Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo Alto, CA 94305, USA.
Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo Alto, CA 94305, USA; Cancer Biology Graduate Program, Stanford University School of Medicine, Palo Alto, CA 94305, USA.
Neuron. 2023 Nov 15;111(22):3604-3618.e11. doi: 10.1016/j.neuron.2023.08.002. Epub 2023 Aug 31.
Myelination depends on the maintenance of oligodendrocytes that arise from oligodendrocyte precursor cells (OPCs). We show that OPC-specific proliferation, morphology, and BMAL1 are time-of-day dependent. Knockout of Bmal1 in mouse OPCs during development disrupts the expression of genes associated with circadian rhythms, proliferation, density, morphology, and migration, leading to changes in OPC dynamics in a spatiotemporal manner. Furthermore, these deficits translate into thinner myelin, dysregulated cognitive and motor functions, and sleep fragmentation. OPC-specific Bmal1 loss in adulthood does not alter OPC density at baseline but impairs the remyelination of a demyelinated lesion driven by changes in OPC morphology and migration. Lastly, we show that sleep fragmentation is associated with increased prevalence of the demyelinating disorder multiple sclerosis (MS), suggesting a link between MS and sleep that requires further investigation. These findings have broad mechanistic and therapeutic implications for brain disorders that include both myelin and sleep phenotypes.
髓鞘形成依赖于少突胶质前体细胞（OPC）产生的少突胶质细胞的维持。我们表明，OPC 特异性增殖、形态和 BMAL1 与昼夜节律有关。在发育过程中敲除小鼠 OPC 中的 Bmal1 会破坏与昼夜节律、增殖、密度、形态和迁移相关的基因表达，导致 OPC 动力学以时空方式发生变化。此外，这些缺陷转化为髓鞘变薄、认知和运动功能失调以及睡眠碎片化。成年期 OPC 特异性 Bmal1 缺失不会改变基线时的 OPC 密度，但会损害由 OPC 形态和迁移变化驱动的脱髓鞘病变的髓鞘再生。最后，我们表明，睡眠碎片化与脱髓鞘疾病多发性硬化症（MS）的患病率增加有关，这表明 MS 与睡眠之间存在联系，需要进一步研究。这些发现对包括髓鞘和睡眠表型在内的脑疾病具有广泛的机制和治疗意义。
