Kudwa A E, Rissman E F
Neuroscience Graduate Program, University of Virginia Medical School, Charlottesville, VA 22908, USA.
J Neuroendocrinol. 2003 Oct;15(10):978-83. doi: 10.1046/j.1365-2826.2003.01089.x.
To test the hypothesis that oestrogen receptor alpha (ERalpha) and ERbeta act together to mediate the actions of oestrogen in the ventromedial hypothalamus (VMH), we used mice with single or double knockout mutations of the ERalpha and ERbeta genes. Ovariectomized mice were implanted with 17beta-oestradiol and killed 5 days later. Oestradiol treatment promoted progestin receptor (PR)-immunoreactivity (-ir) in the VMH of all genotypes, but was maximal in brains of wild-type and ERbetaKO females. Analysis of specific VMH subregions revealed that PR-ir induction was limited to the caudal VMH in ERalphaKO and ERalphabetaKO mice. In the rostral VMH, oestradiol only induced PR-ir in wild-type and ERbetaKO mice, and the number of PR-ir neurones in this region was greater in ERbetaKO than wild-type females. Next, we tested the ability of a dopamine agonist and progesterone to facilitate sexual behaviour in females lacking functional ERalpha, ERbeta, or both receptors. Ovariectomized mice were implanted with oestradiol, and tested for sexual behaviour three times after administration of the dopamine agonist, apomorphine, followed by two tests concurrent with progesterone treatment and a final test with just apomorphine treatment. ERalphaKO and ERalphabetaKO females failed to display lordosis under any testing conditions, while ERbetaKO females exhibited lordosis behaviour equal to that of wild-type females. Our data show that a subpopulation of PR-ir neurones is induced by oestradiol in the caudal VMH of female mice lacking both ERalpha and ERbeta genes. We hypothesize that this action of oestradiol is either mediated by a novel ER or by the mutant portion of the AF2 subregion of the ERalpha gene present in ERalphaKO brain. However, despite the presence of PR in VMH, females lacking a functional ERalpha gene do not display sexual behaviour, via either ligand-dependent or -independent activation.
为了验证雌激素受体α（ERα）和雌激素受体β（ERβ）共同作用介导雌激素在下丘脑腹内侧核（VMH）发挥作用这一假说，我们使用了ERα和ERβ基因单敲除或双敲除突变的小鼠。对去卵巢小鼠植入17β-雌二醇，5天后处死。雌二醇处理可促进所有基因型小鼠VMH中孕激素受体（PR）免疫反应性（-ir），但在野生型和ERβ基因敲除（ERβKO）雌性小鼠的大脑中反应最为强烈。对VMH特定亚区的分析显示，在ERα基因敲除（ERαKO）和ERαβ双基因敲除（ERαβKO）小鼠中，PR-ir的诱导仅限于VMH尾部。在VMH前部，雌二醇仅在野生型和ERβKO小鼠中诱导PR-ir，且该区域PR-ir神经元的数量在ERβKO小鼠中比野生型雌性小鼠更多。接下来，我们测试了多巴胺激动剂和孕酮促进缺乏功能性ERα、ERβ或两种受体的雌性小鼠性行为的能力。对去卵巢小鼠植入雌二醇，在给予多巴胺激动剂阿扑吗啡后进行三次性行为测试，随后在孕酮处理的同时进行两次测试，最后仅用阿扑吗啡处理进行一次测试。在任何测试条件下，ERαKO和ERαβKO雌性小鼠均未表现出脊柱前凸，而ERβKO雌性小鼠表现出与野生型雌性小鼠相同的脊柱前凸行为。我们的数据表明，在同时缺乏ERα和ERβ基因的雌性小鼠VMH尾部，雌二醇可诱导一部分PR-ir神经元。我们推测，雌二醇的这一作用要么由一种新的雌激素受体介导，要么由ERαKO大脑中存在的ERα基因AF2亚区的突变部分介导。然而，尽管VMH中存在PR，但缺乏功能性ERα基因的雌性小鼠无论是通过配体依赖性还是非依赖性激活，均未表现出性行为。
