Regulation of Memory by the microRNA/RISC Pathway

microRNA/RISC 通路对记忆的调节

• 批准号: 8197612
• 负责人: Samuel M Kunes
• 金额: $ 40.6万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-01 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8197612
• 关键词: Acute; Address; Adult; Afferent Neurons; Alzheimer' s Disease; Biochemical; Biochemical Pathway; Biochemistry; Biogenesis; Brain; Cells; Cereals; Characteristics; Clinical; Defect; Development; Disease; Drosophila genus; Epilepsy; Event; Functional disorder; Human; In Situ Hybridization; Invertebrates; Left; Maintenance; Maps; Mediating; Memory; Memory Disorders; Messenger RNA; MicroRNAs; Modification; Molecular; Nervous system structure; Neurons; Neurosciences; Odors; Pathway interactions; Patients; Protein Biosynthesis; Proteins; RNA-Induced Silencing Complex; Regulation; Reporter; Role; Sensory; Shock; Societies; Specificity; Structure; Synapses; Synaptic plasticity; Therapeutic; Therapeutic Agents; Time; Transcript; Vertebrates; Work; calmodulin-dependent protein kinase II; conditioning; cost; design; developmental disease; experience; insight; interest; long term memory; memory recall; multicatalytic endopeptidase complex; neural circuit; new therapeutic target; novel; novel therapeutics; promoter; relating to nervous system; tool; transgene expression

PROJECT SUMMARY/ABSTRACT One of the remaining mysteries of neuroscience is how memories are stored for periods of days, weeks or years. It has been known for some time that the formation of stable memory requires protein synthesis, a feature of memory common to vertebrates and invertebrates. Protein synthesis localized to the synapse is of special interest because it might confer selective synaptic change and the stable modification of a neural circuit. But how protein synthesis is deployed across the nervous system and contributes to the formation of a particular memory is unclear. We have used fluorescent reporter constructs to visualize synaptic protein synthesis in Drosophila that form a long-term memory. The association of an odor with electric shock was correlated with local protein synthesis that displayed features of synaptic specificity, and the induction of mRNA transport to synaptic regions. These features of memory appeared to be controlled by the RNA- Induced Silencing Complex (RISC) in a pathway involving RISC regulation by the Proteasome. A RISC component, Armitage, was found to be ubiquitinated and degraded in a Proteasome-dependent fashion, evidently contributing to the release of synaptic protein synthesis from RISC suppression. These observations raise a number of questions of importance to understanding the mechanisms underlying memory. Can we build a fine-grained neural map of where protein synthesis occurs as a particular memory forms? Can we build a map of where the regulation of protein synthesis is required? What are the temporal characteristics of synaptic protein synthesis and how are they related to the maintenance of a synapse in a stable new state? We have only begun to understand the role and biochemistry of the RISC pathway at the synapse, but as an evident regulator of these events, we believe this understanding will illuminate the biochemical and cellular mechanisms underlying memory. The strong potential of this study to make clinical contributions should not be overlooked, as it is evident that these mechanisms operate at mammalian and human synapses. This study will likely identify new targets for therapeutic efforts to aid patients with disorders of memory (for example, Alzheimer's Disease) and synaptic activity (for example, epilepsy).

项目摘要/摘要 剩下的神经科学谜团之一是如何存储在几天，几周或 年。一段时间以来，人们已经知道稳定记忆的形成需要蛋白质合成，一个 脊椎动物和无脊椎动物常见的记忆特征。定位于突触的蛋白质合成是 特别感兴趣，因为它可能会赋予选择性突触变化和神经的稳定修饰 电路。但是如何在神经系统中部署蛋白质合成，并有助于形成 特定的内存尚不清楚。我们已经使用荧光记者构造来可视化突触蛋白 果蝇中的合成，形成了长期记忆。气味与电击的关联是 与局部蛋白质合成相关，该蛋白质合成显示突触特异性的特征，并诱导 mRNA运输到突触区域。这些记忆的特征似乎是由RNA-控制的 在涉及蛋白酶体RISC调节的途径中引起沉默复合物（RISC）。 Risc 发现成分，Armitage，以蛋白酶体依赖性的方式被泛素化和降解， 显然有助于从RISC抑制中释放突触蛋白合成。 这些观察结果提出了许多重要的问题，以理解这些机制 基础记忆。我们可以构建一个细粒的神经图，以便在哪里蛋白质合成作为一个 特定的内存表格？我们可以构建一张图的地图，说明需要蛋白质合成的调节吗？ 突触蛋白合成的时间特征是什么？ 维持在稳定的新状态下的突触？我们才开始了解角色和 RISC途径在突触中的生物化学，但​​作为这些事件的明显调节者，我们相信 这种理解将阐明记忆下的生化和细胞机制。坚强 这项研究的潜力不应忽略临床贡献，因为很明显这些 机制在哺乳动物和人类突触下运行。这项研究可能会确定针对的新目标 治疗性努力帮助有记忆障碍的患者（例如，阿尔茨海默氏病）和突触 活动（例如癫痫）。