慢性应激期间下丘脑-垂体-肾上腺(HPA)轴的过度活跃对于抑郁症的发病机理至关重要。室旁核(PVN)中cAMP反应元件结合蛋白(CREB)调节的转录共激活因子1(CRTC1)的活性增加起着关键作用。作为一个研究良好的microRNA(miRNA),miR-184有两种形式,miR-184-3p和miR-184-5p。最近,miRNA靶基因预测分析和双荧光素酶报告基因测定鉴定了miR-184-3p对CRTC1表达的抑制作用。因此,我们推测,miR-184-3p调控是慢性应激对PVN中CRTC1影响的原因.各种方法,包括抑郁症的慢性社会失败压力(CSDS)模型,行为测试,西方印迹,免疫共沉淀(Co-IP),定量实时逆转录PCR(qRT-PCR),免疫荧光,和腺相关病毒(AAV)介导的基因转移,被使用。CSDS明显下调miR-184-3p的水平,但不是miR-184-5p,在PVN。在PVN中miR-184-3p的遗传敲低和药理学抑制诱导的各种抑郁样症状(例如,异常行为,HPA多动症,增强CRTC1在PVN神经元中的功能,海马神经发生的下调,和脑源性神经营养因子(BDNF)信号传导降低)。相比之下,miR-184-3p在PVN中的遗传过表达和药理激活对CSDS产生了显著的有益作用.PVN中的MiR-184-3p对于两种众所周知的SSRIs的抗抑郁作用是必需的,氟西汀和帕罗西汀.集体。miR-184-3p也与抑郁症的神经生物学有关,可能是新型抗抑郁药的可行靶标。
Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis during chronic stress is essential for the pathogenesis of depression, and increased activity of cAMP response element binding protein (CREB)-regulated transcription co-activator 1 (CRTC1) in the paraventricular nucleus (PVN) plays a critical role. As a well-investigated microRNA (miRNA), miR-184 has two forms, miR-184-3p and miR-184-5p. Recently, miRNAs target genes predictive analysis and dual-luciferase reporter assays identified an inhibitory role of miR-184-3p on CRTC1 expression. Therefore, we speculated that miR-184-3p regulation was responsible for the effects of chronic stress on CRTC1 in the PVN. Various methods, including the chronic social defeat stress (CSDS) model of depression, behavioral tests, Western blotting, co-immunoprecipitation (Co-IP), quantitative real-time reverse transcription PCR (qRT-PCR), immunofluorescence, and adeno-associated virus (AAV)-mediated gene transfer, were used. CSDS evidently downregulated the level of miR-184-3p, but not miR-184-5p, in the PVN. Genetic knockdown and pharmacological inhibition of miR-184-3p in the PVN induced various depressive-like symptoms (e.g., abnormal behaviors, HPA hyperactivity, enhanced CRTC1 function in PVN neurons, downregulation of hippocampal neurogenesis, and decreased brain-derived neurotrophic factor (BDNF) signaling) in naïve male C57BL/6J mice. In contrast, genetic overexpression and pharmacological activation of miR-184-3p in the PVN produced significant beneficial effects against CSDS. MiR-184-3p in the PVN was necessary for the antidepressant actions of two well-known SSRIs, fluoxetine and paroxetine. Collectively. miR-184-3p was also implicated in the neurobiology of depression and may be a viable target for novel antidepressants.