The Critical Role of Microglia in the Stress Response.

Abstract

Microglia are the principal resident innate immune cells of the central nervous system (CNS). Beyond maintaining brain homeostasis via cytokine secretion and phagocytic clearance, they fulfill essential roles in synaptic pruning, oligodendrocyte maturation, and higher-order functions including learning and memory. In response to stress exposure, microglia undergo robust activation, characterized by morphological remodeling, altered phagocytic activity, and dysregulated inflammatory signaling, positioning them as active mediators of the integrated systemic stress response. This review systematically synthesizes preclinical and clinical evidence regarding the multifaceted contributions of microglia to stress processing, their mechanistic involvement in the pathogenesis of major stress-related disorders-including post-traumatic stress disorder (PTSD), major depressive disorder (MDD), Alzheimer's disease (AD), and Parkinson's disease (PD)-and summarizes emerging microglia-targeted therapeutic strategies. We underscore the substantial mechanistic and translational value of microglial research for advancing our understanding of stress adaptation and associated brain pathologies.