Regulation of monoamine oxidase a by circadian-clock components implies clock influence on mood
Regulation of monoamine oxidase a by circadian-clock components implies clock influence on mood
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DOI：
10.1016/j.cub.2008.04.012
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发表时间：
2008-05-06
期刊：
影响因子：
9.2
通讯作者：
Albrecht, Urs
中科院分区：
文献类型：
--
作者：
Hampp, Gabriele;Ripperger, Juergen A.;Albrecht, Urs
生物钟与成瘾和几种形式的抑郁症有关[1，2]，表明昼夜节律和大脑中的奖励系统之间的相互作用[3-5]。食物、性和药物等奖励部分通过调节中脑边缘多巴胺奖励回路（包括腹侧被盖区（VTA）和腹侧纹状体（NAc））中的多巴胺神经传递来影响该系统。因此，这些大脑区域中多巴胺水平的变化被认为会影响人类和小鼠的情绪[6-10]。为了建立生物钟机制和多巴胺代谢之间的分子联系，我们分析了多巴胺代谢中重要的关键酶编码基因的小鼠启动子。我们发现，单胺氧化酶A（Maoa）启动子的转录调节的时钟组件BMAL 1，NPAS 2和PER 2。小鼠中时钟基因Per 2的突变导致中脑边缘多巴胺能系统中MAOA的表达和活性降低。此外，我们观察到纹状体中多巴胺水平的增加和神经元活动的改变，这些结果可能导致在基于绝望的测试中观察到的Per 2突变小鼠的行为改变。这些发现表明生物钟成分在多巴胺代谢中的作用，突出了生物钟在调节情绪相关行为中的作用。
The circadian clock has been implicated in addiction and several forms of depression [1, 2], indicating interactions between the circadian and the reward systems in the brain [3-5]. Rewards such as food, sex, and drugs influence this system in part by modulating dopamine neurotransmission in the mesolimbic dopamine reward circuit, including the ventral tegmental area (VTA) and the ventral striatum (NAc). Hence, changes in dopamine levels in these brain areas are proposed to influence mood in humans and mice [6-10]. To establish a molecular link between the circadian-clock mechanism and dopamine metabolism, we analyzed the murine promoters of genes encoding key enzymes important in dopamine metabolism. We find that transcription of the monoamine oxidase A (Maoa) promoter is regulated by the clock components BMAL1, NPAS2, and PER2. A mutation in the clock gene Per2 in mice leads to reduced expression and activity of MAOA in the mesolimbic dopaminergic system. Furthermore, we observe increased levels of dopamine and altered neuronal activity in the striatum, and these results probably lead to behavioral alterations observed in Per2 mutant mice in despair-based tests. These findings suggest a role of circadian-clock components in dopamine metabolism highlighting a role of the clock in regulating mood-related behaviors.