Abstract

Despite abundant expression of DNA methyltransferases (Dnmts) in brain, the regulation and behavioral role of DNA methylation remain poorly understood. We found that Dnmt3a expression was regulated in mouse nucleus accumbens (NAc) by chronic cocaine use and chronic social defeat stress. Moreover, NAc-specific manipulations that block DNA methylation potentiated cocaine reward and exerted antidepressant-like effects, whereas NAc-specific Dnmt3a overexpression attenuated cocaine reward and was pro-depressant. On a cellular level, we found that chronic cocaine use selectively increased thin dendritic spines on NAc neurons and that DNA methylation was both necessary and sufficient to mediate these effects. These data establish the importance of Dnmt3a in the NAc in regulating cellular and behavioral plasticity to emotional stimuli.

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Acknowledgements

We thank R. Jaenisch for the generous gift of the Dnmt3a plasmid and W.G. Janssen for animal perfusions. We also thank A.J. Robison for helpful discussions and comments on the manuscript. This work was supported by grants from the National Institute on Drug Abuse and National Institute of Mental Health.

Author information

Affiliations

  1. Fishberg Department of Neuroscience, Mount Sinai School of Medicine, New York, New York, USA.

    • Quincey LaPlant
    • , Vincent Vialou
    • , Herbert E Covington III
    • , Dani Dumitriu
    • , Jian Feng
    • , Brandon L Warren
    • , Ian Maze
    • , David M Dietz
    • , Emily L Watts
    • , Sergio D Iñiguez
    • , Ja Wook Koo
    • , Ezekiell Mouzon
    • , Yanhua Ren
    • , Yasmin L Hurd
    • , Ronald S Oosting
    • , John H Morrison
    •  & Eric J Nestler
  2. Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

    • Quincey LaPlant
    • , William Renthal
    • , Michele A Noonan
    •  & Amelia J Eisch
  3. Department of Psychology, Florida State University, Tallahassee, Florida, USA.

    • Brandon L Warren
    • , Sergio D Iñiguez
    •  & Carlos A Bolaños
  4. Department of Biomedical Sciences, Florida State University, Tallahassee, Florida, USA.

    • Fiona Hollis
    • , Hui Wang
    •  & Mohamed Kabbaj
  5. Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

    • Guanghua Xiao
  6. Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

    • Rachael L Neve
  7. Department of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.

    • Ronald S Oosting
  8. Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.

    • Gouping Fan

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Contributions

Q.L. and E.J.N. were responsible for the overall study design. Q.L., J.F., I.M. and J.W.K. designed and conducted the RNA and ChIP experiments and analyzed the results. Q.L., V.V., H.E.C., I.M., B.W. and R.S.O. designed and performed the CPP, locomotor sensitization, and learning and memory behavioral experiments. Q.L., V.V., R.S.O., B.W., S.D.I. and C.A.B. designed and conducted the submaximal defeat, forced swim and social defeat experiments. Q.L., D.D., D.M.D., J.H.M., B.W. and E.L.W. designed and conducted the dendritic spine analysis. Q.L. carried out confocal imaging of dendritic spines, D.D. performed single-cell filling, V.V., H.E.C., Q.L. and B.W. performed stereotaxic surgeries, W.R. and Q.L. performed HSV cloning of Dnmt3a, F.H., H.W., M.A.N., Y.R., A.J.E., M.K. and Y.L.H. designed and performed the self-administration experiments, R.L.N. prepared new HSV vectors and performed quality-control experiments on all of the HSV vectors, E.M. prepared new AAV vectors and performed quality-control experiments on all of the AAV vectors, Q.X. performed ChIP-chip statistical analyses, G.F. provided loxP-flanked Dnmt mice and Q.L. and E.J.N. wrote the paper with the help of the other authors.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Eric J Nestler.

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DOI

https://doi.org/10.1038/nn.2619

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