Neurovascular and Cognitive Recovery from Spectrum of TBIs Through High-Low Therapy

The prevalence of traumatic brain injury (TBI) among our active-duty military and the detrimental neurobehavioral consequences of TBI in veterans continue to be a significant concern for military medicine. Force readiness is dramatically impacted by poor cognitive performance associated with TBI. This proposal outlines a novel therapeutic strategy using controlled utilization of induced oxygen deficiency (hypoxia) through intermittent exposure to low oxygen levels (11%) over time. This defined high-low oxygen therapy is known to cause an increase in the production of proteins called CXCL12 that are involved in vessel and neuron repair mechanisms and have been shown to reduce the severity of stroke and lung/heart injury. We hypothesize that repeated, brief, mild exposures to low oxygen air after a TBI will have therapeutic effects that attenuate cognitive deficits through its impact the production of the CXCL12 protein and its role in remodeling blood vessels in the brain. In this proposal, we will use a rigorous approach to establish the effect of high-low-oxygen therapy in two mouse models of TBI, mild and moderate/severe, using a combination of state of art the behavioral tests, pathology, high-resolution brain imaging as outcome measures. Our results will help establish the safety and efficacy of repetitive hypoxic exposure as a therapeutic measure for individuals at high risk for TBI, such as active duty servicemembers and athletes, while helping to better understand the injury mechanisms that ultimately lead to cognitive deficits.