Orbitofrontal circuit mechanisms underlying alcohol use disorder

PROJECT SUMMARY The orbitofrontal cortex (OFC) is a major hub in the brain that interacts with numerous other brain circuits to control many behaviors related to learning, memory and decision-making. OFC has also emerged as a significant node of dysfunction in alcohol use disorder (AUD). Nevertheless, how different OFC outputs contribute to AUD remains largely unknown. One major challenge in such an investigation is that AUD develops over long time- scales and is a chronic relapsing condition. Another challenge is that distinct projection outputs of OFC have different functions. Thus, investigation into the neuronal mechanisms underlying AUD will benefit from a longitu- dinal study of projection-specific neurons that spans the long timescale representative of AUD. Recent advances in two-photon microendoscopic calcium imaging allows the longitudinal tracking of the same projection-specific OFC neurons across months. In this proposal, we will use this cutting-edge technology to study the function of two OFC circuits—projections to dorsal striatum (targeting the densest projection near the border between dorsal and ventral striatum) and the ventral tegmental area (VTA) in alcohol related behaviors. These downstream targets are themselves critical regulators of natural reward or alcohol related behaviors, and these projections have been demonstrated to have at least some non-overlapping functions in natural reward learning. The central question of interest in this proposal is whether the encoding adaptations during initial alcohol use in neuronal ensembles within these OFC circuits predict their subsequent encoding and control of aversion-resistant operant alcohol seeking or cue-induced reinstatement. In aim 1, we will image alcohol related neuronal activity weekly in the above OFC outputs while C57/BL6 mice have intermittent access to 20% alcohol in a two-bottle choice paradigm (IA20%2BC) for 7-8 weeks. We will test the hypothesis that OFC→dorsal striatum, but not OFC→VTA, neurons strengthen their responses to alcohol, as animals begin preferring alcohol. In aim 2, we will longitudinally track the same neurons from initial alcohol consumption to subsequent tests of aversion-resistant seeking. Spe- cifically, we will investigate the role of the above circuits during operant self-administration of alcohol with or without quinine adulteration, and test the hypothesis that the same OFC→dorsal striatum neurons that encode initial escalation of alcohol preference also encode and mediate aversion-resistant seeking. In aim 3, we will longitudinally track neurons from initial alcohol use to subsequent extinction and cue-induced reinstatement of operant alcohol seeking. We will test the hypothesis that OFC→VTA neuronal activity predicts and mediates cue-induced reinstatement of operant alcohol seeking. Overall, these studies will yield insights on the extent of overlap of neuronal encoding of alcohol consumption/preference, aversion-resistant operant seeking, and cue- induced reinstatement.