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前额叶ERK信号通路在慢性不确定性应激诱导的认知灵活性损伤及情绪行为改变中的作用
其他题名The role of prefrontal ERK signal pathway in the alterations of cognitive flexibility and emotional behavior induced by chronic unpredictable stress
罗晓敏
学位类型硕士
导师王玮文
2011-06
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
关键词慢性不确定性应激 认知灵活性 抑郁样行为 焦虑样行为 细胞外信号调节激酶
摘要应激及应激相关情绪疾病普遍伴随前额叶依赖的认知灵活性损害且可被多种抗抑郁治疗所改善。日益增加的临床和实验性研究还表明,前额叶功能异常导致固着性认知和情感偏误,可能构成了抑郁症和焦虑症的一个重要的病因学因素。迄今为止,对应激诱导前额叶认知灵活性缺损的细胞分子机理所知甚少。细胞外信号调节蛋白激酶(Extracellular signal-regulated kinase, ERK)广泛参与应激反应、情绪和认知功能调节。本研究旨在探讨前额叶ERK信号蛋白在慢性应激诱导的认知灵活性和情绪行为改变中的作用。首先,研究建立了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(Attentional Set-shifting Task, AST),并比较了不同种系大鼠在注意定势转移任务中的认知表现以及不同AST测定模式的结构效度。其次,研究调查了慢性不确定性应激对大鼠注意定势转移任务不同认知成分和抑郁样及焦虑样行为的影响,并采用Western Blotting分析技术检测了前额叶不同亚区ERK蛋白表达及其磷酸化水平。 研究结果表明: (1)SD和Wistar雄性大鼠在AST中表现出类似的学习模式,但Wistar大鼠在各阶段的认知表现都明显优于SD大鼠,主要表现在更少的达标次数和错误反应率。同时注意定势转移任务五阶段测试模式与目前常用的七阶段测试模式具有相似的结构效度。 (2)慢性不确定性应激导致前额叶皮质不同亚区中ERK1/2蛋白及其磷酸化水平改变:在眶额叶皮质(OFC)中,ERK1/2的磷酸化及总ERK1/2蛋白表达水平降低, ERK2的相对激活水平增加;在内侧前额叶皮质(mPFC)中,ERK1/2的磷酸化和总ERK2蛋白表达水平降低,ERK1/2的相对激活水平也降低。 (3)慢性不确定性应激导致以简单辨别学习和外维度转换损伤为特征的认知灵活性损伤,主要表现在应激组大鼠在AST测试中简单辨别(SD)和外维度转换(ED)阶段达标次数增加。进一步相关性分析显示,认知灵活性的核心指标外维度转换阶段达标次数与mPFC中ERK2和OFC中ERK1/2蛋白、磷酸化ERK1/2水平和ERK2相对活性比值呈负相关关系。 (4)慢性不确定性应激诱导明显的抑郁样行为。应激组大鼠在糖水偏好测试中糖水饮用量明显降低和糖水偏好值一定程度降低,以及旷场测试中水平运动距离减少。进一步相关性分析显示,糖水偏好值、糖水饮用量及旷场水平运动距离与mPFC和OFC中pERK1/2、ERK1/2及ERK1/2相对活性比值多项指标呈显著相关关系。 (5)慢性不确定性应激明显增加大鼠的焦虑水平。应激组大鼠在高架十字迷宫测试中进入开放臂的次数和停留时间降低,以及旷场中的修饰行为增加。进一步的相关性分析显示,开臂停留时间、开臂进入次数及修饰行为与mPFC和OFC中pERK1/2,ERK1/2以及ERK1/2相对活性比值多项指标呈相关关系。 上述结果表明,采用Wistar大鼠建立五阶段注意定势转移任务是一种理想的测试模式。另外,慢性不确定性应激可在诱导认知灵活性损伤的同时诱导情绪行为的改变。综合分析认知及情绪行为与前额叶不同亚区ERK1/2蛋白表达之间的关系,提示mPFC和OFC中ERK1/2蛋白表达及磷酸化水平的改变可能同时介导了慢性应激诱导的认知灵活性与情绪行为改变。
其他摘要 
The impairments of cognitive flexibility associated with the prefrontal lobe dysfunction are increasingly recognized as major components of depression, anxiety and other stress-related mood disorders, and can be reversed by antidepressant treatment. Increasing clinical and preclinical studies have shown that prefrontal dysfunction which can lead to perseverative cognitive and emotional bias was thought to be an important etiological factor of depression and anxiety. To date, little was known about the molecular mechanisms of the stress-induced impairment in prefrontal cortex - mediated cognitive flexibility. Extracellular signal-regulated kinase (ERK) was involved in stress response, emotion and cognitive function. The present study aims at investigating the role of ERK protein in the changes of cognitive flexibility and emotiaonal behaviors induced by chronic stress. Firstly, we established attentional set-shifting task (AST) used to determine the cognitive flexibility in rodents, which was analogue to Wisconsin card sorting test. The cognitive performance of two different rat strains and constructive validity of different testing procedures in AST were also evaluated. Secondly, the present study investigated the effects of chronic unpredictable stress on different cognitive componets in AST, depression-like and anxiety-like behaviors, and the prefrontal ERK expression determined by Western Blotting assay. The results showed that: (1) Adult SD and Wistar male rats had the similar cognitive patern in the AST, but Wistar rats showed higher performance on each stage in AST than SD rats, which demonstrated as less trials of criterion and lower error rate. Also, there was a similar constructive validity between the five-stage and seven-stage procedures of AST. (2) Chronic unpredictable stress exerted differential effects on ERK1/2 protein and their phosphorylation level in the different sub-regions of prefrontal cortex, manifested as: decreased phosphorylation level of ERK 1/2 and total ERK1/2 protein and increased relative activation level of ERK2 in orbitofrontal cortex (OFC), as well as decreased phosphorylation of ERK1/2, total ERK2 protein and relative activation level of ERK 1/2 in medial prefrontal cortex (mPFC). (3) Chronic unpredictable stress induced the deficits of cognitive flexibility characterized by the impairements of simple discrimination (SD) and extra-dimension shifting (ED). The correlation analysis showed that the trials of criterion in ED stage was negatively related to ERK protein, phosphorylation level and relative activation level in mPFC and OFC. (4) Chronic unpredictable stress induced significant depression-like behaviors. Rats in stress group showed a decrease in sucrose intake, sucrose preference and distance traveled in open field. The correlation analysis showed that sucrose intake, sucrose preference and distance traveled was significantly related to pERK1/2, ERK1/2 and ralative activation level in mPFC and OFC. (5) Chronic unpredictable stress induced significant anxiety-like behaviors. Rats in stress group showed a decrease in entries and time on open arm in the elevated-plus maze test and the number of grooming behavior in open field. The correlation analysis showed that entries and time on open arm and the number of grooming were significantly related to pERK1/2, ERK1/2 and ralative activation level in mPFC and OFC. These results indicated that five-stage AST model in Wistar rats was the optimal one. In addition, chronic unpredictable stress induced both cognitive and emotional disturbances. The comprehensive correlation analysis between emotional and cognitive behaviors and prefrontal ERK 1/2 protein expression showed that ERK 1/2 protein expression and phosphorylation level in mPFC and OFC might mediate both the deficits of cognitive flexibility and emotional behaviors induced by chronic stress.
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/311026/20315
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
罗晓敏. 前额叶ERK信号通路在慢性不确定性应激诱导的认知灵活性损伤及情绪行为改变中的作用[D]. 北京. 中国科学院研究生院,2011.
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