The Genetic and Epigenetic Landscape of Oxytocin Signaling in the Social Brain of Humans and Mice

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2021

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Abstract

Human beings are inherently social. As we grow, the interactions we have with those around us become the foundation of the relationships with our families, friends, educators, and caretakers. Aberrant social behavioral traits can put a strain on these relationships and negatively impact an individual's quality of life. When severe, these disruptions represent core etiological features of many neurodevelopmental and behavioral disorders, including addiction, schizophrenia, and autism spectrum disorder (ASD).

Advances in the fields of psychology, psychiatry, neuroscience, and the behavioral sciences have developed a wide range of techniques to disentangle the biological and behavioral components of complex social traits, often with the goal of developing targeted interventions to improve outcomes for affected individuals. Still, there remains a massive unmet need for pharmaceutical interventions that ameliorate these aberrant social phenotypes, and current interventions are costly and labor intensive. A particularly promising candidate to address this unmet need is \Oxy, an endogenously expressed neuropeptide, with demonstrated pro-social effects in both humans and animal models, and low incidence of adverse effects. However, clinical trials of \oxy in ASD have had mixed results, likely due to a range of issues from inadequately powered study designs, difficulty in quantifying changes in social behavior over time, heterogeneous study populations, and an inadequate understanding of the underlying mechanisms of \oxy signaling in the brain.

The work described in this dissertation aims to address some of these gaps in knowledge. First, the results of a collaboration with a phase-2 clinical trial of \inoxy are discussed, in which I contributed to identifying a number of biological markers that were associated with \enoxy production in human participants. I discuss how this may be an important component of predicting an individuals response to \exoxy.

I will then discuss our findings in the \cd{} mouse model of ASD-like behaviors. These mice exhibit a unique socially divergent phenotype in which some mice will display very little social motivation within litters while the others behave normally. Importantly, these antisocial mice are responsive to treatment with \exoxy, but the mechanisms behind their unique social phenotype and responsiveness to \oxy remain unknown. I quantified broad patterns of differential gene expression and DNA methylation in the brains of \cd{} mice and their closely related but highly social \cs{} counterparts. This work identified a pattern of differential gene expression in the hippocampus of \cs{} mice that may offer insights into the nature of their naturally occurring social divergence.

Collectively, the findings of these two projects provide valuable information to the field of \oxy and ASD research. The results of the human trial can be used to guide new studies into the endogenous regulation of \oxy, providing potential targets for future interventions to responsive candidates. The results of the mouse experiments identified a myriad of underlying biological pathways that distinguish \cd{} from \cs{} mice, which can serve as the foundation for new targeted hypotheses and to test expanded pharmaceutical interventions to enhance the effects of \exoxy.

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Siecinski, Stephen Kenneth (2021). The Genetic and Epigenetic Landscape of Oxytocin Signaling in the Social Brain of Humans and Mice. Dissertation, Duke University. Retrieved from https://hdl.handle.net/10161/23112.

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