的是，酗酒（BAU）和创伤性脑损伤（TBI）是最严重的两个 神经残疾的环境风险因素。虽然认知缺陷仍然存在， BAU/TBI病理学的主要表现，非认知稳态异常是BAU/TBI病理学的主要表现， 疾病的一部分。TBI和BAU的常见症状是睡眠/觉醒障碍， 尤其是在晚年，这往往先于认知能力下降，从而导致病理学， 认知功能障碍因此，睡眠/觉醒稳态可能既是罪魁祸首，也是目标。 治疗干预，但代表了一个重大的机会，不仅在基础研究 也用于临床实践。这是由于对因果关系的理解有限， 慢性TBI/ BAU病理学和昼夜节律/睡眠功能障碍。最近的研究（包括我们自己的研究） 表明促炎性NF-kB通路，炎症的关键驱动因素，直接相互作用， 与核心时钟成分BMAL 1结合，并干扰细胞和组织的时钟功能 类型和自发活动节律。此外，NF-kB激活还改变睡眠量， 质量.这些发现，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共病神经炎症和神经病理学 导致昼夜节律和睡眠紊乱。这项研究将首次确定 TBI/BAU神经病理学和睡眠功能障碍的终身时间轴（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，我们将联合收割机结合神经病理学分析和非侵入性纵向 睡眠分析这项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， 睡眠稳态这项研究将在许多神经病理学方面产生广泛的影响。 具有炎症成分的病症。

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.