Alexander G. Ophir - US grants

DESCRIPTION (provided by applicant): The long-term goal of this research program is to understand the neurobiology of monogamy and the social behaviors that comprise this unique mating system. The proposed studies will examine how causal manipulations of a neuropeptide receptor that regulates social behavior, V1aR, influence the behavioral phenotypes constituting mammalian monogamy. Monogamy is characterized by parental care, social affiliation, and territorial aggression. Unfortunately, most studies investigating specific mechanisms underlying monogamy typically focus on these behaviors in isolation. Furthermore, several studies have revealed that each of these behaviors is affected by the action of arginine vasopressin on V1a receptors in a neural structure known as the lateral septum (LS). Because of these common influences, the components of monogamous behavior are probably mechanistically intertwined and best studied in concert. The PI hypothesizes that targeted manipulation of V1aR in the LS will coordinate diverse attributes of temperament related to attachment, aggression and care-giving. The PI utilizes the monogamous prairie vole because much of what has been learned about the neurobiology of attachment has been gained from work with this model species. There are two objectives. Objective 1 will identify the causal role of lateral septum V1aR on monogamous behavior using interfering RNA (RNAi) to silence V1aR gene expression. The innovation of using RNAi for behavioral studies is novel. The PI will artificially eliminate V1aR expression to investigate its role in distinct but related social domains to provide a deeper understanding of the contribution of septal V1aR to 'monogamy'. Objective 2 aims to understand the impact of dysfunctional paternal care on offspring development and social behavior. To this end, the PI will knockdown septal V1aR in fathers and measure how such manipulations affect the physical and behavioral development of their offspring as pups and juveniles. The combination of these studies will provide a clearer picture of the behavioral and developmental consequences of septal function, an area of much interest but little cohesion. This proposal significantly advances the NIH mission to pursue fundamental knowledge about the behavior of living systems and is designed to improve both mental health and health in the process of human development. An implicit third aim of this proposal is to cultivate and retain young scientists, particularly women and underrepresented minorities. This project will support two undergraduate and two graduate students, one of whom is African American, three of whom are women, and all of whom have immense potential. Funding this project will, therefore, train exceptional students interested in understanding the neural mechanisms that subserve social attachment, aggression, parental care, and offspring development, and prepare them for professions in biomedical and behavioral research. This work will reveal much of the neurobiology that underlies fundamental behaviors constituting mammalian monogamy, and could foster a deeper understanding of mechanisms regulating human social behavior and its dysfunction. PUBLIC HEALTH RELEVANCE: By exploring the substrates of socio-emotional behavior and temperament, this work should provide insight into the biological sources of care-giving, and familial violence. These studies could contribute toward progress in understanding and ultimately treating human disorders characterized by deficits in social attachment (such as autism) and those associated with excessive aggression (such as domestic violence, conduct disorder, or psychopathology). Study of the social environment of developing offspring will provide insight into the importance of paternal care on child health and development and its ultimate importance in offspring behavior as adults.

A clear understanding of the neural mechanisms that govern how memory influences reproductive decisions will reveal much about the basic neurobiology that shapes decision-making. Mating and reproductive decisions are among the most important choices an individual will face. To this end, an individual must take stock of the current state of the social context in which it finds itself. This includes knowing with whom and where mating opportunities are to be found. Unfortunately, the influence of social and spatial memory on how individuals in a population tend to mate (e.g., with one or multiple partners, or a mating system) is often ignored. Moreover, we know virtually nothing about the ways the brain modulates these decisions or how memory and mate choice decisions are related. This project will use prairie voles to investigate how expression of two neuroendocrine systems known to be important in social / spatial memory and monogamous reproductive decision making, namely, oxytocin and vasopressin, modulate complex social behavior to shape reproductive choices.

The project will study reproductive choices in the prairie vole, a species that can switch between monogamous and non-monogamous mating tactics, with the aims to determine (1) whether or not mating decisions in natural conditions and laboratory performance in memory tests relate to each other, and (2) how oxytocin or vasopressin in the hippocampus and the retrosplenial cortex, regions implicated in spatial and social cognition, shape these behaviors. The working hypothesis is that nonapeptide neuromodulation governs socio-spatial memory, which in turn, predisposes animals to succeed at either a monogamous or a non-monogamous mating tactic. This hypothesis will be tested using a combination of natural living conditions, behavioral assays to assess social and spatial cognition, radio-tracking to monitor extent of home range and social interactions, DNA sampling to assess mating tactic, radiography to measure oxytocin and vasopressin 1A receptor density, and intra-hippocampal or -retrosplenial delivery of slow-release receptor antisense oligonucleotides to knock down oxytocin and vasopressin 1A receptors in these brain structures. In the process of completing this project, students at all levels will be trained with a broad range of skills that will prepare them to begin competitive careers in biomedical research, medicine, or higher education and academics. The PI will also continue his strong record of promoting research experiences and professional development in students from underrepresented groups. It is essential to understand the influences on behavior under simulated and natural contexts if we are to know how complex behaviors are produced.

DESCRIPTION (provided by applicant): The long-term goal of this research program is to understand the impact of early-life affiliative experiences on social behavior in a bi-parental mammal. We will examine the developmental consequences on neurobiology and behavior resulting from 'broken homes' in which fathers are absent, or mothers compromise offspring care for food acquisition. Parent-offspring interactions provide the principle social experiences for developing young, and may have life-long ramifications that shape social decisions. Humans are bi-parental. Unfortunately, most of what we know about behavioral development comes from species whose social organization differs significantly from our own. The hormones oxytocin (OT) and vasopressin (VP) are inextricably linked with the control of social behavior and are particularly well known for their influences on parental care and affiliation. Our recent work has demonstrated that fathers impact offspring adult social interactions, and the postnatal environment shapes OT and VP receptor expression in the developing brain. Thus, the ontogenetic changes in social behavior are probably rooted in concurrent changes in the social brain. Our hypothesis is: manipulating bi-parental care will produce offspring with varied social and cognitive ability, which will relate to physiological differences in oxytocinergic and vasopressinergic gene expression. The substantial knowledge about prairie vole social behavior (including bi-parental care) and neurobiology (OT and VP systems in particular) makes these socially monogamous animals an exceptional model to test this hypothesis. Our general approach is to determine if the presence or absence of caregivers in the postnatal environment influences cognitive development or social behavior, and determine if developmental differences in OT or VP relate to behavioral outcomes. In Aim 1, we will contrast paternal and maternal care to identify consequences of pre-wean social experience, by either reducing paternal care (removing fathers) or increasing maternal care (inducing licking / grooming). We will determine the importance of fathers on offspring development and if mothers compensate for absent fathers. In Aim 2, we will investigate the influence of 'single working moms' on offspring. By increasing the difficulty for access to food, mothers will be faced with the inherent trade-off between working for food or caring for offspring. In both aims, we will evaluate offspring social anxiety, social cognition, exploration, aggression, and social preferences, and we will characterize the expression of OT, VP and their receptors. These studies will provide a clearer picture of the importance of bi-parental care. This proposal significantly advances the NIH mission to pursue 'fundamental knowledge about the behavior of living systems' and is designed to improve both mental health and health in the process of human development. This work will reveal much of the neurobiology that underlies postnatal development, and could foster a deeper understanding of mechanisms regulating human social behavior and dysfunction.