Depression is a complex etiological disease with limited effective treatments. Previous studies have indicated the involvement of miRNAs in the pathophysiology of mood disorders. In this study, we focused on the role and mechanisms of miR-129-5p in depression by successfully constructing mice models of depressive-like behavior via chronic unpredictable mild stress (CUMS) exposure. Herein, miR-129-5p expression was decreased in the hippocampus of CUMS mice model. Upregulation of miR-129-5p reduced depressive-like behaviors of CUMS mice, as revealed in sucrose preference test, novelty suppressed feeding test, forced swim test, tail suspension test, social interaction test. MiR-129-5p upregulation decreased the concentrations and protein levels of proinflammatory cytokines (IL-6, IL-1β and TNF-α), indicating the inhibitory role of miR-129-5p in inflammation. Furthermore, miR-129-5p was identified to target MAPK1. MAPK1 was negatively regulated by miR-129-5p, and silencing of MAPK1 attenuated depressive-like behaviors in CUMS mice. Moreover, MAPK1 downregulation decreased inflammation in the hippocampus of CUMS mice. Upregulation of MAPK1 reversed the suppressive effects of miR-129-5p upregulation on depressive-like behaviors and inflammation in CUMS mice. In conclusion, the current study identified that miR-129-5p reduces depressive-like behaviors and suppresses inflammation by targeting MAPK1 in CUMS mice, offering a novel molecular interpretation for depression prevention.

抑郁症是一种复杂的病因疾病，有效的治疗方法有限。先前的研究表明 miRNA 参与了情绪障碍的病理生理学。在这项研究中，我们通过慢性不可预测的轻度压力 (CUMS) 暴露成功构建了抑郁样行为的小鼠模型，重点关注 miR-129-5p 在抑郁症中的作用和机制。在此，miR-129-5p 表达在 CUMS 小鼠模型的海马中降低。miR-129-5p 的上调降低了 CUMS 小鼠的抑郁样行为，如蔗糖偏好试验、新奇抑制喂养试验、强迫游泳试验、悬尾试验、社交互动试验所示。MiR-129-5p 上调降低了促炎细胞因子（IL-6、IL-1β 和 TNF-α）的浓度和蛋白质水平，表明 miR-129-5p 在炎症中的抑制作用。此外，miR-129-5p 被鉴定为靶向 MAPK1。MAPK1 受到 miR-129-5p 的负调控，MAPK1 的沉默减弱了 CUMS 小鼠的抑郁样行为。此外，MAPK1 下调减少了 CUMS 小鼠海马的炎症。MAPK1 的上调逆转了 miR-129-5p 上调对 CUMS 小鼠抑郁样行为和炎症的抑制作用。总之，目前的研究发现 miR-129-5p 通过靶向 CUMS 小鼠中的 MAPK1 减少抑郁样行为并抑制炎症，为抑郁症预防提供了新的分子解释。MAPK1 的沉默和沉默减弱了 CUMS 小鼠的抑郁样行为。此外，MAPK1 下调减少了 CUMS 小鼠海马的炎症。MAPK1 的上调逆转了 miR-129-5p 上调对 CUMS 小鼠抑郁样行为和炎症的抑制作用。总之，目前的研究发现 miR-129-5p 通过靶向 CUMS 小鼠中的 MAPK1 减少抑郁样行为并抑制炎症，为抑郁症预防提供了新的分子解释。MAPK1 的沉默和沉默减弱了 CUMS 小鼠的抑郁样行为。此外，MAPK1 下调减少了 CUMS 小鼠海马的炎症。MAPK1 的上调逆转了 miR-129-5p 上调对 CUMS 小鼠抑郁样行为和炎症的抑制作用。总之，目前的研究发现 miR-129-5p 通过靶向 CUMS 小鼠中的 MAPK1 减少抑郁样行为并抑制炎症，为抑郁症预防提供了新的分子解释。