Elucidation of the multifunctional signaling of estrogen using the visualization of estrogen responsible neurons

雌激素在生殖、可塑性和神经保护中起重要作用，并影响中枢神经系统。本研究的目的是在雌激素受体基因启动子转基因大鼠中，利用可视化的雌激素相关神经元来研究雌激素的作用机制。最重要的结果是，在雌激素受体基因启动子控制下的EGFP表达是视前区性二形核的特异性标记。由于该核的性二态性是在围产期由雌激素建立的，因此新的活标记物将有助于阐明性分化的分子机制。另一方面，在海马中观察到EGFP表达，这是雌激素对可塑性和神经发生的作用。本研究测定了生理浓度的雌激素对原代培养的EGFP海马神经元外向钾电流的急性和慢性效应。雌激素处理48 h对未成熟神经元的外向钾电流有易化作用，而对成熟神经元的外向钾电流有抑制作用。雌激素处理48 h后，浴用250 pM雌激素增强钾电流。提示雌激素影响海马神经元的发育和兴奋性。还有一件事要注意的是，在最后区和孤束核中表达EGFP的细胞数量存在性别差异，已知它们在心血管调节中起重要作用。由于雌激素对女性高血压具有抑制作用，因此，雌激素对心血管调节的作用机制有望进一步明确。因此，我们可以展示一些重要的结果，我们希望进一步研究，以明确雌激素在中枢神经系统中的作用的分子机制。

Estrogen plays an essential role for reproduction, plasticity and neuroprotection to affect on the central nervous system. The purpose of the present study is to examine the mechanisms of estrogen action using the visualized neurons that are responsible to estrogen in the estrogen receptor gene promoter transgenic rats. Most important result is that EGFP expression under the control of estrogen receptor gene promoter is a specific marker for the sexually dimorphic nucleus of the preoptic area. Because sexual dimorphism of this nucleus is established by estrogen during the perinatal period, the new, live marker would contribute to clarify the molecular mechanisms of the sexual differentiation. On the other hand, EGFP expression is observed in the hippocampus that is noted function of estrogen for the plasticity and neurogenesis. We determined acute and chronic effects of physiological concentration of estrogen on the outward potassium currents in the primary cultured EGFP hippocampal neurons. Immature neurons showed the facilitated effect of 48 h treatment of estrogen, however, mature neurons exhibited the suppressive effect on the outward potassium currents. After the 48 h treatment of estrogen, bath application of 250 pM estrogen enhanced the potassium currents. These results suggest that estrogen influence the development and excitability of hippocampal neurons. One more thing to be noted is that there is the sex difference in the number of EGFP expressed cells in the area postrema and the nucleus tractus solitarius that are known to play an important role for cardiovascular regulation. Because hypertension is inhibited by estrogen in female, we could expect to clear the mechanisms of estrogen function on the cardiovascular regulation. Thus, we can show a number of the important results and we would like to study further to make clear the molecular mechanisms of estrogen function in the central nervous system.