Role of Orbitofrontal Cortex in Maladaptive Ethanol Seeking

PROJECT SUMMARY Alcohol Use Disorder is a chronic condition that can result in devastating health, social, and financial outcomes. A key characteristic of problematic alcohol drinking is continued use despite negative consequences. In punished alcohol seeking models, subjects must decide between drinking paired with an aversive punishment or abstaining from further drinking. Preliminary evidence suggests that subjects resistant to punishment show similar baseline drinking behaviors as subjects that are sensitive to punishment. Thus, a potential behavioral impairment in aversion resistant subjects compared to their aversion sensitive counterparts could lie in how resistant subjects update the outcomes, or contingencies, of their actions. Recent evidence from pharmacological inactivation and ex-vivo slice studies points to the role of the orbitofrontal cortex (OFC) in mediating aversion resistance. Interestingly, the OFC has also been widely investigated for its role in updating outcome contingencies. However, how contingency updating processes may contribute to punished alcohol seeking behaviors has yet to be elucidated. In my first aim, I seek to evaluate the effects of punished alcohol seeking on OFC activity using microendoscopic calcium imaging. In my second aim, I will use time-locked optogenetics to assess the effects of OFC activation and inhibition during punished alcohol self-administration. In my third aim, I will evaluate how rats classified as aversion sensitive or aversion resistant perform on reversal learning tasks used to assess outcome updating. The central goal of this work is to investigate if dysregulation in OFC activity as well as impairments in contingency updating contribute to individual differences in punished alcohol seeking. The findings of the proposed research will significantly advance our understanding of the neurobiological and behavioral contributions in drinking despite negative consequences.