Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States.
Department of Internal Medicine, University of Michigan, Ann Arbor, United States.
Elife. 2019 Apr 4;8:e43999. doi: 10.7554/eLife.43999.
The brain regulates fertility through gonadotropin-releasing hormone (GnRH) neurons. Estradiol induces negative feedback on pulsatile GnRH/luteinizing hormone (LH) release and positive feedback generating preovulatory GnRH/LH surges. Negative and positive feedbacks are postulated to be mediated by kisspeptin neurons in arcuate and anteroventral periventricular (AVPV) nuclei, respectively. Kisspeptin-specific ERα knockout mice exhibit disrupted LH pulses and surges. This knockout approach is neither location-specific nor temporally controlled. We utilized CRISPR-Cas9 to disrupt ERα in adulthood. Mice with ERα disruption in AVPV kisspeptin neurons have typical reproductive cycles but blunted LH surges, associated with decreased excitability of these neurons. Mice with ERα knocked down in arcuate kisspeptin neurons showed disrupted cyclicity, associated with increased glutamatergic transmission to these neurons. These observations suggest that activational effects of estradiol regulate surge generation and maintain cyclicity through AVPV and arcuate kisspeptin neurons, respectively, independent from its role in the development of hypothalamic kisspeptin neurons or puberty onset.
大脑通过促性腺激素释放激素（GnRH）神经元来调节生育能力。雌二醇对脉冲 GnRH/黄体生成素（LH）释放产生负反馈，对促排卵 GnRH/LH 激增产生正反馈。负反馈和正反馈分别被假定为通过弓状核和前腹侧脑室周围核（AVPV）中的 kisspeptin 神经元介导的。Kisspeptin 特异性 ERα 敲除小鼠表现出 LH 脉冲和激增的中断。这种敲除方法既不是位置特异性的，也不是时间控制的。我们利用 CRISPR-Cas9 在成年期敲除 ERα。AVPV kisspeptin 神经元中 ERα 缺失的小鼠具有典型的生殖周期，但 LH 激增减弱，与这些神经元兴奋性降低有关。弓状核 kisspeptin 神经元中 ERα 下调的小鼠表现出周期性中断，与这些神经元的谷氨酸能传递增加有关。这些观察结果表明，雌二醇的激活作用通过 AVPV 和弓状核 kisspeptin 神经元分别调节激增的产生和维持周期性，而与它在下丘脑 kisspeptin 神经元发育或青春期开始中的作用无关。
