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      The Relative Contribution of Proximal 5′ Flanking Sequence and Microsatellite Variation on Brain Vasopressin 1a Receptor ( Avpr1a) Gene Expression and Behavior

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      PLoS Genetics
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          Abstract

          Certain genes exhibit notable diversity in their expression patterns both within and between species. One such gene is the vasopressin receptor 1a gene ( Avpr1a), which exhibits striking differences in neural expression patterns that are responsible for mediating differences in vasopressin-mediated social behaviors. The genomic mechanisms that contribute to these remarkable differences in expression are not well understood. Previous work has suggested that both the proximal 5′ flanking region and a polymorphic microsatellite element within that region of the vole Avpr1a gene are associated with variation in V1a receptor (V1aR) distribution and behavior, but neither has been causally linked. Using homologous recombination in mice, we reveal the modest contribution of proximal 5′ flanking sequences to species differences in V1aR distribution, and confirm that variation in V1aR distribution impacts stress-coping in the forced swim test. We also demonstrate that the vole Avpr1a microsatellite structure contributes to Avpr1a expression in the amygdala, thalamus, and hippocampus, mirroring a subset of the inter- and intra-species differences observed in central V1aR patterns in voles. This is the first direct evidence that polymorphic microsatellite elements near behaviorally relevant genes can contribute to diversity in brain gene expression profiles, providing a mechanism for generating behavioral diversity both at the individual and species level. However, our results suggest that many features of species-specific expression patterns are mediated by elements outside of the immediate 5′ flanking region of the gene.

          Author Summary

          DNA sequence variation underlies many differences both within and between species. In this paper, we investigate a specific DNA sequence that is thought to influence expression of a gene that modulates behavior, the vasopressin V1a receptor gene ( Avpr1a). Specifically, differences in the expression of V1a receptor in the brain have been causally tied to social behavior differences, but the genetic basis of these differences is not understood. Using transgenic mice, we investigate the role of DNA sequences upstream of this gene in generating species-specific and individual variation in Avpr1a expression. We find that, contrary to our expectation, this region has only a modest influence on differences in expression patterns across rodent species. This indicates that DNA elements outside of this region play a larger role in species-level differences in expression. We confirm that variation in Avpr1a expression mediated by this upstream region translates to differences in behavior. We also find that variable DNA sequences associated with repetitive motifs within this region subtly influence gene expression. Together these findings highlight the complexity of genetic mechanisms that influence diversity in brain receptor patterns and support the idea that variable repetitive elements can influence both species and individual differences in gene expression patterns.

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          Oxytocin, vasopressin, and the neurogenetics of sociality.

          There is growing evidence that the neuropeptides oxytocin and vasopressin modulate complex social behavior and social cognition. These ancient neuropeptides display a marked conservation in gene structure and expression, yet diversity in the genetic regulation of their receptors seems to underlie natural variation in social behavior, both between and within species. Human studies are beginning to explore the roles of these neuropeptides in social cognition and behavior and suggest that variation in the genes encoding their receptors may contribute to variation in human social behavior by altering brain function. Understanding the neurobiology and neurogenetics of social cognition and behavior has important implications, both clinically and for society.
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            Evolution at two levels in humans and chimpanzees.

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              The challenge of translation in social neuroscience: a review of oxytocin, vasopressin, and affiliative behavior.

              Social neuroscience is rapidly exploring the complex territory between perception and action where recognition, value, and meaning are instantiated. This review follows the trail of research on oxytocin and vasopressin as an exemplar of one path for exploring the "dark matter" of social neuroscience. Studies across vertebrate species suggest that these neuropeptides are important for social cognition, with gender- and steroid-dependent effects. Comparative research in voles yields a model based on interspecies and intraspecies variation of the geography of oxytocin receptors and vasopressin V1a receptors in the forebrain. Highly affiliative species have receptors in brain circuits related to reward or reinforcement. The neuroanatomical distribution of these receptors may be guided by variations in the regulatory regions of their respective genes. This review describes the promises and problems of extrapolating these findings to human social cognition, with specific reference to the social deficits of autism. (c) 2010 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Genet
                PLoS Genet
                plos
                plosgen
                PLoS Genetics
                Public Library of Science (San Francisco, USA )
                1553-7390
                1553-7404
                August 2013
                August 2013
                29 August 2013
                : 9
                : 8
                : e1003729
                Affiliations
                [1 ]Division of Integrative Neuroscience, Department of Psychiatry, Columbia University, New York, New York, United States of America
                [2 ]Center for Translational Social Neuroscience, Department of Psychiatry and Behavioral Sciences, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, United States of America
                University of Arizona, United States of America
                Author notes

                The authors have declared that no competing interests exist.

                Conceived and designed the experiments: ZRD LJY. Performed the experiments: ZRD. Analyzed the data: ZRD. Wrote the paper: ZRD LJY.

                Article
                PGENETICS-D-13-00657
                10.1371/journal.pgen.1003729
                3757045
                24009523
                22f2be1f-5e05-406c-afa9-51a73e55139b
                Copyright @ 2013

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 11 March 2013
                : 1 July 2013
                Page count
                Pages: 13
                Funding
                This work was supported by NIH grants MH056897 and MH064692 to LJY and a HHMI Predoctoral Fellowship, a Robert Wood Johnson Health & Society Scholars Postdoctoral Fellowship, and T32 MH015144 to ZRD. Additional support was provided by the National Center for Research Resources P51RR165 to YNPRC, which is currently supported by the Office of Research Infrastructure Programs/OD P51OD11132. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article

                Genetics
                Genetics

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