Search

Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis during chronic stress is essential for the pathogenesis of depression, and increased activity of cAMP response element binding protein (CREB)-regulated transcription co-activator 1 (CRTC1) in the paraventricular nucleus (PVN) plays a critical role. As a well-investigated microRNA (miRNA), miR-184 has two forms, miR-184-3p and miR-184-5p. Recently, miRNAs target genes predictive analysis and dual-luciferase reporter assays identified an inhibitory role of miR-184-3p on CRTC1 expression. Therefore, we speculated that miR-184-3p regulation was responsible for the effects of chronic stress on CRTC1 in the PVN. Various methods, including the chronic social defeat stress (CSDS) model of depression, behavioral tests, Western blotting, co-immunoprecipitation (Co-IP), quantitative real-time reverse transcription PCR (qRT-PCR), immunofluorescence, and adeno-associated virus (AAV)-mediated gene transfer, were used. CSDS evidently downregulated the level of miR-184-3p, but not miR-184-5p, in the PVN. Genetic knockdown and pharmacological inhibition of miR-184-3p in the PVN induced various depressive-like symptoms (e.g., abnormal behaviors, HPA hyperactivity, enhanced CRTC1 function in PVN neurons, downregulation of hippocampal neurogenesis, and decreased brain-derived neurotrophic factor (BDNF) signaling) in naïve male C57BL/6J mice. In contrast, genetic overexpression and pharmacological activation of miR-184-3p in the PVN produced significant beneficial effects against CSDS. MiR-184-3p in the PVN was necessary for the antidepressant actions of two well-known SSRIs, fluoxetine and paroxetine. Collectively. miR-184-3p was also implicated in the neurobiology of depression and may be a viable target for novel antidepressants., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

As a highly prevalent neuropsychiatric disorder worldwide, the pathophysiology of depression is not yet fully understood and based on multiple factors among which chronic stress is critical. Numerous previous studies have shown the role of central mammalian target of rapamycin complex 1 (mTORC1) signaling in depression. However, so far it remains elusive by which way chronic stress down-regulates the activity of central mTORC1. Liver kinase b1 (LKB1) has been demonstrated to regulate the activity of the mTORC1 signaling cascade by phosphorylating AMP activated protein kinase (AMPK). Here, this study aimed to explore whether LKB1 participates in depression by regulating the downstream AMPK-mTORC1 signaling, and various methods including mouse models of depression, western blotting and immunofluorescence were used together. Our results showed that chronic stress significantly enhanced the expression of both phosphorylated LKB1 and total LKB1 in the medial prefrontal cortex (mPFC) but not the hippocampus. Furthermore, genetic knockdown of LKB1 in the mPFC fully reversed not only the depressive-like behaviors induced by chronic stress in mice but also the effects of chronic stress on the activity of AMPK and the mTORC1 system. Taken together, this study preliminarily suggests that LKB1 in the mPFC could be a feasible target for antidepressants. This study also provides support for the potential use of LKB1 inhibition strategies against the chronic stress-related neuropsychiatric disorders., (Copyright © 2021 Elsevier Inc. All rights reserved.)

As a widely-known neuropsychiatric disorder, the exact pathogenesis of depression remains elusive. MiRNA-206 (miR-206) is conventionally known as one of the myomiRs and has two forms: miR-206-3p and miR-206-5p. Recently, miR-206 has been demonstrated to regulate the biosynthesis of brain-derived neurotrophic factor (BDNF), a very popular target involved in depression and antidepressant responses. Here we assumed that miR-206 may play a role in depression, and various methods including the chronic social defeat stress (CSDS) model of depression, quantitative real-time reverse transcription PCR, western blotting, immuofluorescence and virus-mediated gene transfer were used together. It was found that CSDS robustly increased the level of miR-206-3p but not miR-206-5p in the hippocampus. Both genetic overexpression of hippocampal miR-206-3p and intranasal administration of AgomiR-206-3p induced not only notable depressive-like behaviors but also significantly decreased hippocampal BDNF signaling cascade and neurogenesis in naïve C57BL/6J mice. In contrast, both genetic knockdown of hippocampal miR-206-3p and intranasal administration of AntagomiR-206-3p produced significant antidepressant-like effects in the CSDS model of depression. Furthermore, it was found that the antidepressant-like effects induced by miR-206-3p inhibition require the hippocampal BDNF-TrkB system. Taken together, hippocampal miR-206-3p participates in the pathogenesis of depression by regulating BDNF biosynthesis and is a feasible antidepressant target., (Copyright © 2021 Elsevier Ltd. All rights reserved.)