Sexual Dimorphism in the Microglial Inflammatory Response After Traumatic Brain Injury

BACKGROUND: Traumatic brain injury (TBI) is an underrecognized public health threat. Significant long-term complications can occur resulting in motor, cognitive, and behavioral deficits. Trauma occurs predominately in male populations, skewing studies towards men. Creating a critical unmet research need to better understand the pathophysiologic differences in traumatic injury between sexes. Women TBI patients differ in severity and mortality, often suffering from greater long-term neuropsychiatric disorders as compared to men. Sex hormones may account for the observed differences. We hypothesized that microglia would adopt a divergent, sex-dependent, TBI- associated transcriptional profile after TBI. METHODS: Young-adult male and female mice underwent a severe TBI via controlled cortical impact or sham injury. Behavioral phenotyping was performed at 30-days post injury to assess anxiety, memory and motor deficits. A second cohort of mice had brains harvested, microglia sorted via flow cytometry, and single- cell RNA sequencing performed. RESULTS: Female mice demonstrated disinhibition of normal anxiety-like and exploratory behavior in comparison to male mice post TBI. Additionally, female TBI mice had attenuation of memory deficits as compared to male TBI mice. Lastly, we observed a marked divergence in the transcriptional profiles of microglia at baseline and after TBI in female mice as compared to male mice. CONCLUSION: Our data showed a significant difference in anxiety and memory deficits after TBI between male and female mice. Which was associated with a marked difference in the transcriptional profile of microglia between male and female mice. These data suggest that sex needs to be an a priori consideration in clinical TBI trials.