Hippocampal miR-124 Participates in the Pathogenesis of Depression via Regulating the Expression of BDNF in a Chronic Social Defeat Stress Model of Depression

Abstract

Objective: As one of the most prevalent psychiatric disorders, the exact pathogenesis of depression remains elusive. Therefore, there is an urgent need to identify novel antidepressants for effective treatment. MicroRNA-124 (miR-124), the most abundant miRNA in brain tissue, plays a key effect on adult neurogenesis and neuronal differentiation. However, the mechanism of miR-124 in depression has not been clarified so far, the aim of this study is to provide broad insight into the mechanisms underlying depression. Methods: In the study, we used the forced swim test (FST), the tail suspension test (TST), and a Chronic Social Defeat Stress (CSDS) mice model of depression. Quantitative real-time reverse transcription PCR (qRT-PCR), western blotting, immunofluorescence and virus-mediated gene transfer were used together. The level of plasma corticosterone in mice was analyzed by Enzyme Linked Immunosorbent Assay (ELISA). Results: It was found that CSDS robustly increased the level of miR-124 in the hippocampus. Genetic knockdown of hippocampal miR-124 produced significant antidepressant-like effects in the CSDS model of depression. Furthermore, AAV-siR-124-EGFP treatment increased the level of plasma corticosterone in CSDS-induced mice. Moreover, it was found that the antidepressant-like effects induced by miR-124 inhibition required the hippocampal BDNF-TrkB system. Conclusion: Hippocampal miR-124 participated in the pathogenesis of depression by regulating BDNF biosynthesis and was a feasible antidepressant target.

Molecular pattern of a decrease in the rewarding effect of cocaine after an escalating-dose drug regimen

“…We are aware of the pleiotropic effects of miRNAs as they can target many different molecular pathways in cell- and tissue-specific manner, thus further research is needed to confirm the targets of these miRNAs in this context. So far, other studies identified PARP-1 [ 108 ] and BDNF [ 109 ] as plausible direct targets of miRNA-124 in neuronal cells.…”

Biology of cyclooxygenase-2: An application in depression therapeutics

“…Estrogen deficiency can cause depression-like behavior, and Huang et al (44) found in their experiments that estrogen deficiency-induced depression was associated with intestinal flora imbalance and inflammatory response in mice undergoing ovariectomy (OVX), where intestinal flora imbalance caused (45). There is growing evidence that modulation of BDNF expression levels can exert antidepressant effects (46)(47)(48), where BDNF-cAMP response element binding protein (CREB) signaling is one of the most attractive signaling pathways for the treatment of depression (49,50). In summary, gut flora and COX-2mediated inflammatory responses are strongly correlated, but there are fewer studies on how COX-2-mediated pathways and gut flora-brain centers interact and thus mediate depression, and further research is needed (Figure 1).…”

“…BDNF is a neuroprotective molecule that plays a key role in neuroplasticity, neuroinflammation, learning and memory ( 45 ). There is growing evidence that modulation of BDNF expression levels can exert antidepressant effects ( 46 – 48 ), where BDNF-cAMP response element binding protein (CREB) signaling is one of the most attractive signaling pathways for the treatment of depression ( 49 , 50 ). In summary, gut flora and COX-2-mediated inflammatory responses are strongly correlated, but there are fewer studies on how COX-2-mediated pathways and gut flora-brain centers interact and thus mediate depression, and further research is needed ( Figure 1 ).…”

Research progress of miRNA in different depression model samples

“…Abnormalities in either of these areas are intimately associated with the development of depression [74]. MiRNAs in the hippocampus have been reported to be crucial for the regulation of BDNF and to play a significant role in depression [16,17,75,76]. In the hippocampus of depressed mice, miR-139-5p, miR-199a-5p, and miR-124 expression was upregulated, and miR-134 expression was downregulated by mechanisms involved in regulating the BDNF-TrkB (tyrosine kinase receptor B) signaling pathway, acting on WNT2 and CREB/BDNF signaling pathways, regulating BDNF biosynthesis, and binding directly to the 3'UTR of BDNF [16,17,75,76] that induce depression-like behavior.…”

“…MiRNAs in the hippocampus have been reported to be crucial for the regulation of BDNF and to play a significant role in depression [16,17,75,76]. In the hippocampus of depressed mice, miR-139-5p, miR-199a-5p, and miR-124 expression was upregulated, and miR-134 expression was downregulated by mechanisms involved in regulating the BDNF-TrkB (tyrosine kinase receptor B) signaling pathway, acting on WNT2 and CREB/BDNF signaling pathways, regulating BDNF biosynthesis, and binding directly to the 3'UTR of BDNF [16,17,75,76] that induce depression-like behavior. Interestingly, Zhang et al combined in vitro and animal experiments to verify that adenosine deaminase (ADAR1), which acts on RNA1, is involved in antidepressant effects through miR-432 regulation of BDNF [77].…”