Improving Traumatic Brian Injury Outcomes with Exercise Plasma

/Abstract Traumatic brain injury (TBI) is highly prevalent amongst Veterans but is also common in the general US population resulting from falls, motor vehicle accidents and sports related trauma. Most TBI is mild in severity with an annual incidence of 295 per 100,000 persons although both prevalence and impact are influenced significantly by age, sex, and other socioeconomic variables. The financial consequences of TBI are enormous with US costs for non-fatal TBI totaling over $40 billion annually and annual costs for OIF/OEF Veteran care 4-fold higher for those with TBI than those without. Functional and neuropsychological consequences are common after TBI as well. Amongst the most frequent and problematic outcomes of TBI, however, is pain experienced in the head, spine, extremities and other locations. Disability and healthcare utilization after TBI are strongly correlated with pain severity. Exercise is commonly recommended for functional recovery after TBI, maintenance of cognition with aging and for treating many forms of chronic pain. Exercise reduces pain in laboratory models of TBI, although clinical adherence to exercise programs after TBI is poor. Intriguingly, we have observed that the transfer of plasma or extracellular vesicles (ECVs) from exercising to sedentary TBI recipient mice reduces pain sensitization and improves performance in memory tests. The main objectives of our studies are, therefore, to identify key factors impacting the efficacy of exercise plasma, identify the active plasma components, and delineate how these factors mitigate TBI-related pain and neuropsychological outcomes. Our overarching hypothesis is that exercise-induced components of plasma including TIMP2, irisin and ECVs reduce adverse outcomes of TBI by limiting transcriptomic, cellular and circuit-level changes in CNS tissues. In the first aim we use a well characterized mouse model of mild TBI to identify key factors regulating the beneficial effects of exercise plasma on pain, memory and other neuropsychological outcomes after TBI. We hypothesize that the intravenous transfer of exercise plasma for less than one month to TBI mice will confer full beneficial effects. Translationally critical questions including optimal dose, timing relative to TBI, sex dependence and efficacy of exercise plasma on young versus aged subjects will be addressed. In the second aim we pursue rigorous mechanistic questions addressing the effects of exercise plasma on the molecular, cellular and circuit level changes in centers underlying the adverse effects of TBI. We hypothesize that exercise plasma mitigates changes in gene expression and neuroinflammation underlying functional changes in key pain control circuitry and other adverse consequences of TBI. Techniques employed include both selective and high dimensional analysis of gene expression, proteomics and immunohistochemistry. These tools will allow us to determine whether exercise plasma works to limit TBI- induced changes in key centers underlying the behavioral outcomes including the hippocampus, rostroventromedial medulla (RVM), periaqueductal gray mater (PAG), and spinal cord. In the project’s third and final aim, we identify components of plasma responsible for the transferrable beneficial effects of exercise. We hypothesize that ECVs in exercise plasma help to confer its effects as well as exercise induced proteins concentrated in ECVs including the myokine irisin and the endogenous tissue inhibitor of metalloproteinase TIMP2. High dimensional miRNA and protein analysis of mouse and human samples, direct protein administration and transgenic mice will be our principal tools. The studies outlined in this proposal are of particularly high impact as we follow multiple adverse TBI outcomes, use both mouse and human samples and assemble the expertise of several laboratories. We are in excellent position to translate our findings to patients leveraging our VA Polytrauma Rehabilitation Center. Project Number: 1I01RD001421-01A1 | Fiscal Year: 2026 | NIH Institute/Center: Veterans Affairs (VA) | Principal Investigator: DAVID CLARK | Institution: VETERANS ADMIN PALO ALTO HEALTH CARE SYS, PALO ALTO, CA | Activity Code: I01 | Study Section: Special Emphasis Panel[ZRD1 NURP-N (01)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11299654