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Midbrain circuits that set locomotor speed and gait selection

Nature volume 553, pages 455–460 (2018)Cite this article

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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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Figure 1: The control of speed and gait by glutamatergic neurons in the CnF and the PPN.
Figure 2: The PPN and the CnF provide dual control of slower locomotion.
Figure 3: Glutamatergic neurons in the CnF are required and are sufficient for fast, synchronous locomotion.
Figure 4: Coding of speed in glutamatergic neurons in the CnF and the PPN.
Figure 5: Selection of exploration from the PPN.
Figure 6: Neurons in the CnF and the PPN have differential input matrices.

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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

  1. V. Caggiano

    Present address: Computational Biology Center, IBM T.J. Watson Research Center, 1101 Kitchawan Road, Route 134, Yorktown Heights, New York, 10598, USA

  2. J. Bouvier

    Present address: Paris-Saclay Institute of Neuroscience, UMR9197, CNRS and Université Paris-11, 91190, Gif-sur-Yvette, France

  3. V. Caggiano and R. Leiras: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Neuroscience, Mammalian Locomotor Laboratory, Karolinska Institutet, Stockholm, 17177, 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, Copenhagen, 2200, Denmark

    R. Leiras, H. Goñi-Erro, C. Bellardita & O. Kiehn

  3. Department of Neuroscience, Laboratory of Molecular Neuropharmacology, Karolinska Institutet, Stockholm, 17177, 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.

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

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Extended data figures and tables

Extended Data Figure 1 ChR2 expression in the CnF and the PPN.

This figure summarizes the behavioural data in Fig. 1 and Extended Data Fig. 2a, b. a, Expression of ChR2 and fibre-tip positions in the CnF (left) and the PPN (right) for the data in Fig. 1 and Extended Data Fig. 2a–c, e. Coronal brain sections with viral expression from injected Vglut2cre mice were superimposed on sections redrawn from a mouse brain atlas38. The darker contour colours indicate the centre of expression, whereas the lighter colours indicate the border of the most extended expression. The round dots show the tip of the fibre. b, Expression of ChR2 and fibre-tip positions for the PPN data in Extended Data Fig. 2d. The mouse brain schematics in this figure have been reproduced with permission from Elsevier38.

Source data

Extended Data Figure 2 Control of locomotion speed from glutamatergic neurons in the CnF and the PPN.

a, b, Speed profiles of mice after the stimulation of Vglut2+ChR2 CnF (a) and Vglut2+ChR2 PPN (b) neurons. Top panels show the location of optical stimulation in the CnF (a) and the PPN (b). Middle panels show colour plots of individual trials after the stimulation of Vglut2+ChR2 CnF (a) and Vglut2+ChR2 PPN (b) neurons (Fig. 1). The x axis represents time and the y axis represents trials at different stimulation frequencies. Data are aligned to the onset of stimulation (stim.). The colour gradient illustrates speed, with dark blue representing no movement and colours towards yellow representing the increase in speed (up to 120 cm s−1) of the mouse in the linear corridor. Bottom panels show speed profiles obtained as an average of the movements at each stimulation frequency. c, Latencies to onset of locomotion from the stimulation of Vglut2+ChR2 PPN (red) and Vglut2+ChR2 CnF (blue) neurons as a function of the stimulation frequency. Error bars indicate the 25th and 75th percentiles of the distribution. d, Post-stimulus locomotor speed plotted against pre-stimulus locomotor speed in Vglut2cre mice that had been injected in the PPN with AAV-DIO-ChR2–mCherry (n = 50 trials from N = 4 mice). e, Step frequency plotted against speed of locomotion for the stimulation of Vglut2+ChR2 PPN neurons (red, n = 84 trials from N = 5 mice) or Vglut2+ChR2 CnF neurons (blue, n = 173 trials from N = 9 mice).

Extended Data Figure 3 Activation of inhibitory neurons in the CnF or the PPN, and cholinergic neurons in the PPN, does not initiate locomotion but may modulate ongoing locomotion.

a–c, Top panels show the implantation of the optical fibre to stimulate inhibitory cells in the CnF (a) and the PPN (b), and the cholinergic cells in the PPN (c). AAV-DIO-ChR2 virus was injected in Vgatcre mice to target inhibitory cells, whereas cholinergic neurons expressed ChR2 transgenically by crossing Chatcre with RC26-ChR2flx/flx mice. Experiments were performed 3–4 weeks after injection of the virus, with mice locomoting spontaneously in a linear corridor. Middle and bottom panels show colour plots in which the x axis represents time and the y axis represents different trials, when the mice were not locomoting (middle panels, ‘still’) or when they were locomoting (bottom panels, ‘moving’) before the stimulation. Data are aligned to the onset of stimulation (dotted lines). The colour gradient illustrates speed, with dark blue representing no movement and colours towards yellow representing an increase in speed (up to 60–80 cm s−1) of the mouse in the linear corridor. Speed before versus after stimulation: CnF-Vgat inhibitory neurons: from still, P > 0.05, Wilcoxon signed-rank test (two sided) (n = 18, N = 2); when moving, from 27.9 cm s−1 to 4.2 cm s−1 P < 0.05, Wilcoxon signed-rank test (n = 22, N = 2). PPN-Vgat inhibitory neurons: from still, P > 0.05 (n = 5, N = 2); when moving from 27.6 cm s−1 to 8.6 cm s−1, P < 0.05 Wilcoxon signed-rank test (two-sided) (n = 34, N = 2). Stimulation of long-projecting cholinergic cells in the PPN: from still, P > 0.05, Wilcoxon signed-rank test (n = 102, N = 5); when moving: before 47.3 cm s−1, after 22.9 cm s−1, P < 0.05, Wilcoxon signed-rank test (two-sided) (n = 88, N = 5). n, number of trials; N, number of mice. d, Diagram of viral expression and fibre-tip positions in Vgatcre mice in the CnF (left) and the PPN (right). e, Diagram of fibre-tip positions in Chatcre mice. The mouse brain schematics in this figure have been reproduced with permission from Elsevier38.

Extended Data Figure 4 Summary diagram of iDREADD injection sites in the CnF and the PPN.

a, Expression of iDREADD in Vglut2+ neurons of the CnF (left, N = 8) or the PPN (right, N = 9) in mice used in Fig. 2. b, c, Coronal sections showing the expression pattern of iDREADD in Vglut2+CnF (b) and Vglut2+PPN (c) neurons. Scale bars, 500 μm. The mouse brain schematics in this figure have been reproduced with permission from Elsevier38.

Extended Data Figure 5 Control for CNO injection and time course of the silencing effect of glutamatergic neurons in the CnF and the PPN.

a, Average (left) and maximum (right) speeds attained by wild-type mice during treadmill experiments after the intraperitoneal injection of saline (black) and CNO (orange, 1 mg kg−1) (N = 7). There was no significant difference in these speed parameters between the saline and CNO experiments (Wilcoxon signed-rank, two-sided, P > 0.45). b–d, Sites of AAV-DIO-hM4D(Gi)–mCherry injection in Vglut2cre mice in the CnF (b), the PPN (c) or the CnF and PPN (d). CNO was injected intraperitoneally and locomotor performance was tested on a treadmill. e–g, Graphs show the development of the inhibition of glutamatergic cells in the CnF (e, N = 3), the PPN (f, N = 3) or the CnF and PPN (g, N = 5) on maximal locomotor speed over time. Grey bars, baseline. Orange bars, time (in min) after CNO administration. Points show individual trials.

Source data

Extended Data Figure 6 Latencies of the light activation of PPN and CnF neurons, and fractions of Vglut2+ChR2 neurons of the CnF and PPN with speed-related activity.

a, Latencies of light activation of all cells included in the analysis. b, Distribution of Vglut2+ChR2 CnF neurons (blue bars, n = 79 out of 169) and Vglut2+ChR2 PPN neurons (red bars, n = 105 out of 493) showing the correlation of firing activity with the locomotor speed of the mouse. In both panels, grey bars indicate neurons that show no significant correlation with the speed (Spearman correlation test, P > 0.05).

Source data

Extended Data Figure 7 Summary of injection sites in the PPN and the CnF for hole-board stimulation experiments.

a, Expression of ChR2 and fibre-tip positions in the CnF (left) or the PPN (right) for mice used in the experiments shown in Fig. 5d, e. The mouse brain schematics in this figure have been reproduced with permission from Elsevier38.

Extended Data Figure 8 Connectivity between the PPN and the CnF.

a, b, AAV-EF1a-FLEX-GTB helper virus followed by EnvA G-deleted-rabies–mCherry virus were unilaterally injected in the PPN (left, red) or the CnF (right, blue) in Vglut2cre mice to trace inputs to glutamatergic neurons. Schematics summarizing the inputs to Vglut2+PPN neurons (red) and Vglut2+CnF neurons (blue) are shown in a; the thickness of the arrows indicates the amount of connectivity based on the counts of the normalized number of neurons as shown in b. Dashed arrows indicate sparse connectivity.

Source data

Extended Data Figure 9 The CnF and PPN have different descending output matrices.

a, Simultaneous unilateral injection (top) of AAV-DIO-ChR2 virus in the CnF (mCherry, red) and the PPN (eYFP, green) in Vglut2cre mice (N = 3). Sagittal view of the brain (bottom) displaying the location in the brainstem (1–4) and the spinal cord (5) of the coronal sections shown in c. b, Coronal section showing ipsilateral and contralateral projection areas from glutamatergic PPN neurons. c1–5, Schematics and coronal sections showing projection areas from glutamatergic PPN (left, green) and CnF (right, red) neurons onto nuclei in the pons, medulla and spinal cord. In the schematics, the darker shades delineate the areas with the highest density of projections. In coronal sections, labelled processes are seen in black. Anatomical landmarks are indicated in the schematics. Scale bars, 200 μm. 4V, fourth ventricle; 7N, facial motor nucleus; Gi, gigantocellular nucleus; GiA, gigantocellular reticular nucleus, alpha part; GiV, gigantocellular reticular nucleus, ventral part; IOM, inferior olive, medial nucleus; IRt, intermediate reticular nucleus; LC, locus coeruleus; LPGi, lateral paragigantocellular nucleus; LRt, lateral reticular nucleus; MdV, medullary reticular nucleus, ventral part; PnC, pontine reticular nucleus, caudal part; PnV, pontine reticular nucleus, ventral part; py, pyramidal tract; pyx, pyramidal decussation; RMg, raphe magnus; ROb, raphe obscurus; RPa, raphe pallidus. The mouse brain schematics in this figure have been reproduced with permission from Elsevier38.

Supplementary information

Life Sciences Reporting Summary (PDF 71 kb)

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. (MOV 13023 kb)

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. (MOV 6806 kb)

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. (MOV 1048 kb)

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). (MOV 7186 kb)

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Caggiano, V., Leiras, R., Goñi-Erro, H. et al. Midbrain circuits that set locomotor speed and gait selection. Nature 553, 455–460 (2018). https://doi.org/10.1038/nature25448

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