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Interaction of steroid hormones and growth factors in maintaining brain function

类固醇激素和生长因子在维持大脑功能中的相互作用

基本信息

批准号：
17208025
负责人：
NISHIHARA Masugi
金额：
$ 24.54万
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 (A)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17208025/
关键词：
Brain Neuron Steroid hormones Growth factors Neuroeenesis

项目摘要

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.

本研究的目的是阐明类固醇激素和生长因子维持大脑功能的分子机制。我们首先评估了雌激素治疗后去卵巢大鼠齿状回细胞增殖和海马区颗粒素、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。我们发现雌激素处理后，虽然IGF-I和BDNFmRNA的表达没有变化，但颗粒蛋白前体的mRNA表达增加，细胞增殖增加。此外，雌激素可促进雌性大鼠海马区神经前体细胞的体外增殖，其作用可被特异性抗体中和颗粒蛋白所抑制。这些结果表明，雌激素诱导了海马区颗粒蛋白基因的表达，该基因的产物参与了雌激素在齿状回的促分裂作用。然后，我们培育了一组有针对性地破坏颗粒蛋白基因的小鼠，并调查了男性的性行为、攻击性和焦虑。颗粒素缺乏的小鼠射精发生率降低，而坐位和插入的潜伏期和频率都没有变化。颗粒蛋白缺乏的小鼠也表现出更强的攻击性。在野生型小鼠中，雄性表现出比雌性更低的焦虑水平，而雄性颗粒缺乏小鼠表现出更高的焦虑水平，并且没有观察到性别差异。这些结果表明，颗粒蛋白基因在某些性二型性行为的建立中起作用。最后，我们证明了糖皮质激素通过抑制大脑中前列腺素的合成，在防止应激对黑质多巴胺能神经元的有害影响和由此导致的运动迟缓以及GnRH脉冲发生器活动方面发挥了作用。