Manipulating IncRNAs to Disrupt Reconsolidation of Methamphetamine Associated Memories

项目总结 目前，临床医生对精神刺激剂上瘾的人几乎没有希望，比如 冰毒(冰毒)。与吸毒和奖励相关的记忆可以承载一种强大的 激励对行为的影响。因此，该领域现在正在努力制定战略，以操纵 线索-药物联合的消亡和重新巩固是降低其威力的新治疗策略 以引起渴望和复发。在这里，我们建议研究一类新的候选人的贡献，Long- 非编码RNA(LncRNAs)，与冰毒相关的内存。越来越多的功能研究表明 LncRNAs作为调节者参与基因表达的几乎每一个阶段，从表观遗传修饰到 核内向mRNA的稳定和胞浆内的翻译。这一监管潜力，以及 LncRNAs的丰富，意味着lncRNAs可能是广泛的表观遗传网络的一部分。尽管如此 功能洞察，只有一小部分lncRNAs在神经系统和它们的 对物质使用障碍(SUD)的贡献尚不清楚。因为转录和翻译的角色 阐明它们在与SUD有关的脑区的功能将有助于发现新的治疗方法 目标。根据我们自己的初步研究得出的这一建议的中心假设是， LncRNAs介导冰毒相关记忆的重新巩固。为了验证这一假设，我们将使用 药物寻找和复发的动物模型，以识别和操纵体内特定的lncRNAs，目标是 通过阻止再巩固来防止复发。

PROJECT SUMMARY Currently, clinicians can offer little hope to people addicted to psychostimulants, such as methamphetamine (METH). The memories associated with drug use and reward can bear a powerful motivational influence over behavior. Accordingly, the field is now working to develop strategies to manipulate the extinction and reconsolidation of cue-drug associations as novel treatment strategies to reduce their power to induce craving and relapse. Here we propose to study the contribution of a novel class of candidates, long- noncoding RNAs (lncRNAs), to METH-associated memory. An increasing number of functional studies indicate lncRNAs participate as regulators at almost every stage of gene expression, from epigenetic modifications in the nucleus to mRNA stability and translation in the cytoplasm. This regulatory potential, along with the abundance of lncRNAs, implies that lncRNAs may be part of a broad epigenetic network. Despite these functional insights, only a small number of lncRNAs have been studied in the nervous system and their contribution to substance use disorder (SUD) is unknown. Because of the transcriptional and translational roles lncRNAs, elucidating their function in regions of brain implicated in SUD will help identify novel therapeutic targets. The central hypothesis of this proposal, derived from our own preliminary studies, is that specific lncRNAs mediate reconsolidation of METH-associated memories. To test this hypothesis, we will employ animal models of drug seeking and relapse to identify and manipulate specific lncRNAs in vivo with the goal of preventing relapse by blocking reconsolidation.