A history of low-dose ethanol shifts the role of ventral hippocampus during reward seeking in male mice.

Although casual drinkers are a majority of the alcohol drinking population, understanding of the long-term effects of chronic exposure to lower levels of alcohol is limited. Chronic exposure to lower doses of ethanol may facilitate the development of alcohol use disorders, potentially due to ethanol effects on reward learning and motivation. Indeed, our previously published findings showed that chronic low-dose ethanol exposure enhanced motivation for sucrose in male, but not female, mice. As the ventral hippocampus (vHPC) is sensitive to disruption by higher doses of chronic ethanol and tracks reward-related information, we hypothesized that this region is impacted by low-dose ethanol and, further, that manipulating vHPC activity would alter reward motivation. In vivo electrophysiological recordings of vHPC population neural activity during progressive ratio testing revealed that vHPC activity was suppressed in the period immediately after reward seeking (lever press) in ethanol-naïve controls, whereas suppression of vHPC activity anticipated reward seeking in ethanol-exposed mice. In both ethanol-naïve and exposed mice, vHPC activity was suppressed prior to a reward magazine entry. Temporally selective inhibition of vHPC using optogenetics increased motivation for sucrose in ethanol-naïve controls, but not in ethanol-exposed mice. Further, regardless of exposure history, vHPC inhibition promoted checking of the reward magazine, indicating a role for vHPC in reward tracking. There was no effect of chemogenetic inhibition of the vHPC either during training or testing on sucrose reward motivation. These results reveal novel ethanol-induced alterations in vHPC neural activity that shift how vHPC activity is able to regulate reward seeking. Significance Statement A large portion of the population consumes alcohol at levels that are subthreshold for an alcohol use disorder. Low-dose ethanol exposure could help convey susceptibility to alcohol use disorders by disrupting activity in brain regions that are important in reward seeking and motivation like the ventral hippocampus. Here, we found that a history of low-dose ethanol exposure shifted ventral hippocampus encoding of actions in mice, such that it altered the role of ventral hippocampus in reward seeking. These findings further our understanding of the impacts of low-dose ethanol exposure on motivated behavior and reveal ethanol-induced modulations in neural correlates of reward motivation.