Molecular Mechanisms of Cellular Plasticity in a Mouse Model of Excessive Alcohol

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DESCRIPTION (provided by applicant): The goal of the current application is to provide Dr. Igor Ponomarev with career development opportunities under the mentorship of Dr. R. Adron Harris. The excellent research environment, faculty and facilities at the University of Texas at Austin will allow him to sharpen his skills as a young investigator and to learn cellular neuroscience techniques such as brain microinjections and laser capture microdissection. These techniques will allow Dr. Ponomarev to identify and dissect individual neuronal populations for gene expression analysis and also to apply interference RNA and pharmacological agents to test functionality of differentially regulated candidate genes. Training under this award will better prepare Dr. Ponomarev for a career in academic science and compliment his expertise in behavioral neurogenetics and functional genomics. Because excessive alcohol consumption is a prerequisite for the development of alcohol dependence, it is important to identify molecular targets associated with high alcohol intake in order to understand the mechanisms of alcoholism progression, which mediate the switch from controlled alcohol consumption to alcohol abuse and alcohol dependence. The overall goal of this proposal is to determine the effects of genetic factors and drinking high amounts of alcohol on gene expression in specific brain regions believed to be involved in regulation of alcohol consumption and different populations of dopamine neurons projecting to these brain regions. We will use brain microinjections, laser capture microdisections and cDNA microarrays to study patterns of gene expression in brain regions and neurons of genetically selected mice with predisposition to high alcohol consumption. We hypothesize that different brain regions and neuronal populations of alcohol-related neurocircuitry can be distinguished by their individual patterns of gene expression and by their distinct transcriptional responses to genetic selection and alcohol drinking. The long-term goals of these studies are to determine roles of individual neuronal populations in alcohol actions and to identify cell type - specific alcohol-sensitive genes and gene products as potential therapeutic targets for alcoholism.