伏隔核GABA能神经元抗慢性应激诱导抑郁症的研究

发布时间：2018-06-06 09:52

本文选题：抑郁 + 慢性应激抵抗力　；参考：《青岛大学》2017年硕士论文

【摘要】：目的重度抑郁症是一种常见的情绪障碍性疾病,其主要特征是长期情绪低落,兴趣和快感缺失,自我评估低下。抑郁症的发病机制复杂,但是慢性应激被认为是导致抑郁症发生的主要致病因素,能够导致多巴胺系统功能异常、脑源性神经营养因子(BDNF)减少、垂体-下丘脑-肾上腺轴(HPA轴)损伤,最终引起奖赏系统GABA能神经元受损。然而大多数个体经历慢性应激后并没有遭受重度抑郁症的困扰,即表现出对慢性应激的抵抗。边缘系统GABA能神经元对于慢性应激为易感个体而且其损伤与重度抑郁症有关,然而这些神经元在受慢性应激损伤的同时是否也涉及抗慢性应激诱导抑郁症的内在机制还尚不清楚。伏隔核作为边缘系统的一部分,其内的神经元主要是GABA能神经元,同时它还参与奖赏环路的组成,其损伤也与快感缺失行为的发生和发展有关。因此我们提出研究伏隔核GABA能神经元是否涉及抗慢性应激诱导抑郁症的内源性抗抑郁机制。方法首先给予实验组小鼠为期3周的慢性不可预测的温和应激(CUMS)处理,根据它们在糖水偏嗜度实验、Y迷宫实验以及强迫游泳实验中是否有显著的行为改变来确定抑郁样行为和慢性应激抵抗行为,在这三个实验中均表现出显著的行为改变的小鼠被定义为CUMS诱导的抑郁样小鼠,而均无显著的行为改变的则被定义为慢性应激抵抗小鼠。其次运用全细胞膜片钳电生理技术记录并研究CUMS诱导的抑郁样小鼠、慢性应激抵抗组小鼠和对照组小鼠伏隔核GABA能神经元功能的变化。结果我们得到的实验结果如下:1 慢性不可预测的温和刺激(CUMS)能诱导产生抑郁样行为小鼠或慢性应激抵抗小鼠;2 CUMS诱导的抑郁样小鼠伏隔核GABA能神经元对抑制性神经递质GABA的释放减少,即信息输出能力降低,而慢性应激抵抗组小鼠伏隔核GABA能神经元信息输出能力没有变化;3 CUMS诱导的抑郁样小鼠伏隔核GABA能神经元发放连续动作电位的能力降低,即兴奋性降低,而慢性应激抵抗组小鼠伏隔核GABA能神经元兴奋性无变化;4 CUMS诱导的抑郁样小鼠伏隔核GABA能神经元对兴奋性神经递质的接收减少,即兴奋性输入能力降低,而慢性应激抵抗组小鼠伏隔核GABA能神经元兴奋性输入能力增加。即抑郁样小鼠伏隔核GABA能神经元的功能整体表现出下调的状态,而慢性应激抵抗小鼠GABA能神经元的功能正常甚至上调。因而,伏隔核GABA能神经元的功能状态与个体对慢性应激的敏感性和抵抗性有关。结论伏隔核GABA能神经元的损伤与重度抑郁症有关,伏隔核GABA能神经元涉及抗慢性应激诱导抑郁症的内源性抗抑郁机制。
[Abstract]:Objective severe depression is a common disorder, which is characterized by chronic depression, lack of interest and pleasure, and low self-assessment. The pathogenesis of depression is complex, but chronic stress is thought to be the main cause of depression, which can lead to abnormal dopamine system function and decrease of brain-derived neurotrophic factor (BDNF). The damage of pituitary-hypothalamic-adrenal axis leads to the damage of GABA neurons in the reward system. However, most individuals did not suffer from severe depression after chronic stress, that is, they showed resistance to chronic stress. GABA neurons in the limbic system are susceptible to chronic stress and their damage is associated with severe depression. However, it is not clear whether these neurons are involved in the underlying mechanism of chronic stress-induced depression as well as chronic stress damage. As a part of the marginal system, nucleus accumbens is mainly composed of GABA neurons, and it is also involved in the composition of reward loop, and its damage is related to the occurrence and development of pleasure loss behavior. Therefore, we propose to investigate whether GABA neurons in nucleus accumbens are involved in the endogenous antidepressant mechanism of chronic stress-induced depression. Methods the mice in the experimental group were treated with chronic unpredictable mild stress (CUMS) for 3 weeks. Based on whether they had significant behavioral changes in the sugar water bias test, the Y-maze test and the forced swimming test, they were used to determine depressive behavior and chronic stress resistance. In these three experiments, the mice with significant behavioral changes were defined as CUMS induced depressive mice, while those without significant behavioral changes were defined as chronic stress resistant mice. Secondly, whole-cell patch clamp electrophysiological technique was used to record and study the changes of GABA neurons in the nucleus accumbens of depressive mice induced by CUMS, chronic stress resistance group and control group. Results the experimental results were as follows: 1. Chronic unpredictable mild stimulation (CUMS) could induce depression like behavior in mice or depressive septal nucleus GABA neurons induced by 2 CUMS in chronic stress resistant mice. The release of neurotransmitter GABA was decreased. That is, the ability of information output decreased, but the ability of information output of GABA neurons in nucleus accumbens of chronic stress resistance group did not change. The ability of releasing continuous action potential of GABA neurons in nucleus accumbens of depressive mice induced by 3 CUMS was decreased, that is, the excitability was decreased. In chronic stress resistance group, the excitability of GABA neurons in nucleus accumbens was not changed. The GABA neurons in the nucleus accumbens induced by 4 CUMS decreased the reception of excitatory neurotransmitters, that is, the ability of excitatory input decreased. In chronic stress resistance group, the excitatory input ability of GABA neurons in nucleus accumbens was increased. That is, the function of GABA neurons in the nucleus accumbens of depressive mice was down-regulated as a whole, while the function of GABA neurons in chronic stress resistant mice was normal or upregulated. Therefore, the functional state of GABA neurons in nucleus accumbens is related to the sensitivity and resistance of individuals to chronic stress. Conclusion the damage of GABA neurons in nucleus accumbens is related to severe depression. GABA neurons in nucleus accumbens are involved in the endogenous antidepressant mechanism of chronic stress-induced depression.
【学位授予单位】：青岛大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R749.4

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