Postpartum mice display distinct behavioral and neuroimmune responses to chronic circadian disruption

The maternal brain undergoes profound adaptations during peripartum to support offspring development and maternal wellbeing. These adaptations are partly coordinated by neuroimmune signaling, including changes in the density and activity of microglia, the brain's resident immune cells. Microglia are regulated by the circadian system, which coordinates cellular activity across 24-h cycles, and disruption of circadian timing can alter neuroimmune activity and mood-related behaviors. Maternal rhythms are disrupted by offspring care demands; however, how such disruption affects maternal behavior, mood, and neuroimmune function remains unclear. We hypothesized that postpartum females would show greater behavioral and neuroimmune sensitivity to chronic circadian disruption than nulliparous controls. To test this, mice underwent a chronic phase advancement (CPA) paradigm (six-hour phase advance every four days) from postnatal days (P) 0-18 with behavioral testing occurring at an acute (P2-3) and chronic (P14-17) timepoint. Contrary to our prediction, maternal nest building and pup retrieval were maintained in mice after a single-phase shift. Sucrose preference was reduced by phase shifts at both the acute and chronic timepoint, but this reduction was comparable between parous and nulliparous females, showing no distinction based on parity. However, chronic CPA produced parity-dependent effects on behavior: CPA increased grooming and reduced nest preference in parous mice. In the medial preoptic area (MPOA), a brain region critical for maternal behavior, CPA reduced microglia density in parous compared to nulliparous females. MPOA transcriptomic analysis further showed parity × CPA interaction effects on synapse organization and RNA processing pathways. Chronic circadian disruption, therefore, shifts postpartum behavior, neuroimmune activity, and MPOA gene expression, in a distinct manner from nulliparous controls. Elucidating circadian-neuroimmune interactions in the postpartum brain may reveal novel targets for circadian-based interventions for postpartum mood disorders.