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.

中文翻译：

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恐惧印迹的慢性激活会在乙醇暴露的小鼠中诱导类似灭绝的行为。

酒精戒断直接影响大脑的压力和记忆系统，这可能是个体对持续吸毒和酗酒行为易感性的基础。大量研究表明，可能导致戒断的强迫戒酒会损害啮齿动物与恐惧相关的记忆过程，例如灭绝学习；然而，调节这些损伤的潜在神经回路仍然难以捉摸。在这里，我们测试了一种光遗传学策略，旨在减轻雄性 c57BL/6 小鼠在接触酒精（即乙醇）和强制戒酒后的恐惧消退恢复障碍。在第一个实验中，与对照组相比，乙醇暴露小鼠在恐惧条件下的广泛行为消退训练受损。在第二个实验中，在暴露于乙醇的小鼠和对照小鼠中，在背侧海马体中处理情境恐惧记忆的神经元集合被标记并在不同的情境中反复进行光遗传学重新激活。这些细胞的慢性激活导致对照小鼠和乙醇暴露小鼠的恐惧反应出现特定背景的、类似灭绝的减少。这些发现表明，虽然乙醇会损害对灭绝记忆的恢复，但对恐惧记忆的光遗传学操作足以诱导恐惧反应的类似灭绝性减少。