Impact of Alcohol on Claustrum Function

Project Summary / Abstract While cognitive impairment is a key domain of alcohol use disorder, the neurocircuit mechanisms underlying this remain poorly understood. This project invokes the claustrum, a previously unexplored brain region in the context of alcohol, as a potential component of the circuitry impacted by chronic alcohol exposure. Preliminary data has revealed that chronic alcohol vapor reduces membrane capacitance and frequency of excitatory synaptic inputs, electrophysiological signatures of profound alcohol-induced neuronal atrophy in claustrum projection neurons. This project tests the hypothesis that alcohol-induced cognitive control impairments are mediated by blunted activity of ACC-projecting claustrum neurons. Building on prior expertise in whole-cell electrophysiology, this project provides training in detailed neuronal morphology imaging and analysis in aim 1 to determine the impact of chronic alcohol exposure on ACC-projecting claustrum neuron synaptic activity, intrinsic excitability, and morphology. This aim tests the predictions that, following chronic alcohol exposure, fluorescently labeled and biocytin-filled ACC-projecting claustrum neurons will exhibit reduced membrane capacitance and sEPSC frequency as well as dendritic and synaptic atrophy. Further, adding new skills in operant behavior and fiber photometry, experiments in aim 2 will determine the influence of chronic alcohol exposure on claustrum-ACC activity during a cognitively demanding behavioral task. This aim tests the prediction that chronic alcohol vapor exposure blunts claustrum-ACC calcium activity associated with reduced accuracy and increased impulsivity in an attentional set-shifting task. Finally, aim 3 develops technical skills in chemogenetic circuit manipulation and the drinking-in-the-dark behavioral paradigm to test if claustrum-ACC activity regulates inflexible, aversion resistant drinking. This aim tests the prediction that promoting or silencing claustrum-ACC activity will inhibit or enhance aversion-resistant drinking, respectively, as measured by consumption of alcohol adulterated with the bitter tastant quinine. Combined, these aims establish a role for the claustrum-ACC circuit in cognitive impairments associated with alcohol use disorder with translational and therapeutic implications. The technical expertise obtained is bolstered with conceptual training on claustrum and alcohol in relation to cognitive control. Exceptional training is ensured by Dr. Mathur, an expert on neurocircuit studies of alcohol-induced inflexible behaviors, and co-sponsor Dr. Cheer, an expert on neuromodulation and reward decision making in substance use disorder, who both have stellar training records. Seated within an institution boasting state-of-the- art facilities and a vibrant neuroscience community, professional development is further emphasized with focused training in mentorship, teaching, collaboration, publishing, and responsible conduct of research. Complementing prior expertise in synaptic underpinnings of stress-induced hedonic impairment, this proposal stands as an excellent training opportunity to develop the investigator into an independent researcher examining circuit mechanisms underlying impaired cognitive regulation of reward-related behaviors in stress and addiction.