A CREB2-targeting microRNA is required for long-term memory after single-trial learning

Abstract

Although single-trial induced long-term memories (LTM) have been of major interest in neuroscience, how LTM can form after a single episode of learning remains largely unknown. We hypothesized that the removal of molecular inhibitory constraints by microRNAs (miRNAs) plays an important role in this process. To test this hypothesis, first we constructed small non-coding RNA (sncRNA) cDNA libraries from the CNS of Lymnaea stagnalis subjected to a single conditioning trial. Then, by next generation sequencing of these libraries, we identified a specific pool of miRNAs regulated by training. Of these miRNAs, we focussed on Lym-miR-137 whose seed region shows perfect complementarity to a target sequence in the 3’ UTR of the mRNA for CREB2, a well-known memory repressor. We found that Lym-miR-137 was transiently up-regulated 1 h after single-trial conditioning, preceding a down-regulation of Lym-CREB2 mRNA. Furthermore, we discovered that Lym-miR-137 is co-expressed with Lym-CREB2 mRNA in an identified neuron with an established role in LTM. Finally, using an in vivo loss-of-function approach we demonstrated that Lym-miR-137 is required for single-trial induced LTM.

Size-selective molecular recognition based on a confined DNA molecular sieve using cavity-tunable framework nucleic acids

“…Finally, Cage-MB-in was applied to measure the change in abundance of miRNA-21 during drug treatment. As an inhibitor of Dicer activity 63 , poly-L-lysine (PLL) can reduce the production of mature miRNA-21, which was validated by qRT-PCR ( Supplementary Fig. S39).…”

Learning-induced mRNA alterations in olfactory bulb mitral cells in neonatal rats

“…Mir23b down-regulation with a single training trial may be temporally limited such that it effectively supports 24 h, but not 48 h, memory. However, MiRs are also implicated in multiday long-term memories (Korneev et al 2018). It will be of interest to examine differences in mRNA expression in trained and nontrained cohorts at 48 h.…”

The role of microRNAs in learning and long-term memory

“…In addition, impairment of microRNA biosynthesis in dopaminergic neurons due to suppression or depletion of Dicer (tissue-specific inducible suppression) causes dopaminergic cell dysfunction, while pharmacological stimulation is neuroprotective (Chmielarz et al, 2017). In addition, the pharmacological inhibition of Dicer activity with poly-lysine (Poly-L-lysine hydrobromide) disrupts formation of a conditioned reflex with single-trial induced LTM in the mollusk Lymnaea stagnalis (Korneev et al, 2018) and impairs formation of the conditioned defense reflex in the mollusk Helix (Grinkevich, 2019). Thus, the last two studies show that short-term Dicer dysfunction can lead not to improvement, but to impairment of LTM.…”

“…This microRNA is being intensively studied both in connection with the mechanisms of LTM and with various cognitive pathologies, and its functions are very diverse. It has been shown that activation of miR-137 is re quired for long-term memory formation in the pond snail Lymnaea (Korneev et al, 2018). At the same time, miR-137 inhibits the transcription factor CREB2, a negative regulator of the expression of genes necessary for LTM formation.…”