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

TitleSex Differences in Nucleus Accumbens Transcriptome Profiles Associated with Susceptibility versus Resilience to Subchronic Variable Stress.
Publication TypeJournal Article
Year of Publication2015
AuthorsHodes GE, Pfau ML, Purushothaman I, H Ahn F, Golden SA, Christoffel DJ, Magida J, Brancato A, Takahashi A, Flanigan ME, Ménard C, Aleyasin H, Koo JWook, Lorsch ZS, Feng J, Heshmati M, Wang M, Turecki G, Neve R, Zhang B, Shen L, Nestler EJ, Russo SJ
JournalJ Neurosci
Date Published2015 Dec 16
KeywordsAnimals, Anxiety, Chronic Disease, DNA (Cytosine-5-)-Methyltransferase, Feeding Behavior, Female, Gene Expression Regulation, Enzymologic, Gene Knock-In Techniques, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Motor Activity, Nucleus Accumbens, Repression, Psychology, Resilience, Psychological, Sex Characteristics, Stress, Psychological, Swimming, Transcriptome

UNLABELLED: 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.SIGNIFICANCE STATEMENT: Women have a higher incidence of depression than men. However, preclinical models, the first step in developing new diagnostics and therapeutics, have been performed mainly on male subjects. Using a stress-based animal model of depression that causes behavioral effects in females but not males, we demonstrate a sex-specific transcriptional profile in brain reward circuitry. This transcriptional profile can be altered by removal of an epigenetic mechanism, which normally suppresses DNA transcription, creating a hybrid male/female transcriptional pattern. Removal of this epigenetic mechanism also induces behavioral resilience to stress in females. These findings shed new light onto molecular factors controlling sex differences in stress response.

Alternate JournalJ. Neurosci.
PubMed ID26674863
PubMed Central IDPMC4679819
Grant ListR01 MH104559 / MH / NIMH NIH HHS / United States
R21 MH099562 / MH / NIMH NIH HHS / United States
T32 MH087004 / MH / NIMH NIH HHS / United States
P50 MH096890 / MH / NIMH NIH HHS / United States
R01 MH090264 / MH / NIMH NIH HHS / United States
P50MH096890 / MH / NIMH NIH HHS / United States
R21MH099562 / MH / NIMH NIH HHS / United States
R01MH090264 / MH / NIMH NIH HHS / United States