Mechanisms of Ethanol's Influence on Sleep and Circadian Rhythms

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DESCRIPTION (provided by applicant): Two brain regions are particularly important for the initiation and maintenance of sleep. The suprachiasmatic nucleus (SON) is the primary initiator of sleep/wake cycles and the thalamus is involved in the generation and maintenance of brain rhythms that occur during sleep. The following specific aims will serve as the training vehicle and will seek to determine the cellular and molecular influence of ethanol onsleep and circadian rhythms. Aim 1: Behavioral alterations in chronic drinkers. Mice will be chronically administered an ethanol diet ( the T channel blocker ethosuximide). Wheel running activity and videographic records will be used to determine sleep/waking states. I hypothesize a decrease in total sleep time and shifts in circadian phase (delays) in chronic drinkers and animals administered ethosuximide. Aim 2: Molecular alterations in chronic drinkers. RTPCR and Western blot techniques will be used to examine the effect of chronic alcohol consumption on T channel and molecular clock genes and proteins. I hypothesize that the changes in sleep and circadian rhythms observed in Aim 1, will be correlated with changes in gene (increased) and protein (decreased) expression in both thalamic and SCN T channel isoforms, as well as in SCN molecular clock genes and proteins (attenuation and loss of pronounced rhythmicity of gene and protein expression). Aim 3: Electrophysiological characterization of the T-channel in chronic drinking mice. Mice chronically administered an ethanol diet will be used to generate thalamic in vitro brain slices. Whole cell patch recordings will be made while evoking T-current with appropriate voltage protocols. I hypothesize a neuroadaptational decrease in T-current that may underlie the decrease in spindle wave oscillations reported in alcoholic patients. Sleep perturbations by ethanol play a key role in the progression of alcoholism. Continued abuse of ethanol leads to long-term changes in sleep circuitry that last well beyond the cessation of ethanol administration. This research will afford me the opportunity to understand how chronic ethanol consumption alters the cellular and molecular mechanisms underlying the reported disruptions in sleep circuitry, with the hope of identifying novel drug targets for treatment of ethanol's disruption of normal sleep.