Complex cell-state changes revealed by single cell RNA sequencing of 76,149 microglia throughout the mouse lifespan and in the injured brain

Microglia, the resident immune cells of the brain, rapidly change states in response to their environment, but we lack molecular and functional signatures of different microglial populations. In this study, we analyzed the RNA expression patterns of more than 76,000 individual microglia during development, old age and after brain injury. Analysis uncovered at least nine transcriptionally distinct microglial states, which expressed unique sets of genes and were localized in the brain using specific markers. The greatest microglial heterogeneity was found at young ages; however, several states including chemokine-enriched inflammatory microglia persisted throughout the lifespan or increased in the aged brain. Multiple reactive microglial subtypes were also found following demyelinating injury in mice, at least one of which was also found in human MS lesions. These unique microglia signatures can be used to better understand microglia function and to identify and manipulate specific subpopulations in health and disease.