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<p>Major depressive disorder (MDD) is strongly linked to chronic stress, yet its molecular mechanisms remain poorly understood. We hypothesize that chronic stress induces epigenetic alterations in stress-associated genes, contributing to transcriptional dysregulation in the prefrontal cortex&#xa0;(PFC), a key brain region implicated in MDD. To test this, we performed expression levels of stress-associated genes in the PFC of rats subjected to restraint stress, which revealed significant downregulation of <i>CRHR2</i> and <i>NR3C1</i>, both critical regulators of the hypothalamic–pituitary–adrenal (HPA) axis, as well as a trend to decreased expression of <i>BDNF</i> and <i>TRKB</i>, central mediators of synaptic plasticity. Given the well-established role of miRNAs in gene regulation, we further investigated stress-associated miRNA expression changes and identified miR-20b-3p and miR-425-3p as significantly upregulated in the restraint-stressed group. Bioinformatics analysis predicted miR-20b-3p as a potential regulator of <i>NR3C1</i>, a relationship confirmed through RISC-mediated immunoenrichment, demonstrating increased miR-20b-3p binding to <i>NR3C1</i> in stress-exposed rats. To confirm this interaction, we performed parallel analyses in cells ectopically expressing miR-20b-3p mimic, inhibitor, and a non-oligo control. Cells mimicking endogenous miR-20b-3p showed upregulated <i>NR3C1</i> binding enrichment compared to non-transfected controls, while anti-miR-20b-3p treatment repressed its interaction with the <i>NR3C1</i> 3'UTR. These findings suggest that miR-20b-3p actively engages with <i>NR3C1</i> and plays a regulatory role in its expression. Collectively, these results highlight a potential epigenetic mechanism by which chronic stress alters <i>NR3C1</i> expression, possibly contributing to HPA axis dysregulation in MDD. The identification of miR-20b-3p as a key regulator of <i>NR3C1</i> provides new insights into stress-induced molecular changes and suggests potential therapeutic targets for stress-associated psychiatric disorders.</p>

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Stress-Associated Changes in MiR-20b-3p as a Potential Predictor of Underlying Psychopathology in the Depressed Brain: Mechanistic Insights from a Rat Model of Chronic Restraint Stress

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  • 发表日期：

    2025年11月15日

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  • Sarah Ali,
  • Yogesh Dwivedi

摘要

Major depressive disorder (MDD) is strongly linked to chronic stress, yet its molecular mechanisms remain poorly understood. We hypothesize that chronic stress induces epigenetic alterations in stress-associated genes, contributing to transcriptional dysregulation in the prefrontal cortex (PFC), a key brain region implicated in MDD. To test this, we performed expression levels of stress-associated genes in the PFC of rats subjected to restraint stress, which revealed significant downregulation of CRHR2 and NR3C1, both critical regulators of the hypothalamic–pituitary–adrenal (HPA) axis, as well as a trend to decreased expression of BDNF and TRKB, central mediators of synaptic plasticity. Given the well-established role of miRNAs in gene regulation, we further investigated stress-associated miRNA expression changes and identified miR-20b-3p and miR-425-3p as significantly upregulated in the restraint-stressed group. Bioinformatics analysis predicted miR-20b-3p as a potential regulator of NR3C1, a relationship confirmed through RISC-mediated immunoenrichment, demonstrating increased miR-20b-3p binding to NR3C1 in stress-exposed rats. To confirm this interaction, we performed parallel analyses in cells ectopically expressing miR-20b-3p mimic, inhibitor, and a non-oligo control. Cells mimicking endogenous miR-20b-3p showed upregulated NR3C1 binding enrichment compared to non-transfected controls, while anti-miR-20b-3p treatment repressed its interaction with the NR3C1 3'UTR. These findings suggest that miR-20b-3p actively engages with NR3C1 and plays a regulatory role in its expression. Collectively, these results highlight a potential epigenetic mechanism by which chronic stress alters NR3C1 expression, possibly contributing to HPA axis dysregulation in MDD. The identification of miR-20b-3p as a key regulator of NR3C1 provides new insights into stress-induced molecular changes and suggests potential therapeutic targets for stress-associated psychiatric disorders.