Changes in estrogen receptor signaling alters the timekeeping system in male mice
Changes in estrogen receptor signaling alters the timekeeping system in male mice
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DOI：
10.1016/j.bbr.2015.07.060
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发表时间：
2015-11-01
影响因子：
2.7
通讯作者：
Mahoney, Megan M.
中科院分区：
文献类型：
--
作者：
Blattner, Margaret S.;Mahoney, Megan M.
昼夜节律是由类固醇激素调节的；然而，这种作用的机制还不完全清楚，特别是在男性。在女性中，雌二醇调节活动水平、表达模式和自由奔跑期(Tau)。我们测试了这样一种假设，即雄性小鼠的活动水平和分布包括雌激素在雌激素受体亚型1(ESR1)上的经典和“非经典”作用。我们使用了雌激素反应通路发生突变的转基因小鼠：ESR1基因敲除(ERKO)小鼠缺乏通过ESR1对雌激素做出反应的能力。“非经典”雌激素受体敲入(NERKI)小鼠有一个插入的ESR1受体，该受体在雌激素反应元件结合域发生突变，允许通过非基因组和第二信使途径激活。去性腺的雄性NERKI、ERKO和野生型(WT)产仔被给予油、低剂量或高剂量的雌二醇，并对日常活动参数进行量化。雌二醇缩短了亮暗比(LD比)，缩短了tau，提前了活动开始的时间，并改变了对深夜给予光提示的反应，这表明调控是由ESR1非依赖的机制实现的。在NERKI而不是WT男性中，雌激素治疗改变了活动开始的时间、LD比率和对光暗示的行为反应。这些结果可能表明基因组/非基因组或ESR1/ESR2信号通路的平衡被破坏。我们还发现，总活性、LD比率、tau和活动持续时间存在显著的基因型效应。这些数据提供了有关ESR1依赖和独立的信号通路在雄性小鼠计时系统中的作用的新信息。(C)2015爱思唯尔B.V.保留所有权利。
Circadian rhythms are modulated by steroid hormones; however, the mechanisms of this action are not fully understood, particularly in males. In females estradiol regulates activity level, pattern of expression, and free running period (tau). We tested the hypothesis that activity level and distribution in male mice includes both classical and "non-classical" actions of estrogens at the estrogen receptor subtype 1 (ESR1). We used transgenic mice with mutations in their estrogen response pathways: ESR1 knock-out (ERKO) mice lack the ability to respond to estrogens via ESR1. "Non-classical" estrogen receptor knock-in (NERKI) mice have an inserted ESR1 receptor with a mutation in the estrogen-response-element binding domain, allowing activation via non-genomic and second messenger pathways. Gonadectomized male NERKI, ERKO, and wildtype (WT) littermates were given oil, or low or high dose estradiol and daily activity parameters were quantified. Estradiol shortened the ratio of activity in the light relative to dark (LD ratio), shortened tau, advanced the time of activity onset, and altered responsiveness to light cues administered in the late subjective night, suggesting modulation by an ESR1-independent mechanism. Estradiol treatment in NERKI but not WT males altered the timing of activity onset, LD ratio, and the behavioral response to light cues. These results may represent disruptions in the balance of genomic/nongenomic or ESR1/ESR2 signaling pathways. We also found a significant genotype effect on total activity, LD ratio, tau, and activity duration. These data provide new information about the role of ESR1-dependent and independent signaling pathways on the timekeeping system in male mice. (C) 2015 Elsevier B.V. All rights reserved.