Identification of microRNA-9 linking the effects of childhood maltreatment on depression using amygdala connectivity
Related Experiment Video
Updated: Dec 6, 2025
Chronic Social Defeat Stress in Early Adolescent Male Mice
Published on: January 24, 2025
Cancan He1, Ying Bai2, Zan Wang3
1Department of Neurology, Affiliated ZhongDa Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, China.
Abstract:
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.
Insights
Childhood maltreatment impacts major depressive disorder (MDD) via brain changes. MicroRNA-9 (miR-9) and amygdala functional connectivity mediate this link, offering insights into MDD pathophysiology.
Area of Science:
- Neuroscience
- Genetics
- Psychiatry
Background:
- Childhood maltreatment (CM) is a significant risk factor for major depressive disorder (MDD).
- The precise neural mechanisms linking early CM to later depression remain unclear.
- The role of microRNA-9 (miR-9) in this pathway is under investigation.
Purpose of the Study:
- To investigate the neural basis of CM's effects on MDD.
- To explore the role of miR-9 in mediating the relationship between CM and MDD.
- To identify biomarkers for differentiating MDD patients.
Main Methods:
- Resting-state functional magnetic resonance imaging (fMRI) and peripheral blood miR-9 tests were conducted on 40 unmedicated MDD patients and 34 healthy controls (HCs).
- Two-step mediation analysis examined the mediating roles of amygdala functional connectivity (AFC) and miR-9 levels.
- A support vector classifier (SVC) model was used for diagnostic classification.
Main Results:
- MDD patients exhibited higher miR-9 levels, negatively correlated with CM severity and depressive symptoms.
- Shared effects of CM, miR-9, and depression were observed in prefrontal-striatal and limbic AFC networks.
- AFC strength mediated the association between CM severity, miR-9 levels, and depression severity.
- An SVC model integrating CM, miR-9, and AFC achieved 85.1% accuracy in distinguishing MDD patients from HCs.
Conclusions:
- MiR-9 plays a critical role in CM-induced brain alterations in prefrontal-limbic regions, contributing to MDD development.
- Neuroimaging and epigenetic findings offer novel insights into MDD pathophysiology.
- This study highlights potential biomarkers for MDD diagnosis and understanding its developmental trajectory.
