Project Summary/Abstract Traumatic brain injury (TBI) has been referred to as the “signature injury” of recent military combat operations in Iraq and Afghanistan. The form of TBI that is most prevalent among military service members and Veterans is repetitive, mild TBI, or rmTBI. Apart from the immediate effects of a head injury, rmTBI is also associated with a number of significant and chronic co-morbid conditions including cognitive dysfunction, sleep disorders, alterations in visual function, and psychiatric complications (e.g., depression, suicide, anxiety). rmTBI and its co-morbid conditions exact a steep toll on military personnel and Veterans and the cost to the nation of TBI is estimated to be $60 billion annually. The mechanisms by which rmTBI alters brain function are not well understood and all clinical trials of new therapies for TBI thus far have failed. Therefore, an effective treatment for TBI does not exist. Perhaps the most alarming aspect of rmTBI is the possibility that repeated mild impacts to the head do not cause clinically significant or recognizable symptoms but set in motion a cascade which has an endpoint of neurodegeneration and psychiatric illness. The primary goals of this application are to 1) refine and validate a humanized mouse model of rmTBI and 2) test two new mechanism-based therapies for the long-term consequences of rmTBI. These goals will be achieved by employing a new model of rmTBI that is very mild, even after as many as 20 head impacts, and which does not result in any behavioral or neuronal pathology at the end of the treatment period. We include preliminary data showing that rmTBI results in a delayed and progressive emergence of increased reactive gliosis and inflammation along white matter tracts, and increases in the pathologic form of tau, a microtubule stabilizing molecule. In addition, this model of rmTBI results in slowly developing cognitive deficits and psychiatric-like disorders (e.g., anxiety and depression), neither of which are evident immediately after the rmTBI course of treatment. These neuronal and behavioral outcomes are hallmark signs of chronic traumatic encephalopathy (CTE) and have been observed in postmortem brains of military service members exposed to rmTBI. Two new drugs will be tested as therapies for rmTBI and include an inhibitor of histone deacetylase 6 (HDAC6) and a colony-stimulating factor 1 receptor (CSFR1) inhibitor that ablates CNS microglia. The rationale behind the use of an HDAC6 inhibitor for treating rmTBI is compelling for several reasons. First, modification of tau by acetylation protects it from aggregation (i.e., its pathological form) by inhibiting its phosphorylation. Second, HDAC6 has been identified as the specific enzyme that deacetylates tau. Deacetylation of tau allows for modification of tau by phosphorylation. Third, inhibition of HDAC6 should shift the balance of acetylation/phosphorylation to favor acetylation and thereby protect tau against patho...