Transgenerational Inheritance of a Cocaine Resistance Phenotype

可卡因耐药表型的跨代遗传

• 批准号: 8627155
• 负责人: Robert Christopher Pierce
• 金额: $ 44.46万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 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 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8627155
• 关键词: Accounting; Acetylation; Adult; Animal Model; Behavioral; Behavioral Mechanisms; Brain-Derived Neurotrophic Factor; Breeding; CREB1 gene; Characteristics; Cocaine; Cocaine Abuse; DNA Methylation; Data; Dose; Epigenetic Process; Female; Food; Generations; Genes; Genetic; Grooming; Health; Human; Inherited; Learning; Maintenance; Maternal Behavior; Measures; Medial; Mediating; Messenger RNA; Methodology; Methyl-CpG-Binding Protein 2; Methylation; Modeling; Molecular; Neurons; Phenotype; Play; Prefrontal Cortex; Proteins; Psychological reinforcement; Rattus; Relative (related person); Resistance; Risk; Role; Saline; Self Administration; Self-Administered; Viral; Work; addiction; behavior influence; cocaine exposure; design; experience; histone modification; male; novel; offspring; promoter; pup; research study; sperm cell; transcription factor

DESCRIPTION (provided by applicant): Genetic factors contribute significantly to the risk of cocaine abuse in humans. However, the potential role of epigenetic influences on addiction phenotypes remains unclear. A growing body of evidence indicates that environmental information can be inherited. Thus, epigenetic changes in the mammalian germline can act as a transgenerational carrier of environmental perturbations. Here, we describe a rat model developed in order to delineate a heritable phenotype resulting from the self-administration of cocaine. We found that while the male offspring of cocaine-experienced sires (BCocSired) had delayed acquisition and reduced maintenance of cocaine self-administration relative to the offspring of yoked saline controls (BSalSired), there was no difference in the acquisition of cocaine self-administration in female offspring. These novel results suggest that cocaine experienced sires confer a resistance to cocaine reinforcement in their male offspring. The specific aims outlined in this application will assess specific mechanisms that may underlie this paternally transmitted phenotype associated with cocaine self-administration. The experiments in Specific Aim 1 are designed to assess epigenetic and behavioral mechanisms through which paternal cocaine self-administration may influence the behavior of their descendants. In Specific Aim 2 we will evaluate the acquisition of cocaine and food self-administration in the offspring (F1) and grand offspring (F2) of male rats that self-administered cocaine. Specific Aim 3 focuses on the potential role of medial prefrontal cortical brain-derived neurotrophic factor in the acquisition of cocaine self-administration in F1 and F2 CocSired rats. The preliminary data described in this application are novel and establish the inheritance of an addiction-related phenotype using an animal model. Our finding that the cocaine self-administration is reduced in BCocSired relative to BSalSired rats is robust and has significant implications in terms of human health. The next step is to determine the cellular and molecular mechanisms underlying this phenotype. The experiments described in this application will use state-of-the-art cellular, molecular and behavioral methodologies to i) examine epigenetic and behavioral mechanisms whereby cocaine-associated information can be transmitted from sires to offspring, ii) determine if the inherited cocaine resistance phenotype is transgenerational, and iii) assess specific neuronal mechanisms that may underlie this paternally transmitted phenotype associated with cocaine self- administration.

描述（由申请人提供）：遗传因素对人类滥用可卡因的风险有显着影响。然而，表观遗传影响对成瘾表型的潜在作用仍不清楚。越来越多的证据表明环境信息可以遗传。因此，哺乳动物种系的表观遗传变化可以充当环境扰动的跨代载体。在这里，我们描述了一种为了描绘因自我施用可卡因而产生的可遗传表型而开发的大鼠模型。我们发现，虽然与有轭盐水对照组 (BSalSired) 的后代相比，经历过可卡因的雄性 (BCocSired) 的雄性后代延迟了可卡因自我给药的获得并减少了可卡因自我给药的维持，但雌性后代中可卡因自我给药的获得没有差异。这些新颖的结果表明，经历过可卡因的公牛赋予其雄性后代对可卡因强化的抵抗力。本申请中概述的具体目标将评估可能构成与可卡因自我给药相关的父系遗传表型的具体机制。具体目标 1 中的实验旨在评估表观遗传和行为机制，通过这些机制，父亲自我施用可卡因可能会影响其后代的行为。在具体目标 2 中，我们将评估自我施用可卡因的雄性大鼠的后代 (F1) 和孙代 (F2) 中可卡因的获得和食物的自我施用。具体目标 3 重点关注内侧前额皮质脑源性神经营养因子在 F1 和 F2 CocSired 大鼠获得可卡因自我给药过程中的潜在作用。该申请中描述的初步数据是新颖的，并使用动物模型建立了成瘾相关表型的遗传。我们的发现是，与 BSalSired 大鼠相比，BCocSired 大鼠的可卡因自我给药减少，这一发现是可靠的，并且对人类健康具有重大影响。下一步是确定该表型背后的细胞和分子机制。本申请中描述的实验将使用最先进的细胞、分子和行为方法来i)检查可卡因相关信息可以从父亲传递给后代的表观遗传和行为机制，ii)确定遗传性可卡因抗性表型是否是跨代的，以及iii)评估可能构成这种父系传递表型相关的特定神经元机制 可卡因自我给药。