T12-L3 Nerve Transfer-Induced Locomotor Recovery in Rats with Thoracolumbar Contusion: Essential Roles of Sensory Input Rerouting and Central Neuroplasticity.
T12-L3 Nerve Transfer-Induced Locomotor Recovery in Rats with Thoracolumbar Contusion: Essential Roles of Sensory Input Rerouting and Central Neuroplasticity.
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脊髓损伤（SCI）后的运动恢复仍然是一个尚未解决的挑战。神经移植（NT）是将功能性/消耗性周围神经连接到瘫痪的神经根，长期以来一直应用于临床，旨在恢复运动控制。然而，结果并不一致，这表明NT诱导的神经恢复可能需要激活运动轴突再神经支配以外的机制（我们的假设）。我们以前曾报道，以提高大鼠运动后T13-L1半切，T12-L3 NT必须在最佳的时间范围内进行感觉神经再生。在此，对患有亚急性（7-9天）或慢性（8周）轻度（SCImi：10 g × 12.5 mm）或中度（SCImo：10 g × 25 mm）T13-L1胸腰椎挫伤的成年雌性大鼠进行T12-L3 NT。对于慢性损伤，提供了T11-12植入成人hMSC（NT前1周）、NT后肌内递送FGF 2和环境富集/扩大（environmentally enriched/enlarged）（NT）住房。NT，而不是对照程序，在SCImi组和亚急性SCImo动物中定性改善运动。然而，延迟NT并没有产生SCImo大鼠神经系统的规模升级转换。T12腹侧/运动或背侧/感觉根的消融确定T12-L3感觉输入在后肢复活中起关键作用。药理学、电生理学和跨突触追踪分析表明，NT加强了本体脊髓网络、神经元能神经调节和神经肌肉接头的完整性。除了胸腰椎挫伤建模的关键结果外，数据提供了第一个证据，即混合NT诱导的运动功效可能依赖于感觉重新路由和促修复神经可塑性来重新激活神经回路/中央模式发生器。这一发现描述了NT的一种新的神经生物学机制，可用于开发创新的神经化疗法。
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 (our hypothesis). 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 (SCImi: 10 g × 12.5 mm) or moderate (SCImo: 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 SCImi groups and animals with subacute SCImo. However, delayed NT did not produce neurological scale upgrading conversion for SCImo 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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