Abstract

BackgroundStudies on major depressive and anxiety disorders suggest dysfunctions in brain corticolimbic circuits, including altered gamma-aminobutyric acid (GABA) and modulatory (serotonin and dopamine) neurotransmission. Interestingly, sexual dimorphisms in GABA, serotonin, and dopamine systems are also reported. Understanding the mechanisms behind these sexual dimorphisms may help unravel the biological bases of the heightened female vulnerability to mood disorders. Here, we investigate the contribution of sex-related factors (sex chromosome complement, developmental gonadal sex, or adult circulating hormones) to frontal cortex expression of selected GABA-, serotonin-, and dopamine-related genes.MethodsAs gonadal sex is determined by sex chromosome complement, the role of sex chromosomes cannot be investigated individually in humans. Therefore, we used the Four Core Genotypes (FCG) mouse model, in which sex chromosome complement and gonadal sex are artificially decoupled, to examine the expression of 13 GABA-related genes, 6 serotonin- and dopamine-related genes, and 8 associated signal transduction genes under chronic stress conditions. Results were analyzed by three-way ANOVA (sex chromosome complement × gonadal sex × circulating testosterone). A global perspective of gene expression changes was provided by heatmap representation and gene co-expression networks to identify patterns of transcriptional activities related to each main factor.ResultsWe show that under chronic stress conditions, sex chromosome complement influenced GABA/serotonin/dopamine-related gene expression in the frontal cortex, with XY mice consistently having lower gene expression compared to XX mice. Gonadal sex and circulating testosterone exhibited less pronounced, more complex, and variable control over gene expression. Across factors, male conditions were associated with a tightly co-expressed set of signal transduction genes.ConclusionsUnder chronic stress conditions, sex-related factors differentially influence expression of genes linked to mood regulation in the frontal cortex. The main factor influencing expression of GABA-, serotonin-, and dopamine-related genes was sex chromosome complement, with an unexpected pro-disease effect in XY mice relative to XX mice. This effect was partially opposed by gonadal sex and circulating testosterone, although all three factors influenced signal transduction pathways in males. Since GABA, serotonin, and dopamine changes are also observed in other psychiatric and neurodegenerative disorders, these findings have broader implications for the understanding of sexual dimorphism in adult psychopathology.

Highlights

  • Studies on major depressive and anxiety disorders suggest dysfunctions in brain corticolimbic circuits, including altered gamma-aminobutyric acid (GABA) and modulatory neurotransmission

  • We recently examined expression of Sst, and of the GABAsynthesizing enzymes glutamate decarboxylase 67 (Gad67) and Gad65, in the frontal cortex of Four Core Genotypes (FCG) mice in order to independently examine the contribution of developmental gonadal sex, adult circulating hormones, and X/Y sex chromosome complement on expression of those genes under rodent conditions that are homologous to a human depressed state, i.e., after exposure to unpredictable chronic mild stress

  • Contrary to our prediction based on increased Major depressive disorder (MDD) prevalence in women, regardless of gonadal and adult hormonal status, FCG XY mice had lower expression of these three genes compared to XX mice, with concomitant elevated anxiety-like behavior; interestingly, adult testosterone treatment decreased anxiety-like behaviors, but did not affect Sst, Gad67, or Gad65 gene expression [13]

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Summary

Introduction

Studies on major depressive and anxiety disorders suggest dysfunctions in brain corticolimbic circuits, including altered gamma-aminobutyric acid (GABA) and modulatory (serotonin and dopamine) neurotransmission. Contrary to our prediction based on increased MDD prevalence in women, regardless of gonadal and adult hormonal status, FCG XY mice (i.e., genetic males that lack the sex-determining gene Sry on the Y chromosome; see ‘Methods’) had lower expression of these three genes compared to XX mice, with concomitant elevated anxiety-like behavior; interestingly, adult testosterone treatment decreased anxiety-like behaviors, but did not affect Sst, Gad, or Gad gene expression [13] Together, these studies in humans and mice support a general hypothesis of GABA dysfunction in MDD and point to sex chromosome complement as a potential modulator

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