Mechanisms of maternal brain changes with birth interventions

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ABSTRACT: The use of birth interventions, such as induction or augmentation of labor with exogenous oxytocin or surgical delivery via cesarean section, have risen sharply in the past 30 years. These interventions have contributed to a decline in maternal and infant mortality, but the long-term consequences for the mother are not well understood. High levels of exogenous oxytocin during birth dramatically downregulate the oxytocin receptor in the uterus. The role the receptor plays in shaping oxytocin activity in the maternal brain is unknown. Emerging research has begun to link these birth interventions to maternal mental health and specifically to postpartum depression. Postpartum depression is prevalent in as many as 1 in 5 new mothers, yet we know little about the underlying biology of this disorder. Several risk factors have been identified, including changes in circulating levels of oxytocin and epigenetic modification of the oxytocin receptor gene, OXTR. The common use of exogenous oxytocin during birth may have long-term consequences for oxytocin functioning via OXTR epigenetic pathways and, in turn, contribute to the oxytocin system dysfunction that increases risk for postpartum depression. We propose to explore the link between birth intervention, changes in epigenetic markers on OXTR, and maternal behavior in the highly social prairie vole with three specific objectives: (1) to refine a new translational animal paradigm designed to model and study selected features of human birth practices, (2) to test the hypotheses that altered oxytocin levels at birth, whether through labor induction or cesarean section, will influence the behavior and brain of the mother via epigenetic effects on OXTR, and (3) to gain a deeper knowledge of mechanisms through which birth-related interventions may have lasting functional and epigenetic consequences for the mother. We will focus on altered epigenetic regulation of OXTR given the link between the oxytocin receptor, birth interventions, and postpartum depression. The natural pattern of OXTR DNA methylation, hydroxymethylation, and gene transcription will be characterized across gestation and following vaginal birth to gain insight into epigenetic mechanisms that shape the maternal brain in response to a natural, unmanipulated birth experience. Using exogenous oxytocin administration just prior to birth to model induction of labor in women, these same epigenetic markers will be examined in central and peripheral tissues to investigate how a birth with higher levels of oxytocin can alter long-term OXTR functioning and maternal behavior in new mothers. Cesarean delivery will also be used to examine behavioral and epigenetic consequences of opposing birth experiences, or those without pulsatile release of oxytocin during labor. The proposed experiments seek to develop a more complete animal model of maternal oxytocin system functioning following the birth experience, particularly epigenetic control of the receptor gene by DNA methylation and hydroxymethylation. These experiments will provide valuable information on how pregnancy, birth, and common birth interventions effect functioning of oxytocin pathways to shape the maternal brain.