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


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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

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.


  1. 1

    Fawcett, J.W. et al. Guidelines for the conduct of clinical trials for spinal cord injury as developed by the ICCP panel: spontaneous recovery after spinal cord injury and statistical power needed for therapeutic clinical trials. Spinal Cord 45, 190–205 (2007).

    CAS  Article  Google Scholar 

  2. 2

    Dobkin, B. et al. The evolution of walking-related outcomes over the first 12 weeks of rehabilitation for incomplete traumatic spinal cord injury: the multicenter randomized spinal cord injury locomotor trial. Neurorehabil. Neural Repair 21, 25–35 (2007).

    CAS  Article  Google Scholar 

  3. 3

    Weidner, N., Ner, A., Salimi, N. & Tuszynski, M. Spontaneous corticospinal axonal plasticity and functional recovery after adult central nervous system injury. Proc. Natl. Acad. Sci. USA 98, 3513–3518 (2001).

    CAS  Article  Google Scholar 

  4. 4

    Bareyre, F.M. et al. The injured spinal cord spontaneously forms a new intraspinal circuit in adult rats. Nat. Neurosci. 7, 269–277 (2004).

    CAS  Article  Google Scholar 

  5. 5

    Courtine, G. et al. Performance of locomotion and foot grasping following a unilateral thoracic corticospinal tract lesion in monkeys (Macaca mulatta). Brain 128, 2338–2358 (2005).

    Article  Google Scholar 

  6. 6

    Ballermann, M. & Fouad, K. Spontaneous locomotor recovery in spinal cord injured rats is accompanied by anatomical plasticity of reticulospinal fibers. Eur. J. Neurosci. 23, 1988–1996 (2006).

    Article  Google Scholar 

  7. 7

    Raineteau, O. & Schwab, M.E. Plasticity of motor systems after incomplete spinal cord injury. Nat. Rev. Neurosci. 2, 263–273 (2001).

    CAS  Article  Google Scholar 

  8. 8

    Kerschensteiner, M. et al. Remodeling of axonal connections contributes to recovery in an animal model of multiple sclerosis. J. Exp. Med. 200, 1027–1038 (2004).

    CAS  Article  Google Scholar 

  9. 9

    Jankowska, E. & Edgley, S.A. How can corticospinal tract neurons contribute to ipsilateral movements? A question with implications for recovery of motor functions. Neuroscientist 12, 67–79 (2006).

    Article  Google Scholar 

  10. 10

    Jane, J.A., Evans, J.P. & Fisher, L.E. An investigation concerning the restitution of motor function following injury to the spinal cord. J. Neurosurg. 21, 167–171 (1964).

    CAS  Article  Google Scholar 

  11. 11

    Basbaum, A.I. Conduction of the effects of noxious stimulation by short-fiber multisynaptic systems of the spinal cord in the rat. Exp. Neurol. 40, 699–716 (1973).

    CAS  Article  Google Scholar 

  12. 12

    Stelzner, D.J. & Cullen, J.M. Do propriospinal projections contribute to hindlimb recovery when all long tracts are cut in neonatal or weanling rats? Exp. Neurol. 114, 193–205 (1991).

    CAS  Article  Google Scholar 

  13. 13

    Duffy, M.T., Simpson, S.B.J., Liebich, D.R. & Davis, B.M. Origin of spinal cord axons in the lizard regenerated tail: supernormal projections from local spinal neurons. J. Comp. Neurol. 293, 208–222 (1990).

    CAS  Article  Google Scholar 

  14. 14

    Nantwi, K.D., El-Bohy, A.A., Schrimsher, G.W., Reier, P.J. & Goshgarian, H.G. Spontaneous recovery in a paralyzed hemidiaphragm following upper cervical spinal cord injury in adult rats. Neurorehabil. Neural Repair 13, 225–234 (1999).

    Article  Google Scholar 

  15. 15

    Kiehn, O. Locomotor circuits in the mammalian spinal cord. Annu. Rev. Neurosci. 29, 279–306 (2006).

    CAS  Article  Google Scholar 

  16. 16

    Leblond, H., L'Esperance, M., Orsal, D. & Rossignol, S. Treadmill locomotion in the intact and spinal mouse. J. Neurosci. 23, 11411–11419 (2003).

    CAS  Article  Google Scholar 

  17. 17

    Sofroniew, M.V., Galletly, N.P., Isacson, O. & Svendsen, C.N. Survival of adult basal forebrain cholinergic neurons after loss of target neurons. Science 247, 338–342 (1990).

    CAS  Article  Google Scholar 

  18. 18

    Magnuson, D.S. et al. Comparing deficits following excitotoxic and contusion injuries in the thoracic and lumbar spinal cord of the adult rat. Exp. Neurol. 156, 191–204 (1999).

    CAS  Article  Google Scholar 

  19. 19

    Fong, A.J. et al. Spinal cord–transected mice learn to step in response to quipazine treatment and robotic training. J. Neurosci. 25, 11738–11747 (2005).

    CAS  Article  Google Scholar 

  20. 20

    Edgerton, V.R. et al. Retraining the injured spinal cord. J. Physiol. (Lond.) 533, 15–22 (2001).

    CAS  Article  Google Scholar 

  21. 21

    Zaporozhets, E., Cowley, K.C. & Schmidt, B.J. Propriospinal neurons contribute to bulbospinal transmission of the locomotor command signal in the neonatal rat spinal cord. J. Physiol. (Lond.) 572, 443–458 (2006).

    CAS  Article  Google Scholar 

  22. 22

    Courtine, G. et al. Can experiments in nonhuman primates expedite the translation of treatments for spinal cord injury in humans? Nat. Med. 13, 561–566 (2007).

    CAS  Article  Google Scholar 

  23. 23

    Schwab, M.E. Repairing the injured spinal cord. Science 295, 1029–1031 (2002).

    CAS  Article  Google Scholar 

  24. 24

    Filbin, M.T. Myelin-associated inhibitors of axonal regeneration in the adult mammalian CNS. Nat. Rev. Neurosci. 4, 703–713 (2003).

    CAS  Article  Google Scholar 

  25. 25

    Silver, J. & Miller, J.H. Regeneration beyond the glial scar. Nat. Rev. Neurosci. 5, 146–156 (2004).

    CAS  Article  Google Scholar 

  26. 26

    Irwin, N., Li, Y.M., O'Toole, J.E. & Benowitz, L.I. Mst3b, a purine-sensitive Ste20-like protein kinase, regulates axon outgrowth. Proc. Natl. Acad. Sci. USA 103, 18320–18325 (2006).

    CAS  Article  Google Scholar 

  27. 27

    Thuret, S., Moon, L.D. & Gage, F.H. Therapeutic interventions after spinal cord injury. Nat. Rev. Neurosci. 7, 628–643 (2006).

    CAS  Article  Google Scholar 

  28. 28

    Faulkner, J.R. et al. Reactive astrocytes protect tissue and preserve function after spinal cord injury. J. Neurosci. 24, 2143–2155 (2004).

    CAS  Article  Google Scholar 

  29. 29

    Courtine, G. et al. Kinematic and EMG determinants in quadrupedal locomotion of a non-human primate (Rhesus). J. Neurophysiol. 93, 3127–3145 (2005).

    Article  Google Scholar 

  30. 30

    Recktenwald, M.R. et al. Effects of spaceflight on rhesus quadrupedal locomotion after return to 1G. J. Neurophysiol. 81, 2451–2463 (1999).

    CAS  Article  Google Scholar 

Download references


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.

Author information




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)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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).

Download citation

Further reading


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing