Single-nucleus RNA sequencing of striatal microglia reveals distinct transcriptomic signatures of acute stress and chronic exercise

Severe acute stress can produce long lasting decreases in voluntary physical activity that contribute to degraded mental and physical health. Stress also produces enduring molecular changes in the striatum, a brain region that regulates voluntary wheel-running and other motivated behaviors. Microglia, the primary immune cells of the central nervous system, have specialized functions in responding to stress, sensing changes in the striatum, and controlling neuronal activity. Thus, microglia are positioned at the interface between neural responses to stress and neural coordination of voluntary activity; however, the role of striatal microglia in stress-induced long-term suppression of voluntary activity remains unexplored. The present study employs single nucleus RNA-sequencing to investigate how stress and exercise impact the biology of microglia in the striatum. We find that stress-induced decreases in running behavior are associated with specific microglial activation profiles. Furthermore, we show that access to a running wheel is associated with an additional and distinct profile of microglia activation characterized by upregulation of complement components and phagocytosis pathways. Lastly, we find that distinct microglial gene sets are associated with general running (versus not running) and more subtle variation in genes with individual running levels. Taken together, our results contribute to a broader understanding of the diverse states that striatal microglia can assume in response to stress and exercise, and broadly suggest that microglia exhibit more nuanced functional responses to environmental perturbations than previously thought.