The cognitive and emotional disability that commonly results from mild traumatic brain injury (TBI) is a major public mental health problem. Only limited insight is available on how mild TBI alters brain to cause lasting cognitive and emotional symptoms, or how to effectively treat these symptoms. Mild TBI is an extremely common occurrence during military combat, sports, recreational activities, and vehicular accidents. Mild TBI involves closed-head injury from a primary blast shock wave, or head acceleration - deceleration during a collision. The resulting brain injury appears to stem from the rapid brain tissue deformation that results from the shock wave transmitted through brain by the blast, or from the brain compression - expansion during rapid head acceleration - deceleration. The rapidly alternating compression and stretching lead to neuronal alterations that are yet poorly characterized, and unknown secondary degenerative events that can cause lasting and, in the case of chronic traumatic encephalopathy (CTE), even intensifying symptoms. Although TBI has been modeled in animals using a variety of approaches, anxiety, depression, and memory loss caused by mild TBI have typically been characterized only over the short term (1 day - 2 weeks) and rarely over the long term (>1 month). Accordingly, the molecular and cellular events by which a concussive event impairs cells and axons within specific brain regions to cause persistent symptoms or as a delayed effect are ill-defined. We have developed a mouse model of closed-head primary blast mild TBI using a controlled air pressure wave delivered to a small mid-cranial area. This model simulates the temporal and physical dynamics of the forces causing shock wave-mediated mild TBI. We have found that we can create hyper-anxiety and depression, and diffuse axonal injury, in 3-month old male C57BL/6 mice during the first month after 50-60 psi blast with this system. Our model thus recapitulates the insult and at least the short- term outcome commonly associated with mild concussions in humans. We propose to use our blast model of mild TBI to characterize anxiety, fear, depression and memory loss in male C57BL/6 mice over the 9-month period following single or multiple blasts. We will conduct histological assessments to relate behavioral deficits to pathology in specific brain regions, and serological assessments of biomarkers that are predictive and perhaps causally related (for example, autoantibodies against neural antigens) to the process causing secondary brain damage. Our studies will establish the time course over which cognitive and emotional abnormalities develop, wane, or worsen following single or repeat mild TBI. Our multiple blast studies will develop a mouse model for the progressive multi-concussive disorder CTE. The overall findings will provide parameters for reliably producing mild TBI that yields neurocognitive and emotional disorder, to facilitate future studies of the neurobiological and neurogenetic basis of the emotional and cognitive deficits of mild TBI, and for the development of effective treatments.
Lasting anxiety, fearfulness, depression and memory loss are common after mild TBI, but the means by which TBI injures brain to cause such enduring deficits is unknown because suitable animal models of mild TBI that mimic these symptoms have not been developed. We have developed an approach for creating mild TBI in mice by an overpressure air blast to the cranium that yields emotional and cognitive disorder, and accordingly we will further characterize the behavioral and neuropathological effects of single concussive or multiple subconcussive blasts out to a year of age to develop mouse models for the long-term effects of mild TBI and for the progressive neurodegenerative disease chronic traumatic encephalopathy. These models will make it possible to elucidate the mechanisms underlying the brain damage by which mild TBI causes emotional and cognitive disorders, and develop therapies targeting those mechanisms.
| Guley, Natalie H; Rogers, Joshua T; Del Mar, Nobel A et al. (2016) A Novel Closed-Head Model of Mild Traumatic Brain Injury Using Focal Primary Overpressure Blast to the Cranium in Mice. J Neurotrauma 33:403-22 |
| Del Mar, Nobel; von Buttlar, Xinyu; Yu, Angela S et al. (2015) A novel closed-body model of spinal cord injury caused by high-pressure air blasts produces extensive axonal injury and motor impairments. Exp Neurol 271:53-71 |
| Reiner, Anton; Heldt, Scott A; Presley, Chaela S et al. (2015) Motor, visual and emotional deficits in mice after closed-head mild traumatic brain injury are alleviated by the novel CB2 inverse agonist SMM-189. Int J Mol Sci 16:758-87 |
| Heldt, Scott A; Elberger, Andrea J; Deng, Yunping et al. (2014) A novel closed-head model of mild traumatic brain injury caused by primary overpressure blast to the cranium produces sustained emotional deficits in mice. Front Neurol 5:2 |
