Date of Award

2021

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Neuroscience

First Advisor

Matthew S. Kayser

Abstract

Why the brain continues to undergo functional and histopathological decline years and decades after a traumatic injury is a central question in the field of traumatic brain injury (TBI) research. Despite the heterogeneity of TBIs, sustained and aberrant activation of glia is found in nearly all injuries and likely contributes to long-term pathology. This notion is supported by emergent evidence in classical degenerative diseases, such as Alzheimer’s and ALS. In early TBI, glia are thought to have a supportive role in recovery but over time, their continued activation may foment inflammation and decline, though mechanistic understanding of this process is limited. To define disease mechanisms, we performed an unbiased time course RNA-sequencing experiment in a Drosophila model of head injury (dTBI). We identified a rapid and sustained transcriptional response mediated by the conserved complex, AP1. We determined that AP1 activates in glia, in an injury-dose dependent manner. Our functional studies determined that AP1 drives distinct glia behavior in early and late injury. Acutely, glial AP1 is essential for injury recovery; in its absence, a survivable TBI becomes lethal. However, continued activation of AP1 promotes human tau pathology, degeneration, and death. We extend our work in the fly to humans and uncover evidence of chronic AP1 activity in survivors of moderate TBI. In these subjects, AP1 activity positively correlates with microglial activation and tau pathology. Curiously, in flies, we find that glial AP1 also activates during healthy brain aging, suggesting that TBI may accelerate age-onset processes in glia. In summary, transcriptional insights gained from a Drosophila model of TBI uncovered a potentially conserved mechanism by which glia initially protect but in time, promote disease. Our work has broad implications for injury, aging, and disease.

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