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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.

在啮齿类动物中，雌激素受体α（ERα）的激活决定了个体发育特定阶段大脑的性表型。妊娠晚期和新生儿期睾丸分泌的睾酮在脑中芳香化形成雌二醇。雌激素通过ERα的基因组激活使大脑男性化;睾酮的缺乏导致女性表型。大脑性表型决定了成年人的性别特异性行为和内分泌。我们已经表明，性别分化的性二形核的视前区（SDN-POA），这是在男性比女性大，是通过雌激素诱导的神经元迁移，通过使用转基因大鼠的一个特点。在转基因组中，SDN-POA中的神经元被荧光蛋白EGFP标记。通过脑的离体切片培养的延时显微镜观察迁移。进一步的分子生物学实验显示，ERα的基因组激活在coffilin的磷酸化/去磷酸化动力学中达到高潮，其最终通过改变肌动蛋白动力学来调节神经元迁移。记录的神经元活动，从这个结构中的非麻醉，自由活动的大鼠显示，在男性从事性互动与女性的神经元活动增加。我们在催产素-配体敲除小鼠中观察到的雄性典型SDN-POA缺乏雄性典型行为，这表明将来有必要重新评估这种结构的功能。