Assessing the role of circRNAs in memory consolidation

项目总结 在不同的RNA物种中，环状RNA(CircRNAs)特别吸引人，因为它们是 高度耐降解。这类新的RNA在各种真核生物中表达，在 不同的细胞类型，包括神经元，并展示了哺乳动物之间的保守性。此外，它们是 独立于它们的同源线性异构体而被调节。从机制上讲，它们可以作为miRNA海绵发挥作用， 调节剪接和转录，与RNA结合蛋白结合。一些环状RNA具有IRES，因此 可以翻译成中文。然而，CircRNA是否在长期记忆中发挥关键作用尚不清楚。因此，一个 深入理解CircRNAs对LTM的贡献有望提供机械性的见解和 确定LTM的新调节因子。为此，使用情境恐惧记忆作为LTM的模型，我们有 对海马齿状回(DG)亚区CircRNAs的表达进行了无偏倚分析 小鼠海马体。对DG中差异表达的CircRNA的初步分析导致了 识别在恐惧条件动物中上调的三种不同CircRNA(padj&lt；0.05) 与单独的环境或单独的电击控制相比。这些结果表明，CircRNA受到 学习过程中的转录变化。这一提议的中心假设是转录 海马亚区特定CircRNAs的变化调节背景恐惧的巩固 记忆。为了检验这一假说，我们建议进行时间调节的无偏分析。 在情景恐惧条件作用后，海马区三突触回路中CircRNA的表达 差异表达CircRNA的功能剖析。我们预计该项目将顺利完成。 该提案中概述的实验将揭开CircRNAs机制在长期记忆中的新角色 储藏室。

PROJECT SUMMARY Among different RNA species, circular RNAs (circRNAs) are particularly fascinating because they are highly resistant to degradation. This novel class of RNAs is expressed in a variety of eukaryotic organisms, in different cell types including neurons, and demonstrates conservation across mammals. Furthermore, they are regulated independently of their cognate linear isoforms. Mechanistically they can function as miRNA sponges, regulate splicing and transcription, bind to RNA binding proteins. Some circRNAs possess IRES and therefore could be translated. However, whether circRNAs play a critical role in long-term memory is unknown. Thus, a deep understanding of the contribution of circRNAs to LTM is expected to provide mechanistic insights and identify novel regulators of LTM. To this end, using contextual fear memory as a model for LTM, we have carried out an unbiased analysis of expression of circRNAss from the dentate gyrus (DG) subregion of the mouse hippocampus. Preliminary analysis of differentially expressed circRNAs in DG has resulted in the identification of three different circRNAs that are upregulated (padj<0.05) in fear-conditioned animals compared to context alone or shock alone controls. These results suggest that circRNAs are subjected to transcriptional changes during learning. The central hypothesis of this proposal is that the transcriptional changes in specific circRNAs in hippocampal subregions mediate the consolidation of contextual fear memory. To test this hypothesis, we here propose to carry out unbiased analysis of temporal regulation of circRNA expression in the tri-synaptic circuitry of the hippocampus following contextual fear conditioning, and functional dissection of differentially expressed circRNAs. We anticipate that successful completion of the experiments outlined in this proposal will unravel novel roles of circRNAs mechanisms in long-term memory storage.