脊髓损伤(SCI)后的运动恢复仍然是一个未满足的挑战。神经转移(NT),功能性/消耗性周围神经与瘫痪神经根的连接,长期以来一直在临床上应用,旨在恢复电机控制。然而,结果不一致,提示NT诱导的神经恢复可能需要激活运动轴突神经支配以外的机制(我们的假设)。我们以前报道过,为了增强T13-L1半切后的大鼠运动,T12-L3NT必须在感觉神经再生的最佳时间范围内进行。这里,对亚急性(7-9天)或慢性(8周)轻度(SCImi:10g×12.5mm)或中度(SCImo:10g×25mm)T13-L1胸腰椎挫伤的成年雌性大鼠进行T12-L3NT。对于慢性损伤,T11-12成人hMSCs植入(NT前1周),提供了FGF2的NT后肌内递送和环境富集/扩大(EEE)外壳。NT,非控制程序,SCImi组和亚急性SCImo动物的运动能力均得到定性改善。然而,延迟NT未产生SCImo大鼠的神经学量表升级转换。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,和跨突触示踪分析显示NT增强了原脊髓网络的完整性,血清素能神经调节,和神经肌肉接头.除了胸腰椎挫伤建模的关键结果,这些数据提供了第一个证据,即混合NT诱导的运动功效可能主要依赖于感觉重新路由和前修复神经可塑性,从而重新激活神经回路/中枢模式发生器.这一发现描述了一种新的神经生物学机制,可以有针对性地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.