Brain region and sex differences in human microglia morphology and function

Abstract Microglia exhibit complex and dynamic morphology that is linked to function. Altered microglia function has been implicated in multiple diseases of the brain, including elevated phagocytosis of neuronal dendritic spines in schizophrenia. However, understanding the relationship between altered microglia and pathophysiology first requires a clearer picture of microglia morphology in the non-diseased brain, which has yet to be fully established. Here, we deploy immunostaining and confocal microscopy to sample over 1,300 microglia from two prefrontal cortex (PFC) subregions in postmortem human brain (3 males, 3 females). We use Neurolucida 360 to trace the 3-dimensional structure of these microglia and quantify interactions with dendritic spines. We find that PFC microglia in male subjects display overall more complex branching than in female subjects, and subgenual anterior cingulate cortex (sgACC) microglia are more complexly branched with more round somas than those in the dorsolateral PFC (DLPFC), irrespective of sex. Furthermore, a lower proportion of phagocytic burden in sgACC microglia involves engulfment of dendritic spines compared to DLPFC. Overall, our results paint a detailed and nuanced picture of microglia morphology and function in subjects unaffected by psychiatric or neurologic illness that can be used as a benchmark for future studies of the diseased brain.