Unraveling epigenetic mechanisms of opioid addiction susceptibility using multigenerational animal models

吸毒成瘾是一个巨大的公共卫生问题，给我们的 经济和社会。滥用毒品的有害后果远远超出了吸毒者的范围。 并严重影响他们的家庭。越来越多的证据表明， 在怀孕期间服用药物的父亲表现出大脑功能的改变和 行为异常。我们已经建立了一个父亲阿片类药物的高度翻译范例 服药后，利用吗啡自身给药大鼠来研究这一现象。我们的结果 证明长期服用吗啡的父亲(父系)的男性后代更多 容易发展成瘾样特征和自我给药吗啡。这一多代人的 动物模型提供了一个难得的窗口，可以了解更容易发展的一批对象 上瘾，这是一个历史上很难识别的人群。在这里，我们可以可靠地和 系统地生产出表现出更多吸毒行为的动物，这提供了一种独特的 有机会深入研究成瘾易感性的潜在机制。这是多方面的 该项目将结合行为和分子生物学方法来识别功能 具有更高成瘾倾向的相关机制。 拟议的研究将解决两个主要问题：(1)哪个种系表观遗传学 重新编程事件对于将成瘾易感性的发展塑造成 成年期？(2)什么是与功能相关的神经表观遗传过程 在我们几代人的吸毒模式中有类似上瘾的行为吗？这项提议将 通过鉴定精子miRNA表达和DNA的变化来描述成瘾的生物标志物 父亲长期接触吗啡引起的甲基化。我们假设阿片类药物- 衍生的精子分子特征可以预测由此产生的成瘾易感性 后代。我们将通过评估特定功能的相关性来直接测试这一可能性 精子甲基标志和单个精子miRNAs在塑造神经发育向更高层次发展中的作用 成年动物的服药和药物增强效果的提高。我们还将探讨共价 成年吗啡催产者大脑中包装DNA的核组蛋白的修饰 表明吸毒率增加的后代。基因靶向表观遗传编辑将用于 描述神经奖赏回路中调节吸毒行为的组蛋白标记。这 研究将建立一种策略来描述与成瘾有关的功能机制 并开发一个研究环境侮辱如何塑造和影响环境的平台 个人罹患精神疾病的可能性。

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.