Chronic activation of fear engrams induces extinction-like behavior in ethanol-exposed mice

Abstract

<jats:title>ABSTRACT</jats:title><jats:p>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 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 fear extinction learning, optogenetic manipulation of a fear engram is sufficient to induce an extinction-like reduction in fear responses.</jats:p>

Chronic activation of a negative engram induces behavioral and cellular abnormalities

“…Interestingly, chronic optogenetic activation of dorsal hippocampal fear engrams results in context-specific reduction in fear expression that resembles extinction, even in mice with impaired extinction due to ethanol withdrawal (Cincotta et al, 2021). Activation of negative engram cells labeled during chronic social defeat stress induced social avoidance, a behavior common in human patients with MDD .…”

Calcineurin Participation in Hebbian and Homeostatic Plasticity Associated With Extinction

“…More recently, Zhang and collaborators showed that fear extinction memory requires forming a new engram in the basolateral amygdala ( Zhang et al, 2020 ). Furthermore, chronic stimulation of engram cells associated with fear memories in the hippocampus produced a reduction of fear responses, suggesting that optogenetic manipulation of a fear engram is sufficient to induce an extinction-like behavior ( Chen et al, 2019 ; Cincotta et al, 2021 ). Likewise, the inhibition of the assembly activated during cue-paired alcohol self-administration in the medial prefrontal cortex (mPFC), 1 month later prevented relapse of alcohol-seeking ( Visser et al, 2020 ), and optogenetic activation of infralimbic cortex-basolateral amygdala pathway during fear extinction trials, resulted in a stronger extinction compared to non-optogenetic activation ( Bukalo et al, 2021 ).…”