PROJECT SUMMARY An individual's initial level of response (LR) to ethanol (their nave sensitivity) is highly heritable, and LR strongly predicts lifetime liability to develop alcohol dependence. The genes that regulate LR are therefore important targets for study, but despite intense investigation, they remain poorly understood. One limitation is that it has been difficult to apply what we learn about the genes affecting level of response in model organisms to identifying liability loci in human gene association studies. Here, we solve this problem by beginning with candidate genes initially identified in human studies and by using a genetic model to define the biological mechanisms by which these genes are likely to regulate LR and, subsequently, abuse liability. Recently, allelic variation in members of the SWI/SNF chromatin-remodeling protein complex has been associated with a diagnosis of alcohol dependence in humans. The goal of this proposal is to elucidate the mechanism by which this complex controls ethanol responses, and, because the SWI/SNF complex regulates transcription, to determine the downstream genes that mediate these effects. We study the molecular mechanisms by which SWI/SNF influences the neuronal response to ethanol using the genetic model organism, Caenorhabditis elegans. C. elegans is an excellent model for these studies, because there is striking conservation between the machinery of nervous system function in humans and worms, and there are rich genetic resources available to experimentally manipulate nervous system function in worms. C. elegans behavior is affected by relevant doses of ethanol, and genes that modify ethanol responses in worms also modify ethanol responses, including drinking behavior, in mammals. We have found that altering the function of the SWI/SNF complex in C. elegans alters acute behavioral responses to ethanol, demonstrating that the role of SWI/SNF in modifying the effects of ethanol is conserved. We will determine the specific neurons and neural circuits in which the SWI/SNF complex is required for acute ethanol responses, which will implicate specific neurotransmitter systems in these functions. Second, we will use whole genome expression analysis to identify genes that are regulated by the SWI/SNF complex in differentiated neurons; these will be candidates for mediators of acute ethanol responses. Finally, we will use genetic and behavioral analysis to identify the genes that are responsible for the acute behavioral response to ethanol, and determine the biological mechanisms by which they regulate ethanol responses. Together, these studies will provide novel insight into the biological processes that regulate the level of response to ethanol, a phenotype that is predictive of the development of alcohol dependence. Importantly, this work will also provide new candidate genes for liability loci that can be examined in human populations for association with liability to develop alcohol dependence.