Abstract

This study aimed to evaluate the role of miR-383 in the regulation of Wnt-2 signaling in the rat model of chronic stress. The male SD rats with depressive-like behaviors were stimulated with chronic unpredictable mild stress (CUMS) including ice-water swimming for 5 min, food deprivation for 24 h, water deprivation for 24 h, stimulating tail for 1 min, turning night into day, shaking for 15 min (once/s), and wrap restraint (5 min/time) every day for 21 days. The expression levels of miRNAs were detected by qRT-PCR, and the expression levels of Wnt2, depression-impacted proteins (GFAP, BDNF, CREB), brain neurotransmitters (5-HT, NE, DA) and apoptosis-related proteins (Bax and Bcl-2) were evaluated by qRT-PCR and western blot. Bioinformatic analysis and luciferase reporter assay were performed to determine the relationship between miR-383 and Wnt2. Ethological analysis was evaluated by sugar preference test, refuge island test and open field tests. Rescue experiments including knockdown of miR-383, overexpression and silencing of Wnt2 were performed to determine the role of miR-383. High expression levels of miR-383 were observed in the hippocampus of rats submitted to CUMS model. Downregulation of miR-383 significantly inhibited the apoptosis and inflammatory response of hippocampal neurons, and increased the expression levels of GFAP, BDNF and CREB which were impacted in depression, as well as neurotransmitters, then attenuated neural injury in rats induced by CUMS. Furthermore, Wnt family member 2 (Wnt2) was identified as a target of miR-383, and silencing of Wnt2 obviously attenuated the protective effect of miR-383 inhibitor on the apoptosis and inflammatory response in hippocampal neurons, as well as neural injury in CUMS-induced rats. Downregulation of miR-383 ameliorated the behavioral and neurochemical changes induced by chronic stress in rats by directly targeting Wnt2, indicating that the miR-383/Wnt2 axis might be a potential therapeutic target for MDD.

Highlights

  • This study aimed to evaluate the role of miR-383 in the regulation of Wnt-2 signaling in the rat model of chronic stress

  • These key genes are closely involved in the progression of Major depressive disorder (MDD), and miR-221 has been demonstrated to control the progression of MDD in chronic unpredictable mild stress (CUMS) rats by regulating the Wnt family member 2 (Wnt2)/CREB/BDNF signaling in hippocampal n­ eurons19

  • To explore the regulatory network of Wnt2, CUMS was used to induce MDD rat model. It showed that Wnt2 was significantly downregulated in hippocampi tissues of rats submitted to CUMS compared with that in the control group at both mRNA (t test, ­t(10) = 9.820, P = 0.001) (Fig. 1A) and protein (t test, ­t(10) = 7.150, P = 0.002) levels (Fig. 1B)

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Summary

Introduction

This study aimed to evaluate the role of miR-383 in the regulation of Wnt-2 signaling in the rat model of chronic stress. Downregulation of miR-383 significantly inhibited the apoptosis and inflammatory response of hippocampal neurons, and increased the expression levels of GFAP, BDNF and CREB which were impacted in depression, as well as neurotransmitters, attenuated neural injury in rats induced by CUMS. Glial fibrillary acidic protein (GFAP) is an intermediate filament protein that is primarily expressed in astrocytes, and was markedly upregulated in M­ DD18 These key genes are closely involved in the progression of MDD, and miR-221 has been demonstrated to control the progression of MDD in chronic unpredictable mild stress (CUMS) rats by regulating the Wnt2/CREB/BDNF signaling in hippocampal n­ eurons

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