Heather K. Caldwell - US grants

DESCRIPTION (provided by applicant): The vasopressin 1b receptor has been consistently implicated as a key factor in the regulation of social behavior;however, the precise region of the brain where the vasopressin 1b receptor is acting has not been identified. The objective in this application is to identify neural substrates on which vasopressin acts via the vasopressin 1b receptor to affect social behavior in an experimental animal model. Specifically, the proposed experiments have been designed to test the central hypothesis that vasopressin 1b receptor mediated-signaling, specifically within the CA2 region of the hippocampus, contributes to normal displays of social behavior. The rationale for these studies is that identification of the neuroanatomical substrate upon which vasopressin acts via the vasopressin 1b receptor to impact social behavior will potentially further our understanding of aberrant social behavior. This knowledge is relevant to the NIH's mission in that it will potentially provide new targets for psychiatric disease treatment in humans. The specific aim of this proposal is to determine the contribution of the vasopressin 1b receptor within the CA2 region of the hippocampus to social behavior. This will be achieved by coupling experimental animal behavioral studies with targeted, site-specific, gene knockdown to identify pathways important to the regulation of behavior. It is expected that completion of this research will lead to the identification of one of the important neural substrates contributing to the vasopressin 1b receptor's regulation of social behavior. The proposed research is significant because the findings of this work will serve as a foundation for a more focused examination of the interaction between vasopressin and other neurotransmitter systems;ultimately resulting in a more complete understanding of the regulation of social behavior. PUBLIC HEALTH RELEVANCE The proposed studies are important because they have the potential to identify one of the key neural substrates that likely contributes to manifestations of aberrant social behavior. The proposed research has relevance to public health, because the neurochemicals, neurosubstrates, and circuits that underlying the regulation of behavior are evolutionarily conserved. Thus, the findings are ultimately expected to be applicable to the health of human beings.

DESCRIPTION (provided by applicant): In humans, there is evidence that the neuropeptide vasopressin may play a role in the development and/or severity of mental health disorders characterized by aberrant social behavior, such as schizophrenia and autism spectrum disorders. The objective of this R03 application is to develop genetic tools for the exploration of the role of the vasopressin 1b receptor in species that are behaviorally rich and in which vasopressin is known to be important to the neural regulation of social behavior, specifically, Syrian hamsters and prairie voles. The proposed experiments have been designed to test the central hypothesis that across mammalian species the vasopressin 1b receptor is conserved in sequence, distribution, and function. This knowledge is relevant to the mission of the NIMH because it will further our knowledge of the neurochemistry underlying psychiatric disorders characterized by abnormal social behavior. One specific aim is proposed that is designed to determine the sequence and distribution of the vasopressin 1b receptor in Syrian hamsters and prairie voles, as well as to develop genetic tools to use in future functional studies. The proposed research is significant because by determining how conserved the vasopressin 1b system is and how it modulates social behavior and our understanding of the vasopressin system in humans can be improved.

This research project will examine how prenatal hormones can reorganize brain circuits and impact behavior. Understanding how these hormones work during development will provide important insights into the species-specific behaviors that underlie social behavior and social structure.

The goal of this project is to determine how the neurohormone oxytocin acts during development to organize neural structures important for displays of aggressive behavior in adulthood. The Project will use a combination of molecular, behavioral and pharmacological approaches to determine the developmental timing and distribution of oxytocin and the oxytocin receptor in the fetal mouse brain as well as how manipulation of the oxytocin signal during fetal development affects adult male aggressive behavior. As oxytocin and its homologues have evolutionarily conserved roles in the modulation of behavior, this work has implications for understanding the neural underpinnings of social behavior across species and will be the first to delve into the prenatal organizational effects of oxytocin on aggressive behavior. Further, the genes-to-behavior approach of this project is ideal for introducing students to scientific inquiry and to behavioral neuroendocrinology. The conceptual and methodological innovation of this project will allow the students to improve their neuroscience knowledge as well as learn numerous behavioral and molecular techniques.

There is emerging evidence that during development the neuropeptide oxytocin helps to organize neural circuits in the brain and that these organizational effects may help the brain develop the capacity to execute sex-specific and context-appropriate social behaviors later in life. This R15 proposes to use an animal model to better understand the role of oxytocin during fetal development. The working hypothesis of this grant is that fetal oxytocin is important to the development of the neural substrates that support sex-specific social behaviors in adulthood. To test this hypothesis two specific aims are proposed. The first aim will determine how the developing oxytocin system differs between female and males. The second aim will identify how developmental oxytocin differentially impacts female and male neurochemistry. The proposed research is significant because it would be the first to examine the function of oxytocin signaling during fetal development. Thus, it is expected that these experiments will reveal a novel role for oxytocin in organizing sex-specific brain circuits that are critical for typical displays of social behaviors. This knowledge is relevant to the mission of the NIH and to human health because across mammalian species oxytocin is important for social cognition and social functioning, and deficits in social behaviors are characteristic of several neurodevelopmental neuropsychiatric disorders. Thus, the experiments proposed are important because they will provide insight in the contributions of fetal oxytocin to the proper development of the male and female brain and ultimately to the expression of social behaviors.