Our Laboratory of Behavioral Neuroscience collaborates with several molecular geneticists laboratories on the behavioral phenotyping of transgenic and knockout mice with mutations in genes expressed in the brain, relevant to our research interests in animal models of neuropsychiatric diseases. Over the past years, we have developed and refined a multitiered strategy for mouse behavioral phenotyping. Further, we develop new behavioral tasks for mice, and adapt rat behavioral tasks for mice. Dr. Crawley began a new initiative this year to develop a mouse model relevant to autism. This is a collaborative study with investigators at the University of North Carolina Chapel Hill, particularly Dr. Joseph Piven, Director of the Autism STAART project. Mouse behavioral genetics experiments were conceived to discover new genes related to the social deficits that represent the fundamental symptoms of autism. Dr. Crawley designed a three chambered automated apparatus that measures sociability and preference for social novelty in mice. George Dold and coworkers, NIMH Research Services Branch, built the prototype apparatus. Drs. Sheryl Moy and Jessica Nadler and technicians in the UNC Neurodevelopmental Disorders Research Center are testing 20 inbred strains of mice on the social tasks, including C57BL/6J, DBA/2J, FVB/NJ, A/J, C3H/J, AKR/J, and Balb/cJ. Social tendencies were scored consistently and quantitatively with the automated apparatus as compared to human observer scoring. Robust social approach to a stranger mouse, and robust preference for a novel stranger mouse, were detected for most inbred strains. Low social approach was detected in two strains, A/J and Balb/cJ. Drs. Jessica Nadler, David Threadgill, and Terry Magnuson are conducting DNA microarray analyses on five brain regions from the inbred strains. Dr. Fred Wright is analyzing the statistical correlations between gene expression in each brain region for each strain. The goal of these experiments is to identify genes that are uniquely expressed in strains of mice with social deficits. These experiments are designed to discover candidate genes in mice to pursue in human studies into the genetic basis of autism. A second approach toward identifying the genes mediating the core symptoms of autism is to evaluate the behaviors of lines of mice with experimentally targeted mutations in genes relevant to autism. Comprensive behavioral phenotyping is conducted on each new line, consistent with our laboratory's multi-tiered strategy for behavioral phenotyping of transgenic and knockout mice. Dr. Jean Lauder bred and genotyped Fragile X mice for our behavioral phenotyping. Fragile X is a form of mental retardation in which a large proportion of patients also display the symptoms of autism. Dr. Moy discovered that Fragile X mutant mice showed some deficits in components of the automated social task. Dr. Denny Porter, NICHD, contributed his line of mutant mice with a mutation relevant to Smith-Lemli-Opitz syndrome. This human disease, caused by a mutation in a cholesterol metabolizing gene, has several physiological symptoms and autism-like behavioral symptoms in some cases. Staff Scientist Joanna Hill and Howard Hughes student Liz Koenig did not detect a genotype difference in social behaviors in the Smith-Lemli-Opitz mice as compared to wildtype littermate controls, although mixed background genes were problematic in this first characterization. Joanna Hill and Postbaccalaureate Katrina Cuasay are conducting the social behavior task and a range of developmental behavioral tasks on mice that received prenatal treatment with an antagonist of vasoactive intestinal peptide, a developmental neuropeptide that has been implicated in autism. The goal of this research is to identify a mutant mouse model of autism with robust behavioral symptoms relevant to autism, that can be used to test mechanistic hyptheses and evaluate potential treatments for the symptoms of autism. Expanding on our search for genes mediating abnormal social behaviors, we began a new collaboration with Dr. Karen Berman, NIMH. Dr. Berman investigates Williams syndrome, a genetic disease with many physiological and behavioral symptoms, including hypersociability. Dr. Berman, Dr. Alan Koretsky, and Dr. Crawley received an NIH Bench-to-Bedside Award to pursue human imaging and mouse behavioral phenotyping and imaging studies of Williams syndrome. Dr. Niels Galjart, Erasmus University, The Netherlands, kindly contributed breeding pairs of mice with mutations in Cyln2, a microtubule gene located within the region of chromosome 7 that is deleted in Williams syndrome. Dr. Alan Koretsky and coworkers in NINDS are genotyping the offspring for us, and will conduct magnetic resonance imaging of the brains of the Cyln2 mice and their wildtype littermate controls. Howard Hughes student Jordan Cohen, Staff Scientist Joanna Hill, and PI Jacqueline Crawley have begun to test the Cyln2 mice on the automated social task for social approach to a stranger mouse and social preference toward a novel stranger mouse.
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