T12-L3 Nerve Transfer-Induced Locomotor Recovery in Rats with Thoracolumbar Contusion: Essential Roles of Sensory Input Rerouting and Central Neuroplasticity
Locomotor recovery after spinal cord injury (SCI) remains an unmet challenge. Nerve transfer (NT), the connection of a functional/expendable peripheral nerve to a paralyzed nerve root, has long been clinically applied, aiming to restore motor control. However, outcomes have been inconsistent, sugges...
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MDPI AG
2023-12-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/12/24/2804 |
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| author | Dou Yu Xiang Zeng Zaid S. Aljuboori Rachel Dennison Liquan Wu Jamie A. Anderson Yang D. Teng |
| author_facet | Dou Yu Xiang Zeng Zaid S. Aljuboori Rachel Dennison Liquan Wu Jamie A. Anderson Yang D. Teng |
| author_sort | Dou Yu |
| collection | DOAJ |
| description | Locomotor recovery after spinal cord injury (SCI) remains an unmet challenge. Nerve transfer (NT), the connection of a functional/expendable peripheral nerve to a paralyzed nerve root, has long been clinically applied, aiming to restore motor control. However, outcomes have been inconsistent, suggesting that NT-induced neurological reinstatement may require activation of mechanisms beyond motor axon reinnervation (<i>our hypothesis</i>). We previously reported that to enhance rat locomotion following T13-L1 hemisection, T12-L3 NT must be performed within timeframes optimal for sensory nerve regrowth. Here, T12-L3 NT was performed for adult female rats with subacute (7–9 days) or chronic (8 weeks) mild (SCI<sub>mi</sub>: 10 g × 12.5 mm) or moderate (SCI<sub>mo</sub>: 10 g × 25 mm) T13-L1 thoracolumbar contusion. For chronic injuries, T11-12 implantation of adult hMSCs (1-week before NT), post-NT intramuscular delivery of FGF2, and environmentally enriched/enlarged (EEE) housing were provided. NT, not control procedures, qualitatively improved locomotion in both SCI<sub>mi</sub> groups and animals with subacute SCI<sub>mo</sub>. However, delayed NT did not produce neurological scale upgrading conversion for SCI<sub>mo</sub> rats. Ablation of the T12 ventral/motor or dorsal/sensory root determined that the T12-L3 sensory input played a key role in hindlimb reanimation. Pharmacological, electrophysiological, and trans-synaptic tracing assays revealed that NT strengthened integrity of the propriospinal network, serotonergic neuromodulation, and the neuromuscular junction. Besides key outcomes of thoracolumbar contusion modeling, the data provides the first evidence that mixed NT-induced locomotor efficacy may rely pivotally on sensory rerouting and pro-repair neuroplasticity to reactivate neurocircuits/central pattern generators. The finding describes a novel neurobiology mechanism underlying NT, which can be targeted for development of innovative neurotization therapies. |
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| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-08T20:54:38Z |
| publishDate | 2023-12-01 |
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| spelling | doaj.art-4e3f8caf12fe432dbeda10239435e2162023-12-22T13:59:38ZengMDPI AGCells2073-44092023-12-011224280410.3390/cells12242804T12-L3 Nerve Transfer-Induced Locomotor Recovery in Rats with Thoracolumbar Contusion: Essential Roles of Sensory Input Rerouting and Central NeuroplasticityDou Yu0Xiang Zeng1Zaid S. Aljuboori2Rachel Dennison3Liquan Wu4Jamie A. Anderson5Yang D. Teng6Department of Physical Medicine and Rehabilitation, Harvard Medical School, Boston, MA 02129, USADepartment of Physical Medicine and Rehabilitation, Harvard Medical School, Boston, MA 02129, USADepartment of Physical Medicine and Rehabilitation, Harvard Medical School, Boston, MA 02129, USADepartment of Physical Medicine and Rehabilitation, Harvard Medical School, Boston, MA 02129, USADepartment of Physical Medicine and Rehabilitation, Harvard Medical School, Boston, MA 02129, USADepartment of Physical Medicine and Rehabilitation, Harvard Medical School, Boston, MA 02129, USADepartment of Physical Medicine and Rehabilitation, Harvard Medical School, Boston, MA 02129, USALocomotor recovery after spinal cord injury (SCI) remains an unmet challenge. Nerve transfer (NT), the connection of a functional/expendable peripheral nerve to a paralyzed nerve root, has long been clinically applied, aiming to restore motor control. However, outcomes have been inconsistent, suggesting that NT-induced neurological reinstatement may require activation of mechanisms beyond motor axon reinnervation (<i>our hypothesis</i>). We previously reported that to enhance rat locomotion following T13-L1 hemisection, T12-L3 NT must be performed within timeframes optimal for sensory nerve regrowth. Here, T12-L3 NT was performed for adult female rats with subacute (7–9 days) or chronic (8 weeks) mild (SCI<sub>mi</sub>: 10 g × 12.5 mm) or moderate (SCI<sub>mo</sub>: 10 g × 25 mm) T13-L1 thoracolumbar contusion. For chronic injuries, T11-12 implantation of adult hMSCs (1-week before NT), post-NT intramuscular delivery of FGF2, and environmentally enriched/enlarged (EEE) housing were provided. NT, not control procedures, qualitatively improved locomotion in both SCI<sub>mi</sub> groups and animals with subacute SCI<sub>mo</sub>. However, delayed NT did not produce neurological scale upgrading conversion for SCI<sub>mo</sub> rats. Ablation of the T12 ventral/motor or dorsal/sensory root determined that the T12-L3 sensory input played a key role in hindlimb reanimation. Pharmacological, electrophysiological, and trans-synaptic tracing assays revealed that NT strengthened integrity of the propriospinal network, serotonergic neuromodulation, and the neuromuscular junction. Besides key outcomes of thoracolumbar contusion modeling, the data provides the first evidence that mixed NT-induced locomotor efficacy may rely pivotally on sensory rerouting and pro-repair neuroplasticity to reactivate neurocircuits/central pattern generators. The finding describes a novel neurobiology mechanism underlying NT, which can be targeted for development of innovative neurotization therapies.https://www.mdpi.com/2073-4409/12/24/2804nerve transferspinal cord injurycontusionsensory nerveneuroplasticitylocomotion |
| spellingShingle | Dou Yu Xiang Zeng Zaid S. Aljuboori Rachel Dennison Liquan Wu Jamie A. Anderson Yang D. Teng T12-L3 Nerve Transfer-Induced Locomotor Recovery in Rats with Thoracolumbar Contusion: Essential Roles of Sensory Input Rerouting and Central Neuroplasticity Cells nerve transfer spinal cord injury contusion sensory nerve neuroplasticity locomotion |
| title | T12-L3 Nerve Transfer-Induced Locomotor Recovery in Rats with Thoracolumbar Contusion: Essential Roles of Sensory Input Rerouting and Central Neuroplasticity |
| title_full | T12-L3 Nerve Transfer-Induced Locomotor Recovery in Rats with Thoracolumbar Contusion: Essential Roles of Sensory Input Rerouting and Central Neuroplasticity |
| title_fullStr | T12-L3 Nerve Transfer-Induced Locomotor Recovery in Rats with Thoracolumbar Contusion: Essential Roles of Sensory Input Rerouting and Central Neuroplasticity |
| title_full_unstemmed | T12-L3 Nerve Transfer-Induced Locomotor Recovery in Rats with Thoracolumbar Contusion: Essential Roles of Sensory Input Rerouting and Central Neuroplasticity |
| title_short | T12-L3 Nerve Transfer-Induced Locomotor Recovery in Rats with Thoracolumbar Contusion: Essential Roles of Sensory Input Rerouting and Central Neuroplasticity |
| title_sort | t12 l3 nerve transfer induced locomotor recovery in rats with thoracolumbar contusion essential roles of sensory input rerouting and central neuroplasticity |
| topic | nerve transfer spinal cord injury contusion sensory nerve neuroplasticity locomotion |
| url | https://www.mdpi.com/2073-4409/12/24/2804 |
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