Elizabeth A. D. Hammock, Ph.D. - US grants

DESCRIPTION (provided by applicant): This proposal aims to characterize the effects of a variable genetic element in regulation of expression of the vole vasopressin 1a receptor (V1aR) gene. Vasopressin and the V1aR are involved in the regulation of species-specific social behaviors. Receptor distribution patterns are species-specific and correlate with social structure. Monogamous and non-monogamous voles differ in their behavioral response to vasopressin and expression pattern of V1aR in the brain. In addition, there is a tremendous amount of intra-specific variability in V1aR expression in monogamous prairie voles. A large, highly repetitive microsatellite region is found in the 5' flanking region of the VlaR gene of monogamous voles but not in non-monogamous vole species. Within prairie vole, the length of this microsatellite correlates with the level of VlaR binding in the brain. This research proposal will test the hypothesis that i) this polymorphic promoter sequence plays a role in the expression of the VlaR gene, and that ii) the individual variability in V1aR expression resulting from this variable promoter structure translates into individual variability in social behavior. Luciferase reporter assays in cell culture and a selective prairie vole breeding strategy with extensive behavioral characterization and subsequent molecular analysis will be used to test these hypotheses. This research will provide a possible molecular mechanism producing intra-specific variability in gene expression and behavior, which may be relevant to psychopathologies.

Infant attachment to a caregiver is required for the typical development of social behavior and reduces the lifetime risk for mental illness. The underlying molecular and neural mechanisms of infant attachment to a caregiver are not well-characterized. Oxytocin (OXT) plays an important role in adult social behavior and has been hypothesized to play a role in infant attachment. This proposal will test a specific modulatory role for OXT acting at peripheral OXT receptors (OXTR) in infant attachment-related brain and behavior development. We have recently identified OXTR in the periphery of infant mice, including the face and oronasal cavity. Given the presence of OXT in maternal fluids such as saliva and breast milk, this suggests a simple hypothesis that maternal OXT could bind to infant peripheral OXTR to bias brain and behavioral development toward the social environment. In this proposal, we will determine the brain and behavioral effects of OXT acting upon peripheral OXTR in infant mice. First, we will perform anatomical studies to define the relevant circuitry from the periphery to the brain. Second, we will determine if these peripheral OXTR play a role in social orienting and contact behavior in neonates. Finally, we will determine if these peripheral OXTR influence the development of a key player in later social behavior- the infant?s own OXT production. Individual differences in the levels of OXT contribute to individual differences in social behavior and mental health. However, we know very little about how these individual differences in OXT are influenced by social contact in development or how social stimuli elicit OXT activity the socially naïve infant brain. This proposal will help address these knowledge gaps. Using infant mice, the long-term goals of this project are to understand 1) how social contact is transduced into the infant brain, 2) how the socially naïve neonate responds to exogenous OXT at the level of brain and behavior in the neonatal period, and 3) how social contact influences individual differences in OXT levels in the neonate. In addition, by performing these studies in male and female infant mice, we will ascertain potential sex differences in the acute response to social contact and OXT in the neonatal period. Further, because these experiments will clarify the roles of OXTR in the oronasal cavity, the findings may have broader applicability for understanding the mechanism of action of intranasal delivery of clinical doses of OXT. These experiments will determine the mechanisms of acute change in the neonate, with the potential for future experiments to determine the mechanisms of the long term effects of these changes.