Highlights d Acute activation of dorsal and ventral HPC engrams in mice drives reward and aversion d The ventral DG is preferentially reactivated in emotionally salient contexts d Chronic activation of HPC engrams decreases or increases context-specific freezing d Memory enhancement is disrupted when BLA cells processing fear are silenced

The formation and extinction of fear memories represent two forms of learning that each engage the hippocampus and amygdala. How cell populations in these areas contribute to fear relapse, however, remains unclear. Here, we demonstrate that, in male mice, cells active during fear conditioning in the dentate gyrus of hippocampus exhibit decreased activity during extinction and are re-engaged after contextual fear relapse. In vivo calcium imaging reveals that relapse drives population dynamics in the basolateral amygdala to revert to a network state similar to the state present during fear conditioning. Finally, we find that optogenetic inactivation of neuronal ensembles active during fear conditioning in either the hippocampus or amygdala is sufficient to disrupt fear expression after relapse. These results suggest that fear relapse triggers a partial re-emergence of the original fear memory representation, providing new insight into the neural substrates of fear relapse. IntroductionThe biological capacity to produce adaptive behavioral responses in actively changing environments is critical to an animal's survival. Contextual fear conditioning (CFC) is a form of learning whereby an animal learns to associate a conditioned stimulus (i.e. a context) with an unconditioned aversive stimulus (e.g. foot shocks) to produce a conditioned response to the conditioned stimulus (e.g. freezing). Conditioned responses can be mitigated through extinction learning via repeated exposure to the conditioned context in the absence of the foot shock. However, while extinction learning can be effective at attenuating fear, animals are susceptible to fear relapse under several conditions, including exposure to stressors, the passage of time, and re-exposure to the unconditioned stimulus (

Alcohol withdrawal directly impacts the brain's stress and memory systems, which may underlie individual susceptibility to persistent drug and alcohol-seeking behaviors. Numerous studies demonstrate that forced alcohol abstinence, which may lead to withdrawal, can impair fear-related memory processes in rodents such as extinction learning; however, the underlying neural circuits mediating these impairments remain elusive. Here, we tested an optogenetic strategy aimed at mitigating fear extinction retrieval impairments in male c57BL/6 mice following exposure to alcohol (i.e., ethanol) and forced abstinence. In the first experiment, extensive behavioral extinction training in a fear-conditioned context was impaired in ethanol-exposed mice compared to controls. In the second experiment, neuronal ensembles processing a contextual fear memory in the dorsal hippocampus were tagged and optogenetically reactivated repeatedly in a distinct context in ethanol-exposed and control mice. Chronic activation of these cells resulted in a context-specific, extinction-like reduction in fear responses in both control and ethanol-exposed mice. These findings suggest that while ethanol can impair the retrieval an extinction memory, optogenetic manipulation of a fear engram is sufficient to induce an extinction-like reduction in fear responses.

14 The formation and extinction of fear memories represent two forms of learning that each 15 engage the hippocampus and amygdala. How cell populations in these areas contribute to fear 16 relapse, however, remains unclear. Here, we demonstrate that, in mice, cells active during fear 17 conditioning in the dentate gyrus of hippocampus and basolateral amygdala exhibit decreased 18 activity during extinction and are re-engaged after fear reinstatement. In vivo calcium imaging 19 reveals that reinstatement drives population dynamics in the basolateral amygdala to revert to a 20 network state similar to the state present during fear conditioning. Finally, we find that 21 optogenetic inactivation of neuronal ensembles active during fear conditioning in either the 22 hippocampus or amygdala is sufficient to disrupt fear expression after reinstatement. These 23 results suggest that fear reinstatement triggers a partial re-emergence of the original fear memory 24 representation, providing new insight into the neural substrates of fear relapse. 25 26 131ArchT-eYFP to drive expression of the light-sensitive protein archaerhodopsin (ArchT) in cells 132 active during CFC, and subsequently implanted optic fibers above the injection sites ( Figure 133 3a,b). Mice then underwent two EXT sessions, the reinstating shock, and recall the following day 134 (Figure 3c). Mice in both the DG and BLA experimental groups showed significant suppression 135 of freezing during optical inhibition. This manipulation was reversible, as freezing increased 136 again in the following light-off epoch (Figure 3d,e). eYFP controls did not show this decrease in 137

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