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REVIEW article

Front. Behav. Neurosci.

Sec. Emotion Regulation and Processing

Volume 19 - 2025 | doi: 10.3389/fnbeh.2025.1598178

This article is part of the Research TopicBetween Emotional Regulation and Dysregulation: Perspectives, Interventions, Tools and Technologies for Psychological Well-BeingView all 14 articles

The central role of microglia in major depressive disorder and its potential as a therapeutic target

Provisionally accepted
  • 1Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang Province, China
  • 2First Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, China

The final, formatted version of the article will be published soon.

Major depressive disorder (MDD) is a complex neuropsychiatric condition whose multifactorial etiology remains incompletely explained by neuron-centric and neurotransmitter hypotheses alone. This review addresses that gap by positioning microglia-the CNS's resident immune cells-as central drivers of MDD pathogenesis. We organize current evidence around five interrelated themes: hypothalamic-pituitary-adrenal (HPA) axis dysfunction, monoaminergic and kynurenine pathway imbalances, neuroinflammatory overactivation, synaptic and white-matter integrity disruption, and gut-brain axis perturbations. In MDD, microglia shift from a surveillant resting state to either an overactivated or functionally inhibited phenotype, exacerbating pathology via aberrant cytokine release, dysregulated synaptic pruning and impaired myelin support. These changes are modulated by genetic susceptibility, sex differences, environmental stressors and microbiome alterations. We then survey translational advances-traditional and novel therapeutics that modulate microglial polarization, emerging blood-and imaging-based biomarkers, and strategies to harness microglia-oligodendrocyte cross-talk for remyelination-and highlight integrative platforms for stratifying inflammation-driven versus non-inflammatory subtypes. Our principal takeaway is that microglia represent a unifying nexus and actionable target for precision interventions tailored to individual biological profiles.

Keywords: Microglia, Major Depressive Disorder, Pathogenesis, mmmunity, Neuroinflammation, therapeutic targets

Received: 22 Mar 2025; Accepted: 23 Jul 2025.

Copyright: © 2025 Xia, Li, Zou and Wang. 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: Long Wang, First Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, China

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