Sex-related factors influence expression of mood-related genes in the basolateral amygdala differentially depending on age and stress exposure

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.

Sex-Specific Effects of Stress on Mood-Related Gene Expression

“…We used the extensively validated model known as UCMS to induce an elevated depressive-/anxiety-like state in the mice [28, 38, 39]. UCMS elicits a state similar to that of MDD in humans.…”

Sex differences: Transcriptional signatures of stress exposure in male and female brains

“…Parvalbumin mRNA levels in the PFC are upregulated in females, but are unchanged in males . Other genes related to the GABAergic pathway such as Gad67 , Gad65 , and somatostatin ( Sst ) in the BLA are also strongly influenced by the interaction of stress exposure and sex . For instance, using four core genotypes (FCG) mice, Puralewski et al were able to dissect the role of chromosomal sex, gonadal sex, and circulating testosterone in shaping the stress response at the level of GABAergic circuitry.…”

“…Other genes related to the GABAergic pathway such as Gad67 , Gad65 , and somatostatin ( Sst ) in the BLA are also strongly influenced by the interaction of stress exposure and sex . For instance, using four core genotypes (FCG) mice, Puralewski et al were able to dissect the role of chromosomal sex, gonadal sex, and circulating testosterone in shaping the stress response at the level of GABAergic circuitry. Despite not being able to directly compare controls and stressed animals, they identified some GABA‐related genes, such as Sst , that do not show expression differences between sexes (either gonadal or chromosomal) at baseline but do after chronic mild stress.…”

“…101 However, not surprisingly, not every work published agrees. 136,137 Other regions involved in the stress circuitry such as the CeA and basolateral amygdala (BLA), as well as the bed nucleus of the stria terminalis (BNST) show the different extent of sex-specific regulation of such genes and others, including the Bdnf cascade [137][138][139][140] (Tables 3 and 4).…”

What Does Sex Have to Do with It? The Role of Sex as a Biological Variable in the Development of Posttraumatic Stress Disorder

“…Recent evidence in clinical and preclinical studies have also pointed to sex differences in hypothalamic pituitary adrenal (HPA) axis and autonomic response to threat, contributing to risk for PTSD and post-traumatic stress symptoms in females compared to males [27•, 28••, 29••, 30]. …”