Article | Published:

Rapid production of new oligodendrocytes is required in the earliest stages of motor-skill learning

Nature Neuroscience volume 19, pages 12101217 (2016) | Download Citation

Abstract

We identified mRNA encoding the ecto-enzyme Enpp6 as a marker of newly forming oligodendrocytes, and used Enpp6 in situ hybridization to track oligodendrocyte differentiation in adult mice as they learned a motor skill (running on a wheel with unevenly spaced rungs). Within just 2.5 h of exposure to the complex wheel, production of Enpp6-expressing immature oligodendrocytes was accelerated in subcortical white matter; within 4 h, it was accelerated in motor cortex. Conditional deletion of myelin regulatory factor (Myrf) in oligodendrocyte precursors blocked formation of new Enpp6+ oligodendrocytes and impaired learning within the same 2−3 h time frame. This very early requirement for oligodendrocytes suggests a direct and active role in learning, closely linked to synaptic strengthening. Running performance of normal mice continued to improve over the following week accompanied by secondary waves of oligodendrocyte precursor proliferation and differentiation. We concluded that new oligodendrocytes contribute to both early and late stages of motor skill learning.

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Acknowledgements

We thank our colleagues at University College London, especially S. Jolly, U. Grazini and L. Magno, for advice and reagents, and M. Grist and U. Dennehy for technical help. We thank M. Wegner (University of Erlangen, Germany) for the Sox10 antibody. This work was supported by the European Research Council (grant agreement 293544 to W.D.R.), the Wellcome Trust (100269/Z/12/Z to W.D.R.) and the Biotechnology and Biological Sciences Research Council (BB/L003236/1 to H.L.). L.X. was supported by the National Natural Science Foundation of China (grant 31471013). Pdgfra-CreERT2 mice can be obtained through http://www.e-lucid.com/ with a material transfer agreement. Myrf loxP mice are available from Jackson Labs, strain 010607.

Author information

Author notes

    • David Ohayon

    Present address: Centre de Biologie du Développement, University Paul Sabatier, Toulouse, France.

    • Lin Xiao
    •  & David Ohayon

    These authors contributed equally to this work.

    • Huiliang Li
    •  & William D Richardson

    These authors jointly directed this work.

Affiliations

  1. Wolfson Institute for Biomedical Research, University College London, London, UK.

    • Lin Xiao
    • , David Ohayon
    • , Ian A McKenzie
    • , Alexander Sinclair-Wilson
    • , Jordan L Wright
    • , Alexander D Fudge
    • , Huiliang Li
    •  & William D Richardson
  2. Institute of Neuroscience, Second Military Medical University, Shanghai, China.

    • Lin Xiao
  3. Jungers Center for Neurosciences Research, Oregon Health and Science University, Portland, Oregon, USA.

    • Ben Emery

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Contributions

W.D.R. formed the hypotheses and obtained funding. I.A.M. adopted and developed the complex wheel test. B.E. provided MyrfloxP mice, advice and suggestions. W.D.R., I.A.M. and D.O. designed the experiments in Figure 1 and Supplementary Figure 1; D.O. and I.A.M. performed those experiments and DO analyzed the data. W.D.R., H.L. and L.X. designed all the other experiments and L.X. performed them, with assistance from A.S.-W., J.L.W. and A.D.F. H.L. identified Enpp6 and A.F. performed preliminary characterization. H.L. and W.D.R. supervised the work. W.D.R. wrote the paper with input from H.L., L.X. and B.E.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to William D Richardson.

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    Supplementary Figures 1–4 and Supplementary Table 1

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DOI

https://doi.org/10.1038/nn.4351

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