Letter | Published:

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

Nature volume 483, pages 9295 (01 March 2012) | Download Citation


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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1.

    , , , & Molecular and cellular approaches to memory allocation in neural circuits. Science 326, 391–395 (2009)

  2. 2.

    , & Potential role for adult neurogenesis in the encoding of time in new memories. Nature Neurosci. 9, 723–727 (2006)

  3. 3.

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

  4. 4.

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

  5. 5.

    , , & Preferential incorporation of adult-generated granule cells into spatial memory networks in the dentate gyrus. Nature Neurosci. 10, 355–362 (2007)

  6. 6.

    & Synaptic clustering by dendritic signalling mechanisms. Curr. Opin. Neurobiol. 18, 321–331 (2008)

  7. 7.

    , & A clustered plasticity model of long-term memory engrams. Nature Rev. Neurosci. 7, 575–583 (2006)

  8. 8.

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

  9. 9.

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

  10. 10.

    & Integrative properties of radial oblique dendrites in hippocampal CA1 pyramidal neurons. Neuron 50, 291–307 (2006)

  11. 11.

    , , & Development of long-term dendritic spine stability in diverse regions of cerebral cortex. Neuron 46, 181–189 (2005)

  12. 12.

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

  13. 13.

    & Dendritic spine plasticity: looking beyond development. Brain Res. 1184, 65–71 (2007)

  14. 14.

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

  15. 15.

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

  16. 16.

    & Locally dynamic synaptic learning rules in pyramidal neuron dendrites. Nature 450, 1195–1200 (2007)

  17. 17.

    , & LTP promotes a selective long-term stabilization and clustering of dendritic spines. PLoS Biol. 6, e219 (2008)

  18. 18.

    , , & Rapid redistribution of synaptic PSD-95 in the neocortex in vivo. PLoS Biol. 4, e370 (2006)

  19. 19.

    , , & The spread of Ras activity triggered by activation of a single dendritic spine. Science 321, 136–140 (2008)

  20. 20.

    , & Heterosynaptic molecular dynamics: locally induced propagating synaptic accumulation of CaM kinase II. Neuron 61, 351–358 (2009)

  21. 21.

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

  22. 22.

    & Spine plasticity in the motor cortex. Curr. Opin. Neurobiol. 21, 169–174 (2011)

  23. 23.

    & Neuronal structural remodeling: is it all about access? Curr. Opin. Neurobiol. 20, 557–562 (2010)

  24. 24.

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

  25. 25.

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

  26. 26.

    , , , & Functional mapping of single spines in cortical neurons in vivo. Nature 475, 501–505 (2011)

  27. 27.

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

  28. 28.

    , , , & Spine growth precedes synapse formation in the adult neocortex in vivo. Nature Neurosci. 9, 1117–1124 (2006)

  29. 29.

    , & Dendritic spines do not split during hippocampal LTP or maturation. Nature Neurosci. 5, 297–298 (2002)

  30. 30.

    , , , & LTP promotes formation of multiple spine synapses between a single axon terminal and a dendrite. Nature 402, 421–425 (1999)

  31. 31.

    , & Long-term dendritic spine stability in the adult cortex. Nature 420, 812–816 (2002)

  32. 32.

    , , & Experience leaves a lasting structural trace in cortical circuits. Nature 457, 313–317 (2009)

Download references


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


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

    • Min Fu
    • , Xinzhu Yu
    •  & Yi Zuo
  2. Department of Biological Sciences and James H. Clark Center, Stanford University, Stanford, California 94305, USA

    • Ju Lu


  1. Search for Min Fu in:

  2. Search for Xinzhu Yu in:

  3. Search for Ju Lu in:

  4. Search for Yi Zuo in:


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.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Yi Zuo.

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    This file contains Supplementary Notes 1-2, additional references, Supplementary Figures 1-8 with legends and Supplementary Table 1.

About this article

Publication history






Further reading


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.