Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Repetitive motor learning induces coordinated formation of clustered dendritic spines in vivo

Nature volume 483, pages 92–95 (2012)Cite this article

Subjects

Abstract

Many lines of evidence suggest that memory in the mammalian brain is stored with distinct spatiotemporal patterns1,2. Despite recent progresses in identifying neuronal populations involved in memory coding3,4,5, the synapse-level mechanism is still poorly understood. Computational models and electrophysiological data have shown that functional clustering of synapses along dendritic branches leads to nonlinear summation of synaptic inputs and greatly expands the computing power of a neural network6,7,8,9,10. However, whether neighbouring synapses are involved in encoding similar memory and how task-specific cortical networks develop during learning remain elusive. Using transcranial two-photon microscopy11, we followed apical dendrites of layer 5 pyramidal neurons in the motor cortex while mice practised novel forelimb skills. Here we show that a third of new dendritic spines (postsynaptic structures of most excitatory synapses) formed during the acquisition phase of learning emerge in clusters, and that most such clusters are neighbouring spine pairs. These clustered new spines are more likely to persist throughout prolonged learning sessions, and even long after training stops, than non-clustered counterparts. Moreover, formation of new spine clusters requires repetition of the same motor task, and the emergence of succedent new spine(s) accompanies the strengthening of the first new spine in the cluster. We also show that under control conditions new spines appear to avoid existing stable spines, rather than being uniformly added along dendrites. However, succedent new spines in clusters overcome such a spatial constraint and form in close vicinity to neighbouring stable spines. Our findings suggest that clustering of new synapses along dendrites is induced by repetitive activation of the cortical circuitry during learning, providing a structural basis for spatial coding of motor memory in the mammalian brain.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Acquisition of a novel motor skill induces formation of spine clusters.
Figure 2: Clustered new spines form over multiple training sessions of the same, but not different, motor tasks.
Figure 3: The spatial distribution of new spines along dendrites.

References

  1. Silva, A. J., Zhou, Y., Rogerson, T., Shobe, J. & Balaji, J. Molecular and cellular approaches to memory allocation in neural circuits. Science 326, 391–395 (2009)

    Article  CAS  Google Scholar 

  2. Aimone, J. B., Wiles, J. & Gage, F. H. Potential role for adult neurogenesis in the encoding of time in new memories. Nature Neurosci. 9, 723–727 (2006)

    Article  CAS  Google Scholar 

  3. Han, J. H. et al. Selective erasure of a fear memory. Science 323, 1492–1496 (2009)

    Article  ADS  CAS  Google Scholar 

  4. Komiyama, T. et al. Learning-related fine-scale specificity imaged in motor cortex circuits of behaving mice. Nature 464, 1182–1186 (2010)

    Article  ADS  CAS  Google Scholar 

  5. Kee, N., Teixeira, C. M., Wang, A. H. & Frankland, P. W. Preferential incorporation of adult-generated granule cells into spatial memory networks in the dentate gyrus. Nature Neurosci. 10, 355–362 (2007)

    Article  CAS  Google Scholar 

  6. Larkum, M. E. & Nevian, T. Synaptic clustering by dendritic signalling mechanisms. Curr. Opin. Neurobiol. 18, 321–331 (2008)

    Article  CAS  Google Scholar 

  7. Govindarajan, A., Kelleher, R. J. & Tonegawa, S. A clustered plasticity model of long-term memory engrams. Nature Rev. Neurosci. 7, 575–583 (2006)

    Article  CAS  Google Scholar 

  8. Poirazi, P. & Mel, B. W. Impact of active dendrites and structural plasticity on the memory capacity of neural tissue. Neuron 29, 779–796 (2001)

    Article  CAS  Google Scholar 

  9. Sjostrom, P. J. & Hausser, M. A cooperative switch determines the sign of synaptic plasticity in distal dendrites of neocortical pyramidal neurons. Neuron 51, 227–238 (2006)

    Article  CAS  Google Scholar 

  10. Losonczy, A. & Magee, J. C. Integrative properties of radial oblique dendrites in hippocampal CA1 pyramidal neurons. Neuron 50, 291–307 (2006)

    Article  CAS  Google Scholar 

  11. Zuo, Y., Lin, A., Chang, P. & Gan, W. B. Development of long-term dendritic spine stability in diverse regions of cerebral cortex. Neuron 46, 181–189 (2005)

    Article  CAS  Google Scholar 

  12. Segal, M. Dendritic spines and long-term plasticity. Nature Rev. Neurosci. 6, 277–284 (2005)

    Article  CAS  Google Scholar 

  13. Harms, K. J. & Dunaevsky, A. Dendritic spine plasticity: looking beyond development. Brain Res. 1184, 65–71 (2007)

    Article  CAS  Google Scholar 

  14. Feng, G. et al. Imaging neuronal subsets in transgenic mice expressing multiple spectral variants of GFP. Neuron 28, 41–51 (2000)

    Article  CAS  Google Scholar 

  15. Xu, T. et al. Rapid formation and selective stabilization of synapses for enduring motor memories. Nature 462, 915–919 (2009)

    Article  ADS  CAS  Google Scholar 

  16. Harvey, C. D. & Svoboda, K. Locally dynamic synaptic learning rules in pyramidal neuron dendrites. Nature 450, 1195–1200 (2007)

    Article  ADS  CAS  Google Scholar 

  17. De Roo, M., Klauser, P. & Muller, D. LTP promotes a selective long-term stabilization and clustering of dendritic spines. PLoS Biol. 6, e219 (2008)

    Article  Google Scholar 

  18. Gray, N. W., Weimer, R. M., Bureau, I. & Svoboda, K. Rapid redistribution of synaptic PSD-95 in the neocortex in vivo. PLoS Biol. 4, e370 (2006)

    Article  Google Scholar 

  19. Harvey, C. D., Yasuda, R., Zhong, H. & Svoboda, K. The spread of Ras activity triggered by activation of a single dendritic spine. Science 321, 136–140 (2008)

    Article  ADS  CAS  Google Scholar 

  20. Rose, J., Jin, S. X. & Craig, A. M. Heterosynaptic molecular dynamics: locally induced propagating synaptic accumulation of CaM kinase II. Neuron 61, 351–358 (2009)

    Article  CAS  Google Scholar 

  21. Tsuriel, S. et al. Local sharing as a predominant determinant of synaptic matrix molecular dynamics. PLoS Biol. 4, e271 (2006)

    Article  Google Scholar 

  22. Yu, X. & Zuo, Y. Spine plasticity in the motor cortex. Curr. Opin. Neurobiol. 21, 169–174 (2011)

    Article  CAS  Google Scholar 

  23. Chen, J. L. & Nedivi, E. Neuronal structural remodeling: is it all about access? Curr. Opin. Neurobiol. 20, 557–562 (2010)

    Article  CAS  Google Scholar 

  24. Fu, M. & Zuo, Y. Experience-dependent structural plasticity in the cortex. Trends Neurosci. 34, 177–187 (2011)

    Article  CAS  Google Scholar 

  25. Holtmaat, A. & Svoboda, K. Experience-dependent structural synaptic plasticity in the mammalian brain. Nature Rev. Neurosci. 10, 647–658 (2009)

    Article  CAS  Google Scholar 

  26. Chen, X., Leischner, U., Rochefort, N. L., Nelken, I. & Konnerth, A. Functional mapping of single spines in cortical neurons in vivo. Nature 475, 501–505 (2011)

    Article  CAS  Google Scholar 

  27. Yuste, R. Dendritic spines and distributed circuits. Neuron 71, 772–781 (2011)

    Article  CAS  Google Scholar 

  28. Knott, G. W., Holtmaat, A., Wilbrecht, L., Welker, E. & Svoboda, K. Spine growth precedes synapse formation in the adult neocortex in vivo. Nature Neurosci. 9, 1117–1124 (2006)

    Article  CAS  Google Scholar 

  29. Fiala, J. C., Allwardt, B. & Harris, K. M. Dendritic spines do not split during hippocampal LTP or maturation. Nature Neurosci. 5, 297–298 (2002)

    Article  CAS  Google Scholar 

  30. Toni, N., Buchs, P. A., Nikonenko, I., Bron, C. R. & Muller, D. LTP promotes formation of multiple spine synapses between a single axon terminal and a dendrite. Nature 402, 421–425 (1999)

    Article  ADS  CAS  Google Scholar 

  31. Grutzendler, J., Kasthuri, N. & Gan, W. B. Long-term dendritic spine stability in the adult cortex. Nature 420, 812–816 (2002)

    Article  ADS  CAS  Google Scholar 

  32. Hofer, S. B., Mrsic-Flogel, T. D., Bonhoeffer, T. & Hubener, M. Experience leaves a lasting structural trace in cortical circuits. Nature 457, 313–317 (2009)

    Article  ADS  CAS  Google Scholar 

Download references

Acknowledgements

We thank D. States, D. Garcia, L. Hinck, T. Jones, S. Song, W. Thompson and G. Wang for comments on this manuscript. We thank A. Perlik and T. Xu for technical support. This work was supported by grants from the DANA Foundation and the National Institutes of Mental Health to Y.Z.

Author information

Authors and Affiliations

  1. Department of Molecular, Cell and Developmental Biology, University of California, Santa Cruz, 95064, California, USA

    Min Fu, Xinzhu Yu & Yi Zuo

  2. Department of Biological Sciences and James H. Clark Center, Stanford University, Stanford, 94305, California, USA

    Ju Lu

Authors
  1. Min Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xinzhu Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ju Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yi Zuo
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

M.F. and X.Y. did the in vivo imaging and made the figures. M.F. performed behavioural training and all spine analyses, and made figures for repetitive imaging. J.L. and M.F. performed Matlab simulation and statistical analyses. J.L., M.F. and X.Y. participated in discussion about the paper. Y.Z. initiated and designed the project, and wrote the manuscript.

Corresponding author

Correspondence to Yi Zuo.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Notes 1-2, additional references, Supplementary Figures 1-8 with legends and Supplementary Table 1. (PDF 980 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Fu, M., Yu, X., Lu, J. et al. Repetitive motor learning induces coordinated formation of clustered dendritic spines in vivo. Nature 483, 92–95 (2012). https://doi.org/10.1038/nature10844

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature10844

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing