Instituto de Investigação e Inovação em Saúde/Instituto de Engenharia Biomédica (i3S/INEB), University of Porto (UP), Rua Alfredo Allen 208, 4200-135 Porto, Portugal; Instituto de Ciências Biomédicas Abel Salazar (ICBAS), University of Porto (UP), Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal; Brain Mind Institute, École Polytechnique Fédérale de Lausanne (EPFL), Station 19, CH-1015 Lausanne, Switzerland.
Brain Mind Institute, École Polytechnique Fédérale de Lausanne (EPFL), Station 19, CH-1015 Lausanne, Switzerland.
Brain Behav Immun. 2022 Jan;99:397-408. doi: 10.1016/j.bbi.2021.10.018. Epub 2021 Nov 15.
Neuroinflammation is increasingly recognized as playing a critical role in depression. Early-life stress exposure and constitutive differences in glucocorticoid responsiveness to stressors are two key risk factors for depression, but their impacts on the inflammatory status of the brain is still uncertain. Moreover, there is a need to identify specific molecules involved in these processes with the potential to be used as alternative therapeutic targets in inflammation-related depression. Here, we studied how peripubertal stress (PPS) combined with differential corticosterone (CORT)-stress responsiveness (CSR) influences depressive-like behaviors and brain inflammatory markers in male rats in adulthood, and how these alterations relate to microglia activation and miR-342 expression. We found that high-CORT stress-responsive (H-CSR) male rats that underwent PPS exhibited increased anhedonia and passive coping responses in adulthood. Also, animals exposed to PPS showed increased hippocampal TNF-α expression, which positively correlated with passive coping responses. In addition, PPS caused long-term effects on hippocampal microglia, particularly in H-CSR rats, with increased hippocampal IBA-1 expression and morphological alterations compatible with a higher degree of activation. H-CSR animals also showed upregulation of hippocampal miR-342, a mediator of TNF-α-driven microglial activation, and its expression was positively correlated with TNF-α expression, microglial activation and passive coping responses. Our findings indicate that individuals with constitutive H-CSR are particularly sensitive to developing protracted depression-like behaviors following PPS exposure. In addition, they show neuro-immunological alterations in adulthood, such as increased hippocampal TNF-α expression, microglial activation and miR-342 expression. Our work highlights miR-342 as a potential therapeutic target in inflammation-related depression.
神经炎症越来越被认为在抑郁症中发挥着关键作用。生命早期的应激暴露和糖皮质激素对应激源的固有反应差异是抑郁症的两个关键风险因素，但它们对大脑炎症状态的影响仍不确定。此外，需要确定参与这些过程的特定分子，这些分子有可能成为炎症相关抑郁症的替代治疗靶点。在这里，我们研究了青春期前应激（PPS）与皮质酮（CORT）应激反应性（CSR）的差异相结合如何影响成年雄性大鼠的抑郁样行为和大脑炎症标志物，以及这些变化如何与小胶质细胞激活和 miR-342 表达相关。我们发现，经历 PPS 的高 CORT 应激反应性（H-CSR）雄性大鼠在成年后表现出快感缺失和被动应对反应增加。此外，暴露于 PPS 的动物表现出海马 TNF-α表达增加，这与被动应对反应呈正相关。此外，PPS 对海马小胶质细胞产生了长期影响，特别是在 H-CSR 大鼠中，海马 IBA-1 表达增加，形态改变与更高程度的激活相兼容。H-CSR 动物还表现出海马 miR-342 的上调，miR-342 是 TNF-α驱动的小胶质细胞激活的介质，其表达与 TNF-α表达、小胶质细胞激活和被动应对反应呈正相关。我们的研究结果表明，具有固有 H-CSR 的个体在经历 PPS 暴露后特别容易发展出持续的抑郁样行为。此外，它们在成年后表现出神经免疫改变，例如海马 TNF-α表达增加、小胶质细胞激活和 miR-342 表达增加。我们的工作强调了 miR-342 作为炎症相关抑郁症的潜在治疗靶点。
