Impact of cesarean section on the epigenetic and transcriptional state of the maternal brain

Nearly one in three births in the United States happens via a cesarean section. Despite how common this birth intervention is, surprisingly little is known about its long-term consequences for oxytocin system regulation and how this relates to the wellbeing of the mother. During natural vaginal birth, oxytocin is released at high levels during labor and delivery to facilitate uterine contractions, milk letdown, and mother-infant bonding. Cesarean sections, particularly planned cesareans that occur without laboring, can be thought of as a birth with lower than typical levels of endogenous oxytocin release for mothers. Recent findings have shown an association between cesarean delivery and an increased risk for developing 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, disrupted mother-infant interactions and caregiving, and ultimately to long-term behavioral and health consequences for children. Although postpartum depression is common among new mothers, little is known about the potential role of oxytocin as a neurobiological risk factor. Emerging research has suggested that for some women, changes to the oxytocin system may increase risk for postpartum depression, including changes in circulating levels of oxytocin and epigenetic modification of the oxytocin receptor gene, OXTR. The common link between cesarean section birth and postpartum depression risk for some women may well be altered functioning of the oxytocin system. It may be that cesarean delivery avoids the oxytocin surge associated with vaginal birth, resulting in an altered epigenetic state of OXTR for mothers in the early postpartum period that may confer risk for developing postpartum depression. The primary goals of this proposal are (1) to use single gene epigenetic methods to better understand how cesarean delivery impacts the way the oxytocin receptor gene is regulated in the maternal brain; (2) to use whole genome sequencing techniques to examine how cesarean section shapes expression of genes across the maternal transcriptome; (3) to study how cesarean delivery impacts how mothers care for their offspring, how they maintain social bonds with their partner, and whether they show more depressive behaviors after delivery; and (4) to investigate whether exposing mothers to exogenous oxytocin just before cesarean delivery influences the consequences of a cesarean section on these molecular and behavioral markers. The experiments in this proposal will provide valuable information on how natural birth and cesarean section, a very common birth intervention, differentially shape development of the maternal brain and maternal behavior, with the goal of identifying risk factors for non-optimal outcomes in some women and, ultimately, to move toward developing interventions to counter those risk factors and improve postnatal maternal health outcomes. Project Number: 1R01HD115687-01A1 | Fiscal Year: 2025 | NIH Institute/Center: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) | Principal Investigator: Allison Perkeybile | Institution: UNIVERSITY OF VIRGINIA, CHARLOTTESVILLE, VA | Award Amount: $1,603,292 | Activity Code: R01 | Study Section: Behavioral Neuroendocrinology, Neuroimmunology, Rhythms, and Sleep Study Section [BNRS] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01HD11568701A1