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Recovery of supraspinal control of stepping via indirect propriospinal relay connections after spinal cord injury

Nature Medicine volume 14, pages 69–74 (2008)Cite this article

Abstract

Spinal cord injuries (SCIs) in humans1,2 and experimental animals3,4,5,6 are often associated with varying degrees of spontaneous functional recovery during the first months after injury. Such recovery is widely attributed to axons spared from injury that descend from the brain and bypass incomplete lesions, but its mechanisms are uncertain. To investigate the neural basis of spontaneous recovery, we used kinematic, physiological and anatomical analyses to evaluate mice with various combinations of spatially and temporally separated lateral hemisections with or without the excitotoxic ablation of intrinsic spinal cord neurons. We show that propriospinal relay connections that bypass one or more injury sites are able to mediate spontaneous functional recovery and supraspinal control of stepping, even when there has been essentially total and irreversible interruption of long descending supraspinal pathways in mice. Our findings show that pronounced functional recovery can occur after severe SCI without the maintenance or regeneration of direct projections from the brain past the lesion and can be mediated by the reorganization of descending and propriospinal connections4,7,8,9. Targeting interventions toward augmenting the remodeling of relay connections may provide new therapeutic strategies to bypass lesions and restore function after SCI and in other conditions such as stroke and multiple sclerosis.

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Figure 1: Recovery of supraspinal control of stepping after a lateral hemisection at T12.
Figure 2: Long-term loss of supraspinal but not propriospinal connections after a T12 lateral hemisection or after T12 (left) and delayed T7 (right) lateral hemisections.
Figure 3: Recovery of supraspinal control of stepping after delayed but not simultaneous T12 (left) and T7 (right) lateral hemisections.
Figure 4: Excitotoxic ablation of T8–T10 neurons abolishes the recovered control of stepping after a T12 lateral hemisection and after a T12 lateral hemisection followed by a delayed T7 lateral hemisection.

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Acknowledgements

This work was supported by grants from the National Institutes of Health (NS16333), the Christopher and Dana Reeve Foundation, the Adelson Medical Foundation and the Roman Reed Spinal Cord Injury Research Fund of California.

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Authors and Affiliations

  1. Department of Physiological Sciences, University of California, Los Angeles, 90095-1763, California, USA

    Gregoire Courtine, Roland R Roy, Hui Zhong & V Reggie Edgerton

  2. Department of Neurobiology, University of California, Los Angeles, 90095-1763, California, USA

    Bingbing Song, Julia E Herrmann, Yan Ao, Jingwei Qi, V Reggie Edgerton & Michael V Sofroniew

  3. Brain Research Institute, University of California, Los Angeles, 90095-1763, California, USA

    Roland R Roy, V Reggie Edgerton & Michael V Sofroniew

Authors
  1. Gregoire Courtine
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  5. Julia E Herrmann
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  8. V Reggie Edgerton
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Contributions

G.C., R.R.R., V.R.E. and M.V.S. designed the experiments; G.C., B.S., R.R.R., H.Z., J.E.H., Y.A. and J.Q. performed the experiments; G.C., B.S., R.R.R., V.R.E. and M.V.S. analyzed the data and G.C., R.R.R., V.R.E. and M.V.S. wrote the paper.

Corresponding author

Correspondence to Michael V Sofroniew.

Supplementary information

Supplementary Text and Figures

Supplementary Figs. 1–5 (PDF 1512 kb)

Supplementary Video 1

Loss and recovery of supraspinal control of stepping after T12 hemisection. (MOV 72562 kb)

Supplementary Video 2

Delayed (10 wks) contralateral T12 hemisection abolishes recovery of supraspinal control of stepping. (MOV 6097 kb)

Supplementary Video 3a

Permanent lost of stepping after simultaneous hemisections at T12 and T7. (MOV 13026 kb)

Supplementary Video 3b

Loss and recovery of supraspinal control of stepping after T12 and delayed T7 hemisections. (MOV 12859 kb)

Supplementary Video 3c

Delayed complete T7 spinal transection abolishes recovered stepping after T12 hemisection. (MOV 9089 kb)

Supplementary Video 4a

T8- T10 NMDA lesion does not alter stepping in the absence of other injuries. (MOV 15108 kb)

Supplementary Video 4b

T8-T10 NMDA lesion abolishes recovered supraspinal control of stepping after T12 hemisection. (MOV 10986 kb)

Supplementary Video 4c

T8-T10 NMDA lesion abolishes recovered supraspinal control of bilateral stepping after two temporally separated unilateral hemisections at T12 (left) and T7 (right). (MOV 9475 kb)

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Courtine, G., Song, B., Roy, R. et al. Recovery of supraspinal control of stepping via indirect propriospinal relay connections after spinal cord injury. Nat Med 14, 69–74 (2008). https://doi.org/10.1038/nm1682

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