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: 9766748
• 负责人: Kristen Elizabeth Pleil
• 金额: $ 25.37万
• 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/9766748
• 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.

抽象的 吗啡是一种广泛的处方且潜在的阿片类镇痛药，但近年来，其非医疗用途具有 我们正在上升，并促进了阿片类药物使用障碍的增加。反复接触 对吗啡和其他滥用药物导致持久的奖励之间的联系 药物的特性和给药环境。因此，即使是禁欲， 环境是缓解，增强感恩症状和毒品渴望的危险因素。而 介导药物秘密关联和寻求药物行为的神经回路已经大量研究了， 这些关联的特定潜在机制仍然很少理解。在提议中 研究，我们旨在评估以下假设：与 在重复吗啡 - 封闭式配对期间的神经元连接性和令人兴奋为一种机制提供了机制 稳定地募集腹侧海马中少数特定的神经元人群 “ engram”存储吗啡 - 封闭关联的内存。切换这些的甲基化状态 基因改变了基因表达，这会导致与前和前和前后的兴奋和连通性的增加 突触后电路皮质和边缘伴侣，以增强吗啡 - 替代关联并创建一个 持久的内存。通过表征招募的海马神经元中甲基化的变化 合奏并评估对神经元功能和电路可塑性的影响，我们 实验可以为研究阿片类药物成瘾机制的研究提供新的框架 有助于对药物使用障碍的更有效治疗。