Manipulating IncRNAs to Disrupt Reconsolidation of Methamphetamine Associated Memories

项目摘要 目前，临床医生对精神兴奋剂成瘾的人几乎没有希望， 甲基苯丙胺（METH）。与药物使用和奖励相关的记忆可以承受强大的 动机对行为的影响。因此，该领域现在正在努力制定策略， 消除和重新巩固线索药物协会作为新的治疗策略，以减少他们的权力 来诱发渴望和复发在这里，我们建议研究一类新的候选人的贡献，长期- 非编码RNA（lncRNA），以甲基苯丙胺相关的记忆。越来越多的功能研究表明， lncRNA几乎在基因表达的每一个阶段都作为调节因子参与，从表观遗传修饰到基因表达。 细胞核对mRNA在细胞质中的稳定性和翻译的影响。这种监管潜力，沿着 lncRNA的丰度，意味着lncRNA可能是一个广泛的表观遗传网络的一部分。尽管有这些 由于功能上的见解，只有少量的lncRNA在神经系统中被研究， 对物质使用障碍（SUD）的贡献未知。由于转录和翻译的作用， lncRNA，阐明它们在涉及SUD的大脑区域的功能将有助于确定新的治疗方法， 目标的这一建议的中心假设来自我们自己的初步研究， lncRNA介导的METH相关记忆的再巩固。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，以在体内鉴定和操纵特异性lncRNA， 通过阻断再巩固防止复发。

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.