Faculty of Applied Biological Sciences, Gifu University, Gifu, 501-1193, Japan; The Second Department of Physiology, Wakayama Medical University, Wakayama 641-8509, Japan.
The Second Department of Physiology, Wakayama Medical University, Wakayama 641-8509, Japan; Department of Biomedical Engineering, National Cerebral and Cardiovascular Center, Osaka, 564-8565, Japan.
Physiol Behav. 2022 Nov 1;256:113960. doi: 10.1016/j.physbeh.2022.113960. Epub 2022 Sep 15.
Mood disorders such as depression, anxiety, and bipolar disorder are highly associated with disrupted daily rhythms of activity, which are often observed in shift work and sleep disturbance in humans. Recent studies have proposed the REV-ERBα protein as a key circadian nuclear receptor that links behavioural rhythms to mood regulation. However, how the Rev-erbα gene participates in the regulation of mood remains poorly understood. Here, we show that the regulation of the serotonergic (5-HTergic) system, which plays a central role in stress-induced mood behaviours, is markedly disrupted in Rev-erbα mice. Rev-erbα mice exhibit both negative and positive behavioural phenotypes, including anxiety-like and mania-like behaviours, when subjected to a stressful environment. Importantly, Rev-erbα mice show a significant decrease in the expression of a gene that encodes the rate-limiting enzyme of serotonin (5-HT) synthesis in the raphe nuclei (RN). In addition, 5-HT levels in Rev-erbα mice are significantly reduced in the prefrontal cortex, which receives strong inputs from the RN and controls stress-related behaviours. Our findings indicate that Rev-erbα plays an important role in controlling the 5-HTergic system and thus regulates mood and behaviour.
心境障碍，如抑郁症、焦虑症和双相情感障碍，与活动的日常节律紊乱高度相关，这种紊乱在轮班工作和睡眠障碍中经常观察到。最近的研究提出了 REV-ERBα 蛋白作为一种关键的生物钟核受体，将行为节律与情绪调节联系起来。然而，Rev-erbα 基因如何参与调节情绪仍知之甚少。在这里，我们表明，在 Rev-erbα 小鼠中，5-羟色胺能（5-HTergic）系统的调节明显被打乱，5-羟色胺能系统在应激诱导的情绪行为中起着核心作用。Rev-erbα 小鼠在应激环境下表现出焦虑样和躁狂样行为等阴性和阳性行为表型。重要的是，Rev-erbα 小鼠中编码 5-羟色氨酸（5-HT）合成限速酶的基因表达显著减少。此外，Rev-erbα 小鼠的前额叶皮层中 5-HT 水平显著降低，前额叶皮层从前扣带回核（RN）接收强烈的输入，并控制与应激相关的行为。我们的研究结果表明，Rev-erbα 在控制 5-HTergic 系统方面起着重要作用，从而调节情绪和行为。
