慢性应激性抑郁样行为发生中高半胱氨酸参与对海马谷氨酸及其受体的调节

发布时间：2018-05-24 05:21

本文选题：抑郁症 + 海马　；参考：《陕西师范大学》2012年硕士论文

【摘要】：抑郁症(depression)是一种情感精神障碍,以情感持续性低落为基本特征的精神性疾病。抑郁症的危害不仅影响个人的身心健康发展,而且对社会经济也造成一定的损失。抑郁症的发生已具有普遍性,但山于其发病机制的复杂性,导致其具体的发病原因及其机制目前尚未有明确而一致的说法。但是大量研究证明,应激是诱发抑郁的主要因素之一。海马属于边缘系统的主要结构,在学习与记忆中和情感行为与神经内分泌功能的控制方面发挥重要作用。由于海马与前额叶、中脑多巴胺系统有着密切联系,一直是情绪行为研究高度关注的脑区之一。大量文献已经表明,应激使海马中谷氨酸(glutamic acid, Glu)增加,N-甲基-D-天冬氨酸(N-methyl-D-aspartic acid, NMDA)受体过度激活是应激性抑郁发生的重要原因,NMDA受体拮抗剂具有显著的抗抑郁效应,长期的抗抑郁药也能增加α-氨基羟甲基异恶唑丙酸(a-amino-3-hudroxy-5-methylisoxazole-4-propionic acid, AMPA)受体在大鼠海马表达。但关于应激引起海马Glu水平升高,NMDA受体过度激活的具体机制还不清楚,以及海马星形胶质细胞与Glu能神经元在Glu及其受体失调中是否有关,这一重要问题也不清楚。高半胱氨酸(homocysteine, Hcy)是蛋氨酸和半胱氨酸代谢过程中的一个关键中间产物。高Hcy血症与抑郁症、认知障碍、阿尔兹海默病和帕金森病等神经、精神疾病的发生、发展有一定的联系。研究发现,抑郁患者血浆中Hcy升高,52%抑郁患者血浆Hcy水平高于健康和其它神经疾病患者。有关脑中Hcy含量的变化却未见报道。研究表明,在中枢只有星形胶质细胞能产生和释放Hcy,过量的Glu可刺激Hcy释放,对海马神经元的损伤起到一定的作用。Hcy也是通过NMDA受体发挥作用的。但是,海马Hcy是否参与应激性抑郁样行为的发生,是否影响Glu及其NMDA受体、AMPA受体等还不清楚。为了研究应激性抑郁样行为发生中海马胶质细胞释放Hcy的变化及其Glu及其受体的作用,探讨海马胶质细胞与神经元在应激性抑郁发生中的Glu及其受体机制。本研究通过建立慢性不可预见性温和应激(chronic unpredictable mild stress, CUMS)抑郁模型,测量实验动物的体重变化率,运用糖水偏爱测试、旷场实验和悬尾实验等方法检测动物的行为表现,海马单侧微量注射Hcy、NMDA受体拮抗剂MK-801和AMPA受体拮抗剂NBQX,采用高效液相色谱法(high-performance liquid chromatography, HPLC)和Western blot方法检测海马内Glu含量及其DMDA受体和AMPA受体关键亚基的变化,运用酶联免疫吸附(enzyme linked immunosorbent assay, ELISA)法测定谷氨酸NMDA受体和AMPA受体的磷酸化水平和Hcy含量。研究结果如下： ①CUMS诱发大鼠表现出明显的抑郁样行为,且海马Glu和Hcy含量、NMDA受体的NR1亚基和NR2B亚基表达及其磷酸化水平显著升高,而AMPA受体的GluR2/3亚基含量和其磷酸化水平均明显降低。 ②正常大鼠海马微量注射Hcy,也表现出抑郁样行为,且Glu含量明显升高,NMDA受体NR1亚基和NR2B亚基和其磷酸化水平均显著升高,AMPA受体的GluR2/3亚基含量明显升高,但其磷酸化水平明显降低。 ③CUMS和海马注射Hcy引起的抑郁样行为可被海马注射NMDA受体拮抗剂MK801显著改善,同时可以显著限制由Hcy引起的Glu升高,而AMPA受体拮抗剂NBQX不能改善其抑郁样行为,但同样可以使Hcy引起的Glu升高显著降低。以上结果表明：CUMS引起海马星形胶质细胞产生和释放Hcy增加,经NMDA受体和AMPA受体,引起Glu升高的同时,既能提高NMDA受体的NR1亚基和NR2B亚基表达,并促进其磷酸化,提高AMPA受体的GluR2/3亚基表达而降低其磷酸化水平,导致抑郁样行为发生。可见,应激引起星形胶质细胞释放Hcy增加,使海马Glu升高及NMDA受体和AMPA受体表达及磷酸化水平变化而诱发抑郁样行为。
[Abstract]:Depression (depression) is a mental disorder with the basic characteristics of emotional and mental disorder. The harm of depression not only affects the physical and mental health of individuals, but also causes a certain loss to the social economy. The occurrence of depression is universal, but the complexity of its pathogenesis leads to it. The causes and mechanisms of the body are not yet clear and consistent. But a large number of studies have shown that stress is one of the main factors that induce depression. The hippocampus belongs to the main structure of the marginal system and plays an important role in the control of affective behavior and neuroendocrine function in learning and memory. The mesencephalon dopamine system is closely linked and has been one of the most important areas of attention in the study of emotional behavior. A large number of literatures have shown that stress increases glutamic acid (Glu) in the hippocampus and the excessive activation of N- methyl -D- aspartic acid (N-methyl-D-aspartic acid, NMDA) receptor is an important cause of stress depression, NMDA receptor Antagonists have significant antidepressant effects, and long-term antidepressants can also increase the expression of a-amino-3-hudroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor in the hippocampus of rats. However, the specific mechanism of excessive activation of NMDA in hippocampus is unclear as to stress induced Glu in hippocampus, and the hippocampus is not clear, as well as hippocampus It is also unclear whether astrocytes and Glu neurons are involved in the imbalance of Glu and its receptors.
Homocysteine (Hcy) is a key intermediate product of methionine and cysteine metabolism. HyperHcy is associated with depression, cognitive impairment, Alzheimer's disease and Parkinson's disease, and the development of mental illness. There is an increase in plasma Hcy in depressive patients, and plasma Hc in 52% depressive patients. Y levels are higher than those of healthy and other neurological diseases. The changes in the Hcy content in the brain have not been reported. Studies have shown that only astrocytes in the center can produce and release Hcy, excessive Glu can stimulate Hcy release and play a role in the damage of hippocampal neurons,.Hcy is also through the NMDA receptor. But, hippocampal Hcy Whether to participate in the occurrence of stressful depressive like behavior, whether it affects the Glu and its NMDA receptor, AMPA receptor is not clear. In order to study the changes in the release of Hcy in hippocampus glial cells and the role of Glu and its receptor in the occurrence of stress depressive behavior, the Glu and its receptor in the hippocampus and neurotransmitter in the occurrence of stress depression are discussed. Mechanism. By establishing a chronic unpredictable mild stress (chronic unpredictable mild stress, CUMS) depression model, measuring the rate of body weight change in experimental animals, using sugar water preference test, open field experiment and tail suspension test, the behavior of animals was detected, Hcy, NMDA receptor antagonist MK-801 and AM were injected into the hippocampus. PA receptor antagonist NBQX, using high performance liquid chromatography (high-performance liquid chromatography, HPLC) and Western blot method to detect the changes of Glu content in the hippocampus and the changes of the DMDA receptor and AMPA receptor key subunits. The level of phosphorylation and Hcy content were as follows:
(1) CUMS induced obvious depressive behavior in rats, and the content of Glu and Hcy in the hippocampus, the expression of NR1 subunit and NR2B subunit of NMDA receptor and its phosphorylation level were significantly increased, while the GluR2/3 subunit content and its phosphorylation level of AMPA receptor were significantly decreased.
(2) microinjection of Hcy in the hippocampus of normal rats also showed depressive behavior, and the content of Glu increased significantly. The level of NMDA receptor NR1 subunit and NR2B subunit and its phosphorylation level were significantly increased, and the GluR2/3 subunit content of AMPA receptor was significantly increased, but its phosphorylation level was significantly reduced.
(3) the depressive behavior induced by CUMS and hippocampal injection of Hcy can be significantly improved by the injection of NMDA receptor antagonist MK801 in the hippocampus, and can significantly limit the increase of Glu induced by Hcy, while AMPA receptor antagonist NBQX does not improve its depressive behavior, but it can also significantly reduce the increase of Glu in Hcy induced Glu.
These results suggest that CUMS induces the increase of Hcy in hippocampus astrocytes and the increase of Glu by NMDA receptor and AMPA receptor, which can increase the expression of NR1 subunit and NR2B subunit of NMDA receptor, promote its phosphorylation, improve the GluR2/3 subunit of AMPA receptor and decrease its phosphorylation level and lead to depressive behavior. Stress can induce the increase of Hcy in astrocytes, the increase of Glu in the hippocampus, the changes in the expression of NMDA receptor and AMPA receptor and the level of phosphorylation, and induce depressive behavior.
【学位授予单位】：陕西师范大学
【学位级别】：硕士
【学位授予年份】：2012
【分类号】：R749.4

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