Project Summary
Chronic alcohol exposure causes maladaptive behavioral and functional neural adaptations, which increase
alcohol consumption and the risk of relapse. Alcohol-biased choice behaviors result from chronic alcohol-induced
disruptions in reward-guided decision making and reward valuation, increasing the motivational value of alcohol,
compared to alternative non-drug rewards. Importantly, alcohol-biased choice is associated with alcohol use
disorder (AUD) severity and treatment outcomes; therefore, reducing alcohol-biased choice represents a largely
unexplored avenue for potential AUD treatment. While this phenomenon has been well-described in patients
with AUD and replicated in animal models, the mechanism of how chronic alcohol exposure modulates alcohol-
biased choice is largely unknown. The orbitofrontal cortex (OFC) is an understudied region in the alcohol field
and has a heavy role in reward-guided decision making and reward valuation. Patients with AUD show increased
OFC activation in response to alcohol-related cues and alcohol consumption. In mice that have undergone the
chronic intermittent ethanol (CIE) vapor exposure model of alcohol dependence, lateral OFC neurons have
altered intrinsic excitability and responses to alcohol and sucrose seeking and consumption. Reward-specific
neural populations in the OFC respond to and encode the value of available or expected rewards, with a larger
proportion of neurons activated by higher value rewards. The proportion of activated OFC neurons and degree
of reward-associated activation represents reward preference. Studies have identified distinct populations of
OFC neurons that encode drug rewards (cocaine, heroin) and alternative non-drug rewards (sucrose). Similarly,
my preliminary data demonstrates lateral OFC neural populations encode sucrose and EtOH rewards. No studies
to date have investigated chronic alcohol effects on reward-specific lateral OFC ensembles during alcohol-biased
choice assessment. The objective of this research proposal is to determine mechanisms of how chronic alcohol
exposure alters the activity of reward-specific lateral OFC neural populations during reward approach and
consumption to modulate alcohol-biased choice. To accomplish this goal, I have validated a model of chronic
alcohol-induced alcohol biased choice using the CIE model of alcohol dependence and a two-bottle choice
drinking assessment of alcohol-biased choice. Aim 1 of this proposal will focus on characterizing CIE-induced
changes in cFos expression and neural activity in alcohol and sucrose-activated lateral OFC neurons during
alcohol-biased choice assessment. Aim 2 will utilize FosTRAP methodology to specifically inhibit alcohol- and
sucrose-activated lateral OFC neurons to determine how these neural ensembles modulate alcohol-biased
choice. These results will have important scientific impact by determining how chronic alcohol exposure
modulates alcohol-biased choice, a hallmark of AUD, through changes in reward-specific neural ensembles in
the lateral OFC.
