Characterization of the vulnerability to repeated stress in Fischer 344 rats: possible involvement of microRNA-mediated down-regulation of the glucocorticoid receptor
Characterization of the vulnerability to repeated stress in Fischer 344 rats: possible involvement of microRNA-mediated down-regulation of the glucocorticoid receptor
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DOI：
10.1111/j.1460-9568.2008.06218.x
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发表时间：
2008-05-01
影响因子：
3.4
通讯作者：
Watanabe, Yoshifumi
中科院分区：
文献类型：
--
作者：
Uchida, Shusaku;Nishida, Akira;Watanabe, Yoshifumi
在本研究中，我们建立和特点的动物模型的脆弱性，重复的压力。我们发现，对照Sprague-Dawley（SD）大鼠在重复束缚应激14天后，HPA轴反应逐渐下降，而Fischer 344（F344）大鼠没有表现出这种HPA轴习惯化。SD大鼠下丘脑室旁核（PVN）中c-fos mRNA、促肾上腺皮质激素释放激素hnRNA以及磷酸化CREB和磷酸化ERK蛋白的表达也观察到类似的习惯性变化，但F344大鼠中则没有。此外，反复限制F344大鼠表现出减少海马齿状回的细胞增殖和增加焦虑相关的行为，而反复限制SD大鼠表现出选择性增强海马细胞增殖的腹侧区。此外，我们发现糖皮质激素受体（GR）蛋白的表达较低，而不是mRNA，在PVN的F344大鼠相比，SD大鼠。我们还发现，microRNA（miR）-18a抑制GR mRNA在培养的神经元细胞的翻译和增加miR-18 a在PVN中的表达在F344大鼠与SD大鼠相比，观察。在海马和前额皮质中没有发现GR蛋白水平的这些应变差异，并且miR-18 a在这些脑区域中的表达远低于PVN。我们的研究结果表明，F344大鼠可能是一个有用的动物模型，用于研究脆弱性的重复压力，和miR-18 a介导的下调GR翻译可能是一个重要的因素被认为是易感性的压力相关疾病。
In the present study, we established and characterized an animal model of vulnerability to repeated stress. We found that control Sprague-Dawley (SD) rats showed a gradual decrease in the HPA axis response following 14 days of repeated restraint stress, whereas Fischer 344 (F344) rats did not show such HPA axis habituation. Similar habituation was observed in the expression of c-fos mRNA, corticotropin-releasing hormone hnRNA, and phospho-CREB and phospho-ERK proteins in the hypothalamic paraventricular nucleus (PVN) of SD rats, but not in the F344 rats. In addition, repeatedly restrained F344 rats exhibited decreased cell proliferation in the dentate gyrus of the hippocampus and increased anxiety-related behaviours, while repeatedly restrained SD rats exhibited a selective enhancement of hippocampal cell proliferation in the ventral area. Moreover, we found a lower expression of glucocorticoid receptor (GR) protein, but not mRNA, in the PVN of F344 rats compared to SD rats. We also identified that microRNA (miR)-18a inhibited translation of GR mRNA in cultured neuronal cells and that increased expression of miR-18a in the PVN was observed in F344 rats compared with SD rats. These strain differences in GR protein levels were not found in the hippocampus and prefrontal cortex, and the expression of miR-18a was much lower in these brain regions than in the PVN. Our results suggest that F344 rats could be a useful animal model for studying vulnerability to repeated stress, and that miR-18a-mediated down-regulation of GR translation may be an important factor to be considered in susceptibility to stress-related disorders.