We propose to explore the possibility of using fruit flies (Drosophila melanogaster) to study traumatic brain injury (TBI). This research is important because TBI is a major health problem. TBI occurs with high incidence, annually affecting about 1 in 500 people in the U.S., and it is associated with lifelong debilitating physical, cognitive, behavioral, and emotional outcomes. This research is also important because there are no therapies currently available to improve TBI outcomes. Since 1985, at least 21 clinical trials have been conducted, and none have shown a significant benefit in TBI outcomes. The failure to develop therapies is likely due to the complexity of TBI, both in terms of the severity and spatial distribution of injury to the brain and the elaborate responses of the brain to injury. Therefore, there is a need for new experimental models that can help us understand the main cellular and molecular mechanisms that underlie TBI outcomes, with the potential for identifying novel targets for diagnostic and therapeutic intervention. Our fly TBI model is significant because (1) it uses a mechanical force to inflict brain injury, similar to mechanisms that commonly occur in humans, (2) it generates a continuum of injury severity that predicts outcome severity, (3) it generates injury in a reproducible manner, making it possible to determine the contribution of genetic and environmental variables to outcomes, (4) it produces injury outcomes that mimic clinically relevant outcomes of TBI in humans, (5) it uses standardized experimental protocols that are affordable, simple, and widely applicable, and (6) it is supported by the unparalleled knowledge of the fly nervous system and experimental tools that are available for flies. To achieve the goal of determining the extent of similarity between fly and human TBI, we propose to identify genes and secondary events associated with death following TBI.