Targeting computation in prefrontal cortex to improve decision-making and reduce compulsive drinking in rodent models.

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Project Summary Impairments in decision-making are both a risk factor for and consequence of an Alcohol Use Disorder (AUD). These impairments are particularly debilitating as there are currently no approved pharmacotherapies designed to improve this aspect of an AUD. Impulsivity is a behavioral phenotype that reflects alterations in the decision-making process and is broadly characterized as the tendency to act without foresight and can be fractionated into several different subtypes. Non-planning impulsivity is a subtype of impulsivity characterized by the tendency to make decisions in a way that is not guided by plans or future goals. In addition, of all impulsivity subtypes a recent meta-analysis indicates that non-planning impulsivity is a strong predictor of alcohol dependence in humans. Therefore, there is a critical need to explore the neural basis of planning and impulsivity to inspire novel treatment approaches capable of addressing this pathology. In addition, previous work from our group in rodents converges with data from human subjects that indicates targeting the prefrontal cortex (PFC) may provide an effective way to reduce addiction-associated behaviors. The overarching hypothesis of this project is that targeting the pathology of the PFC will rescue impairments in decision-making observed in rodent models of AUD. A series of preclinical studies are proposed that will use rigorous and cutting-edge techniques to measure and manipulate neural activity in awake, behaving rodents. Heterogeneity in the animal models used will broaden the impact of the results by making them applicable to those with and without family history/genetic risk factors for problematic alcohol use as well as sex differences. Our previous work and preliminary data indicate that neural and behavioral signatures of planning are disrupted in excessive drinking animals. To explore the neural basis of this disruption and how to fix it, designer receptors exclusively activated by designer drugs (DREADDs) will be used to target and manipulate the activity of PFC neurons during behavior. In addition, large scale neural recordings from the PFC will be performed while animals are engaged in behavioral tasks designed to either measure impulsivity or the decision to consume alcohol. Finally, novel and rigorous statistical procedures and computational modeling approaches will be used to analyze the neural recordings obtained. These approaches will create a generative model of the data and therefore provide a detailed picture of the computations performed by these neurons. In this way, a clear mechanistic picture of the role that PFC neurons play in guiding behavior will be created by establishing causal inference between neural activity and behavior. In summary, the proposed work will identify how decision-making is altered in rodent models of AUD and how to improve it. This work will bring this program of research closer to its long-term goal of inspiring novel targets for treatment that are capable of addressing impaired decision-making in AUD.