Sex and estrogen receptor β have modest effects on gene expression in the mouse brain posterior cortex

Introduction: Sex differences in brain cortical function affect cognition, behavior, and susceptibility to neural diseases, but the molecular basis of sexual dimorphism in cortical function is still largely unknown. Estrogen and estrogen receptors (ERs), specifically ER{beta}, the most abundant ER in the cortex, may play a role in determining sex differences in gene expression, which could underlie functional sex differences. However, further investigation is needed to address brain region specificity of the effects of sex and ER{beta} on gene expression. The goal of this study was to investigate sex differences in gene expression in the mouse posterior cortex, where sex differences in transcription have never been examined, and to determine how genetic ablation of ER{beta} affects transcription. Methods: In this study, we performed unbiased transcriptomics on RNA from the posterior cortex of adult wild-type and ER{beta} knockout mice (n=4/sex/genotype). We used unbiased clustering to analyze whole-transcriptome changes between the groups. We also performed differential expression analysis on the data using DESeq2 to identify specific changes in gene expression. Results: We found only 27 significantly differentially expressed genes (DEGs) in wild-type (WT) males vs females, of which 17 were autosomal genes. Interestingly, in ER{beta}KO males vs females all the autosomal DEGs were lost. Gene Ontology analysis of the subset of DEGs with sex differences only in the WT cortex revealed a significant enrichment of genes annotated with the function cation channel activity. Moreover, within each sex we found only a few DEGs in ER{beta}KO vs WT mice (8 and 5 in males and females, respectively). Conclusions: Overall, our results suggest that in the adult mouse posterior cortex there are surprisingly few sex differences in gene expression, and those that exist are mainly related to cation channel activity. Additionally, they indicate that brain region-specific functional effects of ER{beta} may be largely post-transcriptional.