Circadian misalignment (CM) caused by shift work can increase the risk of mood impairment. However, the pathological mechanisms underlying these deficits remain unclear. In the present study, we used long-term variable photoperiod (L-VP) in wild-type mice to better simulate real-life shift patterns and study its effects on the prefrontal cortex (PFC) and hippocampus, which are closely related to mood function. The results showed that exposure to L-VP altered the activity/rest rhythms of mice, by eliciting phase delay and decreased amplitude of the rhythms. Mice with CM developed anxiety and depression-like manifestations and the number of mature oligodendrocytes (OL) was reduced in the medial prefrontal cortex and hippocampal CA1 regions. Mood impairment and OL reduction worsened with increased exposure time to L-VP, while normal photoperiod restoration had no effect. Mechanistically, we identified upregulation of Bmal1 in the PFC and hippocampal regions of CM mice at night, when genes related to mature OL and myelination should be highly expressed. CM mice exhibited significant inhibition of the protein kinase B (AKT)/mTOR signaling pathway, which is directly associated to OL differentiation and maturation. Furthermore, we demonstrated in the OL precursor cell line Oli-Neu that overexpression of Bmal1 inhibits AKT/mTOR pathway and reduces the expression of genes OL differentiation. In conclusion, BMAL1 might play a critical role in CM, providing strong research evidence for BMAL1 as a potential target for CM therapy.

中文翻译：

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昼夜节律失调通过 Bmal1 过度表达损害少突胶质细胞髓鞘形成，导致焦虑和抑郁样行为

轮班工作引起的昼夜节律失调（CM）会增加情绪障碍的风险。然而，这些缺陷背后的病理机制仍不清楚。在本研究中，我们在野生型小鼠中使用了长期可变光周期（L-VP），以更好地模拟现实生活中的转变模式，并研究其对与情绪密切相关的前额皮质（PFC）和海马体的影响功能。结果表明，暴露于 L-VP 会引起相位延迟和节律幅度降低，从而改变小鼠的活动/休息节律。患有 CM 的小鼠出现焦虑和抑郁样表现，并且内侧前额皮质和海马 CA1 区域成熟少突胶质细胞 (OL) 的数量减少。情绪障碍和 OL 降低随着 L-VP 暴露时间的增加而恶化，而正常光周期恢复则没有影响。从机制上讲，我们发现 CM 小鼠的 PFC 和海马区 Bmal1 在夜间上调，此时与成熟 OL 和髓鞘形成相关的基因应该高度表达。CM 小鼠表现出对蛋白激酶 B (AKT)/mTOR 信号通路的显着抑制，该信号通路与 OL 分化和成熟直接相关。此外，我们在 OL 前体细胞系 Oli-Neu 中证明，Bmal1 的过度表达会抑制 AKT/mTOR 通路并减少 OL 分化基因的表达。总之，BMAL1可能在CM中发挥关键作用，为BMAL1作为CM治疗的潜在靶点提供了强有力的研究证据。