Abstract
BackgroundWomen are twice as likely to be diagnosed with major depressive disorder (MDD) compared to men, but the molecular mechanisms underlying this sex difference are unclear. Previous studies in the human postmortem brain suggest dysfunction in basolateral amygdala (BLA) inhibitory gamma-aminobutyric acid (GABA) signaling and brain-derived neurotrophic factor (BDNF) function, specifically in females with MDD.MethodsWe investigated the effects of sex chromosome complement, developmental gonadal sex, and circulating testosterone on expression of 3 GABA-related and 2 BDNF-related genes in the BLA using three cohorts of four core genotypes (FCG) mice. Cohort 1 included gonadally intact pre-pubertal FCG mice; results were analyzed using two-way ANOVA (sex chromosome complement-by-gonadal sex). We examined the same genes under adult non-stressed (cohort 2) and chronically stressed conditions (cohort 3). The results for cohorts 2 and 3 were analyzed by three-way ANOVA (sex chromosome complement-by-gonadal sex-by-hormone). The use of heatmaps and Spearman correlation of BLA gene expression and anxiety-like behavior provides a global interpretation of gene expression patterns.ResultsIn weanlings, we found an effect of sex chromosome complement, with lower expression of GABA/BDNF-related genes in XY mice. Most of these effects did not persist into adulthood, although a number of interesting interactions between organizational and activational effects of hormones emerged. In our adult cohorts, we found that testosterone had different effects depending on stress conditions and/or gonadal sex. Notably, in our chronically stressed adults, we found that the BLA pattern of gene expression for the GABA-related gene, somatostatin (Sst), matched the anxiety-like behavior pattern (i.e., lower Sst and higher anxiety-like behavior in XY mice, while testosterone increased Sst and decreased anxiety-like behavior). Additionally, increased Sst gene expression was correlated with decreased anxiety-like behavior.ConclusionsSex chromosome complement is an important factor modulating expression of mood-related genes during pre-pubertal development. The observed sex differences under chronically stressed conditions suggest that different molecular profiles may characterize male and female MDD. Our findings here for Sst are especially interesting, and suggest an underlying XY vulnerability that is typically compensated for by circulating testosterone in “normal” males. Without testosterone, women may have lower SST expression in the amygdala, resulting in increased MDD vulnerability.
Highlights
Women are twice as likely to be diagnosed with major depressive disorder (MDD) compared to men, but the molecular mechanisms underlying this sex difference are unclear
In our chronically stressed adults, we found that the basolateral amygdala (BLA) pattern of gene expression for the gamma-aminobutyric acid (GABA)-related gene, somatostatin (Sst), matched the anxiety-like behavior pattern
Intact four core genotypes (FCG) mice (XXF, XXSry males (XXM), XY− females (XYF), XY−Sry males (XYM)) were sacrificed at the time of weaning (P21, Fig. 1a); this timepoint was selected to precede the onset of puberty
Summary
Women are twice as likely to be diagnosed with major depressive disorder (MDD) compared to men, but the molecular mechanisms underlying this sex difference are unclear. Major depressive disorder (MDD) is a severe and commonly chronic illness characterized by altered mood regulation that is often accompanied by other psychophysiological changes [1]. Women are more likely to have hyperphagia, hypersomnia, a seasonal effect on mood, and a comorbid anxiety disorder along with their depression [8].
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