Department of Neurology, Affiliated ZhongDa Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, China.
Department of Pharmacology, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, China.
Neuroimage. 2021 Jan 1;224:117428. doi: 10.1016/j.neuroimage.2020.117428. Epub 2020 Oct 7.
Childhood maltreatment (CM) is regarded as an important risk factor for major depressive disorder (MDD). However, the neural links corresponding to the process of early CM experience producing brain alterations and then leading to depression later remain unclear. To explore the neural basis of the effects of CM on MDD and the potential role of microRNA-9 (miR-9) in these processes, we recruited 40 unmedicated MDD patients and 34 healthy controls (HCs) to complete resting-state fMRI scans and peripheral blood miR-9 tests. The neural substrates of CM, miR-9, and depression, as well as their interactive effects on intrinsic amygdala functional connectivity (AFC) networks were investigated in MDD patients. Two-step mediation analysis was separately employed to explore whether AFC strength mediates the association among CM severity, miR-9 levels, and depression. A support vector classifier (SVC) model of machine learning was used to distinguish MDD patients from HCs. MDD patients showed higher miR-9 levels that were negatively correlated with CM scores and depressive severity. Overlapping effects of CM, miR-9, and depressive severity on bilateral AFC networks in MDD patients were primarily located in the prefrontal-striatum pathway and limbic system. The connection of amygdala to prefrontal-limbic circuits could mediate the effects of CM severity on the miR-9 levels, as well as the impacts of miR-9 levels on the severity of depression in MDD patients. Furthermore, the SVC model, which integrated miR-9 levels, CM severity, and AFC strength in prefrontal-limbic regions, had good power in differentiating MDD patients from HCs (accuracy 85.1%). MiR-9 may play a crucial role in the process of CM experience-produced brain changes targeting prefrontal-limbic regions and that subsequently leads to depression. The present neuroimaging-epigenetic results provide new insight into our understanding of MDD pathophysiology.
儿童虐待（CM）被认为是导致重度抑郁症（MDD）的一个重要危险因素。然而，早期 CM 经历导致大脑改变，进而导致抑郁的过程中的相应神经联系尚不清楚。为了探讨 CM 对 MDD 的影响的神经基础，以及 microRNA-9（miR-9）在这些过程中的潜在作用，我们招募了 40 名未经治疗的 MDD 患者和 34 名健康对照者（HCs）完成静息态 fMRI 扫描和外周血 miR-9 测试。在 MDD 患者中研究了 CM、miR-9 和抑郁的神经基质，以及它们对内在杏仁核功能连接（AFC）网络的交互作用。我们分别采用两步中介分析来探讨 AFC 强度是否介导 CM 严重程度、miR-9 水平和抑郁之间的关联。使用机器学习的支持向量分类器（SVC）模型来区分 MDD 患者和 HCs。MDD 患者表现出较高的 miR-9 水平，与 CM 评分和抑郁严重程度呈负相关。CM、miR-9 和抑郁严重程度对 MDD 患者双侧 AFC 网络的重叠影响主要位于前额-纹状体通路和边缘系统。杏仁核与前额-边缘回路的连接可以介导 CM 严重程度对 miR-9 水平的影响，以及 miR-9 水平对 MDD 患者抑郁严重程度的影响。此外，该 SVC 模型，整合了前额-边缘区域的 miR-9 水平、CM 严重程度和 AFC 强度，在区分 MDD 患者和 HCs 方面具有很好的能力（准确率为 85.1%）。miR-9 可能在 CM 体验导致针对前额-边缘区域的大脑变化并随后导致抑郁的过程中发挥关键作用。本神经影像学-表观遗传学研究结果为我们理解 MDD 发病机制提供了新的见解。
