Microglia depletion facilitates the display of maternal behavior and alters activation of the maternal brain network in nulliparous female rats.

The peripartum period is accompanied by peripheral immune alterations to promote a successful pregnancy. We and others have also demonstrated significant neuroimmune changes that emerge during late pregnancy and persist postpartum, most prominently decreased microglia numbers within limbic brain regions. Here we hypothesized that microglial downregulation is important for the onset and display of maternal behavior. To test this, we recapitulated the peripartum neuroimmune profile by depleting microglia in non-mother (i.e., nulliparous) female rats who are typically not maternal but can be induced to behave maternally towards foster pups after repeated exposure, a process called maternal sensitization. BLZ945, a selective colony-stimulating factor 1 receptor (CSF1R) inhibitor, was administered systemically to nulliparous rats, which led to ~75% decrease in microglia number. BLZ- and vehicle-treated females then underwent maternal sensitization and tissue was stained for ∆fosB to examine activation across maternally relevant brain regions. We found BLZ-treated females with microglial depletion met criteria for displaying maternal behavior significantly sooner than vehicle-treated females and displayed increased pup-directed behaviors. Microglia depletion also reduced threat appraisal behavior in an open field test. Notably, nulliparous females with microglial depletion had decreased numbers of ∆fosB+ cells in the medial amygdala and periaqueductal gray, and increased numbers in the prefrontal cortex and somatosensory cortex, compared to vehicle. Our results demonstrate that microglia regulate maternal behavior in adult females, possibly by shifting patterns of activity in the maternal brain network.