Transgenerational Effects of Drug-exposure: Epigenetic and Behavioral Impact

描述（由申请人提供）：药物成瘾是一种精神障碍，其特征是从娱乐性药物使用过渡到强迫性药物使用，尽管有严重的负面后果，但仍持续存在。尽管有人试图戒烟，但恢复吸毒的愿望或需要可能持续数月或数年。随着时间的推移，成瘾的持续性表明，暴露于药物会导致大脑的长期适应，这可能涉及转录和遗传调控的改变。除了遗传因素外，表观遗传机制也可能在维持成瘾方面发挥作用，不仅在个体的一生中， 在他/她的后代。然而，尚未描述药物暴露对几代人的潜在影响。到目前为止，还没有进行全面的研究，以确定是否暴露于药物滥用的父母一代导致行为或分子表型在后代的改变。为了解决这个问题，我们将研究两种机制不同的药物（可卡因和吗啡）在三个近交系小鼠品系（C57 BL/6 J，DBA/2 J，A/J），以及一个多代系列的F1杂种的表型后果。除了研究跨代的行为表型，我们将表征RNA表达，DNA甲基化和翻译后组蛋白修饰作为可遗传表观遗传变化的分子特征和机制基础。这些研究将使我们能够确定（1）两种机制不同的药物滥用是否会导致 成瘾相关表型在治疗后通过多代传递，（2）这些表型是否由表观基因组的变化（DNA甲基化、翻译后组蛋白修饰或RNA）介导，以及（3）这些表型是否以印记或等位基因特异性方式根据暴露父母的性别而变化。这些实验将为未来的研究提供信息，旨在阐明滥用药物导致跨代表型的机制。

DESCRIPTION (provided by applicant): Drug addiction is a psychiatric disorder characterized by a transition from recreational to compulsive drug use that continues in spite of severe negative consequences. Despite attempts by individuals to quit, the desire or need to resume drug-taking can last for months or years. The persistence of addiction over time suggests that exposure to drugs results in long-term adaptations in the brain that likely involve alterations in transcription and genetic regulation. In addition to genetic factors, epigenetic mechanisms may also play a role in the maintenance of addictions not only throughout an individual's lifetime, but in his/her descendants. However, the potential impact of drug exposure across generations has not been characterized. To date, no comprehensive study has been undertaken to determine if exposure to drugs of abuse in the parental generation leads to alterations in behavioral or molecular phenotypes in subsequent generations. To address this question, we will examine the phenotypic consequences of two mechanistically different drugs (cocaine and morphine) in three inbred mouse strains (C57BL/6J, DBA/2J, A/J) as well as a multi-generation series of F1 hybrids. In addition to studying behavioral phenotypes across generations, we will characterize RNA expression, DNA methylation, and post-translational histone modifications as both the molecular signature and the mechanistic basis for heritable epigenetic changes. These studies will allow us to determine (1) whether any of 2 mechanistically different drugs of abuse results in transmission of addiction-related phenotypes through multiple generations after treatment, (2) whether these phenotypes are mediated by changes to the epigenome (DNA methylation, post-translational histone modifications, or RNAs), and (3) whether these phenotypes vary according to the sex of exposed parent in an imprinted or allele-specific manner. These experiments will inform future studies aimed at elucidating the mechanisms by which drugs of abuse lead to transgenerational phenotypes.