Department of Biological Sciences and Brain Research Center for 21st Frontier Program in Neuroscience, Seoul National University, Seoul 151-742, Korea.
Department of Brain and Cognitive Sciences, Seoul National University, Seoul 151-742, Korea.
Cell. 2014 May 8;157(4):858-68. doi: 10.1016/j.cell.2014.03.039.
The circadian nature of mood and its dysfunction in affective disorders is well recognized, but the underlying molecular mechanisms are still unclear. Here, we show that the circadian nuclear receptor REV-ERBα, which is associated with bipolar disorder, impacts midbrain dopamine production and mood-related behavior in mice. Genetic deletion of the Rev-erbα gene or pharmacological inhibition of REV-ERBα activity in the ventral midbrain induced mania-like behavior in association with a central hyperdopaminergic state. Also, REV-ERBα repressed tyrosine hydroxylase (TH) gene transcription via competition with nuclear receptor-related 1 protein (NURR1), another nuclear receptor crucial for dopaminergic neuronal function, thereby driving circadian TH expression through a target-dependent antagonistic mechanism. In conclusion, we identified a molecular connection between the circadian timing system and mood regulation, suggesting that REV-ERBα could be targeting in the treatment of circadian rhythm-related affective disorders.
情绪的昼夜节律性质及其在情感障碍中的功能障碍已得到充分认识，但潜在的分子机制仍不清楚。在这里，我们表明，与双相情感障碍相关的昼夜节律核受体 REV-ERBα 会影响小鼠中脑多巴胺的产生和与情绪相关的行为。Rev-erbα 基因的遗传缺失或腹侧中脑 REV-ERBα 活性的药理学抑制会导致类似躁狂的行为，并伴有中枢多巴胺能状态升高。此外，REV-ERBα 通过与核受体相关 1 蛋白 (NURR1) 竞争抑制酪氨酸羟化酶 (TH) 基因转录，NURR1 是另一种对多巴胺能神经元功能至关重要的核受体，从而通过一种依赖于靶标的拮抗机制驱动昼夜节律性 TH 表达。总之，我们确定了昼夜节律计时系统与情绪调节之间的分子联系，表明 REV-ERBα 可能成为治疗与昼夜节律相关的情感障碍的靶点。
