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Cerebellum involvement in cortical sensorimotor circuits for the control of voluntary movements

Nature Neuroscience volume 17, pages 1233–1239 (2014)Cite this article

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Abstract

Sensorimotor integration is crucial to perception and motor control. How and where this process takes place in the brain is still largely unknown. Here we analyze the cerebellar contribution to sensorimotor integration in the whisker system of mice. We identify an area in the cerebellum where cortical sensory and motor inputs converge at the cellular level. Optogenetic stimulation of this area affects thalamic and motor cortex activity, alters parameters of ongoing movements and thereby modifies qualitatively and quantitatively touch events against surrounding objects. These results shed light on the cerebellum as an active component of sensorimotor circuits and show the importance of sensorimotor cortico-cerebellar loops in the fine control of voluntary movements.

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Figure 1: Autofluorescence imaging of sensory and motor cortical inputs in the cerebellum.
Figure 2: vM1 and vS1 inputs form separate pathways in the pontine nucleus and converge in the lateral part of crus I.
Figure 3: Sensory and motor cortical inputs to the cerebellum converge on single cells in the lateral cerebellum.
Figure 4: Inhibition-excitation sequence in the ascending cerebello-thalamo-cortical pathway following optogenetic activation of Purkinje cells.
Figure 5: Activation of the motor cortex after optogenetic stimulation of Purkinje cells in the lateral cerebellum of anesthetized mice.
Figure 6: Optogenetic stimulation of Purkinje cells in the lateral cerebellum modulates whisker movements monitored by high-speed videography in awake mice.
Figure 7: Effect of cerebellar stimulation on touch.

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Acknowledgements

This work was supported by France's Agence Nationale de la Recherche (ANR-09-MNPS-38, ANR-11-BSV4-028 01, ANR-12-BSV4-0027), France's Centre National de la Recherche Scientifique (CNRS), France's Institut National de la Santé et de la Recherche Médicale (INSERM; C.L., D.P.), the Ecole Normale Supérieure (ENS), the Fondation pour la recherche médicale (FRM - FDT20120925324, R.D.P.), Labex Memolife (R.D.P.) and the European Union (CBTOUCH-FP7-People-2011-IEF, M.S.). We are grateful to B. Barbour, V. Ego-Stengel, D. Shulz, L. Bourdieu and J.-F. Léger for careful reading of the manuscript. We thank G. Parésys, Y. Cabirou and B. Mathieu for excellent technical assistance and A. Boudet for help with the autofluorescence video acquisition. This work received support under the program «Investissements d'Avenir» launched by the French Government and implemented by the ANR: ANR-10-LABX-54 MEMO LIFE, ANR-10-LABX-0087 IEC, ANR-11-IDEX-0001-02 PSL* Research University.

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Author notes

  1. Rémi D Proville and Maria Spolidoro: These authors contributed equally to this work.

  2. Daniela Popa and Clément Léna: These authors jointly direct this work.

Authors and Affiliations

  1. Institut de Biologie de l'Ecole Normale Supérieure, Paris, France

    Rémi D Proville, Maria Spolidoro, Nicolas Guyon, Guillaume P Dugué, Daniela Popa & Clément Léna

  2. Centre National de la Recherche Scientifique (CNRS) UMR8197, Paris, France

    Rémi D Proville, Maria Spolidoro, Nicolas Guyon, Guillaume P Dugué, Daniela Popa & Clément Léna

  3. Institut National de la Santé et de la Recherche Médicale (INSERM) U1024, Paris, France

    Rémi D Proville, Maria Spolidoro, Nicolas Guyon, Guillaume P Dugué, Daniela Popa & Clément Léna

  4. Center for Interdisciplinary Research in Biology, Collège de France, Paris, France

    Fekrije Selimi

  5. CNRS UMR7241, Paris, France

    Fekrije Selimi

  6. INSERM U1050, Paris, France

    Fekrije Selimi

  7. Institut des Neurosciences Cellulaires et Intégratives, CNRS UPR 3212, Université de Strasbourg, Strasbourg, France

    Philippe Isope

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Contributions

R.D.P., M.S., D.P. and C.L. designed the experiments and analyzed the data. R.D.P., M.S. and N.G. performed the experiments. G.P.D. helped with optogenetics development and performed pilot experiments. P.I. and F.S. provided access to unpublished tools. R.D.P., M.S. and C.L. wrote the manuscript.

Corresponding authors

Correspondence to Daniela Popa or Clément Léna.

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Integrated supplementary information

Supplementary Figure 1 Autofluorescence imaging of sensory and motor cortical inputs in the cerebellum in awake animals

Schematic representation and localization of the stimulation and imaging areas with examples of autofluorescence evoked on the cerebellar surface by stimulation of vM1 or vS1 and examples of response time courses after cortical stimulation (200-500 µA, 200 µs, 6 Hz for 3 s with 7 s pause; n=20 trials). Scale bar: 500 μm.

Supplementary Figure 2 Retrograde labeling of olivary inputs to lateral or medial crus I.

(a): Injections of red and green retrobeads respectively in medial and lateral Crus I produced labeling in two separate sets of pontine nucleus cells. (b): Injections of red retrobeads in medial Crus I produced labeling in the medial accessory olive (MAO) and dorsal accessory olive (DAO). (c). Injections of green retrobeads in lateral Crus I produced labeling in the most ventral part of the principal olive (PO) nucleus.

Supplementary Figure 3 Spike sorting in stimulation experiments.

(a) Example of raw unfiltered tetrode recordings in the cerebellum after stimulation of vM1. Each trace represents a single tetrode channel. (b) Examples of the same traces after high-pass filtering at 1kHz. Colored vertical bars represent sorted spikes from different cells. (c-d) the spikes isolated during the response period are similar to the spikes in baseline: (c) Example of 3 cells hand-clustered by polygon-cutting in 2-dimensional projections of the parameter space using Xclust (Matt Wilson, MIT). Spikes between stimulations and spikes in the 20 ms following the stimulation are represented with different color/symbol size and they exhibit the same amplitudes on the tetrode channels, and (d) their average unfiltered waveforms recorded from the four tetrode channels are also similar between stimulations in the 20 ms following the stimulations.

Supplementary Figure 4 Golgi cell responses to vS1, vM1.

Latencies of Golgi cell (GC) and Purkinje cell (PC) responses in lateral and medial Crus I; * = p < 0.05.

Supplementary Figure 5 Number of recorded cells.

Number of cells recorded with different stimulations. Note that cells recorded with stimulations of both vM1 and vS1 (M1&S1) are a subset of cells recorded during stimulation of either vM1 or vS1.

Supplementary Figure 6 Activation of the motor cortex after optogenetic stimulation of Purkinje cells in the lateral cerebellum of awake mice.

(a) Schematic representation of ascending cerebello-cortical pathway. (b) Examples of field potentials recorded in vM1 after stimulation of Crus I or Crus II on the cerebellum (green and blue dots respectively).

Supplementary Figure 7 Whisking parameters before and during optogenetic stimulation.

Average speed, period and amplitude of whisking before (Baseline) and during (Stim) lateral stimulation of Crus I

Supplementary Figure 8 Schematic representation of the described cortico-cerebellar loop

Cortical inputs from vS1 and vM1 (blue and red respectively) form two separate pathways in the pontine nucleus. Sensorimotor projection from the pons converge on the same Golgi cell (green) and, via granule cells (deep blue), Purkinje cell (orange) in the cerebellar cortex. Output from the cerebellum contact neurons in the cerebellar nuclei (purple) which in turn project to the motor thalamus (grey). Projections from the motor thalamus to the motor cortex close the cortico-cerebellar loop. Perturbation of activity in this loop leads to modulation of whisking set-point.

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Proville, R., Spolidoro, M., Guyon, N. et al. Cerebellum involvement in cortical sensorimotor circuits for the control of voluntary movements. Nat Neurosci 17, 1233–1239 (2014). https://doi.org/10.1038/nn.3773

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