Traumatic brain injury (TBI) has been a major cause of mortality and morbidity in the recent conflicts in Iraq and Afghanistan. Much concern exists over the role of TBI in the chronic cognitiveandbehavioraleffectsthatcandevelopduringoraftermilitaryservice.Mostinjuriesin the recent conflicts have been mild TBIs (mTBIs) due to blast exposure. Vascular damage is well established as a significant component of blast injury. Indeed under the conditions of exposureinthemodelunderstudyatthehistologicallevelthecerebralvasculatureseemstobe selectively vulnerable. Using micro computed tomography (CT) scanning we found that blast induces widespread attenuation of the brain vasculature. In proteomic studies on isolated microvascular preparations obtained two months following injury one of the most highly altered proteins identified by mass spec (MS) was found to be glial fibrillary acidic protein (GFAP), which was decreased by blast-exposure. This finding was confirmed by Western blotting on isolated microvascular preps. The loss of GFAP seemed to suggest that following blast injury astrocytic endfeet were becoming detached from cerebral vessels and immunostaining of isolated microvascular preps supported this speculation. Interestingly of the first 9 proteins identified by MS several others were neuronal intermediate filament proteins including the neurofilamentheavychain(NF-H)and?-internexin,whichlikeGFAP,weredecreasedfollowing blast injury. Loss of these proteins suggests that nerve terminals become detached from cerebral vessels as well. Disrupted gliovascularand neurovascular connections could affect a number of cerebral functions. The proposed studies will determine the chronic structural and functional consequences of blast injury on the vasculature in a rat model of low-level blast exposure. The studies will utilize quantitative immunohistochemistry, stereology, electron microscopy, Westernblotting of isolated microvascularpreps, micro CT scanningand behavior. We will test the hypothesis that blast injury causes widespread loss of gliovascular and neurovascularconnectionsanddeterminethefunctionalconsequences.Wewillalsodetermine whether a treatment that improves the post-traumatic stress disorder (PTSD)-relatedbehavioral traits that develop in this model stimulates gliovascular and neurovascular connections as well improvesthevascularpathologyobservedonmicroCTscanning.Three-timepointspost- blastexposure will be examined (48hours, 6 weeks and 8 months) to capturethe evolution of theinjuryfromacuteintosubacuteandchronicphases.
Low-level blast overpressures induce altered gliovascular and neurovascular interactions. The proposed research is aimed at characterizing the structural, molecular and functional consequencesofblastinjuryonthebrainvasculatureinaratmodeloflow-levelblastexposure. The findings of this research may be used to develop new therapeutic strategies for the treatmentofveteransaffectedbyblast-relatedbraininjury.
