细胞外信号调节蛋白激酶-cAMP反应元件结合蛋白信号通路在应激所致抑郁行为障碍中的作用
其他题名The role of ERK-CREB signal pathway in depressive-like behaviors induced by stress
亓晓丽
学位类型博士
导师林文娟
2007-06-06
学位授予单位中国科学院心理研究所
学位授予地点心理研究所
关键词应激 抑郁 ERK CREB
摘要应激是导致抑郁等行为障碍的重要因素,但应激转化为抑郁的脑机制却知之甚少。为此,该研究利用应激抑郁动物模型、抗抑郁药物干预、以及定位脑区信号通路阻断等手段,系统的探讨了细胞外信号调节的蛋白激酶(extracellular signal-regulated protein kinase, ERK)- cAMP反应元件结合蛋白(cyclic-AMP-responsive element(CRE)-binding protein, CREB)信号通路在应激导致抑郁脑机制中的作用。主要结果如下: (1) 慢性强迫游泳应激导致动物产生显著的抑郁样行为,损伤了海马和前额叶皮质ERK-CREB信号通路,P-ERK2和P-CREB与抑郁样行为显著相关; (2) 慢性空瓶应激没有导致动物产生显著的抑郁样行为,降低了海马和前额叶皮质P-ERK2水平,未引起P-CREB显著下降; (3) 氟西汀改善了应激动物的抑郁样行为,同时提高了应激动物海马和前额叶皮质ERK-CREB信号通路的活性水平; (4) U0126降低了海马ERK-CREB信号通路的活性水平,导致动物出现抑郁样行为; (5) U0126降低了前额叶皮质ERK-CREB信号通路的活性水平,导致动物出现抑郁样行为。 综上所述,海马和前额叶皮质ERK-CREB信号通路参与了机体的应激反应以及抗抑郁药物逆转应激所致行为损伤的药理作用机制。海马或前额叶皮质ERK-CREB信号通路损伤导致动物产生显著的抑郁样行为。海马或前额叶皮质ERK-CREB信号通路损伤可能是应激导致抑郁的脑机制之一。
其他摘要Stress is the most important factor in the vulnerability to depression and other behavioral disorders, but the mechanisms that stress signals are transferred into depression are far from understanding. To date, the neurotransmitters, neurotrophins and signal pathway have been concerned in the topic focusing on the pathophysiology of depression, but there are still many puzzles. Increasing evidence has indicated that the alteration in neuronal plasticity is the “trace” of stress-induced damages. The extracellular signal-regulated protein kinase(ERK)-cyclic-AMP-responsive element(CRE)-binding protein(CREB)signal pathway is a powerful intracellular signal transduction pathway participating in neuronal plasticity which is involved in higher brain cognitive functions such as learning and memory. However, so far, little is known about the role of the ERK-CREB signal pathway in response to stress and emotional modulations. Thus the aim of the study was to systematically investigate the role of the ERK-CEB signal pathway in depressive-like behaviors induced by stress. Depression animal models, antidepressant agent treatment and disruption of signal pathway in specific brain regions were applied. In the present study, three experiment sessions were designed to make sure whether the ERK-CREB signal pathway was indeed one of pathophysiological mechanisms of depressive-like behaviors induced by stress. In experiment one, two different stress animal models were applied, chronic forced swim stress and chronic empty water bottle stress. After stress, all animals were tested behaviorally using open-field, elevated-plus maze and saccharine preference test, and brain samples were processed for determination of ERK, P-ERK, CREB and P-CREB using western blot. The relationships between the proteins of ERK, P-ERK, CREB and P-CREB in the brain and the behavioral variables were also analyzed. In experiment two, rats were treated with antidepressant agent fluoxetine once a day for 21 consecutive days, then the brain levels of ERK, P-ERK, CREB and P-CREB was determined, the depressive-like behaviors were also examined. In experiment three, mitogen activated extracellular-signal-regulated kinase kinase (MEK) inhibitor U0126 was administrated to inhabit the activation of ERK in the hippocampus and prefrontal cortex respectively, then behavioral measurements and protein detection were conducted. The main results of the study were as the following: (1) Chronic forced swim stress induced animals to suffer depression and disrupted the ERK-CREB signal pathway in hippocampus and prefrontal cortex. There were significant correlations between P-ERK2, P-CREB and multiple variables of depressive-like behaviors. (2) Chronic empty water bottle stress did not induce depressive-like behaviors. Such stress decreased the brain level of P-ERK2 in hippocampus and prefrontal cortex, but the level of P-CREB in the hippocampus was increased. (3) The antidepressant agent fluoxetine relieved depressive-like behaviors and increased the activities of the ERK-CREB signal pathway in stressed animals. (4) Animals treated with U0126 injection into hippocampus showed decreased activities of the ERK-CREB signal pathway in the hippocampus, and suffered depression comorbid with anxiety. (5) Animals treated with U0126 injection into prefrontal cortex showed decreased activities of the ERK-CREB signal pathway in the prefrontal cortex, and exhibited depressive-like behaviors. In conclusion, The ERK-CREB signal pathway in the hippocampus and prefrontal cortex was involved in stress responses and significantly correlated with depressive-like behaviors; The ERK-CREB signal pathway in the hippocampus and prefrontal cortex participated in the mechanism that fluoxetine reversed stress-induced behavioral disorders, and might be the target pathway of the therapeutic action of antidepressants; The disruption of the ERK-CREB signal pathway in the hippocampus or prefrontal cortex led to depressive-like behaviors in animals, suggesting that disruption of ERK-CREB pathway in the hippocampus or prefrontal cortex was involved in the pathophysiology of depression, and might be at least one of the mechanisms of depression induced by stress.
页数124
语种中文
文献类型学位论文
条目标识符http://ir.psych.ac.cn/handle/311026/4550
专题中国科学院心理研究所回溯数据库(1956-2010)
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亓晓丽. 细胞外信号调节蛋白激酶-cAMP反应元件结合蛋白信号通路在应激所致抑郁行为障碍中的作用[D]. 心理研究所. 中国科学院心理研究所,2007.
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