267 Sex Differences in Transcriptomic Response After Experimental Traumatic Brain Injury

INTRODUCTION: Traumatic brain injury (TBI) is common across all age groups resulting in acute and chronic disabilities. Although it is known that TBI causes profound transcriptional changes, the influence of sex on the transcriptional response to TBI has not been adequately elucidated. METHODS: Groups (n=4/group) of adult male and female C57BL\6 mice received a mild-to-moderate injury or sham surgery. Five days post-injury, animals were euthanized and the ipsilateral hippocampus was extracted to isolate total RNA. RNA quantity and integrity were assessed by spectrophotometry and gel electrophoresis. RNA sequencing was then performed by Active Motif and relative mRNA levels compared across groups. RESULTS: Both male and female mice had significant changes in mRNA levels as a result of injury (¦log2-fold change¦ >1, pAdj<0.05). Of the genes that were found to have significant changes in expression after TBI, most were downregulated in male mice. In contrast, although females had fewer genes altered by TBI, their expression tended to be upregulated. Gene set enrichment analysis was subsequently performed to identify overrepresented biological processes and molecular functions. Upregulated genes in both sexes showed an enrichment for immune and inflammatory-related functions, an effect that was more prominent in females. In contrast, down-regulated genes related to chromatin remodeling and histone modification were more prominent after CCI in males. CONCLUSIONS: Male and female mice exhibited gene expression profiles with unique features 5 days post-injury, with male mice have a stronger downregulated response. Additional work will be required to determine the time courses of these changes and their functional consequences on TBI pathology and outcome. This work highlights the need for additional studies in which sex as a biological variable is considered in the development of therapeutic strategies for TBI.