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Neurite growth inhibitors restrict plasticity and functional recovery following corticospinal tract lesions

A Correction to this article was published on 01 August 1998

Abstract

Anatomical plasticity and functional recovery after lesions of the rodent corticospinal tract (CST) decrease postnatally in parallel with myelin formation. Myelin-associated neurite growth inhibitory proteins prevent regenerative fiber growth, but whether they also prevent reactive sprouting of unlesioned fibers is less clear. Here we show that after unilateral CST lesion in the adult rat brainstem, both intact and lesioned tracts show topographically appropriate sprouting after treatment with a monoclonal antibody that neutralizes these inhibitory proteins. Antibody-treated animals showed full recovery in motor and sensory tests, whereas untreated lesioned rats exhibited persistent severe deficits. Neutralization of myelin-associated neurite growth inhibitors thus restores in adults the structural plasticity and functional recovery normally found only at perinatal ages.

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Figure 1: Treatment with IN-1 increases lesion-induced sprouting of the intact CST, as revealed by the increased number of fibers crossing the spinal cord midline.
Figure 2: Corticobulbar axons establish a bilateral projection in the red nucleus and pons after unilateral pyramidotomy and treatment with IN-1.
Figure 3: Treatment with IN-1 induces a partial reinnervation of the dorsal column nuclei after pyramidotomy.
Figure 4: Schematic representation of the lesion site and the corticospinal projections that were examined in this study.
Figure 5: The monoclonal antibody IN-1 leads to functional recovery in the food-pellet reaching task.
Figure 6: Treatment with IN-1 improves performance in the sticky-paper and rope-climbing tests.
Figure 7: Footprint analysis: angle of forelimb rotation.

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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  Google Scholar 

  2. Schnell, L. Schwab, M.E. Axonal regeneration in the rat spinal cord produced by an antibody against myelin-associated neurite growth inhibitors . Nature 343, 269–272 (1990).

    Article  CAS  Google Scholar 

  3. 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  Google Scholar 

  4. Bregman, B.S. et al. Recovery from spinal cord injury mediated by antibodies to neurite growth inhibitors. Nature 378, 498– 501 (1995).

    Article  CAS  Google Scholar 

  5. Whishaw, I.Q. Kolb, B. Sparing of skilled forelimb reaching and corticospinal projections after neonatal motor cortex removal or hemidecortication in the rat: support for the Kennard doctrine. Brain Res. 451, 97–114 (1988).

    Article  CAS  Google Scholar 

  6. Reh, T. Kalil, K. Functional role of regrowing pyramidal tract fibers . J. Comp. Neurol. 211, 276– 283 (1982).

    Article  CAS  Google Scholar 

  7. Barth, T.M. Stanfield, B.B. The recovery of forelimb-placing behavior in rats with neonatal unilateral cortical damage involves the remaining hemisphere . J. Neurosci. 10, 3449– 3459 (1990).

    Article  CAS  Google Scholar 

  8. Kennard, M.A. Age and other factors in motor recovery from precentral lesions in monkeys. Am. J. Physiol. 115, 138–146 (1936).

    Article  Google Scholar 

  9. Farmer, S.F. Harrison, L.M. Ingram, D.A. Stephens, J.A. Plasticity of central motor pathways in children with hemiplegic cerebral palsy. Neurology 41, 1505–1510 (1991).

    Article  CAS  Google Scholar 

  10. Carr, L.J. Harrison, L.M. Evans, A.L. Stephens, J.A. Patterns of central motor reorganization in hemiplegic cerebral palsy. Brain 116, 1223–1247 (1993).

    Article  Google Scholar 

  11. Kalil, K. Reh, T. Regrowth of severed axons in the neonatal central nervous system: establishment of normal connections. Science 205, 1158–1161 (1979).

    Article  CAS  Google Scholar 

  12. Kuang, R.Z. Kalil, K. Specificity of corticospinal axon arbors sprouting into denervated contralateral spinal cord. J. Comp. Neurol. 302, 461–472 ( 1990).

    Article  CAS  Google Scholar 

  13. Kapfhammer, J.P. Schwab, M.E. Inverse patterns of myelination and GAP-43 expression in the adult CNS: neurite growth inhibitors as regulators of neuronal plasticity? J. Comp. Neurol. 340, 194–206 (1994).

    Article  CAS  Google Scholar 

  14. Vanek, P. Thallmair, M. Schwab, M.E. Kapfhammer, J.P. Increased lesion-induced sprouting in the myelin-free rat spinal cord. Eur. J. Neurosci. 10, 45–56 (1998).

    Article  CAS  Google Scholar 

  15. Hicks, S.P. D'Amato, C.J. Motor-sensory and visual behavior after hemispherectomy in newborn and mature rats. Exp. Neurol. 29, 416–438 (1970).

    Article  CAS  Google Scholar 

  16. Kalil, K. Reh, T. A light and electron microscopic study of regrowing pyramidal tract fibers. J. Comp. Neurol. 211, 265–275 (1982).

    Article  CAS  Google Scholar 

  17. Valverde, F. The pyramidal tract in rodents. A study of its relations with the posterior column nuclei, dorsolateral reticular formation of the medulla oblongata, and cervical spinal cord (Golgi and electron microsopic observations). J. Zellforsch. 71, 297–363 ( 1966).

    Article  Google Scholar 

  18. Casale, E.J. Light, A.R. Rustioni, A. Direct projection of the corticospinal tract to the superficial laminae of the spinal cord in the rat. J. Comp. Neurol. 278, 275–286 (1988).

    Article  CAS  Google Scholar 

  19. Kuang, R.Z. Kalil, K. Branching patterns of corticospinal axon arbors in the rodent. J. Comp. Neurol. 292, 585–598 (1990).

    Article  CAS  Google Scholar 

  20. Liang, F.Y. Moret, V. Wiesendanger, M. Rouiller, E.M. Corticomotoneuronal connections in the rat: evidence from double-labeling of motoneurons and corticospinal axon arborizations. J. Comp. Neurol. 311, 356–366 (1991).

    Article  CAS  Google Scholar 

  21. Brösamle, C. Schwab, M.E. Cells Of Origin, Course, and Termination Patterns Of the Ventral, Uncrossed Component Of the Mature Rat Corticospinal Tract. J. Comp. Neurol. 386, 293– 303 (1997).

    Article  Google Scholar 

  22. Flumerfelt, B.A. An ultrastructural investigation of afferent connections of the red nucleus in the rat. J. Anat. 131, 621–633 ( 1980).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Naus, C.G. Flumerfelt, B.A. Hrycyshyn, A.W. An HRP-TMB ultrastructural study of rubral afferents in the rat. J. Comp. Neurol. 239, 453–465 (1985).

    Article  CAS  Google Scholar 

  24. Mihailoff, G.A. Burne, R.A. Woodward, D.J. Projections of the sensorimotor cortex to the basilar pontine nuclei in the rat: an autoradiographic study. Brain Res. 145, 347–354 ( 1978).

    Article  CAS  Google Scholar 

  25. Wiesendanger, R. Wiesendanger, M. The corticopontine system in the rat. II. The projection pattern. J. Comp. Neurol. 208, 227–238 (1982).

    Article  CAS  Google Scholar 

  26. Rouiller, E.M. Moret, V. Liang, F. Comparison of the connectional properties of the two forelimb areas of the rat sensorimotor cortex: support for the presence of a premotor or supplementary motor cortical area. Somatosens. Mot. Res. 10, 269–289 (1993).

    Article  CAS  Google Scholar 

  27. Panto, M.R. Cicirata, F. Angaut, P. Parenti, R. Serapide, F. The projection from the primary motor and somatic sensory cortex to the basilar pontine nuclei. A detailed electrophysiological and anatomical study in the rat. J. Hirnforsch. 36, 7– 19 (1995).

    CAS  PubMed  Google Scholar 

  28. Whishaw, I.Q. Pellis, S.M. Gorny, B. Kolb, B. Tetzlaff, W. Proximal and distal impairments in rat forelimb use in reaching follow unilateral pyramidal tract lesion. Behav. Brain Res. 56, 59–76 (1993).

    Article  CAS  Google Scholar 

  29. Spillmann, A.A. Amberger, V.R. Schwab, M.E. High molecular weight protein of human central nervous system myelin inhibits neuriite outgrowth: An effect which can be neutralized by the monoclonal antibody IN-1. Eur. J. Neurosci. 9, 549–555 (1997).

    Article  CAS  Google Scholar 

  30. Rubin, B.P. Dusart, I. Schwab, M.E. A monoclonal antibody (IN-1) which neutralizes neurite growth inhibitory proteins in the rat CNS recognizes antigens localized in CNS myelin. J. Neurocytol. 23, 209–217 (1994).

    Article  CAS  Google Scholar 

  31. Rouiller, E.M. Liang, F.Y. Moret, V. Wiesendanger, M. Trajectory of redirected corticospinal axons after unilateral lesion of the sensorimotor cortex in neonatal rat; a phaseolus vulgaris-leucoagglutinin (PHA-L) tracing study. Exp. Neurol. 114, 53–65 ( 1991).

    Article  CAS  Google Scholar 

  32. Bandtlow, C. Schiweck, W. Tai, H.H. Schwab, M.E. Skerra, A. The Escherichia coli-derived Fab fragment of the IgM/kappa antibody IN-1 recognizes and neutralizes myelin-associated inhibitors of neurite growth. Eur. J. Biochem. 241, 468–475 (1996).

    Article  CAS  Google Scholar 

  33. Akintunde, A. Buxton, D.F. Origins and collateralization of corticospinal, corticopontine, corticorubral and corticostriatal tracts: a multiple retrograde fluorescent tracing study. Brain Res. 586, 208–218 (1992).

    Article  CAS  Google Scholar 

  34. Antal, M. Termination areas of corticobulbar and corticospinal fibres in the rat. J. Hirnforsch. 25, 647–659 ( 1984).

    CAS  PubMed  Google Scholar 

  35. Castro, A.J. Motor performance in rats. The effects of pyramidal tract section. Brain Res. 44, 313–23 (1972).

    Article  CAS  Google Scholar 

  36. Caroni, P. Schwab, M.E. Antibody against myelin-associated inhibitor of neurite growth neutralizes nonpermissive substrate properties of CNS white matter. Neuron 1, 85–96 (1988).

    Article  CAS  Google Scholar 

  37. Leong, S.K. Lund, R.D. Anomalous bilateral corticofugal pathways in albino rats after neonatal lesions. Brain Res. 62 , 218–221 (1973).

    Article  CAS  Google Scholar 

  38. Naus, C.G. Flumerfelt, B.A. Hrycyshyn, A.W. An anterograde HRP-WGA study of aberrant corticorubral projections following neonatal lesions of rat sensorimotor cortex. Exp. Brain Res. 59, 365–371 (1985).

    Article  CAS  Google Scholar 

  39. Castro, A.J. Mihailoff, G.A. Corticopontine remodelling after cortical and/or cerebellar lesions in newborn rats. J. Comp. Neurol. 219, 112–123 (1983).

    Article  CAS  Google Scholar 

  40. Fagan, A.M. et al. Endogenous FGF-2 is important for cholinergic sprouting in the denervated hippocampus. J. Neurosci. 17, 2499– 2511 (1997).

    Article  CAS  Google Scholar 

  41. Thoenen, H. Neurotrophins and neuronal plasticity. Science 270, 593 –598 (1995).

    Article  CAS  Google Scholar 

  42. Kalil, K. Schneider, G.E. Motor performance following unilateral pyramidal tract lesions in the hamster. Brain Res. 100, 170–174 (1975).

    Article  CAS  Google Scholar 

  43. Castro, A.J. The effects of cortical ablations on digital usage in the rat. Brain Res. 37, 173–85 (1972).

    Article  CAS  Google Scholar 

  44. Endo, K. Araki, T. Yagi, N. The distribution and pattern of axon branching of pyramidal tract cells. Brain Res. 57, 484–491 ( 1973).

    Article  CAS  Google Scholar 

  45. Cao, Y. Vikingstad, E.M. Huttenlocher, P.R. Towle, V.L. Levin, D.N. Functional magnetic resonance studies of the reorganization of the human hand sensorimotor area after unilateral brain injury in the perinatal period. Proc. Natl Acad. Sci.U.S.A. 91, 9612–9616 ( 1994).

    Article  CAS  Google Scholar 

  46. Herzog, A. Brösamle, 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  Google Scholar 

  47. Kartje-Tillotson, G. Castro, A.J. Limb preference after unilateral pyramidotomy in adult and neonatal rats. Physiol. Behav. 24, 293–296 (1980).

    Article  CAS  Google Scholar 

  48. Carlini, E.A. Teresa, M. Silva, A. Cesare, L.C. Endo, R.M. Effects of administration of B-(3,4-dimethoxyphenyl)-ethylamine and B-(3,4,5-trimethoxyphenyl)-ethylamine on the climbing rope performance of rats. Med. Pharmacol. Exp. 17, 534–542 ( 1967).

    CAS  Google Scholar 

  49. Hernandez, T.D. Schallert, T. Seizures and recovery from experimental brain damage. Exp. Neurol. 102, 318– 324 (1988).

    Article  CAS  Google Scholar 

  50. de Medinaceli, L. Freed, W.J. Wyatt, R.J. An index of the functional condition of rat sciatic nerve based on measurements made from walking tracks. Exp. Neurol. 77, 634–643 (1982).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Regula Schneider, Ruedi Kägi and Martina Weber for technical assistance. Roland Schoeb helped with photography and Eva Hochreutener with the graphics. This work was supported by the Swiss National Science Foundation, the International Research Institute of Paraplegia (Zürich) and the American Paralysis Association (Springfield, New Jersey).

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Correspondence to Michaela Thallmair.

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Thallmair, M., Metz, G., Z'Graggen, W. et al. Neurite growth inhibitors restrict plasticity and functional recovery following corticospinal tract lesions. Nat Neurosci 1, 124–131 (1998). https://doi.org/10.1038/373

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