Abstract Background The opioid Morphine is known to affect neurogenesis in the hippocampus. Evidence has shown that several microRNAs modulate morphine-induced neurogenesis, and hence morphine-induced contextual memory. This complex network has yet to be elucidated. In this study, we screened for morphine addiction related microRNA and determined its effects on hippocampal neurogenesis and morphine-induced contextual memory using the conditioned place preference (CPP) model. Methods The previously established CPP model was utilized in this study. For differential expression of miRNA in the hippocampus, the GeneChip miRNA array was used. Lentivirus technology was used to overexpress or downregulate the miRNA, and changes in expression level was verified with qRT-PCR. Protein expression levels were measured with western blot. Immunofluorescence was used to observe the protein expression during the differentiation of NSCs. Results The results showed that morphine administration upregulated microRNA-34c (miR-34c) and Notch1. Downregulating miR-34c in vivo decreased Notch1 expression and partially rescued the morphine-induced inhibition of the differentiation of neural stem cells (NSCs). This did not affect the morphine-induced proliferation of cells. Furthermore, downregulating miR-34c in vivo prolonged the extinction of morphine-induced contextual memory without affecting acquired CPP response. Conclusion The miR-34c regulates the hippocampal neurogenesis in addicted mice by up-regulating Notch1 expression, by inhibiting differentiation of neural precursor cells. The miR-34c/Notch1 pathway may be a new potential target for the prevention and treatment of opioid psychotic dependence.

中文翻译：

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吗啡通过 miR-34c/Notch1 通路调节雄性 ICR 小鼠的海马神经发生和情境记忆消退

摘要背景已知阿片类吗啡会影响海马中的神经发生。有证据表明，几种 microRNA 调节吗啡诱导的神经发生，从而调节吗啡诱导的情境记忆。这个复杂的网络还有待阐明。在这项研究中，我们筛选了与吗啡成瘾相关的 microRNA，并使用条件位置偏好 (CPP) 模型确定了其对海马神经发生和吗啡诱导的情境记忆的影响。方法本研究采用先前建立的CPP模型。对于 miRNA 在海马中的差异表达，使用了 GeneChip miRNA 阵列。慢病毒技术用于过表达或下调 miRNA，并通过 qRT-PCR 验证表达水平的变化。蛋白质表达水平用蛋白质印迹测量。免疫荧光用于观察NSCs分化过程中的蛋白表达。结果结果显示吗啡给药上调microRNA-34c (miR-34c)和Notch1。体内下调 miR-34c 降低了 Notch1 表达并部分挽救了吗啡诱导的神经干细胞 (NSCs) 分化抑制。这不影响吗啡诱导的细胞增殖。此外，体内下调 miR-34c 延长了吗啡诱导的上下文记忆的消失，而不影响获得的 CPP 反应。结论 miR-34c通过上调Notch1表达，抑制神经前体细胞分化，调节成瘾小鼠海马神经发生。