Translational Models of Memory and Cognitive Control (Component 5 of 8)

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There is remarkable conservation of behavioral traits related to vulnerability for mental illness. For example, high trait novelty-seeking in humans is a risk factor for attention deficit/hyperactivity disorder and stimulant dependence, and novelty-seeking is also a heritable trait determined in part by similar genetic mechanisms in other species. This project, designed to bridge the studies of memory mechanisms and response inhibition.components in the Consortium for Neuropsychiatric Phenomics, will evaluate the heritability of a laboratory measures of response inhibition or working memory and naturalistic measures of novelty-seeking and behavioral impulsivity in an established pedigree of nonhuman animals suitable for quantitative trait linkage analyses of phenotypes exhibiting substantial heritability. High density SNP mapping will focus on regions of strongest linkage and on target regions discovered to associate with similar traits in humans. Subsequent to population-wide screening for phenotypes, groups will be constituted according to extreme deviation from normal on the traits of interest (e.g., high novelty-seeking/poor response inhibition), and these groups will be evaluated using non-invasive structural and molecular imaging to evaluate the hypothesis that specific modifications in dopamine transmission mediate the genotype-phenotype relationships. This project, which is tightly coupled to on-going behavioral genetic studies in healthy people and those with psychiatric disorders, is designed to uncover new genetic mechanisms contributing to human neuropsychiatric disease-related traits, characterize new translational models for these traits and generate new insights about the molecular and cellular phenotypes intermediate between genotypes and complex behavioral phenotypes.