PROJECT SUMMARY Mild traumatic brain injury (mTBI, concussion) has emerged as a risk factor for the development of neurodegenerative conditions such as Alzheimer's disease and chronic traumatic encephalopathy, which are characterized by the aberrant aggregation of tau within neural cells. However, the mechanisms linking mTBI to tau pathology later in life remain unknown. The glymphatic system is a recently characterized brain-wide network of perivascular spaces that supports the rapid exchange of cerebrospinal and interstitial fluid. Glymphatic function contributes to the clearance of both amyloid beta and tau, and its impairment is believed to underlie their deposition in the aging brain. Glymphatic pathway function is greatest during sleep and is impaired by traumatic brain injury. Based on these findings, we hypothesize that that impairment of glymphatic function following mTBI slows the clearance of tau and contributes to the development of tau pathology following injury. Using a well-established model of repetitive- blast mTBI, behavioral assessment of cognitive and functional impairment, and histological assessment of tau pathology in a rodent model of tauopathy, we will characterize glymphatic dysfunction following blast mTBI, and test whether its impairment promotes post-traumatic tauopathy. Disruption of the sleep-wake cycle (SWD) is a frequent chronic complaint after mTBI. SWD also accompanies the development of conditions like Alzheimer's disease in aging populations. More recent clinical and translational research suggests that SWD may actually promote the development of Alzheimer's-related pathology, including tau deposition. Based on the common clinical connections between mTBI, SWD, and neurodegenerative disease, we hypothesize that post-traumatic SWD contributes to the development of tauopathy following mTBI. Using parallel techniques above, we will define SWD following blast mTBI, and test whether post-traumatic SWD promotes the development of tau pathology after injury. In both observational clinical studies and in rodent models, post-concussive symptoms exhibit different temporal profiles following single or repetitive mTBI. To comprehensively define the role that glymphatic impairment and sleep disruption play in the development of tau pathology following mTBI, these studies will be carried out in parallel in mouse models of single and repetitive blast mTBI. The results of this study may provide a novel perspective on the mechanisms underlying the development of post-traumatic neurodegeneration, and may support targeting glymphatic pathway function and SWD in the prevention and treatment of conditions such as Alzheimer's disease in Veteran populations with a history of exposure to mTBI.