Millions of athletes participate in contact sports that involve repeated head impacts (e.g., football, ice hockey, boxing), often from a very young age, and it is feared that subsequent impacts can synergize with previous ones so that their effects on the brain become magnified. Repetitive mild traumatic brain injury (rmTBI) has been linked to the development of chronic traumatic encephalopathy (CTE). The neurodegeneration accompanying CTE occurs over many years following repeated head impacts and is characterized by progressive brain atrophy, accumulation of hyper-phosphorylated tau and aggregates of TDP-43, myelinated axonopathy, neuroinflammation and degeneration of white matter tracts. The relationship between head impact parameters (force, number, frequency) and the manifestations of rmTBI is not well understood nor is the severity or frequency of head injury required to trigger CTE. An animal model of rmTBI (i.e., sports-related TBI) is urgently needed to minimize risk of TBI in athletes and the studies described herein confirm that our method bears the attributes necessary to fulfill this need. The studies included in this project validate a method of rmTBI that unequivocally simulates human sports-related head impact in both form and outcome. To our knowledge, this is the first study to administer 30 head impacts over an extended period of time to a lightly anesthetized, completely unrestrained mouse. We have assessed the sensorimotor, psychiatric, and cognitive outcomes of rmTBI at two different time points using different impact conditions. Animals receiving repeated head impacts exhibited outcomes consistent with those observed in athletes with a history of rmTBI including depression-like behavior and cognitive impairment. The neuropathological outcomes of rmTBI included reactive gliosis, axonal degeneration, elevated levels of Aβ (1-42), β-amyloid, p-tau, TDP-43, and significant thinning of several white matter tracts. Notably, these outcomes occurred in mice receiving head impacts that did not delay recovery of the righting reflex indicating that subconcussive impacts present just as serious risk of injury to the CNS as concussive blows. Aside from this outcome, these data indicate that there is a cumulative and dose-dependent effect of repetitive head impacts that exacerbate the neurobehavioral and neuropathological outcomes as seen in humans with a history of rmTBI. This model will enable future study of the most pressing issues associated with sports-related head impact including the relationship between the number and frequency of head impacts to the development of behavioral and CTE-like outcomes. Future studies elucidating the cellular manifestations of rmTBI and its behavioral correlates will aid in the development of potential therapeutics. Finally, these results demonstrate the ability of our method to expand our understanding of the neuropathological, psychiatric, and cognitive sequelae underlying this insidious injury.
|Advisor:||Kuhn, Donald M.|
|Commitee:||Galloway, Matthew P., Mateika, Jason H., Stanley, Jeffrey A.|
|School:||Wayne State University|
|Department:||Psychiatry and Behavioral Neurosciences|
|School Location:||United States -- Michigan|
|Source:||DAI-B 77/09(E), Dissertation Abstracts International|
|Keywords:||Chronic traumatic encephalopathy, Head injuries, Sports-related injuries, Traumatic brain injury|
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