Exercised-induced modulation of insular cortex microcircuitry during alcohol abstinence

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PROJECT SUMMARY Alcohol consumption and related behaviors can account for the third-highest cause of preventable death in the United States. The ongoing COVID-19 pandemic has altered how individuals consume alcohol, which creates a need for new strategies to help and protect the health of individuals with alcohol use disorder (AUD). Studies in animal models suggest that exercise can help improve negative affective behaviors associated with abstinence from alcohol exposure. The insular cortex (IC) is a key component in brain circuitry, contributing to synaptic changes in the extended amygdala during abstinence. We have demonstrated that the IC is critical for expressing negative affective behaviors that emerge from forced alcohol abstinence in mice. The primary motor cortex (MOp) regulates essential information between the IC and extended amygdala during affective behaviors. Voluntary exercise, a behavior dependent on the MOp, causes rapid changes in IC activity in mice. Mice exposed to chronic alcohol intake display negative affective and aversion-resistant behaviors following forced abstinence which is mitigated by exposure to intermittent voluntary wheel running access. There is a need to gain insight into the interconnection of the MOp-IC to determine how exercise modulates forced abstinence-associated behavior following alcohol consumption. The inhibitory neurotransmitter GABA is associated with negative affect in humans. GABAergic somatostatin interneurons (SST-INs) are rich in the neocortex and have been critical in regulating negative affective behaviors in rodent models of substance use disorders. Our data suggest that GABA in the IC plays an important role in stress responsiveness. My preliminary data indicates that MOp neuronal projections innervate IC SST-INs. We need further investigation of MOp-IC microcircuitry to understand how activity within it might be altered by chronic alcohol intake. This information has led me to hypothesize that exercise can decrease negative affect and aversion resistance during abstinence from alcohol via the MOp-insula microcircuit connectivity. Within this fellowship, I will first determine the MOp-mid-IC microcircuit inter-connectivity in the mouse brain via electrophysiological methods. I follow up on these results by investigating how alcohol mediates IC microcircuitry. I will then observe the behavioral implications of this circuit by testing if exercise during alcohol abstinence promotes alterations in the IC SST-IN activity. Completion of this F31 grant will provide me with new techniques and skills to help me advance in my career as an independent academic researcher.