Animal Models Of Neuropsychiatric Disorders

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Our Laboratory of Behavioral Neuroscience collaborates with several molecular geneticists laboratories on 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. During the past year, postdoctoral fellow Dr. Andrew Holmes has expanded the characterization of the serotonin transporter (5-HTT) knockout mouse, generated by Dr. Dennis Murphy and coworkers here in the NIMH IRP. Dr. Holmes had found a striking anxiety-like phenotype that was confirmed in three different anxiety tasks, the elevated plus maze, the light/dark transitions task, and the emergence test in an open field. Aggression scores were lower in 5-HTT -/- as compared to +/+ wildtype littermate controls. Depression-related tasks revealed normal baseline behaviors in 5-HTT -/- but lack of response to antidepressants that act through the serotonin transporter. This year Dr. Holmes and student intern Eric Gold compared the behavioral phenotype of 5-HTT mutants bred onto a C57BL/6J background versus bred onto a 129/SvEvTac background. Qualitaive and quantitative differences indicate protective genes in the 129 background that prevent the deleterious effects of 5-HTT mutation. Further studies this year were conducted by Dr. Holmes and Mr. Gold to evaluate the 5-HTT mutants on cued and contextual fear conditioning, an emotional memory task. Sensitivity to challenge doses of the antidepressants fluoxetine and desipramine indicate differential actions on mutant versus wildtype littermate mice on this emotional memory task. Since serotonin is involved in several human neuropsychiatric disorders, and 5-HTT antagonists such as Prozac are commonly used to treat depression, the 5-HTT mutant mouse represents a useful model system to further understand the role of serotonergic neurotransmission in mental illnesses. 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 social novelty preference in mice. George Dold, NIMH Research Services Branch, built the prototype apparatus. Drs. Sheryl Moy and Jessica Nadler and technicians in the UNC Neurodevelopmental Disorders Research Center tested the model in inbred strains of mice, including C57BL/6J, DBA/2J, FVB/NJ, and A/J. Social tendencies were scored consistently and quantitatively with the new apparatus for all strains.