Autism Spectrum Disorders (ASDs) are characterized by deficits in three core domains: social interaction, communication, and repetitive behaviors. ASDs are highly heritable, yet genetic analyses have been largely unsuccessful at identifying genes contributing significantly to the etiology of the disorder. This is likely because ASDs are a collection of heterogenous disorders with multiple genes contributing to various endophenotypes associated with ASD. Recent data suggests that while all three behavioral domains are highly heritable, separate genes may contribute independently to variation in each domain. Thus, investigating mechanisms underlying variation in each domain separately may prove useful for developing treatment strategies for ASD. This proposal focuses on the role of the vasopressin V1a receptor (V1aR) in generating diversity in social behaviors in an animal model and humans. The V1aR plays a critical regulatory role in several behaviors in the social domain, including social recognition, parental care, and social bonding. Three studies have reported genetic associations between polymorphisms in the gene encoding the V1aR (avprla) and autism. Our studies in socially monogamous prairie voles suggest that variation in a microsatellite sequence in the 5'flanking region of the avprla contributes to variation in expression patterns of the V1aR in the brain and in social behavior. This proposal is designed to test four specific hypotheses. First we will test the hypothesis that polymorphisms in the avpM a microsatellite directly contribute to variation in gene expression in the brain using a knock-in mouse approach. We will then use a viral vector-based siRNA approach to directly test the hypothesis that variation in avprla expression in specific brain regions contributes to variation in social behavior. In the final vole study, we will test the hypothesis that variation in avprla expression is a major source of heritable variation in social behavior by first selectively breeding vole lines based on their tendency to form social bonds, and then examining avprla expression in the brain. Finally, we will directly test the hypothesis that polymorphisms in the human AVPR1A contribute to variation in human social cognition. This will be accomplished by testing for associations between four polymorphic microsatellites near the AVPR1A gene and scores on the Schedules for the Assessment of Social Intelligence (SASI) in 200 families with at least one child diagnosed with ASD and in 567 control children. The SASI provides quantitative phenotypic data on facial expression recognition task, face recognition memory task, a gaze monitoring task and a Theory of Mind task. Results from these studies will provide important information on the relationship of variation in the V1aR system and social behavior and may lead to therapies specifically targeting the social deficits in autism.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH056897-14
Application #
7882703
Study Section
Neuroendocrinology, Neuroimmunology, and Behavior Study Section (NNB)
Program Officer
Simmons, Janine M
Project Start
1997-08-01
Project End
2012-06-30
Budget Start
2010-07-01
Budget End
2011-06-30
Support Year
14
Fiscal Year
2010
Total Cost
$364,425
Indirect Cost
Name
Emory University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Hopkins, William D; Keebaugh, Alaine C; Reamer, Lisa A et al. (2014) Genetic influences on receptive joint attention in chimpanzees (Pan troglodytes). Sci Rep 4:3774
Skuse, David H; Lori, Adriana; Cubells, Joseph F et al. (2014) Common polymorphism in the oxytocin receptor gene (OXTR) is associated with human social recognition skills. Proc Natl Acad Sci U S A 111:1987-92
Charles, Rhonda; Sakurai, Takeshi; Takahashi, Nagahide et al. (2014) Introduction of the human AVPR1A gene substantially alters brain receptor expression patterns and enhances aspects of social behavior in transgenic mice. Dis Model Mech 7:1013-22
Donaldson, Zoe R; Young, Larry J (2013) The relative contribution of proximal 5' flanking sequence and microsatellite variation on brain vasopressin 1a receptor (Avpr1a) gene expression and behavior. PLoS Genet 9:e1003729
Barrett, Catherine E; Keebaugh, Alaine C; Ahern, Todd H et al. (2013) Variation in vasopressin receptor (Avpr1a) expression creates diversity in behaviors related to monogamy in prairie voles. Horm Behav 63:518-26
Hopkins, W D; Donaldson, Z R; Young, L J (2012) A polymorphic indel containing the RS3 microsatellite in the 5' flanking region of the vasopressin V1a receptor gene is associated with chimpanzee (Pan troglodytes) personality. Genes Brain Behav 11:552-8
McGraw, Lisa A; Young, Larry J (2010) The prairie vole: an emerging model organism for understanding the social brain. Trends Neurosci 33:103-9
Donaldson, Zoe R; Spiegel, Lauren; Young, Larry J (2010) Central vasopressin V1a receptor activation is independently necessary for both partner preference formation and expression in socially monogamous male prairie voles. Behav Neurosci 124:159-163
Gobrogge, Kyle L; Liu, Yan; Young, Larry J et al. (2009) Anterior hypothalamic vasopressin regulates pair-bonding and drug-induced aggression in a monogamous rodent. Proc Natl Acad Sci U S A 106:19144-9
Hammock, Elizabeth A D; Young, Larry J (2004) Functional microsatellite polymorphism associated with divergent social structure in vole species. Mol Biol Evol 21:1057-63

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