Original Article | Published:

Stress and glucocorticoids promote oligodendrogenesis in the adult hippocampus

Molecular Psychiatry volume 19, pages 12751283 (2014) | Download Citation

Abstract

Stress can exert long-lasting changes on the brain that contribute to vulnerability to mental illness, yet mechanisms underlying this long-term vulnerability are not well understood. We hypothesized that stress may alter the production of oligodendrocytes in the adult brain, providing a cellular and structural basis for stress-related disorders. We found that immobilization stress decreased neurogenesis and increased oligodendrogenesis in the dentate gyrus (DG) of the adult rat hippocampus and that injections of the rat glucocorticoid stress hormone corticosterone (cort) were sufficient to replicate this effect. The DG contains a unique population of multipotent neural stem cells (NSCs) that give rise to adult newborn neurons, but oligodendrogenic potential has not been demonstrated in vivo. We used a nestin-CreER/YFP transgenic mouse line for lineage tracing and found that cort induces oligodendrogenesis from nestin-expressing NSCs in vivo. Using hippocampal NSCs cultured in vitro, we further showed that exposure to cort induced a pro-oligodendrogenic transcriptional program and resulted in an increase in oligodendrogenesis and decrease in neurogenesis, which was prevented by genetic blockade of glucocorticoid receptor (GR). Together, these results suggest a novel model in which stress may alter hippocampal function by promoting oligodendrogenesis, thereby altering the cellular composition and white matter structure.

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Acknowledgements

We thank David V. Schaffer for feedback; Charles Stiles and David Rowitch for feedback and Olig1 antibody; Amelia Eisch for the Nestin-Cre ERT2/RosaYFP mice; and Ashmi Ullal and Jennifer Shih for research assistance. SC, EDK and DC were supported by CIRM pre-doctoral fellowships; EDK was supported by a DoD NDSEG fellowship. ARF was supported by a NSF fellowship. CM was supported by a NRSA postdoctoral fellowship (1F32AG029733-01A1). This work was supported by NIMH BRAINS (R01 MH087495), Berkeley Stem Cell Center Seed Grant, Hellman Family Foundation and NARSAD awards to DK.

Author information

Author notes

    • S Chetty

    Current address: Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Cambridge, MA, USA.

    • S Chetty
    •  & A R Friedman

    These authors contributed equally to this work.

    • E D Kirby

    Current address: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.

    • C Mirescu

    Current address: Discovery and Preclinical Sciences, Merck Research Labs, Kenilworth, NJ, USA.

    • D Krupik

    Current address: Emergency Department, Meyer Children's Hospital, Rambam Health Care Campus, Haifa, Israel.

    • A Nicholas

    Current address: School of Biological Sciences, University of California, Irvine, CA, USA.

Affiliations

  1. Helen Wills Neuroscience Institute, University of California,Berkeley, CA, USA

    • S Chetty
    • , E D Kirby
    • , A Krishnamurthy
    • , M-K Tsai
    • , A T Wong
    • , D D Francis
    •  & D Kaufer
  2. Department of Integrative Biology, University of California, Berkeley, CA, USA

    • A R Friedman
    • , K Taravosh-Lahn
    • , C Mirescu
    • , D Krupik
    • , A Nicholas
    • , A C Geraghty
    •  & D Kaufer
  3. Institute for Pediatric Regenerative Medicine, University of California, Davis, School of Medicine and Shriners Hospital, Sacramento, CA, USA

    • F Guo
    •  & D Pleasure
  4. School of Public Health, University of California, Berkeley, CA, USA

    • D Krupik
    •  & D D Francis
  5. Department of Molecular and Cell Biology, University of California, Berkeley, CA, USA

    • D Covarrubias
  6. Department of Biological Sciences, Stanford University, Stanford, CA, USA

    • R M Sapolsky
  7. Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA

    • R M Sapolsky
  8. Department of Neurosurgery, Stanford University, Stanford, CA, USA

    • T D Palmer

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The authors declare no conflict of interest.

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Correspondence to D Kaufer.

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DOI

https://doi.org/10.1038/mp.2013.190

Supplementary Information accompanies the paper on the Molecular Psychiatry website (http://www.nature.com/mp)

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