A human-mouse conserved sex bias in amygdala gene expression related to circadian clock and energy metabolism

BACKGROUND: Major depression affects twice as many women as men, but the underlying molecular mechanisms responsible for the heightened female vulnerability are not known. The amygdala, composed of heterogeneous subnuclei, participates in multiple functional circuits regulating emotional responses to stress. We hypothesized that sex differences in molecular structure may contribute to differential mood regulation and disease vulnerability. FINDINGS: Using gene arrays followed by quantitative PCR validation, we compared the transcriptome profiles between sexes in human and mouse amygdala. We now report sexually dimorphic features of transcriptomes in the basolateral nucleus of the amygdala, and these features are highly conserved across species. A functional analysis of differential gene expression showed that mitochondrial-related gene groups were identified as the top biological pathways associated with sexual dimorphism in both species. CONCLUSIONS: These results suggest that the basolateral amygdala is a sexually dimorphic structure, featuring a regulatory cascade of mitochondrial function and circadian rhythm, potentially linked through sirtuins and hormone nuclear receptors. Hence, baseline differences in amygdalar circadian regulation of cellular metabolism may contribute to sex-related differences in mood regulation and vulnerability to major depression.