Interaction of steroid hormones and growth factors in maintaining brain function

本研究的目的是阐明类固醇激素和生长因子维持脑功能的分子机制。我们首先评估了去卵巢大鼠雌激素治疗后齿状回细胞增殖和海马颗粒蛋白、胰岛素样生长因子-I（IGF-I）和脑源性神经营养因子（BDNF）的mRNA表达水平。我们发现，颗粒蛋白前体的mRNA表达和细胞增殖的雌激素处理增加，虽然IGF-Ⅰ和BDNF的mRNA表达保持不变。雌激素对体外培养的雌性大鼠海马神经前体细胞增殖有促进作用，而特异性抗体中和颗粒蛋白可抑制雌激素对神经前体细胞的增殖。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的作用。然后，我们产生了一系列有针对性的颗粒蛋白基因破坏的小鼠，并研究了雄性的性行为，攻击性和焦虑。颗粒蛋白缺陷小鼠表现出射精发生率下降，而潜伏期和频率的安装和插入不变。缺乏颗粒蛋白的小鼠也表现出增强的攻击性。在野生型小鼠中，雄性小鼠表现出比雌性小鼠更低的焦虑水平，而雄性颗粒蛋白缺陷小鼠表现出更高的焦虑水平，并且未观察到焦虑的性别差异。这些结果表明，颗粒蛋白基因在某些两性异形行为的建立中起一定的作用。最后，我们证明，糖皮质激素的分泌增加，在应对压力发挥作用，防止黑质多巴胺能神经元和运动迟缓，以及GnRH脉冲发生器活动的不利影响，通过抑制合成的肾上腺素在大脑中的压力。

The objectives of the present study were to elucidate molecular mechanisms underlying the actions of steroid hormones and growth factors in maintaining brain function. We first assessed cell proliferation in the dentate gyrus and the mRNA expression levels of granulin, insulin-like growth factor-I (IGF-I), and brain-derived neurotrophic factor (BDNF) in the hippocampus after treatment with estrogen in ovariectomized rats. We found that mRNA expression of granulin precursor and cell proliferation were increased by estrogen treatment, although the mRNA expressions of IGF-I and BDNF remained unchanged. In addition, estrogen enhanced the proliferation of neural progenitor cells derived from hippocampal tissue 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 that the product of this gene is involved in the mitogenic effects of estrogen in the dentate gyrus. We then generated a line of mice with targeted disruption of the granulin gene, and investigated male sexual behaviour, aggression and anxiety. Granulin-deficient mice exhibited a decrease in ejaculation incidence, while the latency and frequency of both mount and intromission were unchanged. Granulin-deficient mice also exhibited enhanced aggressiveness. In wild-type mice, males exhibited lower levels of anxiety than females, while male granulin-deficient mice exhibited an elevated level of anxiety and sex difference in anxiety was not observed. These results suggest that granulin gene plays a role in establishing some kinds of sexual dimorphic behaviours. Finally, we demonstrated that glucocorticoids whose secretion is increased in response to stress play a role in preventing the detrimental effect of stress on nigral dopaminergic neurons and resulting bradykinesia, as well as GnRH pulse generator activity, by suppressing the synthesis of prostaglandins in the brain.