Contribution of Estradiol to Female Neural Development

雌二醇对女性神经发育的贡献

• 批准号: 6676366
• 负责人: MICHAEL Jay BAUM
• 金额: $ 18.75万
• 依托单位: BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-16 至 2006-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6676366
• 关键词: aromatase; behavior test; developmental neurobiology; estradiol; ethology; female reproductive system; fos protein; genetic mapping; genetically modified animals; hypothalamus; immunocytochemistry; laboratory mouse; neuroendocrine system; odors; olfactory lobe; olfactory stimulus; polymerase chain reaction; sex behavior; sex differentiation; testosterone

DESCRIPTION (provided by applicant): The proposed research seeks to understand the mechanisms whereby estradiol induces female-typical aspects of neural differentiation in female mice. The classic dogma of sexual differentiation is that testosterone secreted by the testes promotes the development of a male brain whereas a female brain develops in the absence of any sex steroid action. However, in a recent study female aromatase knockout mice, which produce no estradiol due to a targeted mutation in the aromatase gene, showed little interest in approaching volatile odors derived from conspecifics of either sex and showed low levels of sexual receptivity after adult treatment with ovarian hormones. The central hypothesis to be tested is that estradiol makes an essential contribution to the differentiation of the neuroendocrine mechanisms controlling mate recognition and sexual behavior in female mice. An initial study will determine how much estradiol is actually formed in the female's hypothalamus during perinatal development. Additional studies will determine whether estradiol contributes to the development of female-typical aspects of function in the main olfactory system. Experiments will be conducted to determine whether the discriminative capacity of the main olfactory system is impaired in female aromatase knockout mice. First, the capacity of the main olfactory system to respond to volatile urinary odors from male and female mice will be assessed by mapping the spatial distribution of c-fos glomerular activation in the main olfactory bulb. Second, the ability of the main olfactory system to detect volatile urinary odors and to discriminate male and female odors will be assessed using habituation/dishabituation tests as well as a thirst-motivated olfactometer task. The contribution of the main olfactory system to odor preferences and female sexual behavior will be assessed by determining whether destruction of the main olfactory epithelium by zinc sulfate in wild-type females mimicks the syndrome of reduced olfactory investigation and deficient lordosis responsiveness characteristic of ArKO female mice. A final study will determine whether observed deficits in sexual receptivity and olfactory investigation reflect deficits in the capacity of ArKO females to find contacts with conspecifics rewarding as opposed to deficits in olfactory function per se. The proposed studies should provide new information about the contribution of estradiol to the development of essential aspects of female-typical neural and behavioral functions.

描述（由申请人提供）：拟议的研究试图了解雌二醇诱导雌性小鼠神经分化的女性典型方面的机制。性别差异的经典教条是，睾丸分泌的睾丸激素会促进雄性大脑的发展，而在没有任何性类固醇作用的情况下，女性大脑会发育。然而，在最近的一项研究中，由于芳香酶基因的靶向突变，女性芳香酶基因敲除小鼠没有产生雌二醇，显示出对接近性别的挥发异味的兴趣，并且在成人治疗卵巢激素后的性接受水平较低。要测试的中心假设是，雌二醇对控制雌性小鼠伴侣识别和性行为的神经内分泌机制的分化做出了重要贡献。一项最初的研究将确定围产期发育过程中女性下丘脑中实际形成了多少雌二醇。其他研究将确定雌二醇是否有助于主要嗅觉系统中功能的女性典型方面的发展。 将进行实验，以确定在雌性芳香酶基因敲除小鼠中，主嗅觉系统的判别能力是否受损。首先，将通过映射主嗅球中C-FOS肾小球激活的空间分布来评估主要嗅觉系统对雄性和雌性小鼠挥发性尿味反应的能力。其次，将使用习惯/不合时宜的测试以及渴望动机的嗅觉仪任务来评估主要嗅觉系统检测挥发性尿味并区分男性气味的能力。主要的嗅觉系统对气味偏好和女性性行为的贡献将通过确定在野生型雌性中硫酸锌对主要嗅觉上皮的破坏是否模仿减少嗅觉研究的综合征和不足的脊柱症反应能力的特征。最终的研究将确定观察到的性接受性和嗅觉研究的缺陷是否反映了Arko女性的能力缺陷，以找到与奖励嗅觉功能的缺陷相反的特定奖励的接触。拟议的研究应提供有关雌二醇对女性典型神经和行为功能基本方面发展的贡献的新信息。