PDF(Pubmed)
Abstract：
Affective disorders are frequently associated with disrupted circadian rhythms. The existence of rhythmic secretion of central serotonin (5-hydroxytryptamine, 5-HT) pattern has been reported; however, the functional mechanism underlying the circadian control of 5-HTergic mood regulation remains largely unknown. Here, we investigate the role of the circadian nuclear receptor REV-ERBα in regulating tryptophan hydroxylase 2 (Tph2), the rate-limiting enzyme of 5-HT synthesis. We demonstrate that the REV-ERBα expressed in dorsal raphe (DR) 5-HTergic neurons functionally competes with PET-1-a nuclear activator crucial for 5-HTergic neuron development. In mice, genetic ablation of DR 5-HTergic REV-ERBα increases Tph2 expression, leading to elevated DR 5-HT levels and reduced depression-like behaviors at dusk. Further, pharmacological manipulation of the mice DR REV-ERBα activity increases DR 5-HT levels and affects despair-related behaviors. Our findings provide valuable insights into the molecular and cellular link between the circadian rhythm and the mood-controlling DR 5-HTergic systems.
摘要：
情感障碍通常与昼夜节律紊乱有关。中枢5-羟色胺（5-羟色胺，已经报道了5-HT）模式；但是，5-HTergic情绪调节的昼夜节律控制的功能机制在很大程度上仍然未知。这里,我们研究了昼夜节律核受体REV-ERBα在调节色氨酸羟化酶2（Tph2）中的作用，5-HT合成的限速酶。我们证明了在背侧中缝（DR）5-HTergic神经元中表达的REV-ERBα在功能上与PET-1-一种对5-HTergic神经元发育至关重要的核激活剂竞争。在老鼠身上,DR5-HTergicREV-ERBα的遗传消融增加了Tph2的表达，导致DR5-HT水平升高，黄昏时抑郁样行为减少。Further,小鼠DRREV-ERBα活性的药物操作增加DR5-HT水平并影响绝望相关行为。我们的发现为昼夜节律和情绪控制DR5-HTergic系统之间的分子和细胞联系提供了有价值的见解。
