Persistent dopamine-dependent remodeling of the neural transcriptome in response to pregnancy and postpartum

ABSTRACT Pregnancy and postpartum experiences represent transformative physiological states that impose lasting demands on the maternal body and brain, resulting in lifelong neural adaptations 1–6 . 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 hippocampal formation (dHF) as a key site of transcriptional remodeling. Combining single-cell RNA sequencing with a maternal-pup separation paradigm, we additionally demonstrated that chronic postpartum stress significantly disrupts dHF adaptations by altering dopamine dynamics, leading to changes in the dopamine-dependent histone post-translational modification – H3 dopaminylation, with further alterations in transcription, cellular plasticity, and behavior. In human dorsal subiculum, a brain structure within the dHF, we uncovered conserved patterns of parity-dependent alterations in H3 dopaminylation and transcription. We further established the sufficiency of dopamine modulation in regulating these parity-induced adaptations via chemogenetic suppression of dopamine release into the dHF, which recapitulated key epigenomic and behavioral features of parity in virgin female mice. In sum, our findings establish dopamine as a central regulator of parity-induced neuroadaptations in humans and mice, revealing a fundamental transcriptional mechanism by which female reproductive experiences remodel the brain to sustain long-term behavioral adaptations.