Molecular mechanism for sex-specific reorganization of prosocial brain function during puberty

青春期亲社会脑功能性别特异性重组的分子机制

基本信息

批准号：
22390043
负责人：
SAKUMA Yasuo
金额：
$ 11.9万
依托单位：
東京医療学院大学 (2012)Nippon Medical School (2010-2011)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2010
资助国家：
日本
起止时间：
2010 至 2012
项目状态：
已结题

项目摘要

In rodents, activation of estrogen receptor α (ERα) determines sexual phenotype of the brain a particular stage of ontogeny. Testosterone secreted by the testes during late gestational and neonatal periods is aromatized to form estradiol in the brain. Estradiol then masculinizes the brain through genomic activation of ERα; the lack of testosterone culminates in the female phenotype. The brain sexual phenotype determines sex-specific behavior and endocrinology in adults. We have shown that the sexual differentiation of the sexually dimorphic nucleus of the preoptic area (SDN-POA), which is larger in males than in females, is accomplished by estrogen-induced neuronal migration, by using a trait of transgenic rat. In the transgenics, neurons in the SDN-POA were labeled by fluorescent protein, EGFP. Migration was visualized by time-lapse microscopy of ex vivo slice culture of the brain. Further molecular biological experiments revealed the genomic activation of ERα culminates in pho phorylation/dephosphorylation kinetics of coffilin, which eventually regulates neuronal migration by altering actin dynamics. Recordings of neuronal activity in from this structure in the non-anesthetized, free-moving rat showed association of increased neuronal activity in males engaging in sexual interaction with females. Our observation of male-typical SDN-POA in oxytocin-ligand knock-out mice, which lacks mele-typical behavior, suggested the necessity of reassessment of the function of this structure in the future.

在啮齿动物中，雌激素受体α（ERα）的激活确定大脑的性表型是个体发育的特定阶段。在妊娠晚期和新生儿期间由睾丸分泌的睾丸激素被芳香化以在大脑中形成雌二醇。然后，雌二醇通过ERα的基因组激活使大脑男性化。缺乏睾丸激素在女性表型中达到顶峰。大脑性表型决定了成人的性别特定行为和内分泌学。我们已经表明，在雌激素诱导的神经元迁移中，使用转基因大鼠的性状来实现，在男性中，二氧化碳的性二态核的性别分化（SDN-POA）比女性大。在转换中，SDN-POA中的神经元通过荧光蛋白EGFP标记。通过体内切片培养的延时显微镜可以看到迁移。进一步的分子生物学实验揭示了ERα的基因组激活，高潮蛋白的噬菌体/去磷酸化动力学中，最终通过改变肌动蛋白动力学来调节神经元迁移。在非麻醉的，自由移动的大鼠中，这种结构中神经元活性的记录显示了与女性发生性相互作用的男性神经元活性增加的关联。我们对缺乏Mele类典型行为的催产素配体敲除小鼠中男性典型SDN-POA的观察表明，将来对该结构的功能进行了必要的重新评估。