Mesocortical neuromodulation in punishment-resistant alcohol drinking

Project Summary Long-standing hypotheses have posited a critical role for dysregulated dopaminergic neuromodulation of prefrontal cortex in the development of alcohol use disorder (AUD). Despite intense interest in the mesocortical dopamine system, technical challenges have precluded direct, temporally resolved observation of dopamine release patterns in the prefrontal cortex until recently. Accordingly, questions regarding the basic function of mesocortical dopamine as well as its role in AUD have been notoriously difficult to address. Here we propose to use a recently developed genetically-encoded fluorescent dopamine sensor, which allows for direct assessment of dopamine dynamics in vivo with unprecedented specificity and temporal resolution, to dissect dopamine release patterns in the medial prefrontal cortex (mPFC) associated with alcohol self-administration behaviors. In male and female mice, we will first test the responsiveness of dopamine innervation of mPFC to a range of stimuli including alcohol to determine its contribution to basic behavioral processes. Next we will assess how these release patterns evolve during initiation of alcohol self-administration and repeated alcohol exposure to determine if deficits in this system are associated with the emergence of heightened alcohol drinking and seeking. Finally, we will mechanistically investigate mesocortical control of alcohol drinking behaviors by manipulating the activity of this system in vivo and determine alcohol’s direct actions on presynaptic dopamine terminals in the mPFC using ex vivo imaging. Completion of this proposal will provide unprecedented insight and understanding as to the contribution of dysregulated cortical neuromodulation in AUD-relevant behaviors.