Role of Long Noncoding RNA Gas5 in Cocaine Action.
Role of Long Noncoding RNA Gas5 in Cocaine Action.
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DOI：
10.1016/j.biopsych.2020.05.004
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发表时间：
2020-11-15
影响因子：
10.6
通讯作者：
Feng J
中科院分区：
文献类型：
--
作者：
Xu H;Brown AN;Waddell NJ;Liu X;Kaplan GJ;Chitaman JM;Stockman V;Hedinger RL;Adams R;Abreu K;Shen L;Neve R;Wang Z;Nestler EJ;Feng J
长链非编码RNA（lncRNA）是一类长度大于200个核苷酸的转录RNA分子。虽然lncRNA不编码蛋白质，但它们在基因表达调控中发挥许多功能作用。LncRNA在大脑中非常丰富，然而，它们的神经功能在很大程度上仍然未知。我们研究了可卡因给药后成年雄性小鼠中脑核（NAc）中lncRNA（Gas 5）的表达。然后，我们在NAc神经元中进行了病毒介导的Gas5过表达，以确定其在成瘾相关行为中的作用。我们还进行了RNA测序以研究Gas5介导的转录组学变化。我们证明，重复短期或长期可卡因给药降低了NAc中Gas5的表达。病毒介导的NAc神经元Gas5过表达降低可卡因诱导的条件性位置偏爱。同样，Gas5过表达导致可卡因摄入量减少，获得可卡因的动机和强迫性行为减少，并促进可卡因寻求行为的消失。转录组分析确定了许多Gas5介导的基因表达变化，这些变化在相关的神经功能类别中富集。有趣的是，这些Gas5调节的基因表达变化与慢性可卡因诱导的转录组改变显著重叠，这表明Gas5可能是可卡因转录反应的重要调节因子。总之，我们的研究证明了一种新的基于lncRNA的可卡因作用分子机制。
Long non-coding RNAs (lncRNAs) are a class of transcribed RNA molecules greater than 200 nucleotides in length. Although lncRNAs do not encode proteins, they play numerous functional roles in gene expression regulation. LncRNAs are notably abundant in brain, however, their neural functions remain largely unknown. We examined the expression of the lncRNA, Gas5, in nucleus accumbens (NAc), a key brain reward region, of adult male mice after cocaine administration. We then performed viral-mediated overexpression of Gas5 in NAc neurons to determine its role in addiction-related behaviors. We also carried out RNA-sequencing to investigate Gas5-mediated transcriptomic changes. We demonstrated that repeated short- or long-term cocaine administration decreased expression of Gas5 in NAc. Viral-mediated overexpression of Gas5 in NAc neurons decreased cocaine-induced conditioned place preference. Likewise, Gas5 overexpression led to decreased cocaine intake, decreased motivation and compulsive-like behavior to acquire cocaine, and facilitated extinction of cocaine-seeking behavior. Transcriptome profiling identified numerous Gas5-mediated gene expression changes that are enriched in relevant neural function categories. Interestingly, these Gas5-regulated gene expression changes significantly overlap with chronic cocaine-induced transcriptome alterations, which suggests that Gas5 may serve as an important regulator of transcriptional responses to cocaine. Together, our study demonstrates a novel lncRNA-based molecular mechanism of cocaine action.
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