A complete understanding of the molecular basis of depression must include the role of individual genes in generating complex behaviors. Recent advances in gene transfer technology have resulted in the ability to either over-express or knock out the expression of genes of interest in behaving animals. These powerful techniques make it possible to combine a large body of work on the pharmacological effects of anti- depressant drugs with our evolving knowledge of the molecular and cellular adaptions to these agents. We are now able to manipulate the expression of specific gene products both temporally and spatially in the absence of psychotropic drugs, and observe the biochemical, electrophysiological, and behavioral consequences of this manipulation. These techniques will further elucidate the role of individual gene products in the complex behaviors associated with major psychiatric disorders. One goal of The Molecular and Transgenic Core is to oversee the breeding, genotyping, and maintenance of all transgenic and knockout animals to be used by the individual Projects. This includes mice obtained from other laboratories as well as mice to be generated by this Core. By centralizing these services, the Core will result in fewer animals being used for experimentation as well as considerable savings of money and investigator effort. A Second goal of this Core is to generate packaged viral particles to be used for viral-mediated gene transfer experiments in several of the Projects. We have demonstrated the ability of intra-cerebral injections of mutated herpes virus vectors to drive over-expression of proteins of interest in specific brain regions (i.e., CREB and glutamate receptor subunits.) This viral approach will complement the use of mutant mice to characterize the role of specific gene products in the neural adaptations which are relevant to the pathophysiology and treatment of major psychiatric illnesses. The third goal of this Core is to use gene array technology to identify novel genes that are regulated by antidepressant action, behavioral models of depression or over-expression of growth and transcription factors known to be involved in regulation of plasticity in response to these treatments. The Core will make filter- and glass based assays available to the Projects in order to identify novel targets for pharmacological and genetic manipulation. In addition, the Core will develop software to analyze the data generated from gene arrays and will develop high throughput anatomical methods to verify changes in gene transcription in specific brain areas.
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