PROGESTERONE AND SEXUAL DIFFERENTIATION OF THE BRAIN

黄体酮和大脑的性别分化

• 批准号: 2756804
• 负责人: CHRISTINE K WAGNER
• 金额: $ 16.45万
• 依托单位: UNIVERSITY OF MASSACHUSETTS AMHERST
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-01-01 至 2002-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2756804
• 关键词: apoptosis; developmental neurobiology; drug receptors; estrogen receptors; hormone regulation /control mechanism; laboratory rat; placental transfer; preoptic areas; progesterone; progesterone receptors; progestins; receptor binding; receptor expression; sex differentiation

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.

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 大脑中的性别差异。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 也暴露于母体孕酮， 胎盘，可能存在于母乳中。 孕激素受体 在胎儿和新生儿视前内侧核（MPN）中的表达 雄性大鼠的死亡率很高，但雌性大鼠几乎没有死亡率。MPN是一个 大鼠脑中最具性别二态性的结构， 几种不同的性行为这表明，产妇 孕酮可能在性行为中起着以前被忽视的作用， CNS的分化。 这项建议的主要目的是 阐明孕酮及其受体在胚胎发育中的作用 大脑中的性别差异 具体目标一和二将涉及 以前未回答的问题，关于个体发育和激素 调节胎儿和新生儿脑中的垂体素受体。 具体目标III将确定循环之间的关系 孕激素在胎儿/新生儿及其母亲，并将经验 确定母体循环中的孕酮是否可以通过 并与胎儿神经元内的核受体结合 个脑袋 具体目标IV将检查PR中的性别差异是否 MPN调节已知存在于其他基因表达中的性别差异， 类固醇受体 具体目标5将检验以下假设： 孕酮在预防程序性 神经元死亡，一种对性行为至关重要的细胞/分子机制， MPN的分化。 在此提出的实验 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 对于预防流产，表现出各种心理 和行为效应。 然而，围产期的发育影响 暴露于母体孕酮的情况仍然严重缺乏研究。 结果 从这些研究中可以极大地改变我们对性是如何 大脑中的差异就形成了。 通过这项工作， 母亲在婴儿性别分化中的影响作用 大脑和行为可以被揭示。