Studies on the action of sex steroids in the brain

点击翻译按钮获取中文摘要

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.