Department of Psychiatry, University of Colorado Denver, Aurora, CO 80045, USA.
Physiol Behav. 2011 Aug 3;104(2):334-9. doi: 10.1016/j.physbeh.2011.02.032. Epub 2011 Mar 4.
Multiple animal models have been developed to recapitulate phenotypes of the human disease, schizophrenia. A model that simulates many of the cognitive and sensory deficits of the disorder is the use of random variable prenatal stress (PS) in the rat. These deficits suggest a molecular origin in the hippocampus, a brain region that plays a role in the regulation of stress. To study both hippocampal gene expression changes in offspring of prenatally stressed dams and to address genetic variability, we used a random array of prenatal stressors in three different rat strains with diverse responses to stress: Fischer, Sprague-Dawley, and Lewis rats. Candidate genes involved in stress, schizophrenia, cognition, neurotrophic effects, and immunity were selected for assessment by real-time quantitative PCR under resting conditions and following a brief exposure to restraint stress. PS resulted in significant differences in gene expression in the offspring that were strain dependent. mRNA expression for the N-methyl-D-aspartate receptor subtype 2B (Grin2b) was increased, and tumor necrosis factor-alpha (Tnfα) transcript was decreased in PS Sprague-Dawley and Lewis rats, but not in the Fischer rats. Expression of brain-derived neurotrophic factor (Bdnf) mRNA in the hippocampus was increased after an acute stress in all controls of each strain, yet a decrease was seen after acute stress in the PS Sprague-Dawley and Lewis rats. Expression of the glucocorticoid receptor (Nr3c1) was decreased in the Fischer strain when compared to Lewis or Sprague-Dawley rats, though the Fischer rats had markedly higher α7 nicotinic receptor (Chrna7) expression. The expression differences seen in these animals may be important elements of the phenotypic differences seen due to PS and genetic background.
多种动物模型已被开发出来，以重现人类疾病精神分裂症的表型。一种模拟该疾病认知和感觉缺陷的模型是在大鼠中使用随机可变产前应激 (PS)。这些缺陷表明，海马体存在分子起源，海马体在调节应激方面起着重要作用。为了研究产前应激母鼠后代的海马体基因表达变化并解决遗传变异性问题，我们使用了三种不同应激反应大鼠品系的随机产前应激源：费希尔大鼠、斯普拉格-道利大鼠和刘易斯大鼠。选择涉及应激、精神分裂症、认知、神经营养作用和免疫的候选基因，通过实时定量 PCR 在静息状态和短暂束缚应激后进行评估。PS 导致了与应激有关的候选基因在后代中的表达存在显著差异，且这种差异依赖于品系。PS 增加了 N-甲基-D-天冬氨酸受体亚基 2B（Grin2b）的 mRNA 表达，而肿瘤坏死因子-α（Tnfα）转录物在 PS 斯普拉格-道利和刘易斯大鼠中减少，但在费希尔大鼠中没有减少。在所有大鼠品系的对照中，急性应激后海马体脑源性神经营养因子 (Bdnf) mRNA 的表达增加，但 PS 斯普拉格-道利和刘易斯大鼠的表达减少。与刘易斯或斯普拉格-道利大鼠相比，费希尔大鼠的糖皮质激素受体 (Nr3c1) 表达减少，尽管费希尔大鼠的α7 烟碱型乙酰胆碱受体 (Chrna7) 表达明显更高。这些动物中观察到的表达差异可能是由于 PS 和遗传背景导致的表型差异的重要因素。
