Abstract
Premenstrual dysphoric disorder (PMDD) affects over 5% of women, with symptoms similar to anxiety and major depression, and is associated with differential sensitivity to circulating ovarian hormones. Little is known about the genetic and epigenetic factors that increase the risk to develop PMDD. We report that 17β-estradiol (E2) affects the behavior and the epigenome in a mouse model carrying a single-nucleotide polymorphism of the brain-derived neurotrophic factor gene (BDNF Val66Met), in a way that recapitulates the hallmarks of PMDD. Ovariectomized mice heterozygous for the BDNF Met allele (Het-Met) and their matched wild-type (WT) mice were administered estradiol or vehicle in drinking water for 6 weeks. Using the open field and the splash test, we show that E2 add-back induces anxiety-like and depression-like behavior in Het-Met mice, but not in WT mice. RNA-seq of the ventral hippocampus (vHpc) highlights that E2-dependent gene expression is markedly different between WT mice and Het-Met mice. Through a comparative whole-genome RNA-seq analysis between mouse vHpc and lymphoblastoid cell line cultures from control women and women with PMDD, we discovered common epigenetic biomarkers that transcend species and cell types. Those genes include epigenetic modifiers of the ESC/E(Z) complex, an effector of response to ovarian steroids. Although the BDNF Met genotype intersects the behavioral and transcriptional traits of women with PMDD, we suggest that these similarities speak to the epigenetic factors by which ovarian steroids produce negative behavioral effects.
Highlights
Sex hormones and their neurosteroid metabolites contribute to the establishment of sex differences as well as the regulation of mental state [1, 2]
When orthologues of OVX heterozygous for the brain-derived neurotrophic factor (BDNF) Met allele (Het-Met) mice and premenstrual dysphoric disorder (PMDD) lymphoblastoid cell line (LCL) were compared to OVX WT mice and control LCLs, we identified 29 and 416 common genes under vehicle (Fig. 5a,i) and E2 (Fig. 5a,ii) treatment, respectively
We report that BDNF Het-Met female mice show a considerable degree of behavioral lability after non-invasive E2 add-back in OVX mice [29] when compared to OVX WT female mice
Summary
Sex hormones and their neurosteroid metabolites contribute to the establishment of sex differences as well as the regulation of mental state [1, 2]. Natural fluctuations in circulating estrogens across the menstrual cycle are associated with mood and cognitive changes. 3–8% of menstruating women meet diagnostic criteria for premenstrual dysphoric disorder (PMDD), a psychiatric condition that consists of a cluster of affective, behavioral, and somatic symptoms that recur monthly during the luteal phase of the menstrual cycle [3, 4]. The individual variability in the impact of ovarian hormones on brain and behavior depends on several contextual factors including age, environmental influences (e.g., exposure to stress), and genetic risk. Variation in the gene coding for brain-derived neurotrophic factor (BDNF) has been associated with estrogendependent hippocampal function, anxiety, and sex differences both in human and experimental models [5,6,7,8].
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