UC San Diego

Alcohol use disorder (AUD) is characterized by cognitive deficits thought to escalate maladaptive behaviors that increase the vulnerability to relapse. Neurobiological investigations have identified a key role for orbitofrontal cortex (OFC) computations in control of adaptive behavior. OFC-based computations and their underlying circuits have been shown to disrupted in alcohol addiction and other disorders characterized by repetitive behaviors. However, little is known about how these changes manifest in vivo when behaviors are self-initiated and reliant on inferences shaped by action-related information. In this dissertation, I used a mouse neural circuit-dissection approach in conjunction with an unconstrained lever-pressing task to investigate OFC computations made during adaptive behavior and their disruption in alcohol dependence. Chapter 1 explored how alcohol dependence induced changes in OFC neural activity correlates of self-initiated actions and their associated outcomes. Results suggested that chronic alcohol exposure induces long-lasting disruptions to OFC function such that activity associated with volitional actions was enhanced, but OFC activity contributions to outcome-related information was diminished. Chapter 2 investigated how different OFC populations support action-related computations, including computations relating to prior action information. Results identified a novel role for OFC excitatory and inhibitory neurons in the continuous integration of action information for behavioral control. These studies showed that OFC populations differentially encode action-related information in a dynamic manner, and that these cortical representations are significantly altered in alcohol dependence. Overall, this dissertation revealed some of the complexity of OFC’s contributions to adaptive behavior and further support the OFC as a target brain region for the intervention of AUD.