Thibeault Kimberly C, Leonard Michael Z, Kondev Veronika, Emerson Soren D, Bethi Rishik, Lopez Alberto J, Sens Jonathon P, Nabit Brett P, Elam Hannah B, Winder Danny G, Patel Sachin, Kiraly Drew D, Grueter Brad A, Calipari Erin S
Vanderbilt Brain Institute, Vanderbilt University, Nashville, Tennessee; Vanderbilt Center for Addiction Research, Vanderbilt University, Nashville, Tennessee.
Vanderbilt Center for Addiction Research, Vanderbilt University, Nashville, Tennessee; Department of Pharmacology, Vanderbilt University, Nashville, Tennessee.
Biol Psychiatry. 2025 Mar 15;97(6):590-601. doi: 10.1016/j.biopsych.2024.06.008. Epub 2024 Jun 18.
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 Arc-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 Arc+ 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 Arc, which was uniquely capable of modulating reinforcement behavior.
物质使用障碍的特征是与奖赏相关的脑区（如伏隔核）发生持久变化。先前的研究表明，可卡因暴露会在伏隔核中广泛的、基因定义的细胞类型中诱导可塑性；然而，在受到刺激时，只有一小部分神经元具有转录活性，这部分神经元被称为神经元集群。在这里，我们确定了一个表达Arc的神经元集群，该集群在反复（而非急性）可卡因暴露后具有独特的募集轨迹，并因果性地控制药物自我给药行为。
使用Arc-CreER转基因小鼠，我们在因可卡因暴露（急性[腹腔注射1×10毫克/千克]或反复[腹腔注射10×10毫克/千克]）而激活的Arc+集群中表达转基因。使用遗传学、光学和生理学记录及操纵策略，我们评估了这些集群对与物质使用障碍相关行为的作用。
反复可卡因暴露减小了集群的规模，同时增加了其对行为的控制。反复可卡因暴露集群内的神经元兴奋性过高，对它们进行光遗传学刺激足以产生强化作用。最后，损毁反复可卡因暴露（而非急性可卡因暴露）后的集群会减弱可卡因自我给药行为。因此，反复可卡因暴露减小了集群的规模，同时增加了其对药物强化作用的贡献。
我们表明，反复（而非急性）可卡因暴露诱导了一个生理上不同的集群，其特征是立即早期基因Arc的表达，该集群独特地能够调节强化行为。
