Molecular mechanism underlying premenstrual dysphoric disorder

我们在20名健康人和20名经前焦虑症（PMDD）受试者中检测了月经周期的昼夜睡眠节律变化，其中2名PMDD受试者出现了交替性相移综合征（APSS），而健康人均未出现APSS，提示PMDD可能参与了APSS。为了探讨APSS的发病机制，我们研究了雌激素（E）对生物钟所在的视交叉上核（SCN）内生物钟基因（Per 1，Per 2）的昼夜节律的影响。E使Per 2节律的时相提前，但不使Per 1节律的时相提前。E使Per 2的波幅降低，而对Per 1的波幅无影响。当我们检测SCN中E受体（R）亚型时，证实SCN中仅表达ER-□□。我们研究了类固醇受体辅激活因子（SRC 1，2，3）的亚型，它增强了核受体的转录活性，因为E和ER复合物通过在辅激活因子的影响下结合到基因的ERE来调节靶基因的转录。SRC-1在SCN中特异性表达。我们确定SRC-1是否与CLOCK和/或BMAL结合，因为CLOCK和BMAL是时钟基因的正调节因子。我们发现SRC-1与CLOCK结合，因此E通过SRC-1调节时钟基因。

When we examined menstrual variations of circadian sleep rhythms in 20 healthy and 20 PMDD(Premenstrual dysphoric disorder) subjects, 2 PMDD subjects showed APSS(alternative phase shift syndrome) but none of the healthy subjects showed APSS, suggesting that PMDD may be involved in APSS. In order to investigate the mechanisms underlying APSS, we examined the effects of estrogen (E)on the circadian rhythms in clock genes (Per1,Per2) in the suprachiasmatic nucleus (SCN), the site of circadian clock. E advanced the phase of Per2 rhythms but not Per1 rhythms. The amplitude of Per2 was decreased by E but that of Per1 was not affected. When we examined the subtype of E receptor (R) in the SCN, only ER-□□was proved to be expressed in the SCN. We examined the subtype of the steroid receptor coactivator (SRC1,2,3), which enhances the transcriptional activity of nuclear recptors, because E and ER complexes regulate the transcription of a target gene by binding to ERE of the gene under the influence of coactivators. Only SRC-1 was proved to be specifically expressed in the SCN. We determined whether SRC-1 binds to CLOCK and/or BMAL because CLOCK and BMAL are positive-regulators of clock genes. We found that SRC-1 binds to CLOCK, so that E regulates clock genes via SRC-1.