Collaborative Research: Ideas Lab: RNA-encoded Molecular Memory (REMM)

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In most organisms, the genetic information is composed of the molecule deoxyribonucleic acid (DNA). But only a fraction of DNA in the genome—the “coding DNA”—contains biochemical instructions for generating the proteins that perform the vast range of activities essential for life. Indeed, 99% of the human genome is regarded as “non-coding” DNA. Intriguingly, the DNA in this “non-coding” part of the genome can still generate RNA, even though these non-coding RNAs are not translated into proteins, in contrast to the "messenger" RNAs generated by coding DNA. Surprisingly, the functions of non-coding RNAs, which represent a large percentage of the genome, are still largely unknown. A major goal of the present project is to explore potential roles these non-coding RNAs could play in the encoding of memory. At present, memories are widely thought to be stored as changes in the strengths of connections among neurons in the brain. The project will build on prior evidence that some forms of simple memory may instead be encoded as changes in RNA molecules. The project will examine whether one simple form of memory—behavioral sensitization—can be stored by non-coding RNA, or whether non-coding RNA can produce downstream molecular changes that store memory. In addition, the project will enhance the training of future scientists, including graduate students and postdoctoral researchers. Finally, undergraduate and minority students underrepresented in STEM will participate in the proposed research under the mentorship of the principal investigators, and thereby gain a deeper understanding of scientific research.A previous study by one of the principal investigators (PIs) showed that long-term memory (LTM) can be transferred by injecting RNA from trained animals into untrained animals. In this prior work, RNA was extracted from the nervous systems of sensitized (“trained”) marine snails (Aplysia californica), purified, and then injected into untrained snails; injected RNA from trained animals produced sensitization in untrained animals, whereas RNA from untrained donor animals did not. The PIs hypothesize that the expression or post-transcriptional state of one or more non-coding RNAs (ncRNAs) is selectively induced by sensitization training and that this molecular change mediates persistent sensitization memory in Aplysia. To test this hypothesis, the PIs will perform differential RNA-seq on purified RNA from trained and untrained animals and identify species of ncRNA with changes that correlate significantly with LTM. Initial experiments will determine whether the expression levels of specific ncRNAs change as a consequence of sensitization. Based on these results, additional aspects of ncRNA structure, modification state or protein interactions will be probed to explore whether sensitization training induces persistent changes in these ncRNA properties that could mediate memory encoding in Aplysia. This work would set the stage for a future project in which candidate ncRNAs be screened for mnemonic potency by disrupting them with antisense oligonucleotides (ASOs) and assessing the effects on neuronal excitability and synaptic connectivity of Aplysia sensory and motor neurons, as well as the effect of the ASOs on LTM in intact animals.This award was co-funded by the Directorate for Biological Sciences, and the Neural Systems Cluster in the Division of Integrative Organismal Systems.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.