Axonal regeneration and formation of synapses proximal to the site of lesion following hemisection of the rat spinal cord

doi:10.1016/S0014-4886(71)80012-2

Experimental Neurology

Volume 30, Issue 2, February 1971, Pages 336-351

https://doi.org/10.1016/S0014-4886(71)80012-2 Get rights and content

Although the central nervous system of the mammal is reported not to regenerate, axonal sprouting has recently been demonstrated in various regions of brain and spinal cord. The following study investigates the regenerative capacity of 72 rat spinal cords following left hemisection at T2. In addition to nine normals, rats were killed at 5, 7, 14, 30, 60, and 90 days after making the lesion. Three animals per groups were prepared for Golgi, Protargol-eosin-cresyl violet staining, and electron microscopy. Three additional animals had hemisections at C5 and the cord from C5 to T5 was stained by the Fink-Heimer method. Six animals had hemisections at T2 and the cords were subsequently rehemisected 90 days later at C5; three animals were prepared for the Fink-Heimer stain and three for electron microscopy. The dendrites of the reactive motor neurons proximal to the site of lesion became varicose from day 10 to day 60–90 after the lesion, until the entire dendrite was replete with irregularly shaped varicosities. At 15 days postoperatively, processes grew into the reactive neural zone and by day 30 could be identifified as axons (0.1–0.5 μ in diameter) and dendrites. The axons grew in fascicles, usually free of neuroglial cell processes. The amjority of the axons formed axodendritic synapses on the indentations of the dendritic varicosities by 60–90 days postoperatively. The Fink-Heimer stain reveled that a limited number of axons regenerated from long tracts into the reactive neural zone. Most regenerated axons appear to be axonal sprouts from the operated and unoporated portions of the spinal cord. The central nervous system of the rat does regenerate, but the regenerating axons do not grow past the reactive neural zone and thus do not reach the neuroglial scar.

References (28)

AttardiD. et al.
Preferential selection of central pathways by regenerating optic fibers
Exp. Neurol.
(1963)
BernsteinJ.J.
Relation of spinal cord regeneration to age in adult goldfish
Exp. Neurol.
(1964)
BernsteinJ.J. et al.
Regeneration of the long spinal tracts in the goldfish
Brain Res.
(1970)
ClementeC.D.
Regeneration in the vertebrate central nervous system
Int. Rev. Neurobiol.
(1964)
FinkR.P. et al.
Two methods for selective silver impregnation of degenerating axons and their synaptic endings in the central nervous system
Brain Res.
(1967)
GuthL.
Neuromuscular function after regeneration of interrupted nerve fibers into partially denervated muscle
Exp. Neurol.
(1962)
GuthL. et al.
Selectivity in the re-establishment of synapses in the superior cervical sympathetic ganglion of the cat
Exp. Neurol.
(1961)
RaismanG.
Neuronal plasticity in the septal nuclei of the adult rat
Brain Res.
(1969)
ScottD. et al.
Factors promoting regeneration of spinal neurons: Positive influence of nerve growth factor
Progr. Brain Res.
(1964)
BernsteinJ.J. et al.
The enigma of cental nervous regeneration
Exp. Neurol. Suppl.
(1970)

EddsM.V.

Collateral nerve regeneration

Quart. Rev. Biol.

(1953)

GoodmanD.C. et al.

Sprouting of optic tract projections in the brain stem of the rat

J. Comp. Neurol.

(1966)

GoodmanD.C. et al.

Corticospinal pathways and their sites of termination in the albino rat

Anat. Rec.

(1966)

JacobsonK. et al.

Selection of appropriate tectal connections by regenerating optic nerve fibers in adult goldfish

Exp. Neurol.

(1965)

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This correlates closely with studies in humans where, even years after spinal cord lesion, patients with functionally complete spinal cord injuries displayed normal numbers of axons in the corticospinal tract above the lesion site [103]. Moreover, the finding that lesioned corticospinal axons are able to sprout above the lesion site and form new synaptic contacts, strongly argues against significant retrograde degeneration of lesioned neurons or of their axons above the lesion site [89,104,105]. The presence of axonal lesions in MS patients might indicate that the parent neuron has a similar dying-back mechanism as has been shown for axonal lesions in peripheral nervous system (PNS) disorders.
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¹: Supported by NIH grant NS 06164 (HEW).

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Axonal regeneration and formation of synapses proximal to the site of lesion following hemisection of the rat spinal cord

Exp. Neurol.

Exp. Neurol.

Brain Res.

Int. Rev. Neurobiol.

Brain Res.

Exp. Neurol.

Exp. Neurol.

Brain Res.

Progr. Brain Res.

The enigma of cental nervous regeneration

Exp. Neurol. Suppl.

Collateral nerve regeneration

Quart. Rev. Biol.

Sprouting of optic tract projections in the brain stem of the rat

J. Comp. Neurol.

Corticospinal pathways and their sites of termination in the albino rat

Anat. Rec.

Selection of appropriate tectal connections by regenerating optic nerve fibers in adult goldfish

Exp. Neurol.