Targeting persistent stress-enhanced memory through microRNAs.
Targeting persistent stress-enhanced memory through microRNAs.
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通过 microRNA 靶向持续的压力增强记忆。
DOI：
10.1038/s41386-020-00816-3
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发表时间：
2021
期刊：
影响因子：
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通讯作者：
Miller,CourtneyA
中科院分区：
文献类型：
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作者：
Sillivan,StephanieE;Miller,CourtneyA
在创伤后应激障碍(PTSD)中，个体经历创伤的侵入性记忆，伴随着过度唤醒和压力调节障碍。创伤后应激障碍的治疗在很大程度上是无效的，这是一个巨大的未得到满足的需求领域。创伤后应激障碍(PTSD)与急性应激障碍(ASD)的区别是根据症状出现的持续时间来区分的，分别是大于或小于一个月。此外，尽管几乎每个人一生中都至少经历过一次创伤事件，但只有一小部分人会患上创伤后应激障碍。综上所述，这有力地证明了机械研究的重要性，其目的是将创伤记忆的持久性纳入其设计，以及易感性的差异。为此，我们采用了压力增强恐惧记忆(SEFM)方案[1]，在对应激源具有不同敏感性的小鼠中诱导了持久的PTSD样行为和分子变化[2]。我们使用这一方案来研究支持持续应激易感性与韧性的分子通路，重点放在基底外侧杏仁核(BLA)，这是大脑的一个“情绪”记忆中心，在创伤后应激障碍中表现得非常活跃。首先，我们报告了BLA中与易感性相关的转录图谱，其中包括创伤后应激障碍受试者在SEFM训练后至少一个月存在的已知多态基因的差异表达[2]。接下来，我们将重点转移到microRNAs(MiRNA)上，这是一种充当翻译抑制因子的非编码小RNA。MiRNAs是治疗创伤后应激障碍的有吸引力的靶点，因为在过去的十年中，有证据表明它们在记忆调节中的作用。MiRNAs的半衰期可能很长，这与影响记忆持久性的可能性一致。此外，它们通过其广泛的翻译靶点实现复杂的分子调控，基于RNA的疗法的最新发展表明miRNAs是可用药的[3]。有趣的是，单是急性应激就足以诱导BLA miRNAome发生深刻而持久的转变[4]。当结合延迟学习(SEFM)时，我们在训练后一个月确定了BLA中存在的miRNA图谱，这是敏感和有弹性的雄性小鼠所独有的[5]。在这个延迟的时间点使用基于病毒的过度表达或序列特异性抑制剂，我们发现对mir-135B-5P的操纵，一种在易感小鼠中选择性上调的miRNA，双向调节敏感和有弹性的远程记忆表型[5]。MIR-135B-5P也可能作为创伤后应激障碍症状的生物标志物，因为患有创伤后应激障碍的战斗暴露退伍军人的血清水平一直受到调节[5]。我们采用了类似的方法来证明另一种miRNA，mir-598-3p，也以性别相关的方式调节SEFM后一个月的PTSD样易感性[6]。重点研究在应激事件后很长一段时间内存在的机制，这与开发创伤后应激障碍治疗方法有关。第二，诱导差异应激敏感性的动物方案[2]，最好使用一种不需要特殊表型分析来识别易感动物的方法，避免无意中掩盖相关的大脑变化。第三，miRNAs是治疗精神疾病的潜在靶点。这些翻译抑制因子在整个生物体、脑亚区和细胞类型的水平上具有特异性表达，导致它们的蛋白质靶标的差异调节。最后，基于RNA的小分子抑制剂可以直接调节miRNAs，可以开发成治疗药物。
In post-traumatic stress disorder (PTSD), individuals experience intrusive memories of trauma accompanied by hyperarousal and stress dysregulation. Treatments for PTSD are largely ineffective, representing an enormous area of unmet need. PTSD is differentiated from acute stress disorder (ASD) by the duration of symptom presentation; more or less than one month, respectively. Further, while nearly everyone experiences at least one traumatic event in their lifetime, only a subset develop PTSD. Taken together, this makes a strong argument for the importance of mechanistic research efforts aimed at incorporating the persistent nature of traumatic memories into their design, as well as variance in susceptibility. To this end, we adapted a stress-enhanced fear memory (SEFM) protocol [1] to induce long-lasting, PTSD-like behaviors and molecular changes in mice with differential susceptibility to the stressor [2]. We used this protocol to investigate molecular pathways supporting persistent stress susceptibility versus resilience, focusing on the basolateral amygdala (BLA), an “emotional” memory center of the brain that is hyperactive in PTSD. First, we reported a transcriptional profile in the BLA associated with susceptibility that included differential expression of genes with known polymorphisms in PTSD subjects present for at least one month after SEFM training [2]. We next shifted focus to microRNAs (miRNA), small non-coding RNAs that act as translational repressors. miRNAs are attractive therapeutic targets for PTSD because evidence has accrued over the past decade demonstrating their role in memory regulation. miRNAs can have very long half-lives, consistent with the potential to influence memory persistence. Further, they achieve complex molecular regulation through their wide range of translational targets, and recent developments in RNA-based therapeutics indicate miRNAs are druggable [3]. Interestingly, acute stress alone is sufficient to induce a profound, long-lasting shift in the BLA miRNAome [4]. When incorporated with delayed learning (SEFM), we identified miRNA profiles present in the BLA one month after training that were unique to susceptible and resilient male mice [5]. Using viralbased overexpression or sequence-specific inhibitors at this delayed time point, we found manipulation of mir-135b-5p, a miRNA selectively upregulated in susceptible mice, bidirectionally regulates susceptible and resilient remote memory phenotypes [5]. mir-135b-5p may also function as a biomarker of PTSD symptomology, as levels are persistently regulated in serum from combat-exposed military veterans that developed PTSD [5]. We employed a similar approach to demonstrate that another miRNA, mir-598-3p, also regulates PTSD-like susceptibility one month after SEFM in a sex-dependent manner [6].This body of work highlights several critical points for PTSD research. Focusing research on identification of mechanisms present long after a stressful event is relevant to developing PTSD treatments. Second, animal protocols that induce differential stress susceptibility [2], preferably with a method that does not require post hoc phenotyping to identify susceptible animals, avoid inadvertent obscuring of relevant brain changes. Third, miRNAs are potential therapeutic targets for psychiatric disease. These translational repressors are expressed with specificity at the level of whole organism, brain subregions and cell type, resulting in differential modulation of their protein targets. Finally, RNA-based small molecule inhibitors that directly regulate miRNAs can be developed into therapeutics.