Development of drugs for facilitating brain development and memory/learning

在前期的研究中，我们发现短期轻度的产前应激（孕鼠束缚应激，30 min/d，E15 ~ E17共3d，30 min应激组）对胎鼠脑神经元的形态产生神经营养作用，而长期应激（4 h/d，E15 ~ E17共3d，4 h应激组）则引起神经毒性改变。此外，我们已经表明，30分钟的压力组显示出显着更好的记忆和学习表现在成年后代。在此基础上，利用DNA tips（Rat Genome U34 A，Affytelium），对对照组、30分钟应激组和4小时应激组3组的基因表达进行了研究。使用的DNA探针包括大约8800个基因。分析的基因是受体（808）、通道（187）、转运蛋白（138）、酶（1822）、激酶（382）、磷酸酶（129）和转录因子（57）。分析胎脑全脑和海马组织中提取的总RNA。根据重复数据、信号强度、三组间差异的统计学意义对基因表达进行显著性排序。鉴定了与对照组相比，在30分钟应激和4小时应激组中显示表达显著增加或减少的5至20个基因。这些来自海马体的基因包括神经营养因子，以及与阿尔茨海默病和神经元引导相关的基因。人们还注意到，整个大脑和海马体之间表现出显着变化的基因存在很大差异。

In a previous study, we have found that short-lasting mild prenatal stress (restraint stress to pregnant rats, 30min/day for 3 days from E15 to E17, 30-min stress group) induces neurotrophic effects on morphology of fetal brain neurons, while long-lasting stress (4 hours/day for 3days from E15 to E17, 4-hrs stress group) causes neurotoxic changes. In addition, we have shown that the 30-min stress group reveals significantly better memory and learning performance in the adult offspring. Based on these results, using DNA tips, the present experiments were performed to identify genes which are involved in the facilitation of development of brain neurons and enhanced cognitive performance.Gene expression in three groups, control, 30-min stress and 4-hrs stress groups was investigated using 3 pieces of DNA tips (Rat Genome U34A, Affymetrix) for each group. The DNA tips used included about 8800 genes. The genes analyzed were receptors (808), channels (187), transporters (138), enzymes (1822), kinases (382), phosphatases (129), and transcription factors (57). The total RNAs extracted from the whole brain and hippocampal tissue of the fetal brains were analyzed. Gene expression was ranked for significance based on replication of data, signal intensity, statistical significance of differences among the three groups. Five to twenty genes that revealed significant increases or decreases in expression in the 30-min stress and 4-hrs stress group as compared to the control group were identified. These genes from the hippocampus included neurotrophic factors, and genes related to Alzheimer disease and neuronal guidance. It is also noted that genes showing significant changes are greatly different between the whole brain and hippocampus.