Article | Published:

Midbrain circuits that set locomotor speed and gait selection

Nature volume 553, pages 455460 (25 January 2018) | Download Citation

Abstract

Locomotion is a fundamental motor function common to the animal kingdom. It is implemented episodically and adapted to behavioural needs, including exploration, which requires slow locomotion, and escape behaviour, which necessitates faster speeds. The control of these functions originates in brainstem structures, although the neuronal substrate(s) that support them have not yet been elucidated. Here we show in mice that speed and gait selection are controlled by glutamatergic excitatory neurons (GlutNs) segregated in two distinct midbrain nuclei: the cuneiform nucleus (CnF) and the pedunculopontine nucleus (PPN). GlutNs in both of these regions contribute to the control of slower, alternating-gait locomotion, whereas only GlutNs in the CnF are able to elicit high-speed, synchronous-gait locomotion. Additionally, both the activation dynamics and the input and output connectivity matrices of GlutNs in the PPN and the CnF support explorative and escape locomotion, respectively. Our results identify two regions in the midbrain that act in conjunction to select context-dependent locomotor behaviours.

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Acknowledgements

This research was supported by European Research Council grant ERC-693038 (O.K.), NINDs NS 090919 (O.K.), The Swedish Medical Research Council (O.K., G.F.), StratNeuro (O.K.) and Novo Nordisk Foundation Laureate Research grant NNF 15OC0014186 (O.K.). We thank P. Löw for assistance with viral work and K. Deisseroth for providing viral ChR2 vectors.

Author information

Author notes

    • V. Caggiano
    •  & R. Leiras

    These authors contributed equally to this work.

    • V. Caggiano
    •  & J. Bouvier

    Present addresses: Computational Biology Center, IBM T.J. Watson Research Center, 1101 Kitchawan Road, Route 134, Yorktown Heights, New York 10598, USA (V.Cag.); Paris-Saclay Institute of Neuroscience, UMR9197, CNRS and Université Paris-11, 91190 Gif-sur-Yvette, France (J.B.).

Affiliations

  1. Mammalian Locomotor Laboratory, Department of Neuroscience, Karolinska Institutet, 17177 Stockholm, Sweden

    • V. Caggiano
    • , R. Leiras
    • , H. Goñi-Erro
    • , C. Bellardita
    • , J. Bouvier
    • , V. Caldeira
    •  & O. Kiehn
  2. Department of Neuroscience, University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen, Denmark

    • R. Leiras
    • , H. Goñi-Erro
    • , C. Bellardita
    •  & O. Kiehn
  3. Laboratory of Molecular Neuropharmacology, Department of Neuroscience, Karolinska Institutet, 17177 Stockholm, Sweden

    • D. Masini
    •  & G. Fisone

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Contributions

O.K. initiated the project. V.Cag., R.L., H.G.-E. and O.K. designed the experiments with contributions from all authors. V.Cag. and R.L. performed optogenetic experiments, in vivo recordings and analysis. C.B. and H.G.-E. contributed to locomotor gait analysis, and J.B. to the initial optogenetic experiments. H.G.-E. and D.M. were responsible for chemogenetic inactivation experiments together with R.L. and V.Cag., and all analysed the data together with O.K. H.G.-E. and R.L. performed anatomical analysis with V.Cag. V.Cal. carried out in situ hybridizations. V.Cag. and O.K. wrote the paper with contributions from all authors. O.K. supervised all aspects of the work.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to V. Caggiano or R. Leiras or O. Kiehn.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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  1. 1.

    Life Sciences Reporting Summary

Videos

  1. 1.

    Optogenetic activation of glutamatergic CnF neurons

    Vglut2Cre adult mice 5 weeks following the injection of a Cre-dependent AAV-DIO-ChR2 virus in the CnF and chronic implantation of an optical fibre for optogenetic activation of the infected region. The mouse was placed in a linear corridor while filmed at 300 frames/s. Light-activation of transfected CnF neurons was applied at different frequencies, 5 - 50 Hz, keeping the same total stimulus strength. Increasing the frequencies incrementally induced the full range of locomotor speeds with alternating (walk and trot) gaits at slow speed and synchronous (gallop and bound) gaits at higher speeds. Video is shown at 30 frames/s.

  2. 2.

    Optogenetic activation of glutamatergic PPN neurons

    Vglut2Cre adult mice 5 weeks following the injection of a Cre-dependent AAV-DIO-ChR2 virus in the PPN and chronic implantation of an optical fibre for optogenetic activation of the infected region. The mouse was placed in a linear corridor while filmed at 300 frames/s. Light-activation of transfected PPN neurons applied at different frequencies (20 - 50 Hz) with the same total stimulus strength. The stimulation only induced alternating (walk and trot) gaits. Video is shown at 30 frames/s.

  3. 3.

    Chemogenetic inactivation of glutamatergic PPN neurons and optogenetic activation of glutamatergic CnF neurons

    Vglut2Cre adult mice 5 weeks following the injection of a Cre-dependent hM4D(Gi) virus in the PPN and AAV-DIO-ChR2 in CnF. CNO (Clozapine-N-oxide; 1 mg/kg) was given i.p. The mouse was placed in a linear corridor while filmed at 300 frames/s. Upper trace shows CnF stimulation before CNO i.p. injection. Thirty min after inhibition of glutamatergic neurons in PPN, the maximal speeds of locomotion for the same stimulus frequency were reduced without affecting the gaits. Light-activation of transfected CnF neurons with high stimulation frequencies produced gallop or bound. Video is shown at 30 frames/s.

  4. 4.

    Optogenetic activation of glutamatergic PPN neurons during explorative locomotion

    Vglut2Cre adult mice 2 weeks following the injection of a Cre-dependent AAV-DIO-ChR2 virus in the PPN and chronic implantation of an optical fibre for optogenetic activation of the infected region. The mouse was placed in a hole-board while filmed at 30 frames/s. Light-activation of transfected PPN neurons was applied at 40 Hz. Numbers count the explorative head-dips in 10 s chunks before (yellow), during (blue) and after stimulation (yellow).

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https://doi.org/10.1038/nature25448

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