The DNA methylation code governing the ensemble representation of morphine-context association

摘要 吗啡是一种广泛使用的强效阿片类镇痛药，但近年来，其非医疗用途 这一趋势一直在上升，并导致类阿片使用障碍的发病率上升。反复暴露 吗啡和其他药物滥用导致持久的学习之间的联系奖励 药物的性质和给药环境。因此，即使在禁欲，重新暴露于 这种情况是复发、增加戒断症状和毒瘾的一个风险因素。而 已经大量研究了介导药物背景关联和药物寻求行为的神经回路， 对这些关联的具体潜在机制仍知之甚少。拟议 研究中，我们的目的是评估这一假设，即表观遗传学改变的基因甲基化相关， 在重复的吗啡背景配对过程中，神经元连接性和兴奋性提供了一种机制， 腹侧海马中一小部分特定的神经元稳定地募集到海马中， “记忆印迹”存储吗啡关联的记忆。改变这些基因的甲基化状态 基因改变基因表达，这导致兴奋性增加和与前 突触后回路皮层和边缘系统的合作伙伴，以加强吗啡上下文协会，并创造一个 永恒的记忆通过表征招募的海马神经元中甲基化的变化， 集成和评估对神经元功能和电路可塑性的影响，我们 实验可能为阿片成瘾机制的研究提供新的框架， 有助于更有效地治疗物质使用障碍。

Abstract Morphine is a widely-prescribed and potent opioid analgesic, but in recent years its non-medical use has been on the rise and has contributed to the increased incidence of opioid use disorder. Repeated exposure to morphine and other drugs of abuse leads to lasting learned associations between the rewarding properties of the drug and the environment of administration. Therefore even in abstinence, re-exposure to the context is a risk factor for relapse, increasing withdrawal symptoms and drug cravings. While the neural circuits mediating drug-context associations and drug seeking behavior have been studied heavily, the specific underlying mechanisms of these associations remain poorly understood. In the proposed studies, we aim to evaluate the hypothesis that epigenetic alterations in the methylation of genes related to neuronal connectivity and excitability during repeated morphine-context pairings provide a mechanism for the stable recruitment of a small, specific population of neurons in the ventral hippocampus to the ‘engram” storing the memory of morphine-context associations. Switching the methylation status of these genes alters gene expression, which leads to increased excitability and connectivity with pre- and postsynaptic circuit cortical and limbic partners to enhance the morphine-context association and create a lasting memory. By characterizing the changes in methylation in the recruited hippocampal neuronal ensemble and evaluating the consequent effects on neuronal function and circuit plasticity, our experiments may provide a new framework for the study of the mechanisms of opioid addiction and contribute to more effective treatments of substance use disorder.