Ischemic stroke causes neuron loss and long-term functional deficits. Unfortunately, effective approaches to preserve neurons and promote functional recovery remain unavailable. Oligodendrocytes (OLs), the myelinating cells in the CNS, are susceptible to oxygen and nutrition deprivation and undergo degeneration after ischemic stroke. Technically, new OLs and myelin can be generated from the differentiation of oligodendrocyte precursor cells (OPCs). However, myelin dynamics and their functional significance after ischemic stroke remain poorly understood. Here, we reported numerous denuded axons in the lesion of human brain sections with ischemic stroke, accompanied by decreased neuron density, suggesting neuron loss correlates with myelin deficits in the stroke lesion. To understand the longitudinal changes of myelin dynamics after stroke, we label and trace pre-existing or newly-formed myelin, respectively, by using cell-specific genetic approaches. Our results indicated massive OLs death and myelin loss 2 weeks after stroke in the transient middle cerebral artery occlusion (tMCAO) mouse model. In contrast, myelin regeneration remains insufficient 4- and 8-weeks post-stroke. Notably, neuronal loss and functional impairments are further deteriorated in aged brains, along with vanishing new myelin generation. To understand the causal relationship between remyelination and neuron survival, we manipulate myelinogenesis by conditional deletion of Olig2 (a positive regulator) or the muscarinic receptor 1 (M1R, a negative regulator) in OPCs. Deleting Olig2 inhibits remyelination, dampening neuron survival and functional recovery after tMCAO. Conversely, enhancing remyelination by M1R cKO or treating the pro-myelination drug clemastine after tMCAO preserves white matter integrity and neuronal survival, and accelerates functional recovery. Together, our findings demonstrate that enhancing myelinogenesis is a promising strategy to preserve neurons and promote functional recovery after ischemic stroke.

中文翻译：

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长期髓磷脂缺陷导致缺血性中风后神经元损失和功能障碍

缺血性中风会导致神经元损失和长期功能缺陷。不幸的是，保护神经元和促进功能恢复的有效方法仍然不存在。少突胶质细胞（OL）是中枢神经系统中的髓鞘细胞，容易受到氧气和营养缺乏的影响，并在缺血性中风后发生退化。从技术上讲，少突胶质细胞前体细胞 (OPC) 的分化可以产生新的 OL 和髓磷脂。然而，缺血性中风后髓磷脂动力学及其功能意义仍知之甚少。在这里，我们报告了缺血性中风的人脑切片病变中存在大量轴突裸露，并伴有神经元密度降低，表明神经元损失与中风病变中的髓磷脂缺陷相关。为了了解中风后髓磷脂动力学的纵向变化，我们通过使用细胞特异性遗传方法分别标记和追踪预先存在的或新形成的髓磷脂。我们的结果表明，在短暂性大脑中动脉闭塞 (tMCAO) 小鼠模型中，中风后 2 周出现大量 OL 死亡和髓鞘质损失。相比之下，中风后 4 周和 8 周髓磷脂再生仍然不足。值得注意的是，随着新髓磷脂生成的消失，衰老大脑中的神经元损失和功能损伤进一步恶化。为了了解髓鞘再生和神经元存活之间的因果关系，我们通过条件性删除 OPC 中的 Olig2（正调节因子）或毒蕈碱受体 1（M1R，负调节因子）来操纵髓鞘形成。删除 Olig2 会抑制髓鞘再生，抑制 tMCAO 后神经元的存活和功能恢复。相反，在 tMCAO 后通过 M1R cKO 增强髓鞘再生或治疗促髓鞘形成药物氯马斯汀可保留白质完整性和神经元存活，并加速功能恢复。总之，我们的研究结果表明，增强髓磷脂生成是保护神经元并促进缺血性中风后功能恢复的一种有前途的策略。