MATERNAL PROGESTERONE AND FETAL NEURAL DEVELOPMENT

这一建议涉及一个对研究下列问题至关重要的问题： 心理健康：母亲/胎儿相互作用对 大脑的发育和随后的成人行为。暴露于 生殖腺类固醇激素在产前生活有戏剧性的后果， 大脑和行为的发展。虽然暴露的影响 雌激素和雄激素在发育过程中的作用是有据可查的， 没有关于孕酮对神经发育作用的信息 和行为。胎儿通常暴露于母体循环中， 激素，包括孕酮，其水平经历快速和 分娩前和哺乳期的极端变化。人 在美国，数百万妇女在怀孕期间接受黄体酮治疗， 怀孕防止流产表现出多种生理、心理 和行为影响。然而， 暴露于母体孕酮的情况仍然严重缺乏研究。主要 该提案的目的是确定是否唯一高 怀孕期间母体循环中的孕酮水平， 产后会改变后代大脑对类固醇的敏感性 在发育和/或成年期，从而改变随后的激素- 成年后的依赖行为具体目标我会检查时， 在出生前，胎儿的大脑首先对孕酮敏感。 使用免疫细胞化学，将确定胎儿神经元 大脑首先开始表达孕酮的核受体， 孕激素受体水平是否在神经发育过程中受到调节 发展Specific Aim II将使用类固醇激素放射自显影术， 证实母体循环中放射性标记的孕酮可以交叉 胎盘和胎儿血/脑屏障与核类固醇结合 胎儿大脑中的受体。此外，循环水平 孕激素在胎儿和孕激素的来源将是 考察具体目标三将审查产前和产后的影响， 暴露于母体循环中的孕酮， 成年后代的类固醇激素依赖行为。具体目标 IV将检查围产期暴露于孕酮是否会改变 大脑在神经发育过程中对类固醇激素的敏感性， 通过改变孕激素和/或雌激素的表达 已知脑区域中的受体是孕酮的神经靶点 和雌激素在显示依赖性行为中的作用。的 从这些实验的结果将提供洞察力的作用， 孕激素在胎儿大脑发育中的作用 成年期关键生殖行为的表达。

This proposal addresses an issue critically important to the study of mental health: the effects of the maternal/fetal interaction on the development of the brain and subsequent adult behavior. Exposure to gonadal steroid hormones during prenatal life has dramatic consequences on the development of the brain and behavior. While the effects of exposure to estrogen and androgens during development are well documented, almost no information exists on the role of progesterone on neural development and behavior. Fetuses are normally exposed to maternal circulating hormones, including progesterone, the levels of which undergo rapid and extreme changes prior to parturition and during lactation. The children of millions of women in the U.S. who were treated with progesterone during pregnancy to prevent miscarriage show a variety of physical, psychological and behavioral effects.Yet, the developmental effects of perinatal exposure to maternal progesterone remains grossly understudied. The main objective of this proposal is to determine whether the uniquely high levels of progesterone in the maternal-circulation during pregnancy and postpartum can alter the steroid sensitivity of the brain of the offspring during development and/or adult life and thereby alter subsequent hormone- dependent behaviors in adulthood. Specific Aim I will examine when during prenatal life the fetal brain first becomes sensitive to progesterone. Using immunocytochemistry it will be determined when neurons in the fetal brain first begin to express nuclear receptors for progesterone and whether progesterone receptor levels are regulated during neural development. Specific Aim II will use steroid hormone autoradiography to verity that radiolabelled progesterone in maternal circulation can cross the placenta and the fetal blood/brain barrier to bind to nuclear steroid receptors within the fetal brain. In addition, the circulating levels of progesterone in fetuses and the source of the progesterone will be examined. Specific Aim III will examine the effects of pre-and postnatal exposure to progesterone from maternal circulation on the display of steroid hormone dependent behaviors in the adult offspring. Specific Aim IV will examine whether perinatal exposure to progesterone can alter the brains sensitivity to steroid hormones during either neural development or adulthood by altering the expression of progesterone and/or estrogen receptors in brain regions known to be the neural targets for progesterone and estrogen action in the display of hormone-dependent behaviors. The results from these experiments will provide insight as to the role of maternal progesterone in the development of the fetal brain and the expression of critical reproductive behaviors in adulthood.