Dynamical mechanisms for gene regulation mediated by two noncoding RNAs in long-term memory formation

Noncoding RNAs such as miRNAs and piRNAs have long-lasting effects on the regulation of gene expression involved in long-term synaptic changes. To characterize gene regulation mediated by small noncoding RNAs associated with long-term memory in Aplysia, we consider two noncoding RNAs stimulated by 5-HT into a gene regulatory network motif model, including miR-124 that binds to and inhibits the mRNA of CREB1 and piR-F that facilitates serotonin-dependent DNA methylation to lead to repression of CREB2. Codimension-1 and -2 bifurcation analyses of 5-HT regulating both miR-124 and piR-F and a negative feedback strength for oscillation reveal rich dynamical properties of bistability and oscillations robust to variations in all other parameters. More importantly, we verify three stimulus protocols of 5-HT in experiments by our model and find that application of five pulses of 5-HT leads to a transient decrease of miR-124 but increase of piR-F concentrations, which matters sustained high level of CREB1 concentration associated with long-term memory. Furthermore, we perform bifurcation analyses for the concentrations of miR-124 and piR-F as two parameters to explore dynamical mechanisms underlying the epigenetic regulation in long-term memory formation. This study provides insights into revealing regulatory roles of epigenetic changes in gene expression involving noncoding RNAs associated with synaptic plasticity.