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Sensory cortical control of movement

Abstract

Walking in our complex environment requires continual higher order integrated spatiotemporal information. This information is processed in the somatosensory cortex, and it has long been presumed that it influences movement via descending tracts originating from the motor cortex. Here we show that neuronal activity in the primary somatosensory cortex tightly correlates with the onset and speed of locomotion in freely moving mice. Using optogenetics and pharmacogenetics in combination with in vivo and in vitro electrophysiology, we provide evidence for a direct corticospinal pathway from the primary somatosensory cortex that synapses with cervical excitatory neurons and modulates the lumbar locomotor network independently of the motor cortex and other supraspinal locomotor centers. Stimulation of this pathway enhances speed of locomotion, while inhibition decreases locomotor speed and ultimately terminates stepping. Our findings reveal a novel pathway for neural control of movement whereby the somatosensory cortex directly influences motor behavior, possibly in response to environmental cues.

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Fig. 1: Electrophysiological recording of somatosensory activity in freely behaving mice.
Fig. 2: Photostimulation of SI pyramidal neurons induces activity in the lumbar cord.
Fig. 3: Somatosensory cortical connectivity and lumbar spinal cord.
Fig. 4: The sensory cortex increased the frequency of locomotor-like activity in vitro via cervical excitatory neurotransmission.
Fig. 5: Sensory cortex regulates locomotor output.
Fig. 6: The sensory cortical pathway is necessary for maintenance of locomotion.
Fig. 7: Cervical eINs relay the SI motor signal to the lumbar spinal cord.
Fig. 8: Cervical excitatory cells project predominantly to lamina VII of the upper lumbar spinal cord.

Data availability

Source data have been provided for Figs. 1c,d (values in Fig. 1d are the square root of values in Fig. 1c), 2d,e, 4c, 5c,e, 6a,b and 7c. Source data have also been provided for Extended Data Figs. 2b, 5a–c,e, 6, 7a,b and 8. Any additional data pertaining to this manuscript is available from the authors upon reasonable request.

Code availability

Any custom script or code used in this study is available from the authors upon reasonable request.

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Acknowledgements

This research was supported by CIHR Grant MOP13683 (M.G.F.), CIHR Grant MOP 86470 (S.G.), an AOSPINE Young Investigator Research Grant (K.S.), the Halbert Chair in Neural Repair and Regeneration (M.G.F.) and the DeZwirek Foundation (M.G.F.). S.K.K. was supported by the Onassis Foundation. We thank C. Castro and S. Sivakumaran for technical assistance and S. Arber for the FLExFRT-PSAML141F,Y115F-GlyR plasmid (Friedrich Miescher Institute).

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Authors

Contributions

S.K.K., K.S. and M.G.F. designed all experiments. S.K.K. performed viral tracings, anatomical investigations, behavioral experiments and data analysis. K.S. performed viral tracings, anatomical investigations, behavioral experiments, all electrophysiological recordings and data analysis. A.M.L. performed the molecular and viral work, behavioral experiments, data analysis and statistics. L.L. provided technical assistance with the in vitro and in vivo lumbar field potential recordings. D.R. performed behavioral tracking and electrophysiology data analysis for the in vivo SI-cortical recording in freely moving mice. I.W. participated in the cortical electrode implantations. S.K.K., K.S., S.G., A.M.L. and M.G.F. wrote the paper, with contributions from D.R. M.G.F. supervised the work and provided the funding for the work.

Corresponding authors

Correspondence to Spyridon K. Karadimas, Kajana Satkunendrarajah or Michael G. Fehlings.

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Extended data

Extended Data Fig. 1 Decorrelation analysis of animal velocity and somatosensory activity.

Decorrelation of animal velocity and somatosensory activity from panel Fig. 1(c) across artificially shifted temporal correspondence. The correlation plots in Fig. 1(d) correspond to relationship at the zero temporal shift. Positive shift time corresponds to velocity compared to latter somatosensory activity. (n = 8 mice).

Extended Data Fig. 2 Control SI stimulation in ChR2−/− mice does not increase locomotor frequency.

a, Representative ENG recordings of locomotor like activity from ipsilateral L2 and L5 ventral roots induced with 7 uM NMDA and 10 uM 5-HT. of a ChR2-/- mice (baseline). Optogenetic stimulation of the SI neurons in these mice did not evoke an increase in the frequency of locomotor-realted burst activity (SI stimulation) (bottom). b, Relative change in frequency of locomotor-like activity before optical stimulation of SI (red) and during SI optical stimulation (blue) in ChR2-/- mice. No significant difference was revealed between the two conditions (two-tailed paired t-test, p = 0.759). n = 3 mice. Group data are presented as mean ± s.e.m.

Source data

Extended Data Fig. 3 SI pyramidal neurons project to intermediate gray zone of cervical spinal cord.

a, AAVDJ-syn1-DIO-EGFP were injected unilaterally into Emx1::cre mice (n = 3). b, SI pyramidal neurons expressing GFP at the AAVDJ-syn1-DIO-EGFP injection site. c, Confocal images of 30 μm-thick transverse sections of the cervical spinal cord of the same animal contained eGFP+ projections in the intermediate gray matter of C4-7. d, Heat map reveal dense projections mainly in the intermediate gray zone.

Extended Data Fig. 4 Effect of SI stimulation on locomotion after KA washout.

Baseline ENG recordings of locomotor like activity from ipsilateral L2 and L5 ventral roots of a P0-3 Emx1::cre; Ai27D offspring one hour after KA perfusion in the cervical cord has been terminated (Top). Optogenetic stimulation of the SI neurons one hour after KA perfusion in the cervical cord has been terminated increases the frequency of locomotor-like bursting activity. (n = 4 mice) (Bottom).

Extended Data Fig. 5 Manipulation of the SI locomotor pathway does not change the general locomotor capability.

a, Bar graphs showing no change in the stride length after CNO administration. b, Bar graphs demonstrating the forepaw and hindpaw base of support before and after PSEM or CNO administration. c, Regularity index of mice before and after manipulation of the SI locomotor pathway. d, Circular diagrams showing that phase dispersions consistent with the trot gait pattern were preserved after silencing or activation of the SI locomotor pathway. e, Bar graphs demonstrate the lack of effects of the manipulation of the sensory locomotor pathway on the print width and print length of both forepaws and hindpaws. Data were extracted using Catwalk XT software (repeated measures one-way ANOVA with Dunnett’s multiple comparisons test,* indicates p < 0.05. n = 7 mice). Group data are presented as mean ± s.e.m.

Source data

Extended Data Fig. 6 Stimulation of the SI locomotor pathway does not induce neuropathic pain.

Bar graphs showing the intensity of signal obtained from forepaws and hindpaws during locomotion on the Catwalk gait analysis system do not change after CNO administration. Data were analyzed using two-tailed paired t-tests (n = 7 mice). No statistically significant differences were observed (Related to Fig. 3). Group data are presented as mean ± s.e.m.

Source data

Extended Data Fig. 7 Stimulation of the SI locomotor pathway does not change the reaction to noxious stimuli.

a, Bar graphs showing the frequency of forepaw and hindpaw withdrawal resulting from 10 non-consecutive touches on each paw with the 0.4 g von Frey monofilament during both baseline and CNO conditions. b, Bar graph showing the latency to withdrawal of the tail following exposure to mild thermal stimulus in both baseline and CNO conditions, with each data point representing the average of three trials. Data were analyzed by two-tailed paired t-test (n = 7 mice). No statistically significant differences were observed. Group data are presented as mean ± s.e.m.

Source data

Extended Data Fig. 8 Inactivation of the SI neurons projecting to cervical cord does not decrease the forelimb strength.

Bar graph showing mean grip strength for mice before and after PSEM injection to inhibit SI neurons. Data were analyzed by two-tailed paired t-test (n = 7 mice). No statistically significant differences were observed. Group data are presented as mean ± s.e.m.

Source data

Extended Data Fig. 9 Anatomical distribution of the cervical excitatory cells projecting to ventromedial region of upper lumbar spinal cord.

a, Vglut2::cre mice were crossed with an Ai65(RCFL-tdT) line that contains FRT-stop-FRT and LoxP-stop-LoxP double cassettes ahead of tdTomato. Laminae VII/VIII/X of L1 spinal segments of adult Vglut2::cre;Ai65(RCFL-tdT) were unilaterally injected with the retrograde virus CAV2-FLExloxPFlp (n = 2 mice). b, Laminar distribution of the tdTomato-positive lumbar-projecting cervical glutamatergic cells. c, Density plot demonstrating the distribution of the lumbar projecting glutamatergic cells in the cervical enlargement. Group data are presented as mean ± s.e.m.

Supplementary information

Supplementary Information

Supplementary Tables 1 and 2.

Reporting Summary

Supplementary Video 1

Simultaneous motion tracking and SI electrophysiological recording in freely behaving animals. Animal position (indicated by white dot superimposed on mouse) was extracted from the video and used for concurrent velocity calculation.

Supplementary Data

Supplementary data corresponding to Fig. 1. SI activity and velocity values with corresponding time stamps.

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Karadimas, S.K., Satkunendrarajah, K., Laliberte, A.M. et al. Sensory cortical control of movement. Nat Neurosci 23, 75–84 (2020). https://doi.org/10.1038/s41593-019-0536-7

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