PROJECT SUMMARY/ABSTRACT The orbitofrontal cortex (OFC) has been heavily implicated in reward valuation and seeking, and there is a strong association between OFC dysfunction and addiction to drugs of abuse. Accumulating evidence suggests that OFC may be a critical node in the development of compulsive alcohol seeking in alcohol use disorders. Despite the clear relevance of OFC function to alcohol use, however, there have been few direct studies of this relationship and no studies of OFC neuron function during alcohol seeking. We will investigate OFC function during ethanol expectation, seeking, taking, and consumption, as well as how OFC is disrupted in compulsive ethanol motivation following chronic use. Based on previous results, we expect OFC activity to underlie ethanol preference and motivation and to be upregulated during enhanced motivation in compulsive ethanol use. We will record the activity of OFC neuron ensembles in different groups of rats given either short (~1 month) or long (~4 months) access to ethanol. Both male and female rats will be studied in order to understand how differential OFC function underlies previously described sex differences in ethanol use. In short-access animals, we and others have observed striking individual differences in preference for ethanol. We hypothesize that OFC activity will positively correlate with ethanol motivation and negatively correlate with consumption in this group. In long-access animals, ethanol drinking becomes compulsive ? characterized by increased motivation and resistance to adulteration with quinine, which is normally aversive. We hypothesize that, in punishment-resistant compulsive ethanol seekers, OFC neurons will exhibit pathologically enhanced activation during ethanol cues and seeking and diminished inhibition during consumption. In both studies, we will also manipulate OFC activity to assess a causal relationship between OFC and ethanol use. We hypothesize that OFC inhibition will decrease preference and motivation for ethanol. These studies will provide new information regarding the specific ethanol-related behaviors driven by OFC activation as well as mechanisms underlying susceptibility for excessive drinking and problematic alcohol use. By drawing direct connections between OFC function and the transition to compulsive alcohol seeking, these studies have a strong potential to identify an important new target for treatment of alcohol use disorders. The two Specific Aims to be investigated in this project are: 1. Identify OFC signals related to individual differences in behavioral components of ethanol use using Pavlovian and operant tests of ethanol expectation and seeking in short-access rats. We will probe the relationship between OFC function and ethanol motivation focusing on individual and sex differences in behavior. 2. Identify OFC signals related to compulsive motivation for alcohol using the same tests in long-access rats who demonstrate elevated, punishment-resistant ethanol seeking. We will probe how OFC activity related to ethanol seeking and consumption is enhanced or suppressed after chronic ethanol use.