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

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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.