Focal Impact Injury as a Model of Traumatic Brain Injury and the Role Microglia Play in Recovery



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Traumatic brain injury (TBI) is an insult to the brain that progresses from the initial injury to a disease state over time. It is a widespread injury that 1.5 million people sustain within the USA every year, with 230,000 people being hospitalized and another 50,000 dying from the injury. Furthermore, another 90,000 people deal with long-term disability. TBI’s develop in two phases: the acute and chronic phase. The acute phase occurring as the injury is sustained, dealing with the mechanical forces that insult the brain. The chronic phase develops over time and can progress to a disease state that creates the long-term disability. We seek to establish the Xenopus laevis tadpole as a model to complement the strengths of existing mammalian models; our model incorporates a focal impact injury to the tadpole midbrain. To do so, I carried out a transcriptome analysis of injured and sham-treated animals over a 7 day recovery period and I identified key genes that are differentially expressed at time points following injury. I investigated the impact of tamoxifen, a potential therapeutic, on the transcriptome of injured midbrains. Then I evaluated the response of midbrain microglia, a key nervous tissue cell type that functions as the resident immune cell of the brain. I determined that microglia aggregate locally within three hours following injury and that microglia accumulate the most at 24 hours following injury. Expression of inflammatory cytokines and other mediators of inflammation increased dramatically within three hours following injury, subsiding to near-baseline levels within 24 hours. Pharmacological depletion of microglia leads to delayed inflammation, as an elevated inflammatory response is observed at 24 hours, indicating that microglia are required for the rapid inflammation response. Proliferation response is delayed to the 48 hour timepoint, and phagocytosis appears to be depleted. Astrocytes also appeared to behave abnormally in the absence of microglia, reacting earlier in the normal injury response timeline. Ultimately this research shows that microglia contribute to the response to TBI by giving rise to the initial inflammation profile.



Traumatic brain injury, TBI, Xenopus laevis, Microglia, Astrocytes


Portions of this document appear in: Spruiell Eldridge, Sydnee L., Jonathan FK Teetsel, Ray A. Torres, Christina H. Ulrich, Vrutant V. Shah, Devanshi Singh, Melissa J. Zamora, Steven Zamora, and Amy K. Sater. "A Focal Impact Model of Traumatic Brain Injury in Xenopus Tadpoles Reveals Behavioral Alterations, Neuroinflammation, and an Astroglial Response." International Journal of Molecular Sciences 23, no. 14 (2022): 7578.