Microglial state transitions dominate the brain immune response in the subacute phase after cardiac arrest.

Cardiac arrest (CA) is a life-threatening medical emergency, and most victims are elderly. Despite advances in resuscitation, post-CA morbidity and mortality remain high, and this is thought to result largely from brain injury in which neuroinflammation plays a key role. Yet, how individual immune cell populations contribute to the immune response in the post-CA brain is still poorly understood. Here, using single-cell RNA-sequencing (scRNA-seq), we revealed the first immune landscape of the young and aged brain on day 3 after CA. Our data demonstrate that transitions in microglial states constituted a dominant immune change in the post-CA brain. We identified 5 CA-associated microglial states that included 3 major clusters defined by pro-inflammatory signatures, a proliferative phenotype, and high Spp1 expression. These 3 states exhibited age-dependent differences: the inflammatory subset was markedly expanded in aged mice, whereas the proliferative and Spp1⁺ clusters were more prominent in young mice. Such divergent responses likely underpin age-related disparities in neurologic outcome after CA. Notably, Spp1