Hippocampal transcriptomic response to experimental traumatic brain injury in male and female mice

Traumatic brain injury (TBI) often results in acute and chronic deficits that can have profound effects on the affected individual and their families. While TBI is known to trigger widespread transcriptome changes, concurrent evaluation of the influence of sex on these changes has been understudied. To explore transcriptomic-wide responses between sexes after TBI, we administered a moderate-to-severe cortical contusion injury (CCI) or sham surgery to groups of adult male and female C57BL/6 mice. Animals were euthanized 5 days post-injury, the ipsilateral hippocampi were quickly dissected, and total RNA was isolated and sequenced. Differentially expressed genes (DEGs) were identified across all groups using a single factorial analysis and the results used for gene ontology enrichment analysis to gain a high-level overview of differences and similarities in the transcriptomic response to CCI. Both male and female mice exhibited widespread significant changes in gene expression 5 days after injury (│log ₂ -fold change│>0.5, adjusted p-value <0.05). Adult male mice had 3902 genes with significantly altered expression in the hippocampus 5 days post-CCI (3238 downregulated and 664 upregulated) while 899 genes (114 downregulated, 785 upregulated) were altered in females. Gene ontology (GO) analysis of DEGs showed a prominent enrichment for upregulated immune and inflammatory-related biological process terms in both females and males. Genes exhibiting downregulated expression in male mice were associated with dendritic development and synaptic reorganization GO terms while the downregulated female transcriptomic response was not significantly enriched for any terms. Although many of the same GO terms were altered in both sexes, the specific genes within these terms were often unique suggesting that similar biological responses may be achieved through different means in each sex. This work highlights the need for continued studies in which sex as a biological variable is considered in the development of therapeutic strategies for TBI.