Disrupted social engagement is a core feature of autism spectrum disorder (ASD) and other neuropsyciatric disorders. As characterized in primary sensory systems, the development of social behavior is likely to be influenced by gene-environment interactions that govern the ontogeny of brain circuits. These circuits develop in a hierarchical fashion, with the emergence of social behavior first involving the learning of specific stimuli that are most relevant to social engagement, and over time, expressing socially appropriate behavioral responses in complex contexts. The main hypothesis is that disruption of the emergence of these social learning processes is fundamental to the pathophysiology observed in individuals with disturbances of social behavior. Moreover, the degree to which this developmental process is disrupted may define, in part, the variation in atypical social behavior (i.e. social heterogeneity) that is characteristic of the population of individuals with ASD and other disorders. Delineating the mechanisms underlying social-emotional development is the central theme of this application, using translational strategies to investigate the social neuroscience of mental health. In this context, most animal studies to date have focused on measures of social behavior in adult animals, which lack mechanistic developmental explanations. Therefore, structure:function developmental studies are proposed in mice to investigate the potential convergence of circuit components involved in mediating social behavior.
In Aims 1 and 2, experiments will investigate the interactions of the oxytocin (OXT) and arginine-vasopressin (AVP) neuropeptide systems with ?-aminobutyric acid-synthesizing (GABA) interneurons, which are powerful modulators of sensory system development. Determining the ability of genetically manipulated mice to perform a unique social leaning paradigm will be complemented by analysis of alterations in the patterns of circuit activation and changes in OXT, AVP and GABA expression in key forebrain regions in different mutant lines. These studies will be integrated with human studies in two ways. First, the same behavioral task, applied here to human infants, will be used to determine the relationship between early social learning and subsequent social engagement (Aim 3). Second, human genetic studies will build on our recent findings to define novel relationships between social heterogeneity and ASD-associated polymorphisms in five vulnerability genes: the receptor tyrosine kinase MET, which influences interneuron development, the oxytocin receptor (OXTR), the vasopressin receptor 1a (AVPR1A) and their respective ligands (OXT and AVP) (Aim 4).

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH080759-06
Application #
8130664
Study Section
Special Emphasis Panel (ZRG1-BBBP-L (50))
Program Officer
Panchision, David M
Project Start
2007-09-01
Project End
2013-08-31
Budget Start
2011-09-01
Budget End
2013-08-31
Support Year
6
Fiscal Year
2011
Total Cost
$331,208
Indirect Cost
Name
University of Southern California
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
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