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应激激活蛋白激酶JNK 在中枢炎性免疫诱导的 抑郁样行为中的作用
Alternative TitleThe role of stress-activated protein kinase/JNK in depressive-like behavior induced by neuroinflammation
张军涛
Subtype博士
Thesis Advisor林文娟
2019-12
Degree Grantor中国科学院心理研究所
Place of Conferral中国科学院心理研究所
Degree Name理学博士
Degree Discipline健康心理学
Keyword抑郁样行为 JNK 激酶 炎性细胞因子 糖皮质激素受体 缰核 杏仁 核 杏仁 核 内侧前额叶 海马 伏隔核
Abstract

抑郁症与免疫失调和下丘脑-垂体-肾上腺皮质(HPA)轴异常有密切的联系,但内在分子机制仍未完全阐明。c-Jun 应激激活蛋白激酶(c-Jun N-terminal kinase, JNK)是在炎症反应中发挥重要调节作用的一类激酶,而且近年来的研究发现JNK 与中枢神经系统的发育和疾病有重要的关联。然而,是否JNK 参与调节神经炎症诱导的抑郁症尚不清楚。本研究考察了中枢神经系统中JNK 激酶在LPS 注射诱导的炎性抑郁症模型中发挥的作用,选定与抑郁症有重要关联的五个脑区——缰核、杏仁核、内侧前额叶、海马和伏隔核为考察脑区;并且选取与炎症相关的两条JNK 激酶调控通路对JNK 可能的调控机制进行考察:(1)促炎性细胞因子的表达;(2)糖皮质激素受体(Gluococorticoid receptor, GR)的丝氨酸246 位点的磷酸化。已知GR 介导糖皮质激素的免疫抑制作用,并且与HPA 轴的负反馈调节有关。

研究包括以下三个部分实验设计。第一部分: 建立中枢重复LPS 注射诱发的大鼠抑郁样行为模型,通过糖水偏好测试、旷场行为测试和悬尾测试来观察抑郁样行为。然后通过Western blot 检测中枢五个脑区中JNK 的活化水平、促炎性细胞因子的表达水平和GRSer246 位点磷酸化水平是否与正常情况下有差异。第二部分: 通过中枢注射JNK 抑制剂SP600125 抑制LPS 注射导致的JNK 活化,然后观察抑制JNK 后是否对LPS 注射诱导的抑郁样行为产生影响,以考察JNK在炎性抑郁症中的作用;同时也考察五个脑区中炎性细胞因子的表达和GRSer246位点的磷酸化是否也受到SP600125 处理的影响,以考察JNK在炎性抑郁症中可能的调控机制。第三部分:检测抗炎性omega-3 脂肪酸能否对中枢炎性应激诱导的五个脑区中炎性细胞因子的表达、JNK 的活化和GRSer246 位点的磷酸化产生影响,能否对中枢炎性应激诱导的抑郁样行为具有改善作用,通过多渠道考察JNK 的活化在炎性抑郁样行为中的作用,验证其是否和抑郁样行为具有因果联系。

研究结果显示:(一)重复四次中枢LPS 注射诱导了大鼠抑郁样的行为,体现在糖水偏好降低、旷场自主行动和探索性行为减少、悬尾测试中不动时间增加。Western blot 检测发现中枢LPS 注射诱发的抑郁样行为中伴随着大鼠缰核、杏仁核、内侧前额叶、海马和伏隔核中的JNK 磷酸化水平均呈现上升,促炎性细胞因子TNF-α和IL-1β的含量总体增加和GRSer246 位点的磷酸化水平也上升。这些结果说明炎性抑郁样行为伴随着JNK 活性、炎性细胞因子表达和GRSer246 位点磷酸化水平的上调,提示这些分子事件可能与炎性抑郁样行为具有关联性。(二)JNK 抑制剂SP600125 阻断了由LPS 注射引起的JNK 激活,Western blot 检测表明大鼠缰核、杏仁核、内侧前额叶、海马和伏隔核中的JNK 磷酸化水平显著下调。行为检测发现SP600125 明显改善了中枢LPS 注射诱导的抑郁样行为,表现在SP600125 提升了LPS 注射导致的大鼠糖水偏好的降低、增加了旷场测试中的中央停留时间和直立次数,以及缩短了悬尾测试中的不动时间。同时用Westernblot 检测发现SP600125 对LPS 注射诱导的缰核、杏仁核和内侧前额叶中的TNF-α和IL-1β的表达上升和GRSer246 位点的磷酸化水平增加均有抑制作用。该结果说明中枢LPS 注射导致的JNK 激活对炎性抑郁样行为具有促进作用,对TNF-α和IL-1β的表达和GRSer246 位点的磷酸化水平的上升也有调控作用。这些结果说明JNK 的活性与炎性抑郁样行为具有一定的因果关系,并且炎性细胞因子的表达和GRSer246 的磷酸化可能参与到JNK 对抑郁样行为的调控作用中。(三)补充了omega-3 脂肪酸的大鼠在LPS 注射后其中枢JNK 的活性明显下调,TNF-α和IL-1β的表达和GRSer246 位点的磷酸化上升水平也显著下降;在行为方面,omega-3 脂肪酸的补充能够明显缓解LPS 注射诱发的抑郁样行为。该结果再次证明JNK 的活性水平与炎性抑郁样行为具有紧密关联。

综上所述,本研究证明中枢JNK 参与了中枢炎性免疫激活诱导的抑郁样行为调控;抑制中枢炎性诱导的JNK 的激活能够阻止促炎性细胞因子TNF-α和IL-1β的表达增加和GRSer246 的磷酸化水平的上升,提示JNK 参与炎性抑郁样行为调控的作用机制可能涉及炎性细胞因子的表达和GRSer246 的磷酸化。海马,内侧前额叶,缰核,杏仁核和伏隔核中发生的与抑郁样行为具有关联性的分子变化提示这五个脑区均可能参与炎性抑郁症的调节。JNK 抑制剂SP600125 和抗抑郁辅佐剂omega-3 脂肪酸均能在下调JNK 活性的同时改善抑郁样症状,表明JNK激酶可能是治疗抑郁症的一个潜在新靶标。

Other Abstract

Depression is well-known to be associated with immune dysregulation and aberrant hypothalamic-pituitary-adrenal (HPA) axis activity, but the molecular neurobiological mechanisms underlying the associations remain unclear. The c-Jun amino-terminal kinase (JNK), as an important modulator in inflammation and stress response, has been found to be critically involved in the development of diseases of central nervous system. However, whether and how JNK mediates neuroinflammation-induced depression remains largely unknown. In this study we investigated the role of central JNK in depressive-like behaviors induced by central lipopolysaccharide (LPS) infusion and five depression-related brain regions including habenula(Hb), amygdala(Amyg), medial prefrontal cortex(mPFC), hippocampus(Hip) and nucleus accumbens(NAc) were selected to examine the molecular changes .

Three parts of experiments were carried out in the investigation. The partⅠ: Repeated central LPS infusion was used to induce the depressive-like behavior of rats. The body weight gain, sucrose preference test, open-field test and tail suspension test were used to assess the depressive-like behaviors of rats. The phosphorylation of JNK, the expression of TNF-αand IL-1β and the phosphorylation of glucocorticoid receptor (GR) at serine 246 (GR-Ser246) in Hb, Amyg, mPFC, Hip and NAc of depressive rats induced by LPS infusion were examined by Western blot. The part Ⅱ: The JNK inhibitor SP600125 was used to investigate whether the inhibition of JNK could block the occurrence of depressive-like behavior induced by central LPS infusion. The inhibition of JNK phosphorylation was determined, and the impact on the expression of TNF-α and IL-1β and the phosphorylation of GRSer246 by SP600125 treatment were also determined by Western blot. The part Ⅲ: The anti-inflammatory omega-3 fatty acids was used to investigate its effect on the phosphorylation of JNK and the depressive-like behavior induced by LPS infusion. The effect of omega-3 supplement on the expression of TNF-α and IL-1β and the phosphorylation of GRSer246 were also determined.

The results showed that LPS infusion induced depressive-like behaviors and in the meantime, increased proinflammatory cytokines expression, activated JNK and upregulated phosphorylation of GR-Ser246 in Hb, Amyg, mPFC, Hip and NAc. Treatment with JNK inhibitor SP600125 prevented the LPS-induced hyper-activation of JNK in Hb, Amyg, mPFC, Hip and NAc and alleviated depressive-like behaviors. Moreover, LPS-induced upregulation of TNF-α and IL-1β and pGR-Ser246 in Hb, Amyg and mPFC were found to be inhibited by SP600125 treatment. Omega-3 supplement alleviated the depressive-like behaviors induced by LPS, and inhibited the increased phosphorylation of JNK as well as the expression of TNF-α and IL-1β and pGR-Ser246 in Amyg, mPFC and Hip.

In summary, the results show the first evidence that JNK activities in Hb, Amyg, mPFC, Hip and NAc are involved in the modulation of neuroinflammation-induced depression. Block of JNK by either specific inhibitor SP600125 or anti-inflammatory agent omega-3 is associated with ameliorated depressive-like behaviors induced by LPS infusion. Moreover, inhibition of activation of JNK alleviates the increased expression of proinflammatory cytokines and pGRSer246 induced by LPS, which are two pathological factors related to depression, suggesting that they may be involved in the mechanism by which JNK regulates depression. These findings provide new insights into the understanding of the mechanism of neuroinflammation-associated depression and suggest that the JNK pathway may serve as a potential target for the treatment of inflammation-related depression.

Pages122
Language中文
Document Type学位论文
Identifierhttp://ir.psych.ac.cn/handle/311026/30404
Collection健康与遗传心理学研究室
Recommended Citation
GB/T 7714
张军涛. 应激激活蛋白激酶JNK 在中枢炎性免疫诱导的 抑郁样行为中的作用[D]. 中国科学院心理研究所. 中国科学院心理研究所,2019.
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