Role of Prefrontal Cortical Projections to the Midbrain in Alcohol-Induced Cognitive Deficits in Mice

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Project Summary and Abstract Alcohol Use Disorder (AUD) impacts upwards of 15 million Americans in the United States and has many consequences on overall health and quality of life for people affected by this disorder. Despite this, only around seven percent of people with AUD seek treatment and options for care remain limited, creating an urgent need for more research into the development and treatment of AUD. A major source of interest lies in what factors predispose certain individuals who consume alcohol over others to develop AUD, which can provide insight into specific preventative and treatment measures for this population. Deficits in cognitive domains of response inhibition and cognitive flexibility have been implicated as risk factors for later development of AUD and are predictors of more severe alcohol induced cognitive dysfunction. The medial prefrontal cortex (mPFC) is at the center of the brain circuitry that mediates aspects of cognitive function known to be impaired in AUD and studying the underlying neural pathways impacted by alcohol exposure has been a major area of study in the field. Human neuroimaging studies have identified mPFC projecting neurons to ventral tegmental area (VTA) as an important circuit in reward processing and initiation of goal directed behavior as well as alcohol craving in AUD models. The aim of this proposal is to utilize cutting edge techniques in single cell in vivo calcium imaging and behavioral tasks in mice to understand the contribution of this important but understudied pathway to preexisting and alcohol-induced deficits in cognitive function. Using complex operant positive reinforcement behavioral paradigms to test domains of cognitive flexibility and response inhibition in mice combined with single cell in vivo calcium imaging dynamics of mPFC→VTA projections as mice complete the task, I will study how this pathway responds to and changes as mice learn before and after alcohol exposure. I will first study whether there are individual differences in cognitive function in response inhibition and cognitive flexibility in mice at baseline with an operant behavioral task, after which I will characterize the activity pattern of mPFC→VTA projecting neurons using head mounted microendoscopes to capture real time neuronal activity of these projections in the mPFC in freely behaving mice as they learn the tasks. Further, using longitudinal tracking analysis, I will determine if there are individual differences in activity patterns between mice with variations in baseline cognitive function and how these changes evolve after binge drinking alcohol exposure in a two-bottle choice task. Completion of this proposal will provide valuable insight into the circuit level changes that underlie individual differences in vulnerability to alcohol induced cognitive deficits and will provide invaluable training for me as a future independent academic researcher.