Electronic Thesis and Dissertation Repository

Thesis Format

Monograph

Degree

Master of Science

Program

Microbiology and Immunology

Supervisor

Dekaban, Gregory A

Abstract

Concussion is the most common form of mild traumatic brain injury (mTBI). TBI resolution is modulated by neuroinflammation, which is augmented by the infiltration of innate immune cells from the circulation. Peripheral, myeloid immune cells not only invade neural tissues but other organs as well causing local inflammation and tissue damage, known as systemic inflammatory response syndrome. Here, I assessed the temporal and anatomical nature of the neural and systemic cellular inflammatory response to repetitive, mTBI in a 3-hit mouse model of concussion. The results showed significant microglial activity, accumulation of peripheral myeloid cells and prominent axonal damage post-injury. The peripheral immune cells emerged through the brain microvasculature and resided in the parenchyma, along the pia mater and within the ventricles. There was also evidence of systemic inflammation in the lungs as well as in the cervical spinal cords of the mTBI mice.

Summary for Lay Audience

Traumatic brain injury (TBI) has emerged as a silent epidemic of increasing importance and frequency as it has gained global recognition as a high-profile public health issue. Concussion falls under the milder end of the TBI severity spectrum, accounting for 70-90% of all brain injury cases. However, since most individuals survive the initial trauma and do not seek medical treatment, the total number of concussion is greatly underreported. As there are many causes of TBI, injuries pertaining to the brain are often known as “the most complicated disease of the most complex organ in the human body.” Despite this increasing awareness of concussion and the possibility of long-term impairments, effective means of diagnosis, prognosis and treatment options fail to exist and remains as a major unmet clinical need. Furthermore, not only single but repeated occurrences of head injuries constitute mounting concerns, and emerging literature supports both pathological and behavioral differences between a single injury and multiple injuries. This is particularly a major concern in the context of sports or military activities where these individuals are subjected to multiple insults. There is evidence to suggest that immediately following a head trauma, a period of vulnerability window exists and if a second concussion was sustained within that period, a significant and even fatal damage can occur, known as second impact syndrome. Prognosis and effective management guidelines are difficult especially when social pressures exist for individuals to return to play or combat duties. Moreover, there is a high level of uncertainty regarding the threshold for diagnosis, the recovery trajectory and the predicted outcome. Here, I assessed the temporal and anatomical nature of the brain and systemic cellular inflammatory response to repetitive TBI in a 3-hit mouse model of concussion. The results showed significant activity of certain immune cells in the brain called microglia and an accumulation of other types of immune cells in the brain as well as in other organs. Overall, this study characterizes the inflammatory responses following repeated concussive injuries in a mouse model to establish its suitability for testing future therapeutics for clinical translation.

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