Key Laboratory of Medical Electrophysiology, Ministry of Education, Institute of Cardiovascular Medicine; Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease of Sichuan Province; Southwest Medical University, Luzhou, 646009, China.
Department of Biology, University of Toronto Mississauga, 3359 Mississauga Road, Mississauga, ON L5L 1C6, Canada.
Sci Rep. 2017 Oct 3;7(1):12641. doi: 10.1038/s41598-017-13067-y.
It remains unknown whether chronic circadian disturbance (CCD) during pregnancy can lead to mood disorders in the offspring. Here we show that pregnant mice in the F0 generation that were exposed to CCD stress displayed depression-like behaviors, and produced offspring in the F1 and F2 generations that also exhibited mood-associated behavioral phenotypes despite the lack of direct stressful experiences during their postnatal or adult period. Prenatal CCD stress was correlated with the elevation of plasma corticosterone levels in F1 mice. Furthermore, the diurnal expression profiles of core circadian clock genes were disrupted in the suprachiasmatic nucleus of F1 mice. Proteomics analysis revealed that prenatal CCD stress resulted in distinct changes in protein expression in the hypothalamus of female F1 mice, in particular proteins that were associated with cellular activities, metabolism, development and diseases. Sex-specific differences in melanocortin 4 receptor expression were apparent in the CCD F1 generation. We conclude that maternal exposure to chronic circadian disturbance during pregnancy can lead to sex-specific mood disorders that persist for at least two filial generations. The underlying mechanisms may depend on transgenerational changes in plasma corticosterone levels, circadian pacemaking, and hypothalamic protein expression.
目前尚不清楚怀孕期间慢性昼夜节律紊乱（CCD）是否会导致后代出现情绪障碍。在这里，我们发现，在 F0 代中经历 CCD 应激的怀孕小鼠表现出类似抑郁的行为，并且在 F1 和 F2 代中产生的后代尽管在其出生后或成年期没有直接的应激体验，但也表现出与情绪相关的行为表型。F1 小鼠的产前 CCD 应激与血浆皮质酮水平升高相关。此外，F1 小鼠的视交叉上核中核心生物钟基因的昼夜表达谱被打乱。蛋白质组学分析显示，产前 CCD 应激导致雌性 F1 小鼠下丘脑蛋白表达发生明显变化，特别是与细胞活动、代谢、发育和疾病相关的蛋白质。CCD F1 代中黑素皮质素 4 受体的表达存在性别特异性差异。我们的结论是，母亲在怀孕期间暴露于慢性昼夜节律紊乱会导致至少两代后代出现特定于性别的情绪障碍。潜在的机制可能取决于血浆皮质酮水平、昼夜节律起搏和下丘脑蛋白表达的跨代变化。
