Chemotherapy results in a frequent yet poorly understood syndrome of long-term neurological deficits. Neural precursor cell dysfunction and white matter dysfunction are thought to contribute to this debilitating syndrome. Here, we demonstrate persistent depletion of oligodendrocyte lineage cells in humans who received chemotherapy. Developing a mouse model of methotrexate chemotherapy-induced neurological dysfunction, we find a similar depletion of white matter OPCs, increased but incomplete OPC differentiation, and a persistent deficit in myelination. OPCs from chemotherapy-naive mice similarly exhibit increased differentiation when transplanted into the microenvironment of previously methotrexate-exposed brains, indicating an underlying microenvironmental perturbation. Methotrexate results in persistent activation of microglia and subsequent astrocyte activation that is dependent on inflammatory microglia. Microglial depletion normalizes oligodendroglial lineage dynamics, myelin microstructure, and cognitive behavior after methotrexate chemotherapy. These findings indicate that methotrexate chemotherapy exposure is associated with persistent tri-glial dysregulation and identify inflammatory microglia as a therapeutic target to abrogate chemotherapy-related cognitive impairment. VIDEO ABSTRACT.

中文翻译：

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甲氨蝶呤化学疗法引起持续的三胶质细胞调节异常，这是与化学疗法相关的认知障碍的基础。

化学疗法导致长期的神经功能缺损的症状频繁但尚未得到很好的理解。神经前体细胞功能障碍和白质功能障碍被认为是导致这种使人衰弱的综合症的原因。在这里，我们证明了接受化疗的人中少突胶质细胞谱系细胞的持续消耗。建立甲氨蝶呤化疗诱导的神经功能障碍的小鼠模型时，我们发现白质OPC的消耗相似，OPC分化增加但不完全，并且髓鞘持续缺乏。来自未经化疗的小鼠的OPC移植到先前暴露于氨甲蝶呤的大脑的微环境中时，同样表现出更高的分化能力，表明存在潜在的微环境微扰。甲氨蝶呤导致小胶质细胞持续活化，随后的星形胶质细胞活化取决于炎症性小胶质细胞。甲氨蝶呤化疗后，小胶质细胞耗竭可使少突胶质细胞系动力学，髓鞘微结构和认知行为正常化。这些发现表明甲氨蝶呤化疗暴露与持续的三神经胶质细胞失调有关，并确定炎性小胶质细胞是消除化疗相关认知障碍的治疗靶标。视频摘要。这些发现表明甲氨蝶呤化疗暴露与持续的三神经胶质细胞失调有关，并确定炎性小胶质细胞是消除化疗相关认知障碍的治疗靶标。视频摘要。这些发现表明甲氨蝶呤化疗暴露与持续的三神经胶质细胞失调有关，并确定炎性小胶质细胞是消除化疗相关认知障碍的治疗靶标。视频摘要。