Oxytocin is known to regulate social behaviors, stress reactivity, mental health, cardiovascular and immune systems, in part through actions in the central and autonomic nervous systems. Preliminary studies have shown that exposure to exogenous synthetic oxytocin in early life can have long-lasting, epigenetic effects on behavior, neural systems and genes that are dependent on endogenous oxytocin. The proposed translational research will provide the first animal model specifically aimed at testing the behavioral, endocrine, autonomic and epigenetic consequences of exposure to oxytocin associated with the birth process. Although it is likely that many systems throughout the body are affected by oxytocin, we will focus initially on neural processes and genetic pathways known to be sensitive to endogenous oxytocin, including the expression of genes for oxytocin and the related peptide, arginine vasopressin (AVP), and selected receptors for each of these. Using a series of interrelated projects we will examine the consequences of (a) exposure during birth to synthetic oxytocin (Pitocin), commonly used to induce or augment later, and (b) blocking the oxytocin receptor by exposure to oxytocin antagonists (OTA), used to slow the birth process. The specific objectives of this proposal are: (1) to develop a translational animal paradigm designed to model and study selected features of human birth-interventions, (2) to test the hypothesis that the functional presence or absence of the neuropeptide, oxytocin associated with birth will influence the behavior and brain of the offspring, with effects on the oxytocin/AVP pathway (including genes for the peptides and their receptors), (3) to gain a deeper knowledge of neural mechanisms which may be affected by birth-related interventions, and (4) to identify specific epigenetic consequences of oxytocin and other birth-related interventions. Both males and females will be tested, allowing us to examine the hypothesis that the effects of birth-related interventions may be sexually dimorphic. These studies also will test the hypothesis that epigenetic mechanisms, based initially on methylation of DNA for the oxytocin receptor {OXTR), allow the epigenome to be transformed by the birth experience. The newly developed paradigms described here can be used to discover the epigenetic consequences of birth interventions and improve methods for optimizing birth outcomes. Data from this study also will inform the present understanding of the normal developmental biology of social and emotional behaviors and will aid in the evaluation of the consequences for infants of treatments commonly used to manipulate the human birth process. These studies also will increase our basic understanding of neural, autonomic, endocrine and epigenetic mechanisms that underlie fundamental mammalian behaviors, including social behaviors, emotion regulation, and behaviors indicative of anxiety and depression. The animal model used here will be the prairie vole, which has a human-like autonomic nervous system, a social system characterized by high levels of sociality and all parental behavior, long- lasting pair bonds and high levels of oxytocin Measures to be taken in later life include indices of (a) social and emotional behaviors, (b) endocrine changes including measures of endogenous oxytocin and AVP and gene expression (mRNA) for their receptors using PCR, (c) autonomic nervous system function measured by radio telemetry and indexed by heart rate and rhythmic changes in heart rate mediated by vagal efferent pathways, (d) changes in neural activation and circuitry as measured by functional magnetic imaging (fMRI) in response to social cues, and (e) measures of epigenetic modifications of the offspring's genome, using a detailed analysis of CpG DNA methylation of genes in the oxytocin pathway, such as OXTR.

Public Health Relevance

At present the consequences for infants of birth interventions, and in particular the effects of exposure to synthetic oxytocin (Pitocin) or drugs that interfere with endogenous oxytocin remain largely unknown. Most of 4.3 million women giving birth each year in the United States are now exposed to Pitocin, often to facilitate labor or prevent postpartum bleeding. In addition, drugs are being developed to prevent prematurity, which affects 1 in 8 children and costs $26.2 billion annually. However, whether these treatments have detrimental consequences for the infant has not been systematically studied. The proposed studies use a rodent model to examine the consequences for the offspring of these birth-related interventions, and to understand their mechanisms.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Program Projects (P01)
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Freund, Lisa S
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Northeastern University
Schools of Arts and Sciences
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Kenkel, William M; Perkeybile, Allison M; Carter, C Sue (2017) The neurobiological causes and effects of alloparenting. Dev Neurobiol 77:214-232
Dumais, Kelly M; Kulkarni, Praveen P; Ferris, Craig F et al. (2017) Sex differences in neural activation following different routes of oxytocin administration in awake adult rats. Psychoneuroendocrinology 81:52-62
Perkeybile, Allison M; Bales, Karen L (2017) Intergenerational transmission of sociality: the role of parents in shaping social behavior in monogamous and non-monogamous species. J Exp Biol 220:114-123
Carter, C Sue (2017) The Oxytocin-Vasopressin Pathway in the Context of Love and Fear. Front Endocrinol (Lausanne) 8:356
Yee, Jason R; Kenkel, William M; Frijling, Jessie L et al. (2016) Oxytocin promotes functional coupling between paraventricular nucleus and both sympathetic and parasympathetic cardioregulatory nuclei. Horm Behav 80:82-91
Kenkel, William M; Carter, C Sue (2016) Voluntary exercise facilitates pair-bonding in male prairie voles. Behav Brain Res 296:326-330
Yee, J R; Kenkel, W M; Kulkarni, P et al. (2016) BOLD fMRI in awake prairie voles: A platform for translational social and affective neuroscience. Neuroimage 138:221-232
Perry, Adam N; Carter, C Sue; Cushing, Bruce S (2016) Chronic social isolation enhances reproduction in the monogamous prairie vole (Microtus ochrogaster). Psychoneuroendocrinology 68:20-8
Madularu, Dan; Yee, Jason R; Kenkel, William M et al. (2015) Integration of neural networks activated by amphetamine in females with different estrogen levels: a functional imaging study in awake rats. Psychoneuroendocrinology 56:200-12
Kenkel, William M; Yee, Jason R; Porges, Stephen W et al. (2015) Cardioacceleration in alloparents in response to stimuli from prairie vole pups: the significance of thermoregulation. Behav Brain Res 286:71-9

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