Altered Activity of Lateral Orbitofrontal Cortex Neurons in Mice following Chronic Intermittent Ethanol Exposure

The lateral orbitofrontal cortex (LOFC) is thought to encode information associated with consumption of rewarding substances and is essential for flexible decision-making. Indeed, firing patterns of LOFC neurons are modulated following changes in reward value associated with an action outcome relationship. Damage to the LOFC impairs behavioral flexibility in humans and is associated with suboptimal performance in reward devaluation protocols in rodents. As chronic intermittent ethanol (CIE) exposure also impairs OFC-dependent behaviors, we hypothesized that CIE exposure would alter LOFC neuronal activity during alcohol drinking, especially under conditions when the reward value of ethanol was modulated by aversive or appetitive tastants. To test this hypothesis, we monitored LOFC activity using GCaMP6f fiber photometry in mice receiving acute injections of ethanol and in those trained in operant ethanol self-administration. In naive mice, an acute injection of ethanol caused a dose-dependent decrease in the frequency but not amplitude of GCaMP6f transients. In operant studies, mice were trained on a fixed ratio one schedule of reinforcement and were then separated into CIE or Air groups. Following four cycles of CIE exposure, GCaMP6f activity was recorded during self-administration of alcohol, alcohol+quinine (aversive), or alcohol+sucrose (appetitive) solutions. LOFC neurons showed discrete patterns of activity surrounding lever presses and surrounding drinking bouts. Responding for and consumption of ethanol was greatly enhanced by CIE exposure, was aversion resistant, and was associated with signs of LOFC hyperexcitability. CIE-exposed mice also showed altered patterns of LOFC activity that varied with the ethanol solution consumed.