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

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。睾丸激素在妊娠晚期和新生儿时期分泌，在大脑中被芳香化形成雌二醇。然后雌二醇通过ERα的基因组激活使大脑男性化；睾酮的缺乏最终导致了女性的表型。脑性表型决定了成人的性别特异性行为和内分泌学。我们利用转基因大鼠的一种性状，证明雄性视前区性别二态核（SDN-POA）的性别分化是通过雌激素诱导的神经元迁移来完成的，而雄性视前区性别二态核的性别分化比雌性大。在转基因中，SDN-POA中的神经元被荧光蛋白EGFP标记。通过脑离体切片培养延时显微镜观察迁移情况。进一步的分子生物学实验表明，ERα的基因组激活最终导致coffilin的磷酸化/去磷酸化动力学，最终通过改变肌动蛋白动力学来调节神经元迁移。在未麻醉、自由活动的大鼠中，来自该结构的神经元活动记录显示，与雌性发生性行为的雄性大鼠的神经元活动增加。我们在催产素配体敲除小鼠中观察到雄性典型的SDN-POA，缺乏雌性典型的行为，这表明有必要在未来重新评估该结构的功能。

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.