Unraveling epigenetic mechanisms of opioid addiction susceptibility using multigenerational animal models

使用多代动物模型揭示阿片类药物成瘾易感性的表观遗传机制

• 批准号: 10402050
• 负责人: Mathieu Wimmer
• 金额: $ 6.09万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-15 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10402050
• 关键词: Address; Adult; Affect; Animal Model; Animals; Behavior; Behavioral; Biological; Biological Markers; Brain; Child; Chronic; Conceptions; Consumption; DNA; DNA Methylation; Development; Drug Addiction; Drug Modelings; Drug abuse; Environmental Risk Factor; Epigenetic Process; Event; Family; Fathers; Gene Targeting; Histones; Individual; Mental disorders; MicroRNAs; Modification; Molecular; Molecular Profiling; Morphine; Neurobiology; Nuclear; Opiate Addiction; Opioid; Pharmaceutical Preparations; Population; Predisposition; Proteins; Public Health; Rattus; Research; Rewards; Self Administration; Shapes; Signal Pathway; Societies; Substance Use Disorder; Testing; Time; addiction; male; mature animal; neurodevelopment; offspring; relating to nervous system; sperm cell; targeted treatment; therapeutic development; trait

Drug addiction is a massive public health concern that inflicts extensive burdens on our economy and society. The harmful consequences of drug abuse extend far beyond the addicts and gravely impact their families. A growing body of evidence suggests that the children of fathers who consumed drugs around the time of conception show altered brain function and behavioral abnormalities. We have established a highly translational paradigm of paternal opioid drug taking, using morphine self-administration in rats to study this phenomenon. Our results demonstrate that the male progeny of fathers (sires) that took morphine chronically are more susceptible to develop addiction-like traits and self-administer morphine. This multigenerational animal model offers a rare window into a pool of subjects that are more vulnerable to develop addiction, a population that has been historically difficult to identify. Here, we can reliably and systematically produce animals that show increased drug taking behavior, which offers a unique opportunity to delve into the mechanisms underlying addiction susceptibility. This multifaceted project will combine behavioral and molecular biological approaches to identify functionally relevant mechanisms that confer a higher propensity to develop addiction. The proposed studies will address two major questions: (1) which germline epigenetic reprogramming events are critical for shaping development toward addiction vulnerability into adulthood? (2) what are the functionally relevant neuro-epigenetic processes that increase addiction-like behavior in our multigenerational model of drug taking? This proposal will delineate biomarkers of addiction by identifying changes in sperm miRNA expression and DNA methylation caused by chronic paternal morphine exposure. We hypothesize that the opioid- derived sperm molecular signature is predictive of addiction susceptibility in the resulting progeny. We will directly test this possibility by assessing the functional relevance of specific sperm methyl marks and individual sperm miRNAs in shaping neurodevelopment toward higher drug taking and elevated drug reinforcing efficacy in adult animals. We will also probe covalent modifications of nuclear histone proteins that package DNA in the brains of adult morphine-sired progeny that show increased drug taking. Gene-targeted epigenetic editing will be used to characterize histone marks that regulate drug taking behavior in neural reward circuits. This research will establish a strategy to delineate functional mechanisms associated with addiction susceptibility and develop a platform to study how environmental insults can shape and affect the likelihood of individuals to develop psychiatric diseases.

吸毒成瘾是一个巨大的公共卫生问题，给我们带来了巨大的负担 经济与社会。药物滥用的有害后果远远超出了吸毒者 并严重影响他们的家人。越来越多的证据表明 在受孕期间消费毒品的父亲表明大脑功能改变了 行为异常。我们已经建立了高度转化的父亲阿片类药物范式 吸毒，使用吗啡在大鼠中使用吗啡自我给药来研究这种现象。我们的结果 证明父亲的男性后代长期服用吗啡 容易发展出类似成瘾的特征和自助吗啡。这个多代 动物模型提供了一个罕见的窗口，进入一个更容易发生的主题 成瘾，历史上难以识别的人群。在这里，我们可以可靠地 系统地生产出表现出增加药物服用行为的动物，这提供了独特的动物 探究成瘾易感性基础机制的机会。这个多方面 项目将结合行为和分子生物学方法，以识别功能 具有更高倾向成瘾的相关机制。 拟议的研究将解决两个主要问题：（1）哪种种系表观遗传学 重新编程事件对于将发展成瘾脆弱性转化为至关重要 成年？ （2）增加功能相关的神经诊断过程 在我们的多代药物服用模型中类似成瘾的行为？该提议将 通过识别精子miRNA表达和DNA的变化来描述成瘾的生物标志物 由慢性父亲吗啡暴露引起的甲基化。我们假设阿片类药物 - 衍生的精子分子签名可预测结果中成瘾的敏感性 后代。我们将通过评估特定的功能相关性直接测试这种可能性 精子甲基标记和单个精子miRNA，将神经发育朝向更高 药物服用和升高药物增强成人动物的功效。我们还将探测共价 在成年吗啡销售的大脑中包装DNA的核组蛋白的修饰 后代显示吸毒增加。靶向基因的表观遗传编辑将用于 特征的组蛋白标记可以调节在神经奖励电路中服用药物行为的特征。这 研究将制定一种策略来描述与成瘾相关的功能机制 敏感性并开发一个平台来研究环境侮辱如何塑造和影响 个体发展精神病的可能性。