Combined radiation and traumatic injury affect hippocampal structure and function

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DESCRIPTION (provided by applicant): In the context of radiological/nuclear terrorism, radiation exposure will likely occur in combination with another insult, such as trauma. While radiation combined injury (RCI) is recognized as an area of great significance, there generally are few data regarding the mechanisms underlying the interactions between irradiation and other forms of injury, or what countermeasures might be effective in ameliorating such changes. Uncontrolled radiation exposure will necessarily involve a wide range of delivered doses and subsequent tissue/body effects, up to and including the well-described and lethal radiation syndromes. But at doses below the threshold for lethality, or if interventions are able to modulate the radiation response of critical early responding tissues (e.g. bone marrow, gut), the response of other tissues (e.g. brain), may become more problematic. This possible scenario may be particularly relevant in the context of a subsequent or concomitant injury (i.e. RCI), which could exacerbate latent or 'mild' radiation injury, and result in cellular/tissue injury that could ultimately impact organ function. Traumatic brain injury is a likely consequence of a nuclear blast, and is a frequent cause of death and disability when individuals are exposed to explosive forces. With respect to the brain, irradiation and traumatic injury are both known to induce specific hippocampal-dependent impairments that involve spatial learning and memory. The pathogenesis of such cognitive impairment is likely multifaceted, and we hypothesize that RCI will adversely affect neurogenesis, neuronal function as assessed by the molecular distribution of the immediate early gene Arc (activity-regulated cytoskeleton-associated protein), and behavioral performance. We further contend that these effects are mediated, in part, by neuroinflammation, and that reducing the numbers of activated microglia using the polyamine inhibitor a-difluoromethylornithine (DFMO), will ameliorate these adverse effects of RCI. Using well-established animal models, along with an innovative approach of measuring neuronal activity history (i.e. Arc) at the level of mRNA and protein expression, we will analyze specific cellular and molecular factors associated with neurogenesis and neuroinflammation, and determine if they correlate with measures of hippocampal dependent behavior after RCI when the 2 insults are given concomitantly or when they are separated by 30 days. Understanding the pathogenesis of RCI is essential for the development of mitigation or treatment strategies and may have a significant impact in improving post-injury quality of life. In the context of radiological/nuclear terrorism, radiation exposure will likely occur in combination with another insult, such as trauma, i.e. radiation combined injury (RCI). With respect to the brain, RCI involving traumatic injury may result in cellular injury that could ultimately impact tissue function and behavioral performance. Understanding the cellular, molecular and functional consequences of RCI to the brain is crucial for the development of mitigation or treatment strategies and may have a significant impact in improving post-injury quality of life.