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

DNA甲基化密码控制吗啡-背景关联的整体表示

• 批准号: 9906873
• 负责人: Kristen Elizabeth Pleil
• 金额: $ 21.14万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-15 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9906873
• 关键词: Abstinence; Acute; Address; Alleles; Behavior; Brain region; Cells; Chronic; Clinical; Code; DNA Methylation; Data; Development; Digit structure; Drug usage; Economics; Electrophysiology (science); Enhancers; Environment; Epigenetic Process; Exposure to; Future; Gene Expression; Gene Expression Alteration; Genes; Genetic Transcription; Goals; Hippocampus (Brain); Incidence; Investigation; Link; Maintenance; Mediating; Memory; Methylation; Modeling; Morphine; Morphine Dependence; Morphology; Neurons; Nucleus Accumbens; Opiate Addiction; Opioid; Opioid Analgesics; Pharmaceutical Preparations; Play; Population; Property; Relapse; Reporting; Rewards; Risk Factors; Role; Series; Signal Transduction; Slice; Social Problems; Substance Use Disorder; Synapses; United States; Withdrawal Symptom; Work; addiction; digital; drug craving; drug development; drug of abuse; drug relapse; drug seeking behavior; effective therapy; entorhinal cortex; epigenomics; experience; experimental study; high risk; hippocampal pyramidal neuron; innovation; memory recall; methylome; morphine administration; neural circuit; neuronal circuitry; nonmedical use; opioid misuse; opioid use disorder; postsynaptic; predictive modeling; preference; prevent; recruit; relating to nervous system

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.

摘要 吗啡是一种广泛使用的处方和有效的阿片类止痛剂，但近年来它的非医疗用途已经 阿片类药物使用障碍的发生率一直在上升，这也是造成这一现象的原因之一。重复曝光 对吗啡和其他药物的滥用会导致持久的习得性联系 药物的性质和给药环境。因此，即使在禁欲的情况下，重新接触 这一背景是复发的危险因素，增加了戒断症状和对药物的渴望。而当 神经回路调节药物背景联系和药物寻找行为已经被大量研究， 这些关联的具体潜在机制仍然知之甚少。在建议的 研究中，我们的目标是评估一种假说，即基因甲基化的表观遗传改变与 重复吗啡背景配对中的神经元连接和兴奋性提供了一种机制 腹侧海马区少量特定神经元的稳定募集 “记忆记忆”存储了吗啡与上下文的联系。切换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，并与前和 突触后回路皮质和边缘伙伴加强吗啡与上下文的联系并创造 永恒的记忆。通过表征重新招募的海马神经元甲基化的变化 并评估对神经元功能和电路可塑性的后续影响，我们的 实验可能为研究阿片成瘾的机制提供一个新的框架 有助于更有效地治疗药物使用障碍。