Estradiol and Hippocampal Development

描述(申请人提供)：海马体是一个大脑区域，调节两(2)个不同但相关的生命功能；学习和记忆以及调节下丘脑-垂体-肾上腺应激轴。啮齿类动物为研究海马体在这两种反应中的重要性提供了一个强大的模型。在成人中，海马体是性腺和肾上腺类固醇的敏感靶器官。雌二醇调节CA1区的突触可塑性，并改善空间学习任务的认知功能。雌二醇对海马体发育的影响还没有被深入研究，主要是在大脑性别分化的背景下进行的。在这种情况下，起源于睾丸的新生儿雄激素被神经元局部芳香化为雌二醇，从而对神经结构产生男性化效应。然而，我们最近发现，与预期相反，发育中的女性海马体含有高水平的雌二醇。这让我们推测，发育中的女性海马体从胆固醇中重新合成雌二醇，这导致的水平与男性由睾丸雄激素产生的水平相似，从而缩小了成年人认知功能的性别差异。这一原则可以分解为3个可检验的假设：1)发育中的雌性海马体从胆固醇中重新产生雌二醇。2)发育中的男性海马体不是从胆固醇中从头产生雌二醇，而是从睾丸雄激素中产生雌二醇。3)女性发育中的雌二醇合成减少了认知功能的性别差异。我们将通过三(3)个特定的目标来测试这些假设中的每一个，这三个目标涉及确定雌二醇的来源，确定雌二醇对海马体发育的功能意义，以及识别受雌二醇调节的细胞终点。这些结果将为正常的海马体发育提供信息，并可能成为理解成人在学习和记忆以及压力反应方面的性别差异的切入点。

DESCRIPTION (provided by applicant): The hippocampus is a brain region regulating two (2) divergent but related life functions; learning and memory and regulation of the hypothalamatic-pituitary-adrnenal stress axis. The rodent provides a powerful model for investigating the importance of the hippocampus in both these responses. In the adult, the hippocampus is a sensitive target organ for both gonadal and adrenal steroids. Estradiol modulates synaptic plasticity in the CA1 region and improves cognitive functioning on spatial learning tasks. The effects of estradiol on hippocampal development have been less intensively studied and largely framed in the context of sexual differentiation of the brain. In this scenario, neonatal androgens of testicular origin are locally aromatized to estradiol by neurons and thereby exert a masculinizing effect on the neuroarchitechture. However, we recently discovered that contrary to expectation, the developing female hippocampus possesses high levels of estradiol. This lead us to speculate that the developing female hippocampus synthesizes estradiol de novo from cholesterol and this results in levels similar to that of males produced from testicular androgens, thereby reducing sex differences in cognitive functioning in adults. This tenet can be deconstructed into 3 testable hypotheses: 1) The developing female hippocampus makes estradiol de novo from cholesterol. 2) The developing male hippocampus does not make estradiol de novo from cholesterol but instead derives estradiol from testicular androgen. 3) Developmental estradiol synthesis in females reduces sex differences in cognitive function. We will test each of these hypotheses via three (3) specific aims that involve characterizing the source of estradiol, determining the functional significance of estradiol action to hippocampal development and identification of cellular endpoints modulated by estradiol. These results will be informative to normal hippocampal development and may serve as an entry point into understanding adult sex differences in learning and memory and stress responding.