Hippocampal fear engrams modulate ethanol-induced maladaptive contextual generalization in mice

The compounding symptomatology of alcohol use disorder (AUD) and co-occurring mental health disorders gives rise to interactions of maladaptive neurobiological processes, the etiology of which are elusive. Here, we devised an optogenetic strategy aimed at rescuing maladaptive fear processing in male c57BL/6 mice that underwent a chronic ethanol administration and forced abstinence paradigm. In the first experiment, we confirmed that fear acquisition and maladaptive contextual generalization was potentiated in ethanol-exposed mice during fear conditioning and exposure to a novel environment, respectively. In the second experiment, using an activity-dependent tet-tag system, we labeled the neural ensemble selectively activated by contextual fear conditioning in the dorsal hippocampus with an inhibitory opsin to attenuate behavioral dysfunctions resulting from ethanol exposure. We found that acute optogenetic perturbations during exposure to a novel environment suppressed maladaptive generalization in ethanol-exposed mice. These results provide further evidence for a crucial link between ethanol exposure and impaired fear memory processing by providing cellular and behavioral insights into the neural circuitry underlying AUD and maladaptive fear processing.