Stress induced microglial activation contributes to depression

Pharmacol Res. 2022 May:179:106145. doi: 10.1016/j.phrs.2022.106145. Epub 2022 Feb 24.


Major depressive disorder (MDD) is a debilitating neuropsychological disorder, which has caused serious health and socio-economic burdens worldwide. A growing body of evidence indicates that inflated neuroinflammation and aberrant microglial activity are associated with depressive-like symptoms. In the central nervous system (CNS), microglia constantly survey the internal environment, playing crucial roles in injury response and pathogen defense. From developmental stage through the whole adult life, microglia dynamically sculpt neural circuits by modulation of synaptic plasticity or engulfment of redundant synapses. Dysregulated microglia may impact these fundamental biophysiological processes and contribute to the pathogenesis of depressive disorder. In this review, we discuss candidate mechanisms by which stress induces microglia to deviate from its fine-tuned homeostasis in clinical and preclinical studies. These triggering factors include the neuroendocrine system, the noradrenergic system, gut-brain axis, and unbalanced pro- v.s. anti-inflammatory milieu composed of diversified cytokines and neurotransmitters. We argue that functional changes in microglia can strongly influence neuronal network activity due to dysregulated secretion of cytokines and elevated release of neurotoxic metabolites, therefore contributing to the pathological outcomes in stress. Understanding the role that microglia play in the etiology of depression may provide a tantalizing therapeutic target and help with the development of novel intervention strategies against this devastating mental health problem.

Keywords: Cytokine; Depression; Inflammation; MDD; Microglia; Microglial activation; Neurogenesis; Synaptic plasticity.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cytokines / metabolism
  • Depression
  • Depressive Disorder, Major* / metabolism
  • Humans
  • Microglia* / metabolism
  • Neuronal Plasticity / physiology


  • Cytokines