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

Abstract

The Lateral Orbito-Frontal 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 sub-optimal 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 naïve 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 an 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.

Significance Statement: These studies demonstrate that, in intact mice, LOFC neurons are acutely inhibited by alcohol and become hyperexcitable following CIE exposure. Furthermore, we report that unique patterns of LOFC neuronal activity occur during alcohol seeking and consumption. Interestingly, these patterns of activity are modulated following CIE exposure, particularly when the rewarding properties of the alcohol solution are modulated through adulterations with quinine (aversive) or sucrose (appetitive). Conversely, control animals have considerably more stable patterns of LOFC activity following exposure to air. These unique effects of CIE exposure on LOFC activity likely contribute to the development of excessive alcohol consumption and behavioral inflexibility that are associated with the onset of alcohol dependence.