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.

Public Health Relevance

for Supplemental Activities ONLY Circular RNAs (circRNAs) accumulate during normal aging, which is likely a molecular feature of aging across metazoan life. This collaborative research project under the U.S.-Japan BRCP initiative will investigate the impact of removing individual age- and NMD-regulated circRNAs on learning and memory of C. elegans. It also seeks to profile circRNAs in long-term memory training. This work could be relevant to understanding how circRNAs influence age-related decline in memory and disease susceptibility in humans.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Exploratory/Developmental Grants (R21)
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Guo, Max
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University of Nevada Reno
Schools of Arts and Sciences
United States
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