Mapping postnatal oxytocinergic system and offspring neurobehavior after induced birth with oxytocin

Project Summary/ Abstract Exogenous oxytocin (OT) is widely used for the induction of labor in pregnant women. Though induction of labor with OT confers many maternal and neonatal benefits, its use is not without adverse effects. Epidemiological studies suggest an association between OT use and neurodevelopmental disorders, but they are conflicting and do not provide mechanistic information. This knowledge gap is concerning because signaling through the OT receptor (OTR) is critical for the establishment of social behavior in mammalian species. With the rising popularity of elective induction of labor, where labor is induced for convenience and not for maternal or fetal indications, it is important to comprehensively understand the impact of maternally administered OT on the developing brain. Though OTR dysregulation in the developing brain has been suggested as a possible mechanism, mechanistic studies are lacking because of the lack of a high-fidelity animal model that mimics labor management in pregnant women. To address this, we successfully created and validated a pregnant rat model for labor induction by continuously delivering an escalating dose of intravenous OT through a microprocessor-controlled precision pump. In new preliminary studies, we adapted this high-fidelity model to mice with minor technical modifications and confirmed that induced birth with OT was associated with a substantial decrease in OTR gene expression in the neonatal mouse cortex. The fundamental objective of this proposal, therefore, is to chart the developmental trajectory of OTR and OT expression in the postnatal brain after induced birth with OT. To accomplish this, we will induce labor with OT in transgenic reporter mice (OTRvenus/+) and leverage the use of high-resolution brain- wide imaging techniques (serial two-photon tomography and light sheet fluorescent microscopy imaging) to comprehensively visualize the developing OTR-OT system in the postnatal brain (Aim 1). Motivated by our observations of early communicative delay and impaired empathy-like behaviors in male rat offspring after induced birth with OT, we will extend these behavioral studies to mice to enable mapping of dysregulated behavior to brain-wide changes in the OTR-OT system (Aim 2). Successful completion of these experiments will (i) provide a comprehensive perturbation map of how perinatal OT exposure alters the developmental trajectory of the OTR-OT system, and (ii) delineate the neurobehavioral impact of such perturbation. Because these studies are ethically inconceivable in human subjects, combining our mouse model for labor induction with innovative whole brain imaging techniques provides unparalleled opportunities to comprehensively answer this important question. Regardless of the outcome of our research, our findings will have a significant impact — be it a paradigm shift in current dogma or providing scientific reassurance to potential mothers.