Studies on the action of sex steroids in the brain

本研究的目的是阐明脑内性类固醇作用的分子机制，如性别分化、诱导GnRH激增和神经保护。我们已经鉴定出许多基因，这些基因在雄性和雌性新生大鼠下丘脑中表达不同。关于其中一种基因，我们已经成功地培育出了一种缺乏颗粒蛋白基因的小鼠。定向破坏颗粒蛋白基因的小鼠在成熟后表现出雄性性行为减少，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个月大时，雌激素治疗增加了齿状体颗粒蛋白前体mRNA表达和细胞增殖。然而，在12月龄时，雌激素治疗既不影响这三个基因的mRNA表达，也不影响齿状回细胞的增殖。此外，雌激素能促进体外培养的3月龄雌性大鼠海马神经祖细胞的增殖，而这种增殖被特异性抗体中和颗粒蛋白所抑制。这些结果表明，雌激素诱导海马颗粒蛋白基因表达，该基因的产物参与了雌激素在齿状回的有丝分裂作用，尽管这些对雌激素的反应随着年龄的增长而下降。此外，我们发现应激对LH脉搏的抑制是由大脑中的前列腺素介导的，应激反应中内源性糖皮质激素的释放增加通过抑制前列腺素的合成来抵消这种抑制，从而维持生殖功能，无论应激源的性质如何。目前的研究表明，性类固醇和糖皮质激素在保护脑功能方面都起着重要作用，我们正计划研究这些类固醇对神经保护的分子机制。

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.