Alcohol has numerous actions in the nervous system mediated through multiple transmitter signaling pathways. Both acute and chronic actions of alcohol modify sleep related behaviors through undefined mechanisms. We have shown that astrocytes, a type of glial cell, modulate sleep homeostasis by an adenosine receptor 1 (A1R)-dependent mechanism. We have novel evidence that molecular genetic manipulations directed at this glial pathway also impact alcohol-induced behaviors. We propose that alcohol activates the adenosine- dependent astrocytic cell and molecular signaling pathway that normally contributes to the homeostatic drive to sleep. Our overriding hypothesis is that an astrocytic source of adenosine mediates behavioral sensitivity to alcohol, and that the comorbidity of alcoholism and sleep disruptions involves long-term perturbations of this adenosine pathway. This project will be divided into three sections. Initially, we will identify the astrocyte-based signaling pathways that contribute to acute effects of alcohol on behavior (Aim 1). Subsequently, we will study how pre-existing impairments in sleep homeostasis impact alcohol behaviors (Aim 2), and how chronic alcohol exposure modifies sleep homeostasis (Aim 3). Despite numerous clinical reports that emphasize the correlation between sleep homeostasis and alcohol behaviors, few experimental models have been developed to explore this relationship. The significance of this project is reflected in the development of novel experimental models and multiple techniques that will be used to identify the interaction between alcohol behaviors and sleep impairments. The approaches described below offer distinct opportunities for therapeutic intervention. The proposed study uses an innovative integration of multidisciplinary approaches to study the involvement of the astrocyte-dependent sleep homeostat as a key mediator of acute and chronic effects of alcohol. Since astrocytes are now known to express G protein coupled receptors that are not expressed in neurons, results may also enhance the future potential to identify novel targets for ameliorating sleep impairments that haunt recovering alcoholics.
In this study we will test our hypothesis that behavioral actions of alcohol are mediated through glial-based signaling pathways that regulate neuronal synaptic transmission and sleep. Since astrocytes, the subtype of glia under study, are known to express G protein-coupled receptors that are not expressed in neurons, the results of this study have the potential to help identify novel targets for ameliorating the sleep impairments suffered by recovering alcoholics.
|Clasadonte, Jerome; McIver, Sally R; Schmitt, Luke I et al. (2014) Chronic sleep restriction disrupts sleep homeostasis and behavioral sensitivity to alcohol by reducing the extracellular accumulation of adenosine. J Neurosci 34:1879-91|
|Araque, Alfonso; Carmignoto, Giorgio; Haydon, Philip G et al. (2014) Gliotransmitters travel in time and space. Neuron 81:728-39|