Project Summary/Abstract Current research activities in the laboratory of the Nominee concentrate on repetitive mild traumatic brain injury rmTBI), Gulf War Veterans' Illnesses (GWVI), and substance abuse disorders (SUD). Each of these conditions has in common damage to the brain. These conditions can also interact and serve as a co-morbid condition for the others. These illnesses are over-represented in Veterans and represent serious health concerns for them and their families. There are no effective therapies for rmTBI, GWVI and SUD. The overarching goal of this research program is to achieve a better mechanistic understanding of rmTBI, GWVI and SUD so that evidence-based therapies can be developed which will restore and return brain function in Veterans with these disorders. rmTBI is a complex and chronic condition that has remained untouched by therapeutic interventions. Despite numerous treatment successes in animal models, all clinical trials of TBI therapies in humans have failed to date. This situation can be attributed to inappropriate animal models, at least in part. This project will use a new mouse model of rmTBI that closely mimics the human condition insofar as symptoms and pathologies in brain develop very slowly. Treatments directed at arresting increased glial reactivity will be started after head impacts have been completed in order to maintain a translational approach. GWVI is another chronic condition in Veterans of the Gulf War and this condition is characterized by three main symptom clusters- gastrointestinal disorders (like IBD), chronic fatigue, and anxiety/PTSD-like conditions. Perhaps the largest obstacle to achieving better treatments for GWVI is the fact that the toxins to which military personnel were exposed are not known (dose, length of exposure, combinations). This project recognizes that all three of the major symptoms of GWVI can be traced one-by-one to an altered gut microbiome. It also recognizes that any toxins to which military personnel were exposed have been eliminated from their bodies soon after they redeployed home. Therefore, we hypothesize that lifestyle risk factors, common among Veterans (e.g., obesity, smoking, alcohol abuse), all of which can also disrupt the gut microbiome, interact with these exposures to accentuate and prolong symptom expression. Research on this project will therefore target the gut with therapies intended to correct the gut microbiome disruption that results from GWVI-lifestyle interactions (e.g., probiotics, short chain fatty acids, microbiota-accessible carbohydrate and/or low-fat diets). A second phase of this project will develop a humanized mouse model of GWVI by transferring the diseased gut microbiome from Veteran donors into mice and examining the mice for symptoms of the human disorder. This project bypasses the uncertainly regarding toxin exposure in GWVI and will incorporate an important complicating factor in this disorder- human GWVI shows much more symptom vari...