Uncovering microglial pathways driving sex-specific neurobiological effects in stress and depression

Women suffer from major depressive disorder (MDD) more often than men and report greater MDD symptom severity. Mounting evidence suggests that sex differences in MDD may be driven, in part, by sex-specific neurobiological mechanisms. Chronic stress is a significant risk factor in MDD, and preclinical rodent models show differential patterns of stress-induced neural remodeling and cognitive-behavioral dysfunction in males and females. For instance, chronic stress leads to synapse loss in the medial prefrontal cortex in male rodents yet has either no effect on- or increases-synapse number in females. Recent reports have implicated microglia, the immune cells of the brain, in MDD, and findings demonstrate sex-specific microglial signatures in both preclinical stress models and MDD patients. Given that microglia can remodel neural architecture, modulate synaptic transmission, and affect subsequent changes in behavior, it is plausible that microglial pathways contribute to differential stress effects on neuroplasticity and function in males and females. As such, this review examines the evidence for sex-specific microglia-neuron interactions in preclinical stress models and in patients with MDD. Discoveries highlighted herein demonstrate divergent microglial contributions in males and females and suggest that future studies investigating stress-linked disorders should be guided by sex-dependent neurobiological and behavioral findings. Examining these pathways represents a clear avenue toward both a richer understanding of brain, behavior, and immunity, and innovative psychoneuroimmunology-based applications in personalized medicine.