Neuronal activity in vivo enhances functional myelin repair
Neuronal activity in vivo enhances functional myelin repair
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DOI：
10.1172/jci.insight.123434
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发表时间：
2019-05-02
期刊：
影响因子：
8
通讯作者：
Angulo, Maria Cecilia
中科院分区：
文献类型：
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作者：
Ortiz, Fernando C.;Habermacher, Chloe;Angulo, Maria Cecilia
在脱髓鞘疾病中，如多发性硬化症，神经元纤维脱髓鞘损害冲动传导并引起轴突变性。虽然在正常情况下神经元活动刺激少突胶质细胞的产生和髓鞘形成，但目前尚不清楚脱髓鞘轴突的活动是否能恢复其在有害环境中的功能丧失。为了研究这一问题，我们建立了一个模型，在运动皮质水平诱导中度光遗传刺激胼胝体脱髓鞘轴突，使成年自由运动小鼠的皮层回路激活和运动效应降低。我们证明，脱髓鞘轴突的适度激活可增强少突胶质细胞前体细胞向成熟少突胶质细胞的分化，但仅在重复刺激模式下。超微结构分析和复合动作电位记录显示，这种活性依赖性的少突胶质细胞池的增加促进了广泛的髓鞘再生和传导功能的恢复。我们的研究结果表明，需要在受损组织中保留适当的神经元活性，以促进少突胶质细胞分化和再髓鞘形成，可能是通过增强轴突-少突胶质细胞的相互作用。我们的研究结果为脱髓鞘疾病中神经调节的转化研究提供了新的视角。
In demyelinating diseases, such as multiple sclerosis, demyelination of neuronal fibers impairs impulse conduction and causes axon degeneration. Although neuronal activity stimulates oligodendrocyte production and myelination in normal conditions, it remains unclear whether the activity of demyelinated axons restores their loss of function in a harmful environment. To investigate this question, we established a model to induce a moderate optogenetic stimulation of demyelinated axons in the corpus callosum at the level of the motor cortex in which cortical circuit activation and locomotor effects were reduced in adult freely moving mice. We demonstrate that a moderate activation of demyelinated axons enhances the differentiation of oligodendrocyte precursor cells onto mature oligodendrocytes but only under a repeated stimulation paradigm. This activity-dependent increase in the oligodendrocyte pool promotes an extensive remyelination and functional restoration of conduction, as revealed by ultrastructural analyses and compound action potential recordings. Our findings reveal the need for preserving an appropriate neuronal activity in the damaged tissue to promote oligodendrocyte differentiation and remyelination, likely by enhancing axon-oligodendroglia interactions. Our results provide new perspectives for translational research using neuromodulation in demyelinating diseases.