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Studies on the action of sex steroids in the brain

性类固醇在大脑中作用的研究

基本信息

批准号：
13854007
负责人：
NISHIHARA Masugi
金额：
$ 63.81万
依托单位：
The University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (S)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2004
项目状态：
已结题

项目摘要

The objectives of the present study were to elucidate molecular mechanisms underlying the sex steroid actions in the brain, such as sex differentiation, induction of GnRH surge and neuroprotection. We have identified many genes, of which expression were different between male and female neonatal rat hypothalamus. Regarding one of such genes, we have successfully generated a line of mice deficient with the granulin gene. The mice with targeted disruption of the granulin gene displayed decreased male sexual behavior after maturation, suggesting that granulin is indeed involved in sex differentiation of the brain. We also found that, at 3-month old, the mRNA expression of granulin precursor as well as cell proliferation in the dentate gyms were increased with estrogen treatment. At 12-month old, however, neither the mRNA expression of the three genes nor cell proliferation in the dentate gyrus were affected by estrogen treatment. In addition, estrogen enhanced the proliferation of neural progenitor cells derived from hippocampal tissue of 3-month old female rats in vitro, which was inhibited by neutralization of granulin with specific antibody. These results suggest that estrogen induces granulin gene expression in the hippocampus and the product of this gene is involved in the mitogenic effect of estrogen in the dentate gyrus, though these responses to estrogen decline with age. In addition, we found that suppression of LH pulsatility by stress is mediated by prostaglandins in the brain, and increased release of endogenous glucocorticoids in response to stress counteracts this suppression by inhibiting prostaglandin synthesis and thereby maintains reproductive function regardless of the nature of the stressor. The present studies demonstrate that both sex steroid and glucocorticoids play important roles in protecting brain functions, and we are planning to investigate the molecular mechanisms of neuroprotection by these steroids.

本研究的目的是阐明性类固醇在脑内作用的分子机制，如性别分化，诱导GnRH激增和神经保护。我们已经发现了许多基因，其中的表达在雄性和雌性新生大鼠下丘脑中存在差异。关于其中一个这样的基因，我们已经成功地产生了一系列颗粒蛋白基因缺陷的小鼠。有针对性地破坏颗粒蛋白基因的小鼠在成熟后表现出减少的雄性性行为，这表明颗粒蛋白确实参与了大脑的性别分化。我们还发现，在3月龄，颗粒蛋白前体的mRNA表达以及细胞增殖的齿状回与雌激素治疗增加。然而，在12个月大时，雌激素治疗既不影响这三个基因的mRNA表达，也不影响齿状回的细胞增殖。此外，雌激素促进3月龄雌性大鼠海马神经前体细胞的体外增殖，其增殖可被特异性抗体中和颗粒蛋白所抑制。这些结果表明，雌激素诱导颗粒蛋白基因表达在海马和该基因的产品是参与雌激素在齿状回的促有丝分裂作用，虽然这些反应雌激素随着年龄的增长下降。此外，我们发现应激对LH脉动的抑制是由脑中的肾上腺素介导的，应激时内源性糖皮质激素的释放增加通过抑制前列腺素合成来抵消这种抑制，从而维持生殖功能，而不管应激源的性质如何。目前的研究表明，性类固醇和糖皮质激素在保护脑功能中发挥重要作用，我们计划研究这些类固醇的神经保护作用的分子机制。