Background: Alcohol use disorders are characterized by inflexible alcohol seeking that occurs despite adverse consequences. Males and females are differentially sensitive to ethanol (EtOH) reward, but it is unclear whether sex differences in EtOH seeking under reward-aversion conflict are present.Methods: To investigate sex differences in EtOH seeking under conflict, adult male and female C57BL/6J mice underwent chronic intermittent EtOH (CIE) exposure by vapor inhalation or served as air-exposed controls. After CIE, mice were trained in a modified EtOH conditioned place preference paradigm. During 3 conditioning sessions, 2 g/kg EtOH was administered prior to confinement in the "EtOH-paired" chamber. On alternating days, saline was injected prior to confinement in the "salinepaired" chamber. After conditioning, mice experienced a footshock in the EtOH-paired chamber. EtOH-seeking behavior was assessed before and after footshock.Results: Control and CIE-exposed males reduced the time spent in and increased latency to enter the reward-paired chamber following footshock. Control females did not alter EtOH-seeking behavior following footshock. CIE-exposed females spent more time in the EtOH-paired chamber at baseline. However, following a footshock, CIE-exposed females significantly reduced the time spent in and increased latency to enter the EtOH-paired chamber.Conclusions: Nondependent female mice exhibited aversion-resistant alcohol seeking to a greater degree than males. Chronic EtOH exposure did not impact EtOH seeking in males. In females, CIE enhanced EtOH seeking in the absence of conflict, but reduced EtOH seeking after an aversive experience. While these sex-specific effects of CIE are not present when reward seeking is assessed in the absence of an aversive experience, multiple factors may underlie the differences in reward seeking despite adverse consequences, including reward-and aversion-related learning and decision making under conflict. These data highlight the importance of considering sex as a variable influencing EtOH seeking and provide a greater understanding of how sex interacts with EtOH exposure to alter behavior.

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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 vivoelectrophysiological 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 StatementA 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.

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