Dynamic changes of behaviors, dentate gyrus neurogenesis and hippocampal miR-124 expression in rats with depression induced by chronic unpredictable mild stress
Dynamic changes of behaviors, dentate gyrus neurogenesis and hippocampal miR-124 expression in rats with depression induced by chronic unpredictable mild stress
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慢性不可预测轻度应激抑郁大鼠行为、齿状回神经发生和海马miR-124表达的动态变化
DOI：
10.4103/1673-5374.270414
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发表时间：
2020-06-01
影响因子：
6.1
通讯作者：
Wu, Li-Li
中科院分区：
文献类型：
--
作者：
Huang, Yun-Ling;Zeng, Ning-Xi;Wu, Li-Li
抑郁样行为表型、齿状回神经发生和海马miR-124表达是目前抑郁症发病机制和抗抑郁治疗研究的热点。本研究旨在阐明慢性应激诱导抑郁症过程中抑郁样行为、齿状回神经发生和海马miR-124表达的动态变化，揭示抑郁症不同阶段的病理特征，为抑郁症的治疗提供理论依据。将Sprague-Dawley大鼠暴露于各种轻度应激源（包括白色噪声、热游泳、频闪照明、脏笼、与其他3只应激动物配对、冷水游泳、夹尾、束缚和水和食物剥夺）中，建立慢性不可预测的轻度应激抑郁模型。对慢性不可预见性轻度应激模型大鼠进行1~8周的动态观察，并与对照组（正常喂养，无任何应激物）进行比较。为了观察慢性不可预测的轻度应激诱导抑郁时抑郁样行为表型的变化，采用蔗糖偏好试验评价快感缺乏的程度。采用旷场试验评价自发活动和焦虑状态。与对照组相比，慢性不可预见的轻度应激大鼠体重减轻，但在1 - 4周时没有抑郁样行为表型。慢性不可预见性轻度应激大鼠在5 - 8周时表现出对蔗糖的偏好性降低和自发活动减少。此外，慢性不可预测的轻度应激大鼠在1 - 8周的建模期间没有明显的焦虑样行为。为了观察慢性不可预测的轻度应激诱导的抑郁症期间齿状回神经发生功能障碍和神经元数量的变化，通过免疫荧光法评估神经增殖和分化的标记物（DCX和DCX/BrdU）和神经元标记物NeuN。与对照组相比，慢性不可预见性轻度应激组海马齿状回神经发生和神经元数量在2~6周内无明显变化，但海马齿状回神经元增殖和分化能力下降，神经元数量减少，直至第8周。采用实时定量逆转录聚合酶链反应（RT-PCR）和荧光原位杂交技术检测慢性不可预测性轻度应激诱导抑郁模型大鼠海马miR-124的表达。结果显示，与对照组相比，海马miR-124的表达在前4周内无变化，但在5~6周时增加，在7~8周时降低。这些结果表明，在慢性不可预测的轻度应激诱导的抑郁症过程中，行为表型、海马miR-124表达、齿状回神经发生和神经元数量均呈现动态变化，提示抑郁症不同阶段发生了不同的病理变化。
The depression-like behavior phenotype, neurogenesis in the dentate gyrus and miR-124 expression in the hippocampus are the focus of current research on the pathogenesis of depression and antidepressant therapy. The present study aimed to clarify the dynamic changes of depression-like behavior, dentate gyrus neurogenesis and hippocampal miR-124 expression during depression induced by chronic stress to reveal pathological features at different stages of depression and to further provide insight into depression treatment. Chronic unpredictable mild stress depression models were established by exposing Sprague-Dawley rats to various mild stressors, including white noise, thermal swimming, stroboscopic illumination, soiled cages, pairing with three other stressed animals, cold swimming, tail pinch, restraint and water and food deprivation. Chronic unpredictable mild stress model rats underwent dynamic observation from 1 to 8 weeks and were compared with a control group (normal feeding without any stressors). To observe changes in the depression-like behavior phenotype during chronic unpredictable mild stress-induced depression, a sucrose preference test was used to evaluate the degree of anhedonia. An open-field test was used to evaluate locomotor activity and anxiety status. Compared with the control group, chronic unpredictable mild stress rats lost weight but did not have a depression-like behavioral phenotype at 1-4 weeks. Chronic unpredictable mild stress rats presented decreased sucrose preference and locomotor activity at 5-8 weeks. In addition, chronic unpredictable mild stress rats did not have significant anxiety-like behavior during 1-8 weeks of modeling. To observe neurogenesis dysfunctions and changes in neuronal number in the dentate gyrus during chronic unpredictable mild stress-induced depression, markers (DCX and DCX/BrdU) of neural proliferation and differentiation and the neuronal marker NeuN were assessed by immunofluorescence. Compared with the control group, neurogenesis and the neuronal number in the dentate gyrus did not change from 2 to 6 weeks; however, neural proliferation and differentiation in the dentate gyrus decreased, and the number of neurons decreased until the eighth week in the chronic unpredictable mild stress group. Real-time quantitative reverse transcription polymerase chain reaction assays and fluorescence in situ hybridization were used to measure the expression of hippocampal miR-124 during chronic unpredictable mild stress-induced depression. The results showed that the expression of hippocampal miR-124 was unchanged during the first 4 weeks but increased from 5 to 6 weeks and decreased from 7 to 8 weeks compared with the control group. These findings indicate that during chronic unpredictable mild stress-induced depression, the behavioral phenotype, miR-124 expression in the hippocampus, neurogenesis in the dentate gyrus and neuronal numbers showed dynamic changes, which suggested that various pathological changes occur at different stages of depression.