抑郁症患者前额叶中情感调节相关信号通路紊乱的分子基础

发布时间：2018-06-25 19:18

本文选题：前扣带回 + 脑源性神经营养因子　；参考：《中国科学技术大学》2013年博士论文

【摘要】：情感障碍是一类与情绪调节紊乱相关的疾病,约有17%的人会在一生中的某段时间受其影响,造成了严重的个人、社会和经济负担。近年来研究发现,情感障碍患者背外侧前额叶皮层和前扣带回的结构和功能均发生明显改变,而抗抑郁治疗能够减弱或者逆转这些异常变化。但是其生物学机制一直不明。本研究使用实时定量PCR的方法,检测情感障碍患者死后背外侧前额叶皮层和前扣带回灰质中已知参与情绪调节的关键基因的mRNA水平。情绪障碍患者包含双相情感障碍和重度抑郁症患者。对一些重要分子的改变,采用免疫组织化学的方法进一步验证。对于可能的分子机制和因果关系采用体外细胞培养和分子生物学的方法展开探索。主要发现如下： 1)在情感障碍患者的背外侧前额叶和/或前扣带回中,视黄酸信号通路的一些重要分子的mRNA水平显著下降。同时伴随BDNF和TrkB mRNA表达下调。对照组前扣带回中,视黄酸受体a (RARa)和TrkB的mRNA水平呈正相关关系,但是这种正相关在抑郁症患者中却不存在,提示情感障碍患者的RARa和TrkB的某种相互作用发生了变化。免疫组化结果证明该两种受体在前扣带回中共存于同一神经元中,体外染色质免疫沉淀检测和双荧光素酶报告基因检测表明,RARa通过结合一个潜在的视黄酸反应元件激活TrkB启动子。 2)在情感障碍组的前扣带回和/或背外侧前额叶中,盐皮质激素受体(MR)的转录水平显著下调,而糖皮质激素受体(GR)α和MR mRNA水平的比值则有上升。有趣的是,背外侧前额叶和下丘脑室旁核(PVN) MR mRNA水平呈显著的负相关,同时GRa/MR比值也在两个区域内呈负相关关系。已知,前额叶可抑制下丘脑—垂体—肾上腺(HPA)轴的功能活动,前额叶和下丘脑MR的改变,为揭示抑郁症患者HPA轴活性过度升高提供了分子病理学的依据。 3)重度抑郁症患者前扣带回中,细胞色素P45017A1(CYP17A1) mRNA水平显著下调,而羟基类固醇磺基转移酶2A (SULT2A) mRNA水平明显上调,表明DHEA和它的硫酸代谢物DHEA-S的水平发生了改变。免疫组化显示前扣带回中SULT2A和CYP17A1在神经元和胶质细胞中都有表达。半定量结果显示,重度抑郁症患者中的CYP17A1阳性细胞的数量明显减少。在背外侧前额叶中,重度抑郁症患者的SULT2A、11β-氢化类固醇脱氢酶(HSD11B1),双向情感障碍患者的类固醇激素合成急性调节蛋白(StAR)的mRNA水平均明显上升。 4)双相情感障碍患者的前扣带回中神经胶质纤维酸性蛋白α(GFAPα)的mRNA水平明显上升。重度抑郁症患者的前扣带回中蛋白脂质蛋白(PLP)和GFAP8的mRNA水平则明显下降。有趣的是,在对照组的背外侧前额叶中,GFAPα的mRNA在白天(10:01-22:00h)的表达水平显著低于夜晚(22:01-10:00h),这一结果在另外一个大样本的对照组中得到了证实。而GFAPα mRNA表达的昼夜节律现象在情感障碍患者的背外侧前额叶中并不存在。GFAP免疫组化结果显示,双相情感障碍患者的前扣带回中GFAP+信号光密度升高,而GFAP+信号覆盖的面积百分比却下降,提示GFAP标记的细胞突起在双相情感障碍患者的前扣带回中可能发生了回缩。综上所述,本研究研究结果证明在情感障碍患者的背外侧前额叶和／或前扣带回中确实存在着与情绪调节密切相关的某些分子表达水平的变化,这些发现为揭示抑郁症的发病机制提供了分子神经病理学的直接证据。
[Abstract]:Emotional disorder is a kind of disease associated with emotion regulation disorder . Some 17 % of people will be affected by their influence in a lifetime , resulting in a serious personal , social and economic burden . In recent years , it has been found that the structure and function of the frontal cortex and anterior buckle in the back of the patients with affective disorder have changed obviously . However , the study has been carried out by means of real - time quantitative PCR .

1 ) In the patients with affective disorder , the mRNA levels of some important molecules of retinoic acid signaling pathway decreased significantly in the frontal and / or anterior gyrus of the patients with affective disorder . The mRNA levels of retinoic acid receptor a ( RARa ) and TrkB were positively correlated with the expression of BDNF and TrkB mRNA . However , the positive correlation was not present in the patients with depression , suggesting that the RARa and TrkB in patients with affective disorder had changed . Immunohistochemical results showed that RARa activated the TrkB promoter by binding a potential retinoic acid response element .

2 ) There was a significant negative correlation between the levels of glucocorticoid receptor ( GR ) 伪 and MR mRNA in the anterior and / or back lateral frontal lobes of the affective disorder group , while the ratio of glucocorticoid receptor ( GR ) 伪 and MR mRNA increased . Interestingly , the frontal lobe inhibited the function activity of the hypothalamus - pituitary - adrenal ( HPA ) axis , the changes of the frontal lobe and the hypothalamic MR , and provided a molecular pathology basis for revealing the excessive increase of HPA axis activity in patients with depression .

3 ) The mRNA level of cytochrome P450 17A1 ( CYP17A1 ) was down - regulated in patients with severe depression , and the mRNA level of hydroxysteroid sulfotransferase 2A ( SULT2A ) was significantly increased , indicating that the levels of CYP17A1 positive cells were significantly decreased in patients with severe depression .

The expression level of GFAP - 伪 mRNA was significantly lower in the control group than in the control group ( 22 : 01 - 10 : 00h ) . The results showed that the expression of GFAP - 伪 mRNA was significantly lower in the control group than in the control group ( 22 : 01 - 10 : 00h ) .

In conclusion , the results of this study demonstrate that there is indeed a change in the level of expression of certain molecules that are closely related to mood regulation in the dorsolateral forehead and / or anterior ulate gyrus of patients with affective disorder . These findings provide direct evidence of molecular neuropathology for the pathogenesis of depression .
【学位授予单位】：中国科学技术大学
【学位级别】：博士
【学位授予年份】：2013
【分类号】：R749.4

【共引文献】