Extramedullary monopoiesis underlies stress-sensitization and recurring anxiety

Abstract

In humans, chronic stress is associated with an increased prevalence of mental health complications including anxiety and depression. Repeated social defeat (RSD) in mice recapitulates key deficits associated with psychosocial stress in humans. We showed that exposure to sub threshold stress 24 days after RSD caused the recurrence of anxiety that was dependent on monocyte trafficking from the spleen to the brain. We hypothesized that extramedullary production of monocytes in the spleen underlies enhanced monocyte trafficking and recurring anxiety following psychosocial stress. Here, RSD substantially increased the presence of proliferating hematopoietic stem progenitor cells (HSPCs) within the splenic red pulp. BrdU pulse chase experiments confirmed that RSD increased the presence of proliferated monocytes in the spleen. Next, extramedullary hematopoiesis and monocyte proliferation in the spleen was assessed 24 days after RSD. Increased presence of HSPCs was still maintained in the spleen 24 days after RSD. Similarly, BrdU pulse chase 24 days later revealed that the spleen maintained monocyte proliferation over this period. These data indicate that RSD caused extramedullary hematopoiesis that resulted in long term monocyte proliferation in the spleen that persisted for at least 24 days that contributed to enhanced monocyte trafficking and stress-sensitization.