Transgenerational Inheritance of a Cocaine Resistance Phenotype

可卡因耐药表型的跨代遗传

• 批准号: 10365512
• 负责人: Robert Christopher Pierce
• 金额: $ 53.16万
• 依托单位: RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10365512
• 关键词: ATAC-seq; Adult; Animal Model; Anxiety; Behavior; Behavioral; Brain; Brain region; Cell Nucleus; Characteristics; Chromatin; Cocaine; Coupling; DNA Methylation; Data; Epigenetic Process; Female; Funding; Gene Expression; Gene Expression Profile; Generations; Genes; Grant; Health; Heritability; Hippocampus (Brain); Human; Impairment; Inherited; Learning; Maintenance; Measurement; Mediating; Messenger RNA; Methamphetamine; Methodology; MicroRNAs; Modeling; Molecular; Motivation; N-Methyl-D-Aspartate Receptors; Neurons; Nucleus Accumbens; Partner in relationship; Paternal Exposure; Pharmaceutical Preparations; Phenotype; Physiology; Play; Proteins; RNA methylation; Rattus; Receptor Signaling; Reinforcement Schedule; Research; Resistance; Risk Factors; Role; Saline; Self Administration; Serine; Specificity; Sucrose; Synaptic plasticity; Transcript; Transfer RNA; United States National Institutes of Health; Untranslated RNA; Viral; Work; XCL1 gene; addiction; behavior influence; bisulfite sequencing; cocaine exposure; cocaine self-administration; design; epigenome; experimental study; genome-wide; interest; knock-down; male; methamphetamine exposure; new therapeutic target; novel; novel strategies; offspring; overexpression; programs; protective factors; psychostimulant; reinforcer; sex; sperm cell; stimulant dependence; targeted treatment; therapeutic development; transcriptome sequencing; transgenerational epigenetic inheritance

Project Summary The focus of this research program, which has been NIH-funded since 2012, is the influence of paternal psychostimulant self-administration on the physiology and behavior of subsequent generations (i.e. offspring and grand-offspring) using rat models. Our work previously demonstrated that sire cocaine self-administration reprogramed the germline epigenome resulting in decreased cocaine reinforcing efficacy in the male progeny. The current application expands our focus on cocaine alone to encompass the transgenerational effects of paternal methamphetamine (meth), which will be compared and contrasted with cocaine. The proposed research will examine the mechanisms whereby information is passed to meth-sired offspring (and potentially grand-offspring) through epigenetic changes in sperm. We also will define epigenetic and transcriptional profiles in the nucleus accumbens of cocaine- and meth-sired offspring that may underlie the respective influences on psychostimulant self-administration. Specific Aim 1 will examine the behavioral consequences of paternal meth self-administration on psychostimulant self-administration in male and female offspring (F1) and grand-offspring (F2). Intriguingly, our preliminary results indicate that meth and cocaine produce opposite effects on psychostimulant reinforcing efficacy in male offspring. In contrast to our prior results with cocaine, preliminary data indicate that paternal meth self-administration results in increased self-administration of, and motivation for, this psychostimulant selectively in male offspring. Drug naïve F1 rats will be used to generate an F2 generation, where the acquisition, maintenance and reinforcing efficacy of meth will be assessed just as in F1 offspring. In Specific Aim 2 we will assess epigenetic changes in sperm through which paternal psychostimulant self-administration may influence the behavior of offspring. Potential transgenerational cocaine- and meth-induced epigenetic alterations (small noncoding RNAs and DNA methylation) in sperm will be evaluated. Finally, genome-wide assessments of psychostimulant transgenerational effects have not yet been performed on neurons in the nucleus accumbens, a brain region that plays a critical role in modulating psychostimulant-induced behaviors. The experiments in Specific Aim 3 are designed to interrogate the landscape of accessible chromatin and gene expression by coupling single-nuclei ATAC-seq and single-nuclei RNA-seq analyses in the accumbens of experimentally naive meth-sired, cocaine-sired and saline-sired rats. Collectively, the experiments described in this application will use state-of-the-art cellular, molecular and behavioral methodologies to examine epigenetic mechanisms whereby psychostimulant-associated information can be transmitted from sires to offspring and grand-offspring. These cross-generational studies represent a novel strategy to identify transcripts related to risk or protective factors for psychostimulant self- administration, which will illuminate new targets for therapeutic development.

项目摘要 这项研究计划自2012年以来一直由NIH资助，其重点是父亲的影响。 精神兴奋剂自我给药对后代（即后代）的生理和行为的影响 和孙子）使用大鼠模型。我们之前的研究表明， 重新编程生殖系表观基因组，导致可卡因在雄性后代中的增强效力降低。 目前的应用程序扩展了我们对可卡因的关注，以涵盖可卡因的跨代影响。 父亲的甲基苯丙胺（冰毒），这将与可卡因进行比较和对比。拟议 研究将检查信息传递给甲基化后代的机制（并可能 通过精子的表观遗传变化。我们还将定义表观遗传和转录 可卡因和冰毒产生的后代的脑桥核中的分布可能是各自的基础。 影响精神兴奋剂自我管理。具体目标1将研究以下行为的后果： 雄性和雌性后代（F1）中父亲自我给药对精神兴奋剂自我给药的影响，以及 孙代（F2）。有趣的是，我们的初步结果表明，冰毒和可卡因产生相反的 对雄性后代中精神兴奋剂强化功效的影响。与我们之前对可卡因的研究结果相反， 初步数据表明，父亲的甲氨蝶呤自我给药导致增加的甲氨蝶呤自我给药， 这种精神兴奋剂的动机，选择性地在男性后代。将使用未经药物处理的F1大鼠生成 一个F2代，在那里获得，维护和加强甲基的效力将被评估，就像 在F1后代中。在具体目标2中，我们将评估精子中的表观遗传变化， 自我服用精神兴奋剂可能会影响后代的行为。潜在跨代 可卡因和冰毒诱导的精子表观遗传学改变（小的非编码RNA和DNA甲基化）将 被评价。最后，对精神兴奋剂跨代效应的全基因组评估还没有 在神经核中的神经元上进行，神经核是一个在调节神经元活动中起关键作用的大脑区域。 精神兴奋剂引起的行为具体目标3中的实验旨在询问 通过耦合单核ATAC-seq和单核可接近染色质和基因表达的景观 在实验性未接触过甲基、可卡因和盐水的大鼠的睾丸中进行RNA-seq分析。 总的来说，本申请中描述的实验将使用最先进的细胞、分子和生物技术。 行为方法学来检查表观遗传机制， 信息可以从父系传递给后代和孙辈。这些跨代研究 代表了一种新的策略，以确定转录相关的风险或保护因素的精神兴奋剂自我， 管理，这将照亮治疗发展的新目标。