Walter F. Wiggins - US grants

DESCRIPTION (provided by applicant): The focus of the research training project is the effect of multiple chronic alcohol exposure-withdrawal cycles on molecular and behavioral circadian rhythms. Sleep is possibly the most critical physiologic process regulated by circadian rhythms of activity in the brain. While not much is understood regarding the specific mechanisms underlying sleep and its importance, sleep disturbances can have devastating physiologic consequences, including death, if they persist over time. Problems with sleep are one of the most common complaints from individuals undergoing withdrawal from alcohol and also one of the more common reasons given for relapse into alcohol abuse. Recent research has highlighted the importance of the T -type voltage gated calcium channels in the regulation of the molecular "clock" believed to generate circadian rhythms in the brain. Our lab has identified a specific variant of the T-type calcium channels - called Ca(v)3.2 - whose expression correlates strongly with the circadian disturbances associated with chronic alcohol exposure and withdrawal. The aims of the project seek to evaluate the effect of multiple chronic alcohol exposure-withdrawal cycles on normal molecular and behavioral circadian rhythms in a mouse model in which this T -type calcium channel has been either pharmacologically inhibited or genetically silenced. The approach will provide training in both molecular and behavioral laboratory techniques, including relative quantitation of gene expression using quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis and Western blot techniques, as well as behavioral analysis and sleep scoring using continuous electroencephalographic (EEG) monitoring. Furthermore, the analysis of the results will provide training in the mathematical modeling of physiologic rhythms, as well as the statistical analysis and interpretation of subsequent findings. The guidance and training provided by the advisor, research associates, and postdoctoral fellows in the lab will assist the applicant in troubleshooting experiments, analyzing pitfalls and unexpected results, and developing innovative approaches to answering the questions that arise at each point in the process of completing the project. In summary, this project will provide the training and skills necessary to develop and carry out a rigorous study of a physiologic problem related to alcohol abuse on both a molecular and behavioral level. PUBLIC HEALTH RELEVANCE: According to the NIH and CDC, respectively, approximately 43 percent of Americans exhibit moderate-to-high risk drinking habits and 70 percent do not get enough sleep. Furthermore, 36 to 72 percent of chronic drinkers cite sleep problems as a major reason for their relapse into alcoholism from 'withdrawal and at least 30 percent of insomniacs use alcohol as a sleep-aid, putting them at increased risk of alcoholism. Hence, the relationship between alcohol and sleep disturbance is a matter of great importance to public health in the United States.