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 presumably normal brain. By creating animals with the same genetic changes and even some carrying 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. From this approach the normal function of these genes can be defined. This approach 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 our research projects that suggests the scope of the areas of investigations that have benefited from animal models produced by the core facility. These projects cover a wide range of neuroscience experiments at the level of specific molecules, gene expression, cell biology, neural circuits, learning, complex behavior, and include studies of specific diseases. 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: In the past year transgenic mouse models have been used to show the role of specific protein synthesis on learning and memory. Other 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. Neurogenesis: From mid-gestation and into old age, new neurons are produced in the brain. The role of these new cells that appear in adults is especially interesting, and suggests a function in learning and memory and potential treatments for neurodegenerative disorders. 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. The lines that carry either a human normal or disease gene are being created in the core. Those are crossed into a null line to replace the endogenous IKBKAP gene with its human disease equivalent. The core produced several new lines this year to test the effect of multiple copies of the gene. Activity in glial cells: 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. Manipulating circuitry: Mice in which specific neurons could be rendered transiently inactive have been produced for two separate laboratories. Those laboratories are investigating different neural circuits that are active in learning and addiction. Reporter and effector mice: Several lines that express effector molecules like CRE recombinase at specific temporal and spatial compartments were produced. Other lines that were used to report the activity of these and other recombinases were created. Mice, such as those from the Gensat project were rederived and exported. Transgenic rats: Technological development projects have allowed the core to produce transgenic rats for investigators in three NIH intramural institutes.
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