The alteration of adult neural network by pre/post-natal alcohol and addictive drug exposure

我们分析了胎儿期和青年期乙醇暴露对损伤脑细胞生物学的影响，重点关注神经网络维持功能的改变。首先，我们通过培养细胞和动物模型研究了乙醇对Ca^<2+>信号通路和Ca^<2+>结合蛋白的影响，并证明了NF-kB激活和CREB减少在过早神经元细胞发育和成熟神经元存活损伤中的关键作用。利用培养的胎鼠脑神经干细胞，进一步分析乙醇对脑神经网络变化的分子机制，发现乙醇能抑制神经干细胞向神经元的分化，但能促进其向星形胶质细胞和少突胶质细胞的分化，并呈剂量依赖性。上述结果表明，神经营养因子信号的减少和转录抑制因子NRSF/REST的激活在乙醇诱导的神经干功能改变中起重要作用。在另外的实验中，我们证明了在胎儿酒精综合征模型中培养的神经干细胞增殖活性降低，胶质细胞生成增加。结果表明，第二次乙醇暴露后，神经干细胞的分化明显降低。这些结果强烈提示，产前暴露乙醇可诱导胎儿大脑神经干细胞功能受损，并可能对儿童大脑神经网络异常发育造成严重影响。

We analyzed cellbiological change of damaged brain by prenatal and young adult ethanol exposure, focusing on the alteration of neural network maintenance function. First, we investigated the effect of ethanol on the Ca^<2+> signaling and Ca^<2+> binding protein using cultured cells and animal models and demonstrated pivotal role of NF-kB activation and CREB reduction on the impairment of premature neuronal cell development and mature neuron survival. We next proceeded the analysis of molecular mechanism of brain neural network change by ethanol using cultured neural stem cells derived from fetal rat brain, and revealed that ethanol decreased neural stem cell differentiation to neurons, but promoted their differentiation to astrocytes and to oligodendrocytes dose dependently. These were indicated that the reduction of neurotrophic factor signaling and activation of transcriptional suppressor NRSF/REST play an important role on the neural stem function change induced by ethanol. In the additional experiment, we demonstrated the decrease activity of neural stem cell proliferation and increase of gliogenesis in cultured neural stem cells derived from the fetal alcohol syndrome model. It was also indicated that the differentiation of neural stem cells derived from the model, sensitively decreased by the 2nd time ethanol exposure. These results strongly suggest that prenatal exposure of ethanol can induce neural stem cell function impairment in fetus brain, and might cause serious incidence on the neural network abnormal development of children's brain.