PROGESTERONE AND SEXUAL DIFFERENTIATION OF THE BRAIN

该提案解决了一个对于研究至关重要的问题 心理健康：母婴互动对心理健康的影响 大脑中性别差异的发展。大脑的性别差异 结构和功能可能是行为差异的基础 男性和女性之间。 胎儿睾丸激素指导性行为 大脑的分化和随后的行为。 然而，胎儿 也暴露于母体黄体酮，它很容易穿过 胎盘中可能存在于母乳中。 孕激素受体 在胎儿和新生儿内侧视前核 (MPN) 中的表达 大鼠中雄性的比例较高，但雌性中几乎不存在。 MPN 是一 大鼠大脑中最具性别二态性的结构并介导 一些性别差异的行为。这表明产妇 黄体酮可能在性方面发挥着以前被忽视的作用 中枢神经系统的分化。 该提案的主要目标是 阐明黄体酮及其受体在发育中的作用 大脑中的性别差异。 具体目标 I 和 II 将解决 先前未解答的有关个体发育和激素的问题 胎儿和新生儿大脑中孕激素受体的调节。 具体目标 III 将确定循环之间的关系 胎儿/新生儿及其母亲体内的黄体酮，并根据经验 确定母体循环中的黄体酮是否可以穿过 胎盘并与胎儿神经元内的核受体结合 大脑。 具体目标 IV 将检查 PR 中的性别差异是否存在 MPN 调节已知存在于其他表达中的性别差异 类固醇受体。 具体目标 V 将检验以下假设： 黄体酮在预防程序性妊娠中发挥着重要作用 神经元死亡，一种对性至关重要的细胞/分子机制 MPN 的分化。 本文提出的实验 应用对心理健康也有临床意义。的 美国妇女在怀孕期间接受孕激素治疗的孩子 为预防流产，表现出多种心理 和行为影响。 然而，围产期的发育影响 对母体黄体酮暴露的研究仍然严重不足。 结果 这些研究可能会极大地改变我们对性行为的看法 大脑的差异就形成了。 通过这项工作 母亲在性别分化中的重要作用 大脑和行为可能会被揭示。

This proposal addresses an issue critically important to the study of mental health: the effect of the maternal/fetal interaction on the development of sex differences in the brain. Sex differences in brain structure and function presumably underlie behavioral differences between males and females. Fetal testosterone directs the sexual differentiation of the brain and subsequent behavior. However, fetuses are also exposed to maternal progesterone which readily crosses the placenta and is presumably present in mother's milk. Progestin receptor expression in the medial preoptic nucleus (MPN) of fetal and neonatal rats is high in males but virtually absent in females. The MPN is one of the most sexually dimorphic structures in the rat brain and mediates several sexually differentiated behaviors. This suggests that maternal progesterone may play a previously overlooked role in the sexual differentiation of the CNS. The main objective of this proposal is to elucidate the role of progesterone and its receptor in the development of sex differences in the brain. Specific Aims I and II will address previously unanswered questions regarding the ontogeny and hormonal regulation of the progestin receptor in the fetal and neonatal brain. Specific Aim III will determine the relationship between circulating progesterone in fetuses/neonates and their mothers and will empirically determine whether progesterone in maternal circulation can cross the placenta and bind to nuclear receptors within the neurons of the fetal brain. Specific Aim IV will examine if the sex difference in PR in the MPN regulates sex differences known to exist in the expression of other steroid receptors. Specific Aim V will test the hypothesis that progesterone plays an important role in prevention of programmed neuronal death, a cellular/molecular mechanism critical to the sexual differentiation of the MPN. The experiments proposed in this application have clinical implications for mental health as well. The children of women in the U.S. treated with progestins during pregnancy for the prevention of miscarriage, exhibit a variety of psychological and behavioral effects. Yet, the developmental effects of perinatal exposure to maternal progesterone remains grossly understudied. Results from these studies could dramatically change our thinking about how sex differences in the brain are formed. Through this work an influential role of the mother in the sexual differentiation of the brain and behavior may be revealed.