Amygdalar expression of the microRNA miR-101a and its target Ezh2 contribute to rodent anxiety-like behaviour.
Amygdalar expression of the microRNA miR-101a and its target Ezh2 contribute to rodent anxiety-like behaviour.
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DOI：
10.1111/ejn.13624
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发表时间：
2017-10
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影响因子：
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通讯作者：
Clinton SM
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文献类型：
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作者：
Cohen JL;Jackson NL;Ballestas ME;Webb WM;Lubin FD;Clinton SM
为了开发更好的治疗干预措施，需要更好地了解导致焦虑的神经机制。目前的研究探讨了一种塑造焦虑样行为的新分子机制，证明 microRNA miR-101a-3p 及其靶标（杏仁核中 zeste 同源物 2 (Ezh2) 的增强子）有助于啮齿类动物的焦虑样行为。我们利用针对情绪和应激反应差异进行选择性培育的大鼠，结果表明，与表现出高特质焦虑的低新奇反应（LR）大鼠相比，表现出低特质焦虑的高新奇反应（HR）大鼠杏仁核中的 miR-101a-3p 水平较低。为了确定杏仁核 miR-101a-3p 与焦虑行为之间是否存在因果关系，我们使用病毒方法在 HR 大鼠的杏仁核中过度表达 miR-101a-3p，并测试它是否会增加它们通常较低水平的焦虑样行为。我们发现，杏仁核中 miR-101a-3p 的增加增加了 HR 在旷场测试和高架十字迷宫中的焦虑样行为。病毒介导的 miR-101a-3p 过表达还降低了组蛋白甲基转移酶 Ezh2 的表达，该酶通过组蛋白 3 在赖氨酸 27 (H3K27me3) 处的三甲基化介导基因沉默。用短干扰 RNA (siRNA) 敲低 Ezh2 也增加了 HR 的焦虑样行为，但程度低于 miR-101a-3p 过表达。总体而言，我们的数据表明，杏仁核中 miR-101a-3p 表达的增加会增加焦虑样行为，并且这种效应至少部分是通过抑制 Ezh2 介导的。这项工作增加了越来越多的证据表明 miRNA 和表观遗传调控是焦虑行为的分子介质。
A greater understanding of neural mechanisms that contribute to anxiety is needed in order to develop better therapeutic interventions. The current study interrogates a novel molecular mechanism that shapes anxiety-like behavior, demonstrating that the microRNA miR-101a-3p and its target, enhancer of zeste homolog 2 (Ezh2) in the amygdala, contribute to rodent anxiety-like behavior. We utilized rats that were selectively-bred for differences in emotionality and stress reactivity, showing that high novelty responding (HR) rats, which display low trait anxiety, have lower miR-101a-3p levels in the amygdala compared to low novelty responding (LR) rats that characteristically display high trait anxiety. To determine if there is a causal relationship between amygdalar miR-101a-3p and anxiety behavior, we used a viral approach to over-express miR-101a-3p in the amygdala of HR rats and test whether it would increase their typically low levels of anxiety-like behavior. We found that increasing miR-101a-3p in the amygdala increased HRs’ anxiety-like behavior in the open field test and elevated plus maze. Viral-mediated miR-101a-3p over-expression also reduced expression of the histone methyltransferase Ezh2, which mediates gene silencing via tri-methylation of histone 3 at lysine 27 (H3K27me3). Knockdown of Ezh2 with short-interfering RNA (siRNA) also increased HRs’ anxiety-like behavior, but to a lesser degree than miR-101a-3p over-expression. Overall our data demonstrate that increasing miR-101a-3p expression in the amygdala increases anxiety-like behavior and that this effect is at least partially mediated via repression of Ezh2. This work adds to the growing body of evidence implicating miRNAs and epigenetic regulation as molecular mediators of anxiety behavior.