Ethanol modulation of a NE-astrocyte-DA arousal pathway

Project Summary Alcohol Use Disorder (AUD) is a highly prevalent public health problem for which there are few effective treatments. Sleep disturbances are highly comorbid with AUD and contribute significantly to disorder progression. Moreover, sleep disturbances can be more difficult to treat in individuals with AUD. Thus a critical need is to understand the mechanisms by which alcohol regulates sleep behavior. Alcohol is well known to reduce sleep latency, however this is followed by increased sleep fragmentation and problems with insomnia in individuals with AUD. Alcohol is well known to have sedative properties, and subsequent insomnia-related AUD symptoms have been proposed to be due to tolerance related disruptions in sleep-related setpoints. Recently, we uncovered a novel pathway by which norepinephrine engages wake- active dopamine neurons in the ventral periaqueductal gray (vPAG) to produce arousal. We find in preliminary data that ethanol engages the activation of this pathway, providing a novel potential mechanism through which alcohol can paradoxically drive wake behavior. Thus in the project we propose to explore the mechanisms through which acute and chronic ethanol exposure regulate this vPAG signaling pathway, and to explore the participation of this pathway in acute and chronic alcohol-dependent alterations in sleep-related behaviors.