title: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
authors.forename: Georgia E
authors.initials: GE
authors.lastname: Hodes
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
authors.forename: Madeline L
authors.initials: ML
authors.lastname: Pfau
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
authors.forename: Immanuel
authors.initials: I
authors.lastname: Purushothaman
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
authors.forename: H Francisca
authors.initials: HF
authors.lastname: Ahn
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
authors.forename: Sam A
authors.identifier: http://orcid.org/0000-0002-2104-2272
authors.initials: SA
authors.lastname: Golden
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
authors.forename: Daniel J
authors.identifier: http://orcid.org/0000-0002-6303-5134
authors.initials: DJ
authors.lastname: Christoffel
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
authors.forename: Jane
authors.initials: J
authors.lastname: Magida
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, Department of Science for Health Promotion and Mother and Child Care, University of Palermo, 90127 Palermo, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Brancato
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, Laboratory of Behavioral Neuroendocrinology, University of Tsukuba, Tsukuba, Ibaraki 305-8577, Japan.
authors.forename: Aki
authors.initials: A
authors.lastname: Takahashi
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
authors.forename: Meghan E
authors.identifier: http://orcid.org/0000-0002-3185-7459
authors.initials: ME
authors.lastname: Flanigan
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
authors.forename: Caroline
authors.identifier: http://orcid.org/0000-0001-8202-7378
authors.initials: C
authors.lastname: Ménard
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
authors.forename: Hossein
authors.initials: H
authors.lastname: Aleyasin
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
authors.forename: Ja Wook
authors.initials: JW
authors.lastname: Koo
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
authors.forename: Zachary S
authors.identifier: http://orcid.org/0000-0002-3152-9287
authors.initials: ZS
authors.lastname: Lorsch
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
authors.forename: Jian
authors.identifier: http://orcid.org/0000-0002-1177-9377
authors.initials: J
authors.lastname: Feng
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
authors.forename: Mitra
authors.initials: M
authors.lastname: Heshmati
authors.affiliation: Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
authors.forename: Minghui
authors.initials: M
authors.lastname: Wang
authors.affiliation: McGill Group for Suicide Studies, Douglas Mental Health University Institute, Department of Psychiatry, Montreal, Quebec H4H 1R3, Canada.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Turecki
authors.affiliation: Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, and.
authors.forename: Rachel
authors.initials: R
authors.lastname: Neve
authors.affiliation: Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
authors.forename: Li
authors.initials: L
authors.lastname: Shen
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
authors.forename: Eric J
authors.identifier: http://orcid.org/0000-0002-7905-2000
authors.initials: EJ
authors.lastname: Nestler
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, scott.russo@mssm.edu.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Russo
mesh_terms: D000818:Animals; D001007:Anxiety / Q000235:genetics / Q000523:psychology; D002908:Chronic Disease; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000096:biosynthesis / Q000235:genetics; D000090205:DNA Methyltransferase 3A; D005247:Feeding Behavior; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D055879:Gene Knock-In Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity; D009714:Nucleus Accumbens / Q000503:physiopathology*; D012094:Repression, Psychology; D055500:Resilience, Psychological; D012727:Sex Characteristics; D013315:Stress, Psychological / Q000235:genetics* / Q000523:psychology*; D013550:Swimming / Q000523:psychology; D059467:Transcriptome / Q000235:genetics*
chemical_list: C000717967:DNMT3A protein, human; C000715535:Dnmt3a protein, mouse; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A
keywords: behavior; depression; epigenetics; nucleus accumbens; sex differences; stress