• A Corrigendum to this article was published on 10 April 2018

This article has been updated

Abstract

Major depressive disorder (MDD) is a leading cause of disease burden worldwide. While the incidence, symptoms and treatment of MDD all point toward major sex differences, the molecular mechanisms underlying this sexual dimorphism remain largely unknown. Here, combining differential expression and gene coexpression network analyses, we provide a comprehensive characterization of male and female transcriptional profiles associated with MDD across six brain regions. We overlap our human profiles with those from a mouse model, chronic variable stress, and capitalize on converging pathways to define molecular and physiological mechanisms underlying the expression of stress susceptibility in males and females. Our results show a major rearrangement of transcriptional patterns in MDD, with limited overlap between males and females, an effect seen in both depressed humans and stressed mice. We identify key regulators of sex-specific gene networks underlying MDD and confirm their sex-specific impact as mediators of stress susceptibility. For example, downregulation of the female-specific hub gene Dusp6 in mouse prefrontal cortex mimicked stress susceptibility in females, but not males, by increasing ERK signaling and pyramidal neuron excitability. Such Dusp6 downregulation also recapitulated the transcriptional remodeling that occurs in prefrontal cortex of depressed females. Together our findings reveal marked sexual dimorphism at the transcriptional level in MDD and highlight the importance of studying sex-specific treatments for this disorder.

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Change history

  • 07 March 2018

    In the version of this article initially published, the last name of author Andrew Kasarskis was misspelled as "Kazarskis". The error has been corrected in the PDF and HTML versions of the article.

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Acknowledgements

We thank V. Vialou for his in vivo expertise, K. Gleason at The University of Texas Southwestern Medical Center and Josée Prud'homme and Danielle Cecyre at the Douglas Bell-Canada Brain Bank for their help with procuring human brain samples, and O. Jabado for his expert advice on RNA-seq. This work was funded by National Institute of Mental Health (NIMH) grants P50MH096890 and R01MH051399 and by the Hope for Depression Research Foundation (HDRF) to E.J.N. B.L. was supported by a Frederick Banting and Charles Best postdoctoral fellowship from the Canadian Institute for Health Research (CIHR) and now by a Research Chair in Molecular Neurobiology of Mood Disorders and a Fond de Recherche du Québec-Santé (FRQ-S) Junior 1 award.

Author information

Author notes

    • Bin Zhang
    • , Li Shen
    •  & Eric J Nestler

    These authors contributed equally to this work.

Affiliations

  1. Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

    • Benoit Labonté
    • , Olivia Engmann
    • , Immanuel Purushothaman
    • , Caroline Menard
    • , Joseph R Scarpa
    • , Gregory Moy
    • , Yong-Hwee E Loh
    • , Michael Cahill
    • , Zachary S Lorsch
    • , Peter J Hamilton
    • , Erin S Calipari
    • , Georgia E Hodes
    • , Orna Issler
    • , Hope Kronman
    • , Madeline Pfau
    • , Aleksandar L J Obradovic
    • , Scott Russo
    • , Li Shen
    •  & Eric J Nestler
  2. Department of Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

    • Junshi Wang
    •  & Yan Dong
  3. Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.

    • Chunfeng Tan
    •  & Carol Tamminga
  4. Department of Genetics and Genomic Sciences and Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

    • Joseph R Scarpa
    • , Andrew Kasarskis
    •  & Bin Zhang
  5. Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

    • Rachael L Neve
  6. Department of Psychiatry, McGill University, Montreal, Québec, Canada.

    • Naguib Mechawar
    •  & Gustavo Turecki
  7. McGill Group for Suicide Studies, Douglas Mental Health University Institute, McGill University, Montreal, Québec, Canada.

    • Naguib Mechawar
    •  & Gustavo Turecki

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Contributions

B.L. and E.J.N. conceived the project, designed the experiments and wrote the manuscript. B.L. also generated and analyzed all of the data. B.Z. and L.S. oversaw all bioinformatics analyses. A.K., Y.D., C. Tamminga, S.R., N.M. and G.T. also contributed to the study design. O.E., G.M., Z.S.L., P.J.H., E.S.C., O.I., H.K. and A.L.J.O. contributed to the cloning, in vivo surgeries and behavioral experiments. G.E.H. M.P., G.M. and A.L.J.O. contributed to the behavioral experiments. C.M., C. Tan, G.M. and M.C. helped with the protein and IHC experiments. J.W. and Y.D. generated the electrophysiological data. I.P., J.R.S., Z.S.L. and Y.-H.E.L. contributed to the differential expression and network analyses. R.L.N. packaged the viruses. C. Tamminga, N.M. and G.T. contributed brain samples. All authors contributed to the preparation of the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Eric J Nestler.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–10 and Supplementary Tables 1, 5, 6 and 12.

  2. 2.

    Life Sciences Reporting Checklist

Excel files

  1. 1.

    Supplementary Table 2

    List of genes differentially expressed across brain regions in MDD versus control males.

  2. 2.

    Supplementary Table 3

    List of genes differentially expressed across brain regions in MDD versus control females.

  3. 3.

    Supplementary Table 4

    NanoString validation data in males and females.

  4. 4.

    Supplementary Table 7

    Statistics from the inter-region overlap analysis (Fisher's exact test) in human males with and without MDD.

  5. 5.

    Supplementary Table 8

    Statistics from the inter-region overlap analysis (Fisher's exact test) in human females with and without MDD.

  6. 6.

    Supplementary Table 9

    Summary statistics from Fisher's exact test overlap analyses.

  7. 7.

    Supplementary Table 10

    Summary of the gene ontology overlap analyses performed in males and females.

  8. 8.

    Supplementary Table 11

    List of genes differentially expressed between males and females at baseline (controls only).

  9. 9.

    Supplementary Table 13

    Summary table of the gene network analysis results in male MDD.

  10. 10.

    Supplementary Table 14

    Summary table of the gene network analysis results in female MDD.

  11. 11.

    Supplementary Table 15

    Male MDD preservation analysis summary.

  12. 12.

    Supplementary Table 16

    Female MDD preservation analysis summary.

  13. 13.

    Supplementary Table 17

    List of genes differentially expressed across brain regions in stressed versus control males.

  14. 14.

    Supplementary Table 18

    List of genes differentially expressed across brain regions in stressed versus control females.

  15. 15.

    Supplementary Table 19

    Inter-species overlap analysis summary for gene differentially expressed in males and females.

  16. 16.

    Supplementary Table 20

    Inter-species overlap analysis summary for gene ontology terms enriched in males and females with MDD or stress.

  17. 17.

    Supplementary Table 21

    Gene ontology analysis summary for terms associated with MDD in humans (males and females) and stress in mice (males and females).

  18. 18.

    Supplementary Table 22

    Summary table for the correlation values of the top three covariates' principal components.

  19. 19.

    Supplementary Table 23

    List of gene differentially expressed across brain regions in males and females with MDD from the publicly available microarray validation cohort.

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DOI

https://doi.org/10.1038/nm.4386

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