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免疫激活诱导的大鼠抑郁样行为以及缰核和海马p38MAPK和细胞因子的变化
其他题名The depressvie-like behaviors and the changes of p38MAPK pathway and cytokines in habenular and hippocampus induced by immunity activation
潘玉芹
学位类型博士
导师林文娟
2013-05
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
关键词脂多糖 抑郁样行为 缰核 细胞因子 p38MAPK信号通路
摘要
对于抑郁症机制的探讨是目前抑郁症研究的重点。“抑郁症的细胞因子假说”认为免疫激活在抑郁症中具有重要作用,缰核和海马作为参与抑郁的重要核团,他们的免疫激活在抑郁症发生中的作用以及中枢炎性发生的胞内机制并不清楚。 
为探讨缰核和海马免疫激活在抑郁行为中的作用,特别是p38MAPK信号通路在中枢免疫激活中的机制,本研究利用重复中枢注射脂多糖造模抑郁行为,采用体重增长、糖精水偏爱、旷场测试和悬尾测试观察行为指标;免疫组化和实时荧光定量PCR(real-time Polymerase Chain Reaction,RT-PCR)方法测定细胞因子的蛋白表达和 mRNA表达;利用western blot 蛋白质半定量分析技术检测p38总蛋白及其磷酸化水平的变化。
研究分为四个实验:实验一,考察缰核与抑郁症相关的细胞因子包括白细胞介素-1β  (interleukin-1β,IL-1β),白细胞介素-6 (interleukin-6,IL-6),干扰素-γ(interferon-γ, IFN-γ)、肿瘤坏死因子-α  (tumor necrosis factor-α)和白细胞介素-10(interleukin-10, IL-10)的产生和表达,确定缰核是否存在并能通过 LPS 免疫激活产生细胞因子;实验二,考察中枢重复注射 LPS 所致的抑郁样行为、缰核和海马区p38总蛋白及其磷酸化水平的变化及与炎性和抗炎性细胞因子的关系; 实验三,考察抗抑郁药氟西汀对慢性免疫激活大鼠行为的影响以及对缰核与海马的免疫激活和p38MAPK信号通路的影响;实验四,考察p38阻断剂SB203580对慢性免疫激活大鼠行为的影响以及对缰核与海马的免疫激活机制的影响。
主要研究结果如下:
1、急性中枢 LPS 注射后 2 小时,缰核区细胞因子 IL-1β,IL-6,IFN-γ,TNF-α 和IL-10mRNA和蛋白表达都升高;
2、重复中枢注射 LPS 导致大鼠出现显著的抑郁样行为,以及缰核和海马区TNF-α升高和IL-10下降以及p38MAPK信号通路激活;
3、慢性注射氟西汀能够改善重复中枢注射LPS诱导的抑郁样行为,降低了缰核和海马区 LPS  诱导的 IL-6 和 TNF-α 升高,并提高了缰核和海马区的 IL-10表达,同时降低了p38MAPK信号通路激活;
4、中枢慢性注射 p38 阻断剂 SB203580 抑制了重复中枢注射 LPS 诱导的p38MAPK 信号通路激活,改善了大鼠的抑郁样行为,同时降低了缰核和海马区LPS  诱导的IL-1β,IL-6 和TNF-αmRNA 升高,提高了缰核和海马区的IL-10mRNA表达;
5、激活的p38磷酸化蛋白主要在缰核和海马区的胶质细胞表达。
综上所述,缰核是重要的中枢免疫激活脑区之一。缰核和海马区炎性细胞因子IL-6和TNF-α及抗炎性细胞因子IL-10在抑郁样行为的形成中具有重要作用。
p38MAPK信号通路的激活可能介导了中枢免疫激活导致的炎症反应和抑郁样行
为的发生。
其他摘要Depression is one of the most important psychological diseases to threaten human health. “Cytokine theory of depression” suggests that immunity activation may play an important role in depression. Previous research showed that the habenular and hippocampus were  closely related with  the development of depressive disorder.
However, so far, whether the neuroimmune activations in habenular and hippocampus play a role  in depression  and the intracellular  mechanism  of central  immunity activation have not been reported Thus,  the  aim of the present  study was to systematically investigate the modulation role  of  cytokines and  p-p38 pathway  of  habenular and hippocampus in depressive-like behavior  induced by immune  inflammation. The behavioral paradigm used was the central repeated administration of LPS induced depressive-like behavior. The animal behaviors were  assessed  by the body weight gain, saccharin preference test, open field test and tail suspend test. The cytokine proteins and mRNA expression were measured using immunohistochemistry and RT-PCR. The p38 and p-p38 protein expressions were measured using western blot and immunohistochemistry.  
Four experiments were  carried out in the  present study. In experiment 1, acute central immune  activation by single LPS central injection was applied to test the expression of protein and mRNA of cytokines including interleukin-1β  (IL-1β), interleukin-6  (IL-6),  interferon-γ  ( IFN-γ), tumor necrosis factor-α  (TNF-α) and interleukin-10 (IL-10) in  habenular.  In experiment 2,  the changes of p38MAPK pathway and cytokines in  habenular  and hippocampus and the depressive-like behaviors  induced  by repeated central LPS administration were investigated.  In experiment 3,  the effects of  antidepressant  fluoxetine  on p38MAPK pathway and cytokines in habenular and hippocampus and the depressive-like behaviors induced by repeated central LPS administration were examined. In experiment four, the effects of p38MAPK inhibitor  SB203580  on p38MAPK pathway and cytokines in  habenular and hippocampus and the depressive-like behaviors  induced by repeated central LPS administration were examined.
The main results of the present study were as the following:
1.  Acute LPS central administration induced increased level of protein and mRNA of cytokines including IL-1β,IL-6,IFN-γ,TNF-α and IL-10 in habenular.
2.  Repeated central LPS administration induced significant depressive-like behavior, increased  the level of TNF-α,  decreased  the level of  IL-10, as well as increased level of p-p38 in habenular and hippocampus.
3.  Chronic antidepressant fluoxetine relived the depressive-like behavior induced by repeated central LPS administration, decreased the level of TNF-α and IL-6 and increased the level of IL-10, as well as decreased the level of p-p38 in habenular and hippocampus.
4.  SB203580 relived the depressive-like behavior induced by repeated central LPS administration, decreased the level of TNF-α, IL-1β  and IL-6 mRNA and increased the level of IL-10mRNA, as well as decreased the level of p-p38 in habenular and hippocampus.
5.  The p-p38 was expressed in microgial in habenular and hippocampus.
Taken together,  the habenular  contributed to  the pathphysiclogy of behavioral depression induced by immune activation as one of central immunity- activated brain regions. These findings demonstrated that the changes of pro-inflammation cytokines IL-6 and TNF-α and anti-inflammation cytokine IL-10 in habenular and hippocampus are  correlated  with the  occurrence  of depressive-like behavior induced by central inflammation. The p38MAPK pathway activation is involved in mediating the central inflammation response which results in depressive-like behavior.
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/311026/19643
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
潘玉芹. 免疫激活诱导的大鼠抑郁样行为以及缰核和海马p38MAPK和细胞因子的变化[D]. 北京. 中国科学院研究生院,2013.
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