Dataset Information

Sex Differences in Nucleus Accumbens Transcriptome Profiles Associated with Susceptibility versus Resilience to Subchronic Variable Stress

ABSTRACT: Depression and anxiety disorders are more prevalent in females, but the majority of research in animal models, the first step in finding new treatments, has focused predominantly on males. Here we report that exposure to subchronic variable stress (SCVS) induces depression-associated behaviors in female mice, whereas males are resilient as they do not develop these behavioral abnormalities. In concert with these different behavioral responses, transcriptional analysis of nucleus accumbens (NAc), a major brain reward region, by use of RNA sequencing (RNA-seq) revealed markedly different patterns of stress regulation of gene expression between the sexes. Among the genes displaying sex differences was DNA methyltransferase 3a (Dnmt3a), which shows a greater induction in females after SCVS. Interestingly, Dnmt3a expression levels were increased in the NAc of depressed humans, an effect seen in both males and females. Local overexpression of Dnmt3a in NAc rendered male mice more susceptible to SCVS, whereas Dnmt3a knock-out in this region rendered females more resilient, directly implicating this gene in stress responses. Associated with this enhanced resilience of female mice upon NAc knock-out of Dnmt3a was a partial shift of the NAc female transcriptome toward the male pattern after SCVS. These data indicate that males and females undergo different patterns of transcriptional regulation in response to stress and that a DNA methyltransferase in NAc contributes to sex differences in stress vulnerability.

ORGANISM(S): Mus musculus

PROVIDER: GSE85136 | GEO | 2016/08/04

SECONDARY ACCESSION(S): PRJNA336339

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Despite depression being one of the most prevalent and debilitating disorders worldwide, it has been difficult to understand its pathophysiology and to develop more effective treatments. Maladaptive transcriptional regulation within limbic neural circuits, including reward processing regions such as the nucleus accumbens (NAc), in response to chronic stress is thought to be a major contributor to the development of the syndrome. Epigenetic events?in particular, histone writers and erasers?that alter chromatin structure to regulate programs of gene expression have increasingly been associated with depression-related behavioral abnormalities in animal models and in depressed humans examined postmortem. However, very little is known about the ATP-dependent chromatin remodelers that control nucleosome positioning and the packing state of chromatin. Here we show that the ACF complex, part of the ISWI family of chromatin remodelers, is persistently and selectively upregulated in the NAc of mice that are susceptible to chronic social stress, as well as in the NAc of depressed human. We further establish that ACF induction is both necessary and sufficient for susceptibility to stress-induced depressive-like behaviors. Using ChIP-seq, we demonstrate that altered ACF binding after chronic stress is strongly correlated with altered nucleosome positioning, in particular, around the transcriptional start sites of affected genes. These alterations in ACF binding and nucleosome repositioning are associated with repressed expression of a subset of genes in animals that are susceptible to chronic stress. Together, these findings establish that active ATP-dependent chromatin remodeling by the ACF complex is a key regulator in the repression of genes that mediate susceptibility to social stress, and provide novel candidate targets for improved therapeutics of depression and other stress-related disorders. c57bl/6 mice underwent chronic social defeat stress (CSDS), and social interaction test was used to separate animals into control, susceptible and resilient groups. Nucleus accumbens (NAc) tissue was collected 48 hours after the last defeat session, and then Acf1, SNF2H ChIP-seq or H3 MNase-seq were performed based on the control, susceptible, and resilient groups. Three sequencing replicates were performed on each group.

Project description:Background: Major depressive disorder (MDD) is a recurring affective disorder that is two times more prevalent in females than males. Evidence supports immune system dysfunction as a major contributing factor to MDD, notably in a sexually dimorphic manner. Nuclear factor erythroid 2-related factor 2 (Nrf2), a regulator of antioxidant signaling during inflammation, is dysregulated in many chronic inflammatory disorders, however its role in depression and the associated sex differences have yet to be explored. Here we investigated the sex-specific antidepressant and immunomodulatory effects of the potent Nrf2 activator dimethyl fumarate (DMF), as well as the associated gene expression profiles. Methods: Male and female rats were treated with vehicle or DMF (25 mg/kg) while subjected to 8 weeks of chronic unpredictable stress. The effect of DMF treatment on stress-induced depression- and anxiety-like behaviours, as well as deficits in recognition and spatial learning and memory were then assessed. Hippocampal (HIP) microglial activation and alterations in gene transcripts were also evaluated. Results: DMF treatment during stress exposure had antidepressant effects in male but not female rats, with no anxiolytic effects in either sex. Recognition learning and memory and spatial learning and memory were impaired in chronically stressed males and females, respectively, however DMF treatment rescued these deficits. DMF treatment also prevented stress-induced HIP microglial activation in males. Conversely, females displayed no HIP microglial activation associated with stress exposure. Lastly, chronic stress elicited sex-specific alterations in HIP gene expression, many of which were normalized in animals treated with DMF. Of note, several differentially expressed genes in males were related to inflammatory or immune responses. Conclusions: Collectively, these findings support a greater role of immune processes in males than females in a rodent model of depression. This suggests that pharmacotherapies that target Nrf2 have the potential to be an effective sex-specific treatment for depression. Major depressive disorder is two times more prevalent in females than males. Further, immune system dysfunction has been shown to contribute to the development of depression, with previous studies consistently reporting chronic low-grade inflammation in depressed individuals. Not surprisingly, the immune system dysfunction associated with depression appears to be sex specific. As such, while anti-inflammatory drugs have shown antidepressant effects in preclinical studies, the sex differences in these effects are seldomly investigated. Thus, this study sought to determine the sex-specific antidepressant and immune modulatory effects of dimethyl fumarate (DMF) treatment. DMF is a drug that activates the protein nuclear factor erythroid 2-related factor 2 to initiate anti-inflammatory signaling pathways. Here, male and female rats were exposed to 8 weeks of chronic stress while receiving daily DMF treatment. Subsequently, their expression of depression- and anxiety-like behaviours, as well as learning and memory deficits were assessed. Changes in the levels of an inflammatory marker in the brain and alterations in gene expression were also evaluated. DMF treatment had antidepressant effects in male rats only but did not have anti-anxiety effects in either sex. The learning and memory deficits in both sexes were rescued with DMF treatment. Notably, chronic stress only increased inflammatory marker levels in male rats, which was prevented by DMF treatment. Additionally, DMF normalized several of the sex-specific gene alterations induced by chronic stress, with many of the male-specific genes relating to inflammatory processes. These data suggest that anti-inflammatory drugs may be an effective antidepressant treatment in males.

Dataset Information

Sex Differences in Nucleus Accumbens Transcriptome Profiles Associated with Susceptibility versus Resilience to Subchronic Variable Stress

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets