Excessive, uncontrolled alcohol consumption is a hallmark characteristic of individuals with alcohol use disorder (AUD). Chronic alcohol drinking produces neuroadaptations in corticothalamic and corticostriatal circuits that may reduce behavioral flexibility and diminish engagement in behaviors for non-alcohol rewards. While deficits in executive cognitive functioning in individuals with AUD hinder treatment and lead to relapse, the mechanisms and neural circuits driving excessive alcohol drinking and alcohol-biased choice behaviors represent a substantial gap in our understanding of factors that lead to the development and maintenance of AUD. The mediodorsal thalamus (MDT) is a higher-order thalamic nucleus that integrates cortical and subcortical signaling via its reciprocal glutamatergic projections with the prefrontal and orbitofrontal cortex. The MDT is innervated by reward-processing mesolimbic structures and contributes to adaptive goal-directed choice behavior and higher- order cognitive flexibility. However, it is unknown if the MDT is a critical region in addiction-related circuitry involving PFC dysfunction and alcohol-biased choice behaviors. In alcoholics, the pathway between the MDT and medial PFC is degenerated, and our preliminary data demonstrates that chronic intermittent ethanol (CIE) exposure increases intrinsic excitability of MDT projection neurons. Moreover, we provide evidence that voluntary alcohol drinking in FosTRAP2 mice activates cells in the MDT and chemogenetic activation of the MDT reduces alcohol intake. Thus, the overarching hypothesis of this research project in the Charleston Alcohol Research Center (ARC) is that cortical-projecting MDT neurons drive excessive alcohol drinking and alcohol- biased choice behaviors.
In Aim 1, we will identify neural ensembles and characterize functional adaptations in MDT neurons that are activated by alcohol drinking and CIE exposure, and project to the infralimbic (IfL) cortex, a region that controls excessive alcohol intake. Studies in Aim 2 will use fiber photometry to test the hypothesis that activity of MDT?IfL neurons will be modulated by alcohol drinking and this pattern of activity will be altered in alcohol-dependent mice.
In Aim 3, studies will test the hypothesis that MDT?IfL projecting neurons drive excessive drinking and alcohol-biased choice behaviors in dependent mice. The results from this project using emerging technology and circuit-based approaches will identify specific subsets of neural populations in the MDT that are activated by excessive alcohol drinking in dependent mice. Collectively, the proposed research will identify unique functional signatures and novel neurocircuits that control heavy drinking and contribute to loss of reward-based flexible behaviors. The focus of this new Charleston ARC project on thalamocortical projections and alcohol-biased choice behaviors complements the overarching theme and overlaps extensively on conceptual, technical, and circuitry levels with the other basic science and clinical projects in this Center renewal.
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