Biological mechanism of sex differences in mental rotation: Evidence from multimodal MRI, transcriptomic and receptor/transporter data

Sex differences in mental rotation are a well-documented phenomenon in cognitive research, with implications for the differing prevalence of neuropsychiatric disorders such as autism spectrum disorder (ASD), Alzheimer's disease (AD) and major depressive disorder (MDD) between the sexes. Despite extensive documentation, the biological mechanism underpinning these differences remain elusive. This study aimed to elucidate neural, genetic, and molecular bases of these disparities in mental rotation by integrating data from multimodal magnetic resonance imaging (MRI), transcriptomic and receptor/transporter. We first calculated the dynamic regional homogeneity (dReHo), gray matter volume (GMV) and fractional anisotropy (FA) in voxel-wise manner and parceled them into 246 brain regions based on Brainnetome Atlas. Subsequent analyses involved Pearson Correlations to examine the association between mental rotation performance and dReHo/GMV/FA and two-sample t-tests to delineate gender differences in these indices. Based on the above results, further mediation analysis was conducted to explore the relationship between sex, brain biomarkers and mental rotation. In addition, transcriptome-neuroimaging association analysis and correlation analysis between brain biomarkers and neurotransmitter receptor/transporter distribution were also performed to uncover genetic and molecular mechanisms contributing to the observed sex differences in mental rotation. We found correlations between mental rotation performance and dReHo, GMV and FA of the inferior parietal lobule (IPL) and superior temporal gyrus (STG) and sex effects on these brain biomarkers. Notably, the dReHo of the left IPL mediated the relationship between sex and mental rotation. Further correlation analysis revealed that the proton-coupled oligopeptide transporter PEPT2 (SLC15A2) and interleukin 17 receptor D (IL17RD) were associated with sex-related t-statistic maps and mental rotation-related r-statistic maps of dReHo. Moreover, γ-aminobutyric acid subtype A (GABA_A) receptor availability was correlated with the r-statistic of dReHo, while norepinephrine transporter (NET) availability was correlated with its t-statistic. Serial mediation models revealed the indirect effect of these genes on the r-statistic maps through the transporter/receptor and t-statistic maps. Our findings provide novel insights into the biological mechanism underlying sex differences in mental rotation, identifying potential biomarkers for cognitive impairment and explaining variations in prevalence of certain mental disorders between the sexes. These results highlight the necessity of considering sex in research on mental health disorders.