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Abstract：
Recent studies found that non-coding RNAs (ncRNAs) played crucial roles in drug addiction through epigenetic regulation of gene expression and underlying drug-induced neuroadaptations. In this study, we characterized lncRNA transcriptome profiles in the nucleus accumbens (NAc) of mice exhibiting morphine-conditioned place preference (CPP) and explored the prospective roles of novel differentially expressed lncRNA, lncLingo2 and its derived miR-876-5p in the acquisition of opioids-associated behaviours. We found that the lncLingo2 was downregulated within the NAc core (NAcC) but not in the NAc shell (NAcS). This downregulation was found to be associated with the development of morphine CPP and heroin intravenous self-administration (IVSA). As Mfold software revealed that the secondary structures of lncLingo2 contained the sequence of pre-miR-876, transfection of LV-lncLingo2 into HEK293 cells significantly upregulated miR-876 expression and the changes of mature miR-876 are positively correlated with lncLingo2 expression in NAcC of morphine CPP trained mice. Delivering miR-876-5p mimics into NAcC also inhibited the acquisition of morphine CPP. Furthermore, bioinformatics analysis and dual-luciferase assay confirmed that miR-876-5p binds to its target gene, Kcnn3, selectively and regulates morphine CPP training-induced alteration of Kcnn3 expression. Lastly, the electrophysiological analysis indicated that the currents of small conductance calcium-activated potassium (SK) channel was increased, which led to low neuronal excitability in NAcC after CPP training, and these changes were reversed by lncLingo2 overexpression. Collectively, lncLingo2 may function as a precursor of miR-876-5p in NAcC, hence modulating the development of opioid-associated behaviours in mice, which may serve as an underlying biomarker and therapeutic target of opioid addiction.
摘要：
最近的研究发现，非编码RNA（ncRNAs）通过基因表达的表观遗传调控和潜在的药物诱导的神经适应在药物成瘾中起着至关重要的作用。在这项研究中,我们表征了表现出吗啡条件位置偏爱（CPP）的小鼠的伏隔核（NAc）中的lncRNA转录组谱，并探索了新型差异表达lncRNA的前瞻性作用。lncLingo2及其衍生的miR-876-5p在获得阿片类药物相关行为中的作用。我们发现lncLingo2在NAc核心（NAcC）内下调，但在NAc壳（NAcS）内未下调。发现这种下调与吗啡CPP和海洛因静脉内自我给药（IVSA）的发展有关。由于Mfold软件显示lncLingo2的二级结构包含pre-miR-876的序列，将LV-lncLingo2转染入HEK293细胞显着上调miR-876的表达，并且成熟miR-876的变化与lncLingo2的表达呈正相关。吗啡CPP训练小鼠的NAcC。将miR-876-5p模拟物递送到NAcC中也抑制吗啡CPP的获得。此外，生物信息学分析和双荧光素酶检测证实miR-876-5p与其靶基因结合,Kcnn3选择性调节吗啡CPP训练诱导的Kcnn3表达改变。最后,电生理分析表明，小电导钙激活钾通道（SK）的电流增加，导致CPP训练后NAcC神经元兴奋性较低，这些变化被lncLingo2过表达逆转。总的来说，lncLingo2可能是NAcC中miR-876-5p的前体，因此调节小鼠阿片类药物相关行为的发展，它可以作为阿片类药物成瘾的潜在生物标志物和治疗靶点。
