The wars waged by the US forces in Iraq and Afghanistan span more than a decade. Over this period more than 2.4 million US military personnel have deployed to Afghanistan and Iraq and for whom repetitive combat exposure to high explosives has been a common occurrence. Detonation of high explosives can inflict brain injury by multiple means. Even in the absence of direct blunt impacts to the head from flying objects or appreciable acceleration/deceleration of the head, the primary shock wave or blast overpressure (BOP) generated by high explosives is capable of injuring the brain. It is becoming increasingly clear that repetitive mild traumatic brain injury (mTBI) experienced by boxers and football players is associated with chronic traumatic encephalopathy (CTE) that is evidenced upon autopsy by significant tau and glial pathology;and which shares important similarities to several other chronic neurodegenerative diseases. Importantly, TBI increases the risk of developing Alzheimer's disease (AD). There is growing evidence that repetitive blast exposure may similarly place US combat service members and Veterans at risk for also developing CTE- related neurodegenerative disorders. Thus, there is an urgent need to better understand the nature of brain injuries caused by repetitive BOP. Currently, the mechanisms and pathophysiology underlying mild blast exposure on the brain are not well- understood. In particular the role played by astrocytes-which are crucial in protecting the brain from CNS insults-is largely unknown with regards to mild blast-induced mTBI. In addition, the relationship between blast-induced pathologic tau expression and astrocyte pathology remains to be explored. These gaps in our mechanistic understanding currently impede the search for new ways to ameliorate the risk of blast-induced mTBI from developing into a progressive neurodegenerative disorder. We have established a murine model of BOP-induced mTBI that is in keeping with well-established and validated approaches that accurately mimics battlefield-relevant open-field explosions. Using this approach we have found evidence that mild blast exposure provokes increased pathologically-related phospho-tau and loss of several important astrocytic molecules that play critical roles in preventing CNS toxicity;specifically the glutamate transporters GLT-1/EAAT2, GLAST/EAAT1, and glutamine synthetase (GS) that is responsible for detoxifying glutamate and recycling it into glutamine. In this project we will test the following hypotheses: (i) that mild repetitive blast exposure give rise to long lasting disturbances in astrocyte function that impair the ability of the brain to clear and metabolize the neurotransmitter glutamate;(ii) that loss of GLT-1/EAAT2 will render the brain more susceptible to blast- induced tau pathology, particularly in the context of repetitive BOP exposures;(iii) that mild blast exposure induces pathologic astrocytic dysmorphology that will be investigated using real-time in vivo imaging approaches;and (iv) that mild repetitive blast-induced astrocytic and tau pathology will give rise to cognitive and behavioral dysfunction. Successful completion of the aims of this proposal will provide new insights into the mechanisms by which repetitive blast-related mTBI harms the brain and facilitate the search for new strategies to reduce the long- term health risks associated with repetitive blast exposure.
The occurrence of mild traumatic brain injury (mTBI) in Veterans of the Iraq and Afghanistan conflicts is more common today than it was in previous wars-due in part to the frequent use of powerful improvised explosive devices (IEDs) by insurgents. TBI is a well-established risk factor for developing Alzheimer's disease (AD) and other dementing neurological disorders. Thus, there is concern that blast-exposed Veterans face significant risk of developing service-related cognitive dysfunction and dementia. There is a great need to better understand the nature of brain injuries that can be caused by repetitive BOP exposure. Correspondingly, there is great need to employ animal models of mild, repetitive BOP-induced TBI. We propose to investigate a mouse model of repetitive blast-induced mild TBI that will be used to understand the mechanisms of BOP- induced injury and evaluate the role of astrocyte-related genetic TBI risk factors.
