Mechanisms of maternal brain changes with birth interventions

Nearly one in three births in the United States occurs after a labor induced with exogenous oxytocin, yet surprisingly little is known about the long-term consequences of this birth intervention for maternal health. Research indicates a link between labor induction and increased risk for experiencing postpartum hemorrhage, the leading cause of maternal mortality worldwide. Notably, incidence of severe postpartum hemorrhage has risen over the past decade. Labor induction has also been linked to increased risk for postpartum depression. Nearly one in five mothers will be diagnosed with postpartum depression, a serious mental health condition that can lead to decreased quality of life for mothers and disrupted mother-infant interactions and caregiving. Despite the rising rates of severe postpartum hemorrhage and the high prevalence of postpartum depression, little is known about factors that increase risk for these outcomes. For some women, changes to the oxytocin system may increase risk for postpartum hemorrhage and postpartum depression, including epigenetic modification of the oxytocin receptor gene, OXTR. Interestingly, OXTR genotype interacts with the methylation state of the gene to increase risk for these adverse outcomes. The common link between labor induction, postpartum hemorrhage risk, and postpartum depression risk may well be altered functioning of the oxytocin system. The prairie vole, a model of birth and labor intervention, has a polymorphism within Oxtr that naturally alters expression of a novel, unstudied Oxtr transcript (OxtrH). During the previous funding period, the changing epigenetic and transcriptional state of Oxtr was mapped across gestation, birth, and postpartum in mothers; it was discovered that variability in OxtrH expression is associated with differential response to exogenous oxytocin given just prior to birth and impacts the DNA methylation state of Oxtr and transcriptional response to birth. This proposal aims to: (1) understand the role of the OxtrH transcript in epigenetic regulation of Oxtr and expression of its alternative transcripts in natural, unmanipulated vaginal birth, (2) understand the ways labor induction with exogenous oxytocin alters how OxtrH shapes the DNA methylation and transcriptional state of Oxtr, (3) assess the influence of the OxtrH transcript on regulation of gene expression across the maternal transcriptome, and (4) determine the impact of OxtrH on maternal behavior. The experiments in this proposal will provide valuable information on how natural birth and labor induction, a very common birth intervention, differentially shape development of the DNA methylation state of the maternal uterus and brain and how genotype can influence the molecular outcomes of the state of Oxtr in mothers postpartum. The goal is to model and functionally characterize risk factors for non- optimal outcomes in some women and, ultimately, develop interventions to counter those risk factors and improve maternal health. Project Number: 2R01HD098117-06A1 | Fiscal Year: 2025 | NIH Institute/Center: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) | Principal Investigator: JESSICA CONNELLY (+1 co-PI) | Institution: UNIVERSITY OF VIRGINIA, CHARLOTTESVILLE, VA | Award Amount: $706,302 | Activity Code: R01 | Study Section: Biobehavioral Regulation, Learning and Ethology Study Section[BRLE] View on NIH RePORTER: https://reporter.nih.gov/project-details/2R01HD09811706A1