Morphine modulates hippocampal neurogenesis and contextual memory extinction via miR-34c/Notch1 pathway in male ICR mice

Abstract

AbstractBackgroundThe 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.MethodsThe 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.ResultsThe 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.ConclusionThe 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.