Sustained stress-induced changes in mice as a model for chronic depression
Sustained stress-induced changes in mice as a model for chronic depression
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DOI：
10.1007/s00213-010-1835-6
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发表时间：
2010-06-01
影响因子：
3.4
通讯作者：
Tordera, Rosa M.
中科院分区：
文献类型：
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作者：
Elizalde, Natalia;Garcia-Garcia, Alvaro L.;Tordera, Rosa M.
重度抑郁症是一种慢性致残性疾病，通常先有压力。尽管临床上对抑郁症持续发作和/或增加复发易感性的机制产生了兴趣，但很少有人关注实验模型中解决这些方面的问题。在这里，我们研究了慢性轻度应激（CMS）的长期神经适应性效应以及一个疗程的抗抑郁药治疗的有效性。CMS应用了6周，帕罗西汀从第三周开始服用，并持续2周。为了验证我们的 CMS 程序，我们首先研究了短期（CMS 后 24 小时）海马细胞增殖和神经发生，以及快感缺失样行为。随后，我们检查了长期（CMS后1个月）快感缺乏、海马神经发生、不同区域c-Fos免疫反应性和神经递质水平的调节以及皮层棘密度和海马突触蛋白的表达。CMS诱导短期神经发生减少，但在长期内完全恢复。此外，CMS 诱导持久的快感缺乏以及神经元活动（c-Fos 免疫反应性）和神经递质（谷氨酸和 GABA）水平的区域特异性变化。重复帕罗西汀可逆转这些影响，但齿状回 (DG) 神经元活动和腹侧海马 GABA 水平降低除外。此外，CMS 下调了 GAD65 和 VGLUT1 的表达。这项研究显示了 CMS 诱导的区域特异性长期神经生物学适应以及帕罗西汀治疗后残留的海马体征。我们建议使用该模型来研究涉及慢性抑郁症和易复发性的分子机制。
Major depression is a chronic disabling disorder, often preceded by stress. Despite emerging clinical interest in mechanisms perpetuating episodes of depression and/or establishing increased vulnerability for relapse, little attention has been paid to address these aspects in experimental models. Here, we studied the long-term neuroadaptive effects of chronic mild stress (CMS) as well as the effectiveness of a course of an antidepressant treatment.CMS was applied for 6 weeks, and paroxetine was administered from the third week and continued for 2 weeks thereafter. In order to validate our CMS procedure, we first studied short-term (24 h after CMS) hippocampal cell proliferation and neurogenesis, along with anhedonic-like behaviour. Subsequently, we examined the long-term (one month after CMS) anhedonia, hippocampal neurogenesis, the regulation of c-Fos immunoreactivity and neurotransmitter levels in different areas as well as cortical spine density and hippocampal expression of synaptic proteins.CMS induced a decrease in short-term neurogenesis that was fully recovered in the long term. In addition, CMS-induced lasting anhedonia and region-specific changes in neuronal activity (c-Fos immunoreactivity) and neurotransmitter (glutamate and GABA) levels. Repeated paroxetine reverted these effects with the exception of decreased neuronal activity in the dentate gyrus (DG) and GABA levels in the ventral hippocampus. Moreover, CMS downregulated the GAD65 and VGLUT1 expressions.This study shows region-specific long-term neurobiological adaptations induced by CMS and residual hippocampal signs after paroxetine treatment. We propose the use of this model to study molecular mechanisms involved in chronic depression and vulnerability for relapse.