Inflammatory Signatures of Microglia in Hypercortisolemia-Related Depression

Abstract

Microglia-mediated inflammation has been recognized as a key feature of major depressive disorder. Although hypercortisolemia commonly occurs in depressed patients and can be predictive of treatment response, how chronic exposure to this stress hormone influences microglia is incompletely characterized. Here, we exploited a standard mouse model of depressive-like behaviors induced by peripheral administration of corticosterone. Microglia in the prefrontal cortex of mice were profiled by bulk RNA sequencing, which exhibited the up-regulation of inflammatory markers. In addition, single-cell RNA sequencing identified distinct molecular patterns of microglial responses. Moreover, we revealed the elevation of PU.1 and IRF8, the two central transcription factors governing microglia-mediated inflammation, in the prefrontal cortex and hippocampus of corticosterone-treated mice, which was similarly observed in the single-nucleus RNA sequencing dataset of depressed patients' microglia. Together, these results have established the inflammatory signatures of microglia in hypercortisolemia-related depression, providing valuable insights into diagnostic and therapeutic strategies.