UC Irvine

Every year, there are 3.8 million traumatic brain injuries in the United States leading to an estimated 5.3 million Americans that are currently living with a disability due to these injuries. Of these traumatic brain injuries (TBI), 75% are considered to be mild in severity. Importantly, while a single mild TBI has transient symptoms and associated neuropathological features, multiple mild TBI can result in a wide range of debilitating chronic symptoms and neuropathological features. Laboratory rodent models of traumatic brain injury have primarily focused on acute outcomes following TBI, and have also not focused heavily on repeated mild closed head injuries. This dissertation first reviews the literature outlining rodent models of traumatic brain injury, and the lack of assessments at chronic timepoints following injury. We found that 68% of papers did not evaluate a functional outcome past 1-month post TBI, and 90% of papers reviewed did not make a functional assessment 2 or more months following injury. Of these papers that investigated a 2 month timepoint, 84% demonstrated a functional deficit in a behavioral measure, stressing the persistence of chronic deficits and the important of studying them. Next, we focus on the development of a rodent model of repeated mild traumatic brain injury. We utilized components of classic rodent models of TBI to develop a model and protocol for repeated mild closed head injuries (rmCHI) that can be easily reproduced across users and laboratories, and mimics the clinical presentation. The parameters of our model of rmCHI produce behavioral changes and neuropathological features for multiple impacts, but not single impacts, at chronic timepoints of 1, 2, and 6 months post injury. Behavioral changes in measures of anxiety, depression, and learning are also closely associated with neuropathological features including white matter atrophy and cortical neuronal loss. rmCHI results in 33-35% corpus callosum loss, developing by 2 months and lasting out to 6 months post injury. Lastly, we dive deeper into the mechanisms underlying white matter loss, test more mild injury parameters to find injury thresholds, test rmCHI in an immunocompromised mouse strain, and explore potential novel therapeutics for rmCHI.