Role of age-accumulated circRNAs in long-term memory

仅针对补充活动的项目摘要 与年龄相关的认知衰退是正常衰老的显著特征。理解分子变化 神经系统功能是如何在衰老过程中改变的，这对于理解记忆丧失很重要 随着年龄的增长和神经退行性疾病。和人类一样，线虫也经历了认知 在衰老过程中会下降，但这些下降的原因还不是很清楚。年龄的一个很好的指标- 神经元功能的相关变化是转录因子CREB(cAMP负责元件)的水平 结合蛋白)。我们的父母赠款的初步工作表明，删除年龄积累的循环 来自宿主CREB的RNA CIRC-CRH-1导致线虫的平均寿命更长，这表明 CIRC-CRH-1加速正常衰老。CircRNA可能在健康的大脑功能中发挥作用，特别是学习和 记忆，由于它们在突触中的定位；然而，它们在长期记忆中的直接作用从来不是 测试过。此外，已发现CircRNA水平的改变与神经退行性疾病有关。 例如阿尔茨海默氏症。在这份美日BRCP合作研究倡议的行政副刊中， 我们建议(1)在长期联想记忆中测试包括CIRC-CRH-1在内的CircRNAs产生的突变体 (LTAM)，以及(2)使用我们开发的工具来分析CircRNA在 在LTAM训练之后。通过这些研究，特定CircRNA的贡献及其在全球范围内的变化 功能认知将被用来确定治疗认知衰退的最佳干预靶点 随着年龄的增长。我们的提案是由UNR(Miura博士和Van Der Linden博士)和OIST(丸山博士)在 并为私人投资机构提供了独特的机会，让他们学习LTAM中的复杂方法。作为回报，私家侦探 将向东道主实验室的受训人员提供关于衰老和CircRNA图谱分析的指导。这项建议符合 自然与NIA的计划一致，并将大幅推进父拨款(R21AG058955)的工作，以创建新的 关于个体环状RNA在年龄相关行为中的作用的知识，如认知能力下降。

Project Summary for Supplemental Activities ONLY Age-related cognitive declines are prominent features of normal aging. Understanding the molecular changes and how nervous system function is altered by the process of aging is important to understand loss of memory with age and in neurodegenerative diseases. As in humans, the nematode C. elegans experiences cognitive declines during aging, but the causes of these declines are not well-understood. One good indicator of age- related changes in neuronal function are the levels of the transcription factor CREB (cAMP responsible element binding protein). Preliminary work from our parent grant has shown that removing the age-accumulated circular RNA, circ-crh-1, derived from the host CREB results in C. elegans with a longer mean life-span, suggesting that circ-crh-1 accelerates normal aging. CircRNAs may have roles in healthy brain function, particularly learning and memory, due to their localization at synapses; however, their direct role in long-term memory has never been tested. Moreover, altered circRNA levels have been found to be associated with neurodegenerative diseases such as Alzheimer’s. In this administrative supplement for the U.S.-Japan BRCP collaborative research initiative, we propose to (1) test generated mutants of circRNAs including circ-crh-1 in long-term associative memory (LTAM), and (2) use our developed tools to profile genome-wide expression changes of circRNAs before and after LTAM training. Through these studies, the contributions of specific circRNAs and their global changes in functional cognition will be used to identify the best targets of therapeutic intervention to treat cognitive decline with age. Our proposal is a joint effort from UNR (Drs. Miura and Van Der Linden) with OIST (Dr. Maruyama) in Japan, and provides unique opportunities for the PIs to learn sophisticated methods in LTAM. In return, the PIs will provide instruction to trainees in the host lab on aging and circRNA profiling analysis. The proposal aligns naturally with NIA’s plan and will significantly advance work on the parent grant (R21AG058955) to create new knowledge on the role of individual circRNAs in age-related behaviors such as cognitive decline.