The potential associations between human genes and mental disorders are being increasingly identified, but with these associations comes a conspicuous lack of understanding of how these genes function in an afflicted, or even a persumably normal brain. By creating animals with the same genetic changes and even some carrying entire human disease genes these associations can be tested. By producing mice with human disease alleles neuroscientists can study the behavioral, developmental, anatomical, cellular and biochemical levels of the disease. This approach allows the investigator to define the normal function of these genes. This method has been used to provide animal models for many research projects at the NIH IRP as well as with collaborators in the extramural program. The details of these experiments are described in investigators own reports. Below is a partial list of research projects the Transgenic core has pursued in the last year. A wide range of areas of investigation have benefited from animal models produced by the core facility. These projects can elucidate function at the level of specific molecules, gene expression, cell biology, neural circuits, learning, or complex behavior, and include studies of specific diseases. Schizophrenia: Mice with behavioral characteristics that resemble schizophrenia were produced by mating effecter mice from the core facility with responder mice. The latter carried a conditional ablation of the NMDA receptor. The offspring of these matings were engineered to lack NMDA receptors in a subset of corticolimbic interneurons. They displayed behavioral deficits in normal mating, nest-building and anxiety-like behavior. Memory dysfunction was also revealed in these animals. Stress: The role of a specific gene (catachol-O-methyltransferase) in the susceptibility to stress was demonstrated in mice that were engineered to have reduced levels of this gene. Learning and memory: The effect of specific and tightly controlled protein synthesis on learning and memory was studied. In addition, transgenic mouse models have been used to show the role of specific peptide-expressing cells to influence the link between fear and behavior and learning. Manipulating circuitry: Mice have been produced for two separate laboratories which have specific neurons that could be rendered transiently inactive by light activated ion channels. Those laboratories are investigating different neural circuits that are active in learning and addiction. Drug addiction: Lines of transgenic rats that express GFP in response to afferent input activation of the fos gene were generated in the core facility. These rats are being used by Bruce Hopes laboratory in NIDA to study patterns of neural activity in response to addictive drugs. Neurogenesis: Transgenic mice and, more recently, transgenic rats have been generated to study the role of neurogenesis in adults. From mid-gestation and continuing into old age, new neurons are produced in the brain. The role of new cells appearing in adults is especially interesting, and suggests a function in learning and memory and potential treatments for neurodegenerative disorders. Autism and Phelan-McDermid syndrome: Mice are being produced in the core facility in which expression of the SHANK3 gene can be manipulated. SHANK3 is the only gene to be conclusively linked to an autism spectrum disorder. Mucolipidosis IV: The mouse model of this disease resulted from a long-standing collaboration with the Slaugenhaupt laboratory and has continued to yield results, including a description of the neuropathy that may be associated with this disease. The core facility continues to distribute these animals. Familial dysautonomia: Another collaboration with the Slaugenhaupt lab resulted in a model for this disease. Lines carrying either a human normal or disease gene are being created in the core. These lines are crossed into a null line to replace the endogenous IKBKAP gene with its human disease equivalent. Glial activity reporters: The core produced a mouse line with a transgene that indicated the concentration of calcium in glial cells. By changes in its fluorescent properties, the calcium concentration and associated activity has been demonstrated in these cells. Reporter and effector mice and rats: Several lines that express effector molecules such as CRE recombinase at specific temporal and spatial compartments were produced. The core also created other lines that were used to report the activity of these and other recombinases. Mice, such as those from the Gensat project, were rederived and exported.
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