室旁核中的 MiR-184-3p 通过调节下丘脑-垂体-肾上腺轴参与抑郁症的神经生物学。

IF 4.6 2区 医学 Q1 NEUROSCIENCES
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引用次数: 0

摘要

慢性应激时下丘脑-垂体-肾上腺(HPA)轴的过度活跃是抑郁症发病机制的关键,而脑室旁核(PVN)中由 cAMP 反应元件结合蛋白(CREB)调控的转录共激活因子 1(CRTC1)活性的增加起着至关重要的作用。作为一种已被广泛研究的微小RNA(miRNA),miR-184有两种形式,即miR-184-3p和miR-184-5p。最近,miRNAs 靶基因预测分析和双荧光素酶报告实验确定了 miR-184-3p 对 CRTC1 表达的抑制作用。因此,我们推测miR-184-3p调控是慢性应激影响PVN中CRTC1的原因。我们采用了多种方法,包括慢性社会挫败应激(CSDS)抑郁模型、行为测试、Western印迹、共免疫沉淀(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。CSDS明显下调了PVN中miR-184-3p的水平,但没有下调miR-184-5p的水平。基因敲除和药物抑制 PVN 中的 miR-184-3p,可诱导天真雄性 C57BL/6J 小鼠出现各种类似抑郁症的症状(如行为异常、HPA 过度活跃、PVN 神经元中 CRTC1 功能增强、海马神经发生下调和脑源性神经营养因子(BDNF)信号传导减少)。与此相反,miR-184-3p在PVN中的遗传过表达和药物激活对CSDS产生了显著的有益影响。PVN中的miR-184-3p对两种著名的SSRIs(氟西汀和帕罗西汀)的抗抑郁作用是必需的。总之,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物的一个可行靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
MiR-184-3p in the paraventricular nucleus participates in the neurobiology of depression via regulation of the hypothalamus-pituitary-adrenal axis

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.

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来源期刊
Neuropharmacology
Neuropharmacology 医学-神经科学
CiteScore
10.00
自引率
4.30%
发文量
288
审稿时长
45 days
期刊介绍: Neuropharmacology publishes high quality, original research and review articles within the discipline of neuroscience, especially articles with a neuropharmacological component. However, papers within any area of neuroscience will be considered. The journal does not usually accept clinical research, although preclinical neuropharmacological studies in humans may be considered. The journal only considers submissions in which the chemical structures and compositions of experimental agents are readily available in the literature or disclosed by the authors in the submitted manuscript. Only in exceptional circumstances will natural products be considered, and then only if the preparation is well defined by scientific means. Neuropharmacology publishes articles of any length (original research and reviews).
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