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Title: "Modeling Acute and Chronic Effects of Blast- and Impact-Related Neurotrauma in Mice" Committee: Lee Goldstein, BUSM Psychiatry, BME (Advisor) Steve Colburn, BME (Chair) Dimitrije Stamenovic, BME Neil Kowall, BUSM Neurology William Moss, Lawrence Livermore National Laboratory Abstract: Military-related blast exposure and sports-related closed-head impact injury are associated with traumatic brain injury (TBI) and chronic traumatic encephalopathy (CTE), a tau protein neurodegenerative disease. Despite growing awareness of links between TBI and CTE, the mechanisms underpinning this association, and relationship to concussive and subconcussive head injury, are poorly understood. This dissertation addresses the hypothesis that blast exposure and impact injury induce traumatic acceleration of the head and injurious forces in the brain that led to structural brain damage (TBI) and chronic sequelae, including CTE. This hypothesis was addressed in five specific aims: 1) Develop a blast shock tube instrument and impact instrument to deliver relevant blast exposure and impact injury to mice. 2) Validate a mouse model of single-blast exposure that recapitulates brain pathology in blast-exposed military veterans diagnosed with CTE. 3) Validated a mouse model of single-repeat closed-head impact injury that recapitulates brain pathology in contact sport athletes diagnosed with CTE. 4) Compare biomechanics of blast and impact models matched for head kinematics. 5) Deploy kinematically-matched mouse models of single blast exposure and single-repeat closed-head impact injury to investigate mechanisms that trigger experimental concussion and post-traumatic sequelae. Blast and impact injuries were shown to cause similar CTE-linked brain pathologies, including microvasculopathy, neuroinflammation, astrogliosis, and phosphorylated tauopathy. Despite similarities in chronic consequences, blast exposure and impact injury produced different acute neurological responses. Surprisingly, impact-injured mice demonstrated signs of experimental concussion, whereas blast-exposed mice with comparable head kinematics did not. Computational modeling indicated that point loading of forces during impact, as oppose to distributed loading in blast, caused ipsilateral spikes in cortical shear stress which we conclude to be responsible for experimental concussion. The developed models of blast exposure and impact injury have been and will continue to be invaluable tools for elucidating the mechanisms of and relationships between concussion, TBI, and CTE.