Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

The injured spinal cord spontaneously forms a new intraspinal circuit in adult rats

Abstract

In contrast to peripheral nerves, central axons do not regenerate. Partial injuries to the spinal cord, however, are followed by functional recovery. We investigated the anatomical basis of this recovery and found that after incomplete spinal cord injury in rats, transected hindlimb corticospinal tract (CST) axons sprouted into the cervical gray matter to contact short and long propriospinal neurons (PSNs). Over 12 weeks, contacts with long PSNs that bridged the lesion were maintained, whereas contacts with short PSNs that did not bridge the lesion were lost. In turn, long PSNs arborize on lumbar motor neurons, creating a new intraspinal circuit relaying cortical input to its original spinal targets. We confirmed the functionality of this circuit by electrophysiological and behavioral testing before and after CST re-lesion. Retrograde transynaptic tracing confirmed its integrity, and revealed changes of cortical representation. Hence, after incomplete spinal cord injury, spontaneous extensive remodeling occurs, based on axonal sprout formation and removal. Such remodeling may be crucial for rehabilitation in humans.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Innervation of the cervical spinal cord (cervical segment C5 presented here) by collaterals of the corticospinal tract originating from the hindlimb motor cortex.
Figure 2: Anatomical localization of retrogradely labeled propriospinal neurons in the cervical cord (cervical segment C4 presented here) of intact rats.
Figure 3: Quantification of close appositions formed by hindlimb CST collaterals on short (a,c,e,g) or long (b,d,f,h) propriospinal neurons in the cervical gray matter.
Figure 4: Contacts between long PSN axons and lumbar motor neurons.
Figure 5: Localization of the trans-synaptic retrograde tracer PRV in the spinal cord and motor cortex after hindlimb injection.
Figure 6: Spontaneous partial recovery of the hindlimb placing response to light touch of the foot in mid-thoracic dorsal hemisected rats includes a CST contribution.
Figure 7: Electrophysiological assessment of the CST reorganization.
Figure 8: Cortical localization of the CST neurons labeled retrogradely trans-synaptically by PRV from the hindlimb.

Similar content being viewed by others

References

  1. Schwab, M.E. & Bartholdi, D. Degeneration and regeneration of axons in the lesioned spinal cord. Physiol. Rev. 76, 319–370 (1996).

    Article  CAS  PubMed  Google Scholar 

  2. Rossignol, S., Drew, T., Brustein, E. & Jiang, W. Locomotor performance and adaptation after partial or complete spinal cord lesions in the cat. Prog. Brain Res. 123, 349–365 (1999).

    Article  CAS  PubMed  Google Scholar 

  3. Wernig, A. & Muller, S. Laufband locomotion with body weight support improved walking in persons with severe spinal cord injuries. Paraplegia 30, 229–238 (1992).

    CAS  PubMed  Google Scholar 

  4. Dietz, V., Wirz, M., Curt, A. & Colombo, G. Locomotor pattern in paraplegic patients: training effects and recovery of spinal cord function. Spinal Cord 36, 380–390 (1998).

    Article  CAS  PubMed  Google Scholar 

  5. Hiersemenzel, L.P., Curt, A. & Dietz, V. From spinal shock to spasticity: neuronal adaptations to a spinal cord injury. Neurology 54, 1574–1582 (2000).

    Article  CAS  PubMed  Google Scholar 

  6. Holaday, J.W. & Faden, A.I. Spinal shock and injury: experimental therapeutic approaches. Adv. Shock Res. 10, 95–98 (1983).

    CAS  PubMed  Google Scholar 

  7. Gensert, J.M. & Goldman, J.E. Endogenous progenitors remyelinate demyelinated axons in the adult CNS. Neuron 19, 197–203 (1997).

    Article  CAS  PubMed  Google Scholar 

  8. Lawrence, D.G. & Kuypers, H.G. The functional organization of the motor system in the monkey. I. The effects of bilateral pyramidal lesions. Brain 91, 1–14 (1968).

    Article  CAS  PubMed  Google Scholar 

  9. Pettersson, L.G., Lundberg, A., Alstermark, B., Isa, T. & Tantisira, B. Effect of spinal cord lesions on forelimb target-reaching and on visually guided switching of target-reaching in the cat. Neurosci. Res. 29, 241–256 (1997).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Fouad, K., Pedersen, V., Schwab, M.E. & Brosamle, C. Cervical sprouting of corticospinal fibers after thoracic spinal cord injury accompanies shifts in evoked motor responses. Curr. Biol. 11, 1766–1770 (2001).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  13. Murray, M. & Goldberger, M.E. Restitution of function and collateral sprouting in the cat spinal cord: the partially hemisected animal. J. Comp. Neurol. 158, 19–36 (1974).

    Article  CAS  PubMed  Google Scholar 

  14. Jankowska, E., Lundberg, A., Roberts, W.J. & Stuart, D. A long propriospinal system with direct effect on motoneurones and on interneurones in the cat lumbosacral cord. Exp. Brain Res. 21, 169–194 (1974).

    Article  CAS  PubMed  Google Scholar 

  15. Miller, S., van Berkum, R., van der Burg, J. & van der Meche, F.G. Interlimb co-ordination in stepping in the cat. J. Physiol. 230, 30P–31P (1973).

    CAS  PubMed  Google Scholar 

  16. Giovanelli Barilari, M. & Kuypers, H.G. Propriospinal fibers interconnecting the spinal enlargements in the cat. Brain Res. 14, 321–330 (1969).

    Article  CAS  PubMed  Google Scholar 

  17. Alstermark, B., Lundberg, A., Pinter, M. & Sasaki, S. Subpopulations and functions of long C3–C5 propriospinal neurones. Brain Res. 404, 395–400 (1987).

    Article  CAS  PubMed  Google Scholar 

  18. Alstermark, B., Lundberg, A., Pinter, M. & Sasaki, S. Long C3–C5 propriospinal neurones in the cat. Brain Res. 404, 382–388 (1987).

    Article  CAS  PubMed  Google Scholar 

  19. Alstermark, B., Kummel, H., Pinter, M.J. & Tantisira, B. Branching and termination of C3–C4 propriospinal neurones in the cervical spinal cord of the cat. Neurosci. Lett. 74, 291–296 (1987).

    Article  CAS  PubMed  Google Scholar 

  20. Alstermark, B., Isa, T., Kummel, H. & Tantisira, B. Projection from excitatory C3–C4 propriospinal neurones to lamina VII and VIII neurones in the C6-Th1 segments of the cat. Neurosci. Res. 8, 131–137 (1990).

    Article  CAS  PubMed  Google Scholar 

  21. Neafsey, E.J. et al. The organization of the rat motor cortex: a microstimulation mapping study. Brain Res. 396, 77–96 (1986).

    Article  CAS  PubMed  Google Scholar 

  22. De Ryck, M., Van Reempts, J., Duytschaever, H., Van Deuren, B. & Clincke, G. Neocortical localization of tactile/proprioceptive limb placing reactions in the rat. Brain Res. 573, 44–60 (1992).

    Article  CAS  PubMed  Google Scholar 

  23. Z'Graggen, W.J. et al. Compensatory sprouting and impulse rerouting after unilateral pyramidal tract lesion in neonatal rats. J. Neurosci. 20, 6561–6569 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Li, W.W., Yew, D.T., Chuah, M.I., Leung, P.C. & Tsang, D.S. Axonal sprouting in the hemisected adult rat spinal cord. Neuroscience 61, 133–139 (1994).

    Article  CAS  PubMed  Google Scholar 

  25. Aoki, M., Fujito, Y., Satomi, H., Kurosawa, Y. & Kasaba, T. The possible role of collateral sprouting in the functional restitution of corticospinal connections after spinal hemisection. Neurosci. Res. 3, 617–627 (1986).

    Article  CAS  PubMed  Google Scholar 

  26. Jankowska, E. & Hammar, I. Spinal interneurones; how can studies in animals contribute to the understanding of spinal interneuronal systems in man? Brain Res. Brain Res. Rev. 40, 19–28 (2002).

    Article  CAS  PubMed  Google Scholar 

  27. Mariani, J. Elimination of synapses during the development of the central nervous system. Prog. Brain Res. 58, 383–392 (1983).

    Article  CAS  PubMed  Google Scholar 

  28. Chen, C. & Regehr, W.G. Developmental remodeling of the retinogeniculate synapse. Neuron 28, 955–966 (2000).

    Article  CAS  PubMed  Google Scholar 

  29. Hubel, D.H., Wiesel, T.N. & LeVay, S. Plasticity of ocular dominance columns in monkey striate cortex. Philos. Trans. R. Soc. Lond. B Biol. Sci. 278, 377–409 (1977).

    Article  CAS  PubMed  Google Scholar 

  30. Colman, H., Nabekura, J. & Lichtman, J.W. Alterations in synaptic strength preceding axon withdrawal. Science 275, 356–361 (1997).

    Article  CAS  PubMed  Google Scholar 

  31. Masson, R.L., Jr., Sparkes, M.L. & Ritz, L.A. Descending projections to the rat sacrocaudal spinal cord. J. Comp. Neurol. 307, 120–130 (1991).

    Article  PubMed  Google Scholar 

  32. Jankowska, E., Lundberg, A. & Stuart, D. Propriospinal control of last order interneurones of spinal reflex pathways in the cat. Brain Res. 53, 227–231 (1973).

    Article  CAS  PubMed  Google Scholar 

  33. Raineteau, O., Fouad, K., Noth, P., Thallmair, M. & Schwab, M.E. Functional switch between motor tracts in the presence of the mAb IN-1 in the adult rat. Proc. Natl. Acad. Sci. USA 98, 6929–6934 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Bareyre, F.M., Haudenschild, B. & Schwab, M.E. Long-lasting sprouting and gene expression changes induced by the monoclonal antibody IN-1 in the adult spinal cord. J. Neurosci. 22, 7097–7110 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Gordon, T., Yang, J.F., Ayer, K., Stein, R.B. & Tyreman, N. Recovery potential of muscle after partial denervation: a comparison between rats and humans. Brain Res. Bull. 30, 477–482 (1993).

    Article  CAS  PubMed  Google Scholar 

  36. Card, J.P. et al. Neurotropic properties of pseudorabies virus: uptake and transneuronal passage in the rat central nervous system. J. Neurosci. 10, 1974–1994 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Strack, A.M., Sawyer, W.B., Platt, K.B. & Loewy, A.D. CNS cell groups regulating the sympathetic outflow to adrenal gland as revealed by transneuronal cell body labeling with pseudorabies virus. Brain Res. 491, 274–296 (1989).

    Article  CAS  PubMed  Google Scholar 

  38. Steward, O., Zheng, B. & Tessier-Lavigne, M. False resurrections: Distinguishing regenerated from spared axons in the injured central nervous system. J. Comp. Neurol. 459, 1–8 (2003).

    Article  PubMed  Google Scholar 

  39. Sloan, T.B. Anesthetic effects on electrophysiologic recordings. J. Clin. Neurophysiol. 15, 217–226 (1998).

    Article  CAS  PubMed  Google Scholar 

  40. Sanes, J.N., Suner, S. & Donoghue, J.P. Dynamic organization of primary motor cortex output to target muscles in adult rats. I. Long-term patterns of reorganization following motor or mixed peripheral nerve lesions. Exp. Brain Res. 79, 479–491 (1990).

    Article  CAS  PubMed  Google Scholar 

  41. Donoghue, J.P. Plasticity of adult sensorimotor representations. Curr. Opin. Neurobiol. 5, 749–754 (1995).

    Article  CAS  PubMed  Google Scholar 

  42. Kaas, J.H., Florence, S.L. & Jain, N. Subcortical contributions to massive cortical reorganizations. Neuron 22, 657–660 (1999).

    Article  CAS  PubMed  Google Scholar 

  43. Bruehlmeier, M. et al. How does the human brain deal with a spinal cord injury? Eur. J. Neurosci. 10, 3918–3922 (1998).

    Article  CAS  PubMed  Google Scholar 

  44. Chen, R., Corwell, B., Yaseen, Z., Hallett, M. & Cohen, L.G. Mechanisms of cortical reorganization in lower-limb amputees. J. Neurosci. 18, 3443–3450 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Nguyen, Q.T., Sanes, J.R. & Lichtman, J.W. Pre-existing pathways promote precise projection patterns. Nat. Neurosci. 5, 861–867 (2002).

    Article  CAS  PubMed  Google Scholar 

  46. Schnell, L. & Schwab, M.E. Sprouting and regeneration of lesioned corticospinal tract fibres in the adult rat spinal cord. Eur. J. Neurosci. 5, 1156–1171 (1993).

    Article  CAS  PubMed  Google Scholar 

  47. Merkler, D. et al. Locomotor recovery in spinal cord-injured rats treated with an antibody neutralizing the myelin-associated neurite growth inhibitor Nogo-A. J. Neurosci. 21, 3665–3673 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Jons, A. & Mettenleiter, T.C. Green fluorescent protein expressed by recombinant pseudorabies virus as an in vivo marker for viral replication. J. Virol. Methods 66, 283–292 (1997).

    Article  CAS  PubMed  Google Scholar 

  49. Herzog, A. & Brosamle, C. 'Semifree-floating' treatment: a simple and fast method to process consecutive sections for immunohistochemistry and neuronal tracing. J. Neurosci. Methods 72, 57–63 (1997).

    Article  CAS  PubMed  Google Scholar 

  50. Roof, R.L., Schielke, G.P., Ren, X. & Hall, E.D. A comparison of long-term functional outcome after 2 middle cerebral artery occlusion models in rats. Stroke 32, 2648–2657 (2001).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors would like to thank T. Misgeld for discussion, B. Klupp (TCM laboratory) for providing the PRV and the RK13 cells, K. Fouad, B. Haudenschild and J. Scholl for technical help and R. Schoeb for help with the photographs. The Swiss National Science Foundation (SNF, grant 31-63633.00), the SNF NCCR "neural plasticity and repair" and the Christopher Reeve Paralysis Foundation (Spinal Cord Consortium, Springfield, NJ) supported this work.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Florence M Bareyre.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Original photomicrographs of Fig. 1a-c without highlighting of CST collaterals. Legend equal to Fig. 1. (JPG 38 kb)

Supplementary Fig. 2

Quantification of sprouting of the intact ventral CST component in response to mid-thoracic dorsal hemisection in rats. (a): Sprouting of ventral CST collaterals into the cervical grey matter at 3 and 12 weeks after the lesion. (b): Sprouting of ventral CST collaterals into the lumbar grey matter at 3 and 12 weeks after the lesion. The quantification of "ventral collaterals/ main ventral CST" was performed in the cervical and lumbar enlargements of the spinal cord, in the segments C3 to C5 and L2 to L4 respectively. The absolute number of collaterals emanating from the main ventral CST tract and entering the gray matter was counted in 20 consecutive transverse sections. In order to correct for inter animal variation in the tracing efficiency, we divided the absolute number of ventral collaterals by the number of traced fibers in the main ventral CST. No significant differences were found between rats sustaining a mid-thoracic dorsal hemisection 3 or 12 weeks prior to the evaluation and their respective controls in the cervical cord. It is therefore unlikely that additional contacts between ventral CST collaterals and long propriospinal cell bodies are created in injured animals compared to control animals and contribute to the functional recovery described in our manuscript. However, the number of ventral collaterals per main ventral CST doubled in the lumbar cord in rats sustaining a mid-thoracic dorsal hemisection 3 or 12 weeks prior to the evaluation compared to their respective controls. Even if the difference did not reach statistical significance, it remains possible that ventral collaterals in the lumbar cord may also contribute to some of the functional recovery seen in our study e.g. by directly contacting lumbar motoneurons. This additional level of reorganization would be in line with a previous study10 in which the authors demonstrated that after bilateral section of the dorsal CST at cervical level C3, substantial sprouting from the spared ventral corticospinal tract occurred onto medial motoneuron pools in the cervical spinal cord caudal to the lesion. (JPG 38 kb)

Supplementary Fig. 3

Quantification of the close appositions formed by hindlimb CST collaterals on long propriospinal neurons in the cervical grey matter after treatment with the mIN-1 antibody, a control anti-HRP antibody or without treatment. No significant differences were found between the injured groups. (JPG 22 kb)

Supplementary Table 1 (PDF 14 kb)

Supplementary Note (PDF 7 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bareyre, F., Kerschensteiner, M., Raineteau, O. et al. The injured spinal cord spontaneously forms a new intraspinal circuit in adult rats. Nat Neurosci 7, 269–277 (2004). https://doi.org/10.1038/nn1195

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn1195

This article is cited by

Search

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