Dual Role of LH-GABA Neurons in Encoding Alcohol Reward and Aversive Memories

Abstract

One of the core aspects of alcohol use disorder is continued use despite negative consequences. Individuals with an alcohol use disorder typically engage in behaviors which represent a failure to integrate the aversive consequences of their actions. The neural mechanisms of learning about conflicting experiences remain poorly understood. Previous research has highlighted the critical role of GABAergic neurons in the Lateral Hypothalamus (LH-GABA) in rewarding memories. However, whether this role extends to aversive outcomes, and competition between rewarding and aversive outcomes remains unexplored. In this study, we sought to elucidate the role of LH-GABA neurons in encoding and expressing alcohol reward and aversive memories using fiber photometry calcium imaging. We used a dual-virus approach to confine expression of jGCaMP7f to GABAergic neurons in LH of male and female Long-Evans rats. In our first experiment, following acquisition of a cue-alcohol association, a mild foot shock was introduced on 50% of the trials. In the second experiment, we used three different cues to signal alcohol, foot-shock, or no consequence. Subsequently, we combined these conditioned stimuli in pairs to evoke motivational conflict. Our results reveal that LH-GABA activity is associated with cues predictive of both appetitive and aversive outcomes and is highest to a cue predictive of an aversive outcome. Additionally, the response of LH-GABA activity to an aversive shock stimulus is attenuated in the presence of alcohol. In summary, our findings show the activity of LH-GABA neurons is involved in learning both appetitive and aversive associations, and their interaction in conflict. Significance statement.This study addresses a critical knowledge gap in understanding the neural mechanisms behind learning in conflicting situations. Focusing on the GABAergic neurons in Lateral Hypothalamus, which have previously been associated with rewarding memories and motivation, we explore their role in the competition between rewarding and aversive motivation. We used fiber photometry to record LH-GABA neurons and found that their activity is heightened for aversive outcomes, irrespective of certainty. Notably, in situations of motivational conflict, this activity to the shock is dampened in the presence of alcohol. These insights not only enhance our understanding of the neural basis of emotional adaptation but also hold implications for psychiatric disorders like alcohol use disorder, depression, and anxiety, providing potential avenues for therapeutic interventions.