miR-124 通过靶向 CREB1 和 BDNF 减少抑郁样行为。

OBJECTIVE: As a brain-specific microRNA, the mechanism of miR-124 in depression has not been clarified so far. The present study aimed to explore the role of miR-124 in depression and its potential targets. METHODS: The depression model was first replicated by the chronic unpredictable mild stress (CUMS) method. miR-124 antagomir was injected into the hippocampus of CUMS rats. Sucrose preference test (SPT), open-field test (OFT), elevated-plus maze (EPM), and forced swimming test (FST) were used to analyze the depression-like behavior. The content of norepinephrine (NE), dopamine (DA) and 5-hydroxytryptamine (5-HT) in the hypothalamus was analyzed by ELISA. qRT-PCR and western blot assay were used for functional analysis. RESULTS: miR-124 expression was up-regulated in the hippocampus of CUMS -induced depression model rats, while CREB1 and BDNF were down-regulated. Administration of miR-124 antagomir in the hippocampus inhibited miR-124 expression in the hippocampus of CUMS rats. Additionally, SPT, OFT, EPM, and FST also showed that miR-124 antagomir can reduce the depression-like behavior of CUMS rats. Furthermore, miR-124 antagomir injection increased the levels of NE, DA and 5-HT in the hypothalamus of CUMS rats. Moreover, miR-124 antagomir injection increased the expression of cyclic AMP-responsive element-binding protein1 (CREB1) and brain-derived neurotrophic factor (BDNF) in the hippocampus. Using the dual-luciferase reporter assay, it was confirmed that miR-124 directly targets 3'UTR of CREB1 and BDNF genes. CONCLUSION: Knockdown of miR-124 can improve depression-like behavior in CUMS-induced depressive rats, which may be related at least in part to the up-regulation of CREB1 and BDNF expression in the hippocampus.

目的：miR-124 作为一种脑特异性 microRNA，其在抑郁症中的作用机制尚不清楚。本研究旨在探讨 miR-124 在抑郁症中的作用及其潜在靶点。

方法：首先采用慢性不可预知性轻度应激（CUMS）方法复制抑郁症模型。将 miR-124 拮抗剂注入 CUMS 大鼠海马区。采用蔗糖偏好试验（SPT）、旷场试验（OFT）、高架十字迷宫（EPM）和强迫游泳试验（FST）分析抑郁样行为。采用 ELISA 法分析下丘脑去甲肾上腺素（NE）、多巴胺（DA）和 5-羟色胺（5-HT）含量。qRT-PCR 和 Western blot 检测进行功能分析。

结果：CUMS 诱导的抑郁症模型大鼠海马区 miR-124 表达上调，而 CREB1 和 BDNF 表达下调。海马区给予 miR-124 拮抗剂可抑制 CUMS 大鼠海马区 miR-124 的表达。此外，SPT、OFT、EPM 和 FST 也显示，miR-124 拮抗剂可减少 CUMS 大鼠的抑郁样行为。进一步研究发现，miR-124 拮抗剂注射可增加 CUMS 大鼠下丘脑 NE、DA 和 5-HT 的含量。此外，miR-124 拮抗剂注射可增加海马区 cAMP 反应元件结合蛋白 1（CREB1）和脑源性神经营养因子（BDNF）的表达。双荧光素酶报告基因检测证实，miR-124 可直接靶向 CREB1 和 BDNF 基因的 3'UTR。

结论：下调 miR-124 可改善 CUMS 诱导的抑郁大鼠的抑郁样行为，这至少部分与海马区 CREB1 和 BDNF 表达的上调有关。