Project Summary Traumatic brain injury (TBI) has recently been identified as an independent risk factor for ischemic and hemorrhagic stroke. A history of TBI confers enhanced risk of stroke incidence at a rate similar to other traditional stroke risk factors including smoking and hypertension. In addition, TBI survivors who subsequently have a stroke have increased likelihood of mortality, suggesting that TBI renders brain tissue more vulnerable to ischemic damage. Here we present data generated in mice demonstrating that mild closed head traumatic brain injuries transiently, but significantly, limit central glucose utilization, impair insulin receptor sensitivity and reduce mitochondrial energy production. Furthermore, when ischemic stroke (induced via middle cerebral artery occlusion) occurs one week after TBI, the inflammatory responses, infarct size and functional deficits are all markedly worse than in mice without a history of TBI. Treating metabolic dysfunction pharmacologically attenuated TBI-induced exacerbation of ischemic outcome. The overarching hypothesis of this application is that TBI-induced metabolic dysfunction renders the brain less able to utilize metabolic fuels, and in turn more vulnerable to ischemic damage. The three specific aims will (1) compare the effects of TBI history on stroke-induced CNS inflammation, metabolic physiology, and neuronal death in male and female mice and determine the time course of vulnerability after injury (2) determine whether normalizing insulin signaling during the first several days after prevents the exacerbation of stroke damage and improves mitochondrial respiration and (3) take steps to gain independent funding. Together, these studies will raise awareness of the elevated stroke risk among TBI patients, and by determining the underlying physiological mechanism may offer new directions for TBI treatment that will minimize stroke risk and improve outcomes for individuals who have suffered a TBI.