Dataset Information

MiR-30 Family miRNAs Mediate the Effect of Chronic Social Defeat Stress on Hippocampal Neurogenesis in Mouse Depression Model.

ABSTRACT: Depression is a debilitating psychiatric disorder with a high rate of relapse and a low rate of response to antidepressant treatment. There is a dearth of new antidepressants due to an incomplete understanding of the molecular mechanisms involved in its etiopathology. Chronic stress appears to be one of the foremost underlying causes of depression. Studies in animal models in the past decade have implicated epigenetic mechanisms in mediating the negative effects of chronic stressful events on the progression/manifestation of depression and other co-morbid neuropsychiatric disorders. However, non-coding RNAs, another layer of epigenetic regulation is relatively less studied in depression. Here, using the chronic social defeat stress (CSDS)-induced depression model, we hypothesized dysregulation in miRNA-mRNA networks in the neurogenic dentate gyrus (DG) region of male C57BL/6 mice. Among several dysregulated miRNAs identified via miRNA arrays, the most striking finding was the downregulation of miRNAs of the miR-30 family in stressed/defeated mice. To investigate miRNAs in the DG-resident neural stem/progenitor cells (NSCs/NPCs), we used the in vitro neurosphere culture, where proliferating NSCs/NPCs were subjected to differentiation. Among several differentially expressed miRNAs, we observed an upregulation of miR-30 family miRNAs upon differentiation. To search for the gene targets of these miRNAs, we performed gene arrays followed by bioinformatics analysis, miRNA manipulations and luciferase assays. Our results suggest that miR-30 family miRNAs mediate chronic stress-induced depression-like phenotype by altering hippocampal neurogenesis and neuroplasticity via controlling the epigenetic and transcription regulators such as Mll3 and Runx1; and cell signaling regulators like Socs3, Ppp3r1, Gpr125, and Nrp1.

SUBMITTER: Khandelwal N

PROVIDER: S-EPMC6694739 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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miR-30 Family miRNAs Mediate the Effect of Chronic Social Defeat Stress on Hippocampal Neurogenesis in Mouse Depression Model.

Khandelwal Nitin N Dey Sandeep Kumar SK Chakravarty Sumana S Kumar Arvind A

Frontiers in molecular neuroscience 20190808

Depression is a debilitating psychiatric disorder with a high rate of relapse and a low rate of response to antidepressant treatment. There is a dearth of new antidepressants due to an incomplete understanding of the molecular mechanisms involved in its etiopathology. Chronic stress appears to be one of the foremost underlying causes of depression. Studies in animal models in the past decade have implicated epigenetic mechanisms in mediating the negative effects of chronic stressful events on th ...[more]

PMID: 31440139

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Project description:Depression, anxiety and related mood disorders are major psychiatric illnesses worldwide, and chronic stress appears to be one of the primary underlying causes. Therapeutics to treat these debilitating disorders without a relapse are limited due to the incomplete molecular understanding of their etiopathology. In addition to the well-studied genetic component, research in the past two decades has implicated diverse epigenetic mechanisms in mediating the negative effects of chronic stressful events on neural circuits. This includes the cognitive circuitry, where the dynamic hippocampal dentate gyrus (DG) neurogenesis gets affected in depression and related affective disorders. Most of these epigenetic studies have focused on the impact of acetylation/deacetylation and methylation of several histone lysine residues on neural gene expression. However, there is a dearth of investigation into the role of demethylation of these lysine residues in chronic stress-induced changes in neurogenesis that results in altered behaviour. Here, using the chronic social defeat stress (CSDS) paradigm to induce depression and anxiety in C57BL/6 mice and ex vivo DG neural stem/progenitor cell (NSCs/NPCs) culture we show the role of the members of the JMJD2/KDM4 family of histone lysine demethylases (KDMs) in mediating stress-induced changes in DG neurogenesis and mood disorders. The study suggests a critical role of JMJD2D in DG neurogenesis. Altered enrichment of JMJD2D on the promoters of Id2 (inhibitor of differentiation 2) and Sox2 (SRY-Box Transcription Factor 2) was observed during proliferation and differentiation of NSCs/NPCs obtained from the DG. This would affect the demethylation of repressive epigenetic mark H3K9, thus activating or repressing these and possibly other genes involved in regulating proliferation and differentiation of DG NSCs/NPCs. Treatment of the NSCs/NPCs culture with Dimethyloxallyl Glycine (DMOG), an inhibitor of JMJDs, led to attenuation in their proliferation capacity. Additionally, systemic administration of DMOG in mice for 10 days induced depression-like and anxiety-like phenotype without any stress exposure.

Dataset Information

MiR-30 Family miRNAs Mediate the Effect of Chronic Social Defeat Stress on Hippocampal Neurogenesis in Mouse Depression Model.

Publications

miR-30 Family miRNAs Mediate the Effect of Chronic Social Defeat Stress on Hippocampal Neurogenesis in Mouse Depression Model.

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