REVIEW article
Front. Psychiatry
Sec. Psychopathology
Volume 16 - 2025 | doi: 10.3389/fpsyt.2025.1666599
This article is part of the Research TopicNeurobiological mechanisms and psychological processes involved in the origin and development of trauma and depressionView all 3 articles
From Trauma to Depression: Structural, Synaptic, Epigenetic, and Molecular Pathways Linking Early Stress to Lifelong Vulnerability
Provisionally accepted
- The University of Alabama at Birmingham, Birmingham, United States
Select one of your emails
You have multiple emails registered with Frontiers:
Notify me on publication
Please enter your email address:
If you already have an account, please login
You don't have a Frontiers account ? You can register here
Major depressive disorder (MDD) is a complex and debilitating condition with high global prevalence. While pharmacological treatments are available, the long-term biological underpinnings – especially those linked to adverse childhood experiences (ACEs), remain incompletely understood. ACEs, including physical, sexual, and emotional abuse, neglect, and other traumas, significantly increase lifelong vulnerability to depression and reduce responsive to treatment. Epigenetic mechanisms such as DNA methylation and altered expression of mRNA and short and long non-coding RNAs such as microRNAs (miRNAs) are emerging as key mediators of the relationship between early environmental adversity and brain development and function. Specific miRNAs (e.g., miR-124, miR-135) influence neuroinflammation, and affect synaptic plasticity and monoaminergic signaling. Concurrently, DNA methylation in promoter regions can silence genes critical for stress regulation. For example, hypermethylation of the NR3C1 gene (encoding the glucocorticoid receptor) has been linked with altered HPA axis feedback and cortisol imbalance following ACEs. These epigenetic changes, together with trauma-induced microglial activation and neuroinflammation, may create lasting neural vulnerability. This paper explores how the interplay between childhood trauma, hormonal dysregulation, microglial activation, and epigenetic modification contributes to the pathophysiology of depression. Synthesizing evidence across epigenetic networks and neurobiological systems can deepen an understanding of trauma-related mood disorders. This may inform targeted interventions, identify biomarkers for diagnosis and treatment, and support personalized approaches to care and suicide prevention.
Keywords: Adverse childhood experiences, childhood trauma, abuse (including physical, sexual and emotional), neglect, Adrenocorticotrophic hormone (ACTH), α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, Amygdala, Apoptosis
Received: 15 Jul 2025; Accepted: 16 Sep 2025.
Copyright: © 2025 Takahashi and Shelton. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Mina Takahashi, mtakahas@uab.edu
Richard Shelton, rcshelton@uabmc.edu
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.