Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States.
Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States.
Adv Pharmacol. 2021;90:173-216. doi: 10.1016/bs.apha.2020.09.006. Epub 2021 Feb 19.
Beyond their rapid rewarding effects, drugs of abuse can durably alter an individual's response to their environment as illustrated by the compulsive drug seeking and risk of relapse triggered by drug-associated stimuli. The persistence of these associations even long after cessation of drug use demonstrates the enduring mark left by drugs on brain reward circuits. However, within these circuits, neuronal populations are differently affected by drug exposure and growing evidence indicates that relatively small subsets of neurons might be involved in the encoding and expression of drug-mediated associations. The identification of sparse neuronal populations recruited in response to drug exposure has benefited greatly from the study of immediate early genes (IEGs) whose induction is critical in initiating plasticity programs in recently activated neurons. In particular, the development of technologies to manipulate IEG-expressing cells has been fundamental to implicate broadly distributed neuronal ensembles coincidently activated by either drugs or drug-associated stimuli and to then causally establish their involvement in drug responses. In this review, we summarize the literature regarding IEG regulation in different learning paradigms and addiction models to highlight their role as a marker of activity and plasticity. As the exploration of neuronal ensembles in addiction improves our understanding of drug-associated memory encoding, it also raises several questions regarding the cellular and molecular characteristics of these discrete neuronal populations as they become incorporated in drug-associated neuronal ensembles. We review recent efforts towards this goal and discuss how they will offer a more comprehensive understanding of addiction pathophysiology.
除了快速的奖励效应外，滥用药物还会持久地改变个体对环境的反应，正如药物相关刺激引发的强迫性药物寻求和复发风险所表明的那样。即使在停止使用药物后很长时间，这些关联仍然存在，这表明药物对大脑奖励回路留下了持久的印记。然而，在这些回路中，神经元群体受到药物暴露的影响不同，越来越多的证据表明，相对较小的神经元亚群可能参与编码和表达药物介导的关联。在药物暴露时募集的稀疏神经元群体的鉴定，得益于即时早期基因（IEGs）的研究大大受益，IEGs 的诱导对于启动最近激活的神经元中的可塑性程序至关重要。特别是，操纵表达 IEG 的细胞的技术的发展对于暗示广泛分布的神经元群体被药物或药物相关刺激同时激活，并随后因果地确定它们在药物反应中的参与，具有重要意义。在这篇综述中，我们总结了关于不同学习范式和成瘾模型中 IEG 调节的文献，以强调它们作为活性和可塑性标志物的作用。随着对成瘾中神经元群体的探索提高了我们对与药物相关的记忆编码的理解，它也提出了一些关于这些离散神经元群体的细胞和分子特征的问题，因为它们被纳入与药物相关的神经元群体中。我们回顾了最近在这方面的努力，并讨论了它们将如何提供对成瘾病理生理学的更全面理解。
