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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.

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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.

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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.

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Correspondence to Florence M Bareyre.

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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)

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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

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