Abstract

β-catenin is a multi-functional protein that has an important role in the mature central nervous system; its dysfunction has been implicated in several neuropsychiatric disorders, including depression. Here we show that in mice β-catenin mediates pro-resilient and anxiolytic effects in the nucleus accumbens, a key brain reward region, an effect mediated by D2-type medium spiny neurons. Using genome-wide β-catenin enrichment mapping, we identify Dicer1—important in small RNA (for example, microRNA) biogenesis—as a β-catenin target gene that mediates resilience. Small RNA profiling after excising β-catenin from nucleus accumbens in the context of chronic stress reveals β-catenin-dependent microRNA regulation associated with resilience. Together, these findings establish β-catenin as a critical regulator in the development of behavioural resilience, activating a network that includes Dicer1 and downstream microRNAs. We thus present a foundation for the development of novel therapeutic targets to promote stress resilience.

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Accessions

Primary accessions

Gene Expression Omnibus

Data deposits

All sequencing data have been deposited into the Gene Expression Omnibus with accession numbers GSE61294 and GSE61295.

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Acknowledgements

We thank O. Jabado and M. Mahajan for support and S. Borkan for providing β-catenin constructs. This work was supported by grants from the National Institute of Mental Health and the Hope for Depression Research Foundation (HDRF).

Author information

Author notes

    • Caroline Dias
    •  & Jian Feng

    These authors contributed equally to this work.

    • Michelle S. Mazei-Robison
    • , Pamela Kennedy
    • , Vincent Vialou
    •  & Deveroux Ferguson

    Present addresses: Department of Physiology, Michigan State University, East Lansing, Michigan 48824, USA (M.S.M.-R.); Department of Psychology, UCLA College of Life Sciences, Los Angeles, California 90095, USA (P.K.); Institut National de la Santé et de la Recherche Médicale (INSERM) U1130; CNRS UMR8246; UPMC UM18, Neuroscience Paris Seine, 75005 Paris, France (V.V.); Department of Basic Medical Sciences, The University of Arizona College of Medicine-Phoenix, Arizona 85004, USA (D.F.).

Affiliations

  1. Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA

    • Caroline Dias
    • , Jian Feng
    • , Haosheng Sun
    • , Ning yi Shao
    • , Michelle S. Mazei-Robison
    • , Diane Damez-Werno
    • , Kimberly Scobie
    • , Rosemary Bagot
    • , Benoit LaBonté
    • , Efrain Ribeiro
    • , XiaoChuan Liu
    • , Pamela Kennedy
    • , Vincent Vialou
    • , Deveroux Ferguson
    • , Catherine Peña
    • , Erin S. Calipari
    • , Ja Wook Koo
    • , Ezekiell Mouzon
    • , Li Shen
    •  & Eric J. Nestler
  2. Department of Psychiatry, University of Texas Southwestern, Dallas, Texas 75390, USA

    • Subroto Ghose
    •  & Carol Tamminga
  3. Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA

    • Rachael Neve

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Contributions

C.D. and J.F. conceived the project, designed research, conducted experiments, interpreted the results, and wrote the manuscript; H.S., M.S.M.-R., D.D.-W., K.S., R.B., B.L., E.R., P.K., V.V., D.F., C.P., E.C., J.K. and E.M. conducted experiments; S.G., C.T. provided reagents and tools; R.N. conducted experiments and provided reagents; N.S., X.L. performed bioinformatic analysis; L.S. performed and supervised bioinformatic analysis; E.J.N. conceived the project, designed and supervised research, interpreted the results, and wrote the manuscript. All authors discussed the results and commented on the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Li Shen or Eric J. Nestler.

Extended data

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    This file contains Supplementary Tables 1-9 and Supplementary Notes.

Excel files

  1. 1.

    Supplementary Data 1

    β-catenin ChIP-seq dataset: contains peak lists from each of three conditions and three pair-wise differential peak lists.

  2. 2.

    Supplementary Data 2

    H3K4me3 and H4K16 ChIP-seq datasets: contains differential peak lists as compared to control.

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DOI

https://doi.org/10.1038/nature13976

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