Substance use disorder is characterized by long-lasting changes in reward-related brain regions, such as the nucleus accumbens. Previous work has shown that cocaine exposure induces plasticity in broad, genetically defined cell types in the nucleus accumbens; however, in response to a stimulus, only a small percentage of neurons are transcriptionally active—termed an ensemble. Here, we identify an -expressing neuronal ensemble that has a unique trajectory of recruitment and causally controls drug self-administration after repeated, but not acute, cocaine exposure. Using Arc-CreER transgenic mice, we expressed transgenes in + ensembles activated by cocaine exposure (either acute [1 × 10 mg/kg intraperitoneally] or repeated [10 × 10 mg/kg intraperitoneally]). Using genetic, optical, and physiological recording and manipulation strategies, we assessed the contribution of these ensembles to behaviors associated with substance use disorder. Repeated cocaine exposure reduced the size of the ensemble while simultaneously increasing its control over behavior. Neurons within the repeated cocaine ensemble were hyperexcitable, and their optogenetic excitation was sufficient for reinforcement. Finally, lesioning the repeated cocaine, but not the acute cocaine, ensemble blunted cocaine self-administration. Thus, repeated cocaine exposure reduced the size of the ensemble while simultaneously increasing its contributions to drug reinforcement. We showed that repeated, but not acute, cocaine exposure induced a physiologically distinct ensemble characterized by the expression of the immediate early gene , which was uniquely capable of modulating reinforcement behavior.

中文翻译：

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可卡因激活的整体在尺寸减小的同时增强了对行为的控制


物质使用障碍的特点是与奖励相关的大脑区域（例如伏核）发生长期变化。先前的研究表明，接触可卡因会诱导伏隔核中广泛的、基因定义的细胞类型的可塑性。然而，为了响应刺激，只有一小部分神经元具有转录活性——称为神经元整体。在这里，我们确定了一个表达神经元群，它具有独特的招募轨迹，并在重复但非急性可卡因暴露后因果控制药物的自我给药。使用 Arc-CreER 转基因小鼠，我们在可卡因暴露（急性[1 × 10 mg/kg 腹膜内]或重复[10 × 10 mg/kg 腹膜内]）激活的群体中表达转基因。使用遗传、光学和生理记录和操作策略，我们评估了这些整体对与物质使用障碍相关的行为的贡献。反复接触可卡因缩小了群体的规模，同时增强了其对行为的控制。重复可卡因群内的神经元高度兴奋，它们的光遗传学兴奋足以强化。最后，破坏重复的可卡因，但不破坏急性可卡因，整体削弱了可卡因的自我施用。因此，反复接触可卡因减少了整体的规模，同时增加了其对药物强化的贡献。我们发现，重复但不是急性的可卡因暴露会诱导一种生理上独特的整体，其特征是立即早期基因的表达，该基因具有独特的调节强化行为的能力。