The Neurobiology of Blast-Related Brain Injury in a Rat Model of mTBI

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Mild traumatic brain injury (mTBI) has been a major cause of morbidity in the wars in Iraq and Afghanistan. In both theatres of operation, blast exposure has been the most common cause of TBI. One striking feature of the clinical presentations of OIF/OEF veterans with mTBI is the prominence of post-traumatic stress disorder (PTSD). Indeed the high prevalence of PTSD and depression in returning OIF/OEF veterans with mTBI is well documented and distinction between the two disorders has proven clinically challenging. The association between PTSD and mTBI might be explained by co-incident exposures to TBI events and PTSD stressors. However, an alternative hypothesis that we have been exploring is that blast-related mTBI damages brain structures that are important in mediating responses to psychological stressors and thus enhances the likelihood of developing PTSD. In collaboration with a Department of Defense investigator, Dr. Stephen Ahlers, we have been studying a rat model of blast injury that mimics mTBI. We have found that animals tested several months post-exposure exhibit PTSD-related traits including increased acoustic startle, increased anxiety, an altered response to a predator scent challenge and an increased cued response in a fear conditioning paradigm. These observations suggest that blast exposure in the absence of any psychological trauma induces PTSD related traits that are chronic and persistent. Dr. Ahlers has found that plasma corticosterone levels become elevated after blast exposure and that these levels remain high for at least one month. PTSD is commonly thought to result from an abnormal and prolonged stress response with abundant evidence suggesting that abnormalities in the hypothalamic/pituitary/adrenal axis are chronically present. These observations have lead us to postulate that blast injury to the brain induces a chronic state of stress that even in the absence of any psychological trauma produces PTSD-related traits and exaggerated responses to subsequent PTSD-related stressors. Here we will examine whether stress responses in the brain are chronically altered by exposure to blast injury and determine whether treatment with a glucocorticoid receptor antagonist is able to block the development of or reverse PTSD-related behavioral traits. We will also examine whether blast injury induces structural effects in the medial prefrontal cortex, amygdala and hippocampus, the principal anatomic substrates that are thought to underlie the neurobiological basis of PTSD. These studies will further understanding of the relationship of blast injury to PTSD related traits and will have implications for designing treatment strategies for veterans who have suffered blast induced mTBIs.