Multimodal Insights Into The Cellular Consequences Of Traumatic Brain Injury

Traumatic brain injury (TBI) significantly increases the likelihood of developing neurodegeneration and other pathological conditions later in life. However, the mechanisms linking TBI to neurodegeneration remain unclear. A growing body of evidence demonstrates that chronic oxidative stress, neuroinflammation, and dysfunctional neuronal communication likely contribute to poor long-term post-TBI outcomes. These consequences arise at the cellular and subcellular level immediately following injury. However, experimental systems that facilitate studies on how these sequalae arise and interact after injury at the cellular level are often subject to a multitude of confounding variables and offer limited cellular and subcellular resolution of these mechanisms.

This dissertation describes the development of the TBI-on-a-Chip model, an in vitro injury platform to deliver impact and blast-induced TBIs to neuronal networks and study the resulting changes at the cellular and subcellular level. Using immunocytochemical analysis and electrophysiological recording before, during, and after injury, I demonstrate the capabilities and strengths of the novel TBI-on-a-Chip in vitro system to study the cellular and subcellular effects of injury. I use TBI-on-a-Chip to quantify key biochemical consequences of TBI and how these consequences interact to promote progressive damage and pathology long after injury. In particular, I relate changes in oxidative stress, inflammation, neurodegeneration, and synaptic function to one another and across two different injury types. The results in this thesis show that in vitro biochemical changes at the cellular level are synergistic and similar between impact injury and mild blast injury, supporting the notion that treatment approaches targeting biochemical cascades could be universal in improving outcomes of all types of TBI. Additionally, pathological changes arise in cells within 6-24 hours after injury, suggesting that limiting biochemical cascades shortly after injury is sustained might reduce functional and pathological changes more effectively than treatments administered later. The results in this thesis also suggest that combination therapies designed to target multiple post-injury biochemical cascades will be more effective than targeting individual components alone, and that restoring synaptic function by limiting both oxidative stress and neuroinflammation will likely improve TBI outcomes. Together, the results in this thesis offer insights, not only into the mechanisms of TBI trauma and associated neurodegeneration, but also diagnosis and treatment strategies for TBI.