Assessing the role of circRNAs in memory consolidation

评估 circRNA 在记忆巩固中的作用

• 批准号: 10676541
• 负责人: Sathyanarayanan V Puthanveettil
• 金额: $ 8.54万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10676541
• 关键词: Assessing; role; circRNAs; memory; consolidation

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.

项目概要 在不同的 RNA 种类中，环状 RNA (circRNA) 特别令人着迷，因为它们 高度耐降解。这类新型 RNA 在多种真核生物中表达， 包括神经元在内的不同细胞类型，并展示了哺乳动物之间的保守性。此外，他们是 独立于其同源线性异构体进行调节。从机制上讲，它们可以充当 miRNA 海绵， 调节剪接和转录，与 RNA 结合蛋白结合。一些 circRNA 具有 IRES，因此 可以翻译。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 深入了解 circRNA 对 LTM 的贡献有望提供机制见解和 确定 LTM 的新调节因子。为此，使用情境恐惧记忆作为 LTM 模型，我们有 对齿状回（DG）亚区的 circRNAss 表达进行了公正的分析 小鼠海马体。对DG中差异表达的circRNA的初步分析得出 鉴定出在恐惧条件下的动物中上调的三种不同的 circRNA（padj<0.05） 与单独的环境或单独的冲击对照相比。这些结果表明 circRNA 受到 学习过程中的转录变化。该提案的中心假设是转录 海马次区域特定 circRNA 的变化介导情境恐惧的巩固 记忆。为了检验这个假设，我们在这里建议对时间调节进行无偏分析 情境恐惧调节后海马三突触回路中的 circRNA 表达，以及 差异表达的circRNA的功能解剖。我们预计顺利完成 该提案中概述的实验将揭示 circRNA 机制在长期记忆中的新作用 贮存。