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Principal Investigator: Hye Jean Yoon
Organization: VANDERBILT UNIVERSITY
Fiscal Year: 2024
Award: $34,285
Funding agency: National Institute on Alcohol Abuse and Alcoholism
PROJECT SUMMARY/ABSTRACT
Alcohol use disorder (AUD) is characterized by problematic alcohol consumption that evolves over an
individual’s drinking history. While initial alcohol use is thought to be driven by its positive reinforcing effects,
following long-term drinking, negative affective states emerge during withdrawal. These states are associated
with increases in alcohol seeking, tolerance, and levels of consumption that follow repeated bouts of
abstinence. This has led to the hypothesis that negative reinforcement becomes the primary motivational
drive – where individuals consume alcohol to alleviate these negative states. However, the circuit-based
mechanisms that control this switch to negative reinforcement are unclear. The goal of this proposal is to
outline how alcohol-associated cues recruit circuits that control negative reinforcement before and after chronic
alcohol exposure. Our preliminary data show that D2 medium spiny neurons (MSNs) are a critical a negative
reinforcement circuit and control the motivational drive to avoid aversive stimuli in an environment. This
proposal will test the hypothesis, that alcohol-associated cues recruit D2 MSNs activation in vivo and drive
drinking after chronic exposure to alcohol. By combining optical approaches to record from and bidirectionally
modulate D2 MSNs in the NAc during alcohol drinking I will define exactly when and how their activity is
recruited over a history of drinking and how it controls drinking behavior. In Aim 1& 2, I will optically inhibit or
activate D2 MSN activity at the time of an alcohol-predictive cue to determine how this controls operant
drinking before and after chronic intermittent ethanol (CIE) exposure. In Aim 3, I will determine if the dynamics
of D2 MSNs during operant alcohol drinking are predictive of specific drinking patterns by combining fiber
photometry with operant behavior and doing deep-phenotyping analysis. I hypothesize that D2 MSNs – which
function as a negative reinforcement signal – are recruited by alcohol associated cues only after a history of
CIE exposure, when alcohol use is driven by negative reinforcement.
Taken together, the experiments in this proposal will determine the negative reinforcement circuits that
are recruited in the later phases of alcohol drinking and whether the dynamics of these neuronal circuits could
be predictive of alcohol drinking phenotypes. This proposal encompasses technical and theoretical training that
will provide the foundational expertise and conceptual thinking needed to address larger questions regarding
how long-term exposure of alcohol changes the brain and drives continued alcohol use. Additionally, these
findings can ultimately inform our understanding of underlying reward and learning process and lead to more
efficacious treatment interventions for AUD.
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