Exploring the neurogenetics of sociality: Creation of models to assess the functional role of V1a receptor diversity.

摘要

Understanding the biological mechanisms regulating individual and species differences in behavior has implications for both evolutionary biology and human mental health. The vasopressin V1a receptor (V1aR) system provides an ideal model for exploring the relationship between genetic sequence diversity, protein expression, and behavioral variation. Activation of V1aR modulates a wide array of behaviors including social memory, anxiety, and many species-specific affiliative and aggressive behaviors. In both humans and rodents, diversity in these behaviors is hypothesized to result from polymorphic repetitive DNA elements located upstream of the V1a receptor gene (AVPR1A). These elements are thought to influence gene expression, thereby altering neural V1aR expression patterns. However, despite significant interest in this system, there remain a number of unanswered questions, and studies to date have not been able to establish causality with respect to AVPR1A genetic diversity, V1aR expression, and behavior. Therefore, the goal of this dissertation is to establish various models that will allow us to directly investigate the V1aR gene-brain-behavior relationship. In order to do so, I first explore evolution and novel genetic diversity within the primate AVPR1A locus. I then establish genetically modified rodent models which will be used to explore the causal relationship between genetic diversity, protein expression, and social behavior. Specifically, within three congenic mouse lines, the relationship between genetic polymorphsims and V1aR expression will be directly examined through targeted introduction of variable repetitive elements upstream of the avpr1a transcription start site. In voles, I establish transgenic and RNAi technologies to generate voles with reduced V1aR expression which will be used to directly investigate the behavioral role of V1aR and V1aR variability. These varied models will build on previous correlational studies and lay the foundation for understanding the role of genetic and protein diversity in determining individual and species differences in behavior.