MICROGLIA MEDIATED MECHANISMS OF VASCULATURE AND NEURONAL NETWORK DYSFUNCTION FOLLOWING REPETITIVE TRAUMATIC BRAIN INJURY

Adverse neurobehavioral changes resulting from repetitive traumatic brain injuries (TBIs) are one of the main challenges facing the combat readiness of our troops. With the frequent use of improvised explosive devices in the battlefield and improved armor and healthcare, soldiers are experiencing and surviving more concussive blast injuries and direct head trauma. However, the initial damage is not readily apparent and, as the soldier remains in the battlefield, subsequent injuries lead to brain pathologies that build upon each other and have a greater probability of inducing debilitating cognitive changes. Key to our ability to prevent and treat TBI related injuries is the capacity to detect the initial damage and guide the cellular response towards repair and regeneration. Currently, our understanding of the mechanisms underlying neurobehavioral changes resulting from TBI is insufficient to adequately control or alter the TBI outcome. Microglia are the sentries of the central nervous system and have the capacity to mount a defense against infiltrating pathogens or respond to damage by clearing away dead or dying neurons, and isolate breaks in the bloodbrain-barrier. Unfortunately, in the process, microglia initiate inflammatory responses that can exacerbate damage from the initial injury. Additionally, microglia can remain activated for extended periods of times and/or may be primed and retain postactivated signature. Thus ¿activated¿ and postactivated microglia continue adversely affecting cognitive abilities and behaviors long after the initial series of injuries. The most recent advances in in vivo imaging techniques and microglia labeling methods make it possible to study the role of microglia in TBI. Our research focuses on identifying microglia mediated mechanisms of vasculature and neuronal network dysfunction following repetitive traumatic brain injury. By understanding what factors push microglia towards detrimental impacts on neurovasculature and remodelling of neuronal networks following TBI, we will be able to prevent the onset of adverse microglia activities, attenuate their detrimental impact or enhance their restorative functions. In summary, using a combination of novel in vivo approaches we will produce mechanistic preclinical insights into the roles of microglia in neurovasculature and neuronal networks affected by TBI towards the development of new therapeutic interventions.