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社会击败应激和前额叶ERK信号转导抑制对大鼠认知灵活性的影响
其他题名Effects of social defeat stress and ERK signaling inhibition in PFC on cognitive flexibility of rats
王琼
学位类型硕士
导师王玮文
2012-06
学位授予单位中国科学院研究生院
学位授予地点北京
学位专业心理学
关键词社会击败应激 前额叶 认知灵活性 细胞外信号调节激酶 源性神经营养因子
摘要前额叶依赖的认知灵活性障碍在抑郁症发病、病理生理和药物治疗中发挥重要作用。抑郁症相关认知灵活性障碍及其神经机理研究日益受到重视。这个方向上的重要一步是开展抑郁症动物模型从单纯情绪维度向认知维度扩展的综合研究。不同方面的研究证实社会击败应激是一种有效的致抑郁动物模型。社会击败应激对前额叶认知灵活性的影响特征目前还不清楚。单胺能系统与前额叶交互作用参与认知灵活性不同成分的调节,但神经递质之后的分子事件尚缺乏了解。本研究将建立社会击败应激模型,采用拟人类威斯康辛卡片分类测试的啮齿类动物认知灵活性检测模型——注意定势转移任务评价社会击败应激对认知灵活性不同成分的影响。在此基础上进一步采用Western Blotting分析技术检测应激对前额叶细胞外信号调节蛋白激酶(Extracellular signal-regulated kinase, ERK),其下游重要底物之一cAMP反应元件结合蛋白(cyclic-AMP-responsive element binding protein, CREB)及CREB调控的脑源性神经营养因子(brain derived neurotrophic factor,BDNF)表达的影响及其相互关系。最后,研究将通过立体定位手术和脑内微注射技术调查前额叶不同脑区ERK信号转导抑制对认知灵活性以及CREB和BDNF表达的影响。 主要研究结果如下: (1)社会击败应激诱导大鼠AST中以逆反学习(Reversal Learning, REL)和外维度定势转换(Extra-dimensional shifting, EDS)损伤为特征的认知灵活性损害,表现在社会击败应激组大鼠与相应对照组相比 REL和EDS阶段的达标训练次数和错误率均明显增加,且REL损伤与应激刺激强度显著相关。进一步的错误率动态分析显示社会击败应激诱导的EDS损害主要来自动物对已习得相关维度的异常固着性反应。 (2)社会击败应激在mPFC主要诱导ERK2 信号转导异常,而在OFC中诱导更为广泛的包括ERK1信号转导在内的异常。社会击败应激同时降低OFC和mPFC中pCREB及BDNF表达水平。 (3) OFC中微注射ERK信号转导抑制剂明显降低该部位的ERK2激活水平,诱导大鼠AST中EDS损伤为特征的认知灵活性损伤,对pCREB和BDNF水平没有显著影响。 (4) mPFC中微注射ERK信号转导抑制剂明显降低该部位ERK2激活水平,但对认知灵活性不同成分及pCREB和BDNF水平均没有显著影响。 上述结果表明,社会击败应激诱导以逆反学习和外维度注意转移障碍为特征的认知灵活性缺陷。应激和药物处置对认知功能和信号转导分子的影响差异提示,ERK信号转导可能依赖于作用脑区在认知灵活性不同成分调节中发挥复杂影响。ERK及CREB-BDNF在认知灵活性调节中的作用可能是分离的。CREB和BDNF表达呈现一致性的,但与ERK不同的反应变化,它们在应激诱导的认知灵活性变化中的作用及调控其表达的潜在上游信号转导分子和通路还需要进一步的研究辨识。上述研究促进了应激相关情绪疾病与认知功能障碍的神经分子基础的认识,并为情绪疾病认知灵活性障碍有效治疗提供了潜在分子靶点。
其他摘要The impairments of cognitive flexibility associated with the prefrontal lobe dysfunction are increasingly recognized as one of the major components in the etiology, pathophysiology of depression and antidepressive treatment. With recent strategies of behavioral modeling of depression supporting expansion beyond “pure” depression domains, experimental models based on targeting these plus cognitive domains represent further important directions of research. Although social defeat stress has been widely used as a model of depression, the effects of social defeat on cognitive flexibility are still unclear. It has been shown that the interactions between monoaminergic system and prefrontal cortex are involved in the modulation of cognitive flexibility. However, it remains uncertain which downstream molecular events affected by neurotransmitters are critical to their effects on cognitive function. The present study aims to investigate the effects of social defeat stress and ERK signal pathway in prefrontal cortex on cognitive flexibility of rats. Firstly, we established a social defeat stress model and examined the effect of social defeat on different cognitive components in Attentional Set-shifting Task (AST), a model adapted from human-based cognitive task, called Wisconsin Card Sorting Test (WCST). Secondly, the expressions of extracellular signal-regulated kinase (ERK), cAMP response components combined with protein (CREB) and brain derived neurotrophic factor (BDNF) in prefrontal cortex were determined using Western Blotting assay. Finally, the effects of ERK signaling inhibitor administered either in medial prefrontal cortex (mPFC) or in orbitofrontal cortex (OFC) on cognitive flexibility and the levels of CREB and BDNF were examined. The results showed that: (1) Social defeat stress induced deficits of cognitive flexibility, characterized by the impairment of reversal learning (REL) and extra-dimension shifting (EDS) in AST. The stressed rats showed a significant increase in the trials to criterion and the errors to criterion in REL and EDS compared to non-stressed rats. Morever, the number of REL trials was significantly correlated with the number of defeated behaviors in stressed rats. A further analysis of error rate showed that the perseveration to previous relevant dimension could contribute to the impairment of EDS performance induced by social stress. (2) Social defeat exerted differential effects on ERK1/2 proteins and their phosphorylation levels in the different sub-regions of prefrontal cortex. Stress only induced a decrease in ERK2 signal transduction in mPFC, while more extensive decrease in both ERK1 and pERK1/2 expression in OFC. Social defeat stress downregulated the phosphorylation of CREB (pCREB) and BDNF expression both in OFC and mPFC. (3) ERK inhibitor injected into OFC led to a reduction of pERK2 and the impairment of EDS, but the levels of pCREB and BDNF were not changed. (4) ERK inhibitor injected into mPFC led to a reduction of pERK2, but had no effects on cognitive flexibility and the expression of pCREB and BDNF. These results indicated that social defeat stress induced cognitive disturbances both in REL and EDS. The different effects of Stress and pharmaceutical treatment on cognitive functions and signal molecules suggested that ERK exerted complex effects on different cognitive components depending on the places of action. CREB and BDNF had a consistent response to stress and drug treatment, but different from ERK. Further studies are needed to identify the effects of above proteins on stress-induced cognitive impairment and upstream signaling molecules. All these findings promote the understanding on potential signaling pathway underlying stress-induced deficits of cognitive function.
学科领域医学心理学
语种中文
文献类型学位论文
条目标识符http://ir.psych.ac.cn/handle/311026/20399
专题健康与遗传心理学研究室
作者单位中国科学院心理研究所
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GB/T 7714
王琼. 社会击败应激和前额叶ERK信号转导抑制对大鼠认知灵活性的影响[D]. 北京. 中国科学院研究生院,2012.
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