BREAKING THE INTERGENERATIONAL CYCLE OF MATERNAL STRESS WITH POSTPARTUM CARBETOCIN, AN OXYTOCIN ANALOGUE

Aims: Early-life adversity, including gestational stress and impaired maternal care, induces long-lasting neurodevelopmental and behavioral vulnerability that can be transmitted across generations. However, the underlying mechanisms—particularly in the context of postpartum depression—remain poorly understood, leaving a major therapeutic gap.
Methods: Using a rat model of perinatal stress (PRS) combining gestational stress with compromised maternal care, we investigated intergenerational neurobiological consequences of maternal dysfunction, focusing on oxytocin-related mechanisms. Epigenetic, molecular, and hormonal profiling was performed across generations, including F0 and F1 dams and their F1 and F2 offspring, to characterize alterations in stress-regulatory pathways.
Results: PRS disrupted maternal nursing behavior and induced a corticosterone (CORT)/oxytocin (OT) imbalance that was transmitted to F1 offspring and maintained into the F2 generation, supporting intergenerational transmission of a biological signature of impaired maternal care. In PRS offspring, hippocampal levels of apoptotic proBDNF and circulating BDNF were increased and were associated with reduced methylation of the BDNF gene. In parallel, mineralocorticoid and glucocorticoid receptor transcript levels were suppressed through promoter hypermethylation. Crucially, early postpartum treatment of stressed dams with carbetocin—an oxytocin receptor agonist engaging Gq signaling—rescued maternal nursing behavior, restored the CORT/OT balance in dams and their descendants, and normalized offspring proBDNF levels.
Conclusions: Postpartum targeting of OTR/Gq signaling disrupts intergenerational stress transmission, rescues maternal care, and reduces long-term offspring vulnerability. Serum BDNF emerges as a sex-independent biomarker, supporting oxytocin-based postpartum interventions to prevent transgenerational risk.