Persistent dopamine-dependent remodeling of the neural transcriptome in response to pregnancy and postpartum [snRNA-seq]

Pregnancy and postpartum experiences represent transformative physiological states that impose lasting demands on the maternal body and brain, resulting in lifelong neural adaptations. However, the precise molecular mechanisms driving these persistent alterations remain poorly understood. Here, we used brain-wide transcriptomic profiling to define the molecular landscape of parity-induced neural plasticity, identifying the dorsal hippocampus (dHpc) as a key site of transcriptional remodeling. Combining single-cell RNA sequencing with a maternal separation paradigm, we additionally demonstrated that chronic postpartum stress significantly disrupts dHpc adaptations by altering dopamine dynamics, leading to dysregulated transcription, altered cellular plasticity, and impaired behavior. We further established the sufficiency of dopamine modulation in the regulation of these parity-induced adaptations via chemogenetic suppression of dopamine release into dHpc, which recapitulated key transcriptional and behavioral features of parity in virgin females. In sum, our findings establish dopamine as a central regulator of parity-induced neuroadaptations, revealing a fundamental transcriptional mechanism by which female reproductive experiences remodel the maternal brain to sustain long-term behavioral adaptations.