The interplay of small, noncoding microRNAs (miRNAs), mRNAs and proteins plays crucial roles in almost all cellular processes. MiR-124, widely known as a memory-related miRNA, can regulate LTM by binding to the mRNA of CREB1 stimulated with 5-HT. In this paper, we establish a regulatory network model of CREB1 and miR-124 stimulated by 5-HT, in which miR-124 inhibits CREB1, which in turn enhances miR-124. Our model validates three protocols based on 5-HT in experiments on the induction of LTM in Aplysia. A steady-state analysis and numerical bifurcations of the abstracted system beyond memory formation, when the fast reaction has been in the equilibrium, can facilitate more abundant dynamical behaviors such as bistability and oscillation. The original system also exhibits bistability under appropriate feedback strengths, which is relevant to the mechanism of LTM formation. Furthermore, we specifically show a change in the transition from a reversible switch to an irreversible switch via bifurcations of the negative regulation of miR-124 on CREB1, which eventually maintains a high phosphorylated CREB1 level after initially elevated by 5-HT. These findings indicate that miR-124 provides an inhibitory constraint on long-term synaptic plasticity through the regulation of CREB1.

中文翻译：

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通过基因调节网络中的分叉，从可逆的双稳态开关变为不可逆的双稳态开关。

小型非编码microRNA（miRNA），mRNA和蛋白质的相互作用在几乎所有细胞过程中都起着至关重要的作用。MiR-124，众所周知的与记忆有关的miRNA，可以通过结合5-HT刺激的CREB1的mRNA来调节LTM。在本文中，我们建立了5-HT刺激的CREB1和miR-124的调控网络模型，其中miR-124抑制CREB1，从而增强了miR-124。我们的模型验证了在Aplysia中诱导LTM的实验中基于5-HT的三种方案。当快速反应处于平衡状态时，超出记忆形成范围的抽象系统的稳态分析和数值分支将有助于更丰富的动力学行为，例如双稳态和振荡。原始系统在适当的反馈强度下也具有双稳态，这与LTM的形成机制有关。此外，我们具体显示了通过对CREB1上的miR-124负调控分叉，从可逆开关向不可逆开关的过渡变化，该变化最终在最初由5-HT升高后最终保持了高磷酸化CREB1水平。这些发现表明，miR-124通过调节CREB1抑制了长期突触可塑性。