Investigating the influence of risk factors on the cellular changes after mild traumatic brain injury

Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. TBI is most prevalent in people during their productive years and frequently results in prolonged or lifelong motor and/or cognitive impairments, putting a significant economic burden on society. Mild TBI (mTBI), comprising over 80% of TBI cases, frequently results in acute neurosensory deficits and subacute ongoing neurological deficits with long-term implications, including the potential development of neurodegenerative diseases. Factors including the age at injury, sex, number of injuries and interval between injuries have the potential to affect pathological changes and the recovery process following mTBI, however, how these factors interact remains unclear. Therefore, the underlying cellular and subcellular responses evoked by mTBI need to be fully elucidated in order to understand how these factors affect outcomes following mTBI, and furthermore to develop effective therapeutic interventions. The current thesis is based on the hypothesis that specific cellular and subcellular responses (including neuronal and glial changes) differentially characterize pathological changes and recovery processes after mTBI. This thesis investigated how the age at injury affects outcomes after mTBI. Studies focused on the cellular and subcellular reactions after injury. Studies found non-injured aged brains were characterized with cortical atrophy, higher astrocyte and microglial activation, as well as increased axonal degeneration compared to younger brains. Furthermore, using a mild lateral fluid percussion injury mouse model, results showed that although select cortical changes after injury were independent of the age at injury, astrocytic and microglial activation, as well as axonal degeneration after injury were age and post injury time interval dependent. This thesis suggests that the cellular and subcellular responses after mTBI are age dependent. This thesis further investigated a potential drug intervention for mTBI. Neuronal cytoskeletal changes, including the morphological and functional changes of microtubules are recognized as a pathological feature of degeneration after TBI. Thus, I hypothesized that a microtubule stabilizing agent would have beneficial therapeutic potential following TBI. This study found that epothilone D was not toxic to cortical neurons and did not have any significant effects on the glial response in young and adult mice. With regards to axonal degeneration, in young mice that received a mTBI injury and subsequent EpoD treatment, measures of axon degeneration were also found to be similar compared to untreated animals. In older animals, however, the measures of axon degeneration were worse in injured animals after EpoD treatment compared to untreated injured animals. This thesis highlights the need for age dependent drug therapy for mTBI patients. Finally, this thesis investigated how sex and an additional injury influence the outcome after mTBI. Conflicting literature exists regarding whether females have better outcomes than males in both experimental and clinical studies of TBI. Our results suggest that glial activation was distinctive between sexes, as well as different axonal degeneration between sexes with increased axonal degeneration after injury resolving earlier in females but exacerbated in male mice. Furthermore, our study also found a second injury, 48 hours following the first, significantly increased glial activation, as well as reduced the cortical thickness and exacerbated axonal degeneration after injury in male mice. This thesis suggested both sex and an additional injury differentially affected glial and axonal responses, which may further support the need for sex dependent and repetitive injury dependent clinical management of mTBI patients. In summary, this thesis shows how risk factors including age at injury, sex and a second injury effected the cellular and subcellular reaction following mTBI in a mouse model. Furthermore, it suggests a potential need for age and sex dependent therapeutic interventions in mTBI patients