Transgenerational Inheritance of a Cocaine Resistance Phenotype

描述(由申请人提供)：遗传因素对人类滥用可卡因的风险有很大影响。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，环境信息是可以遗传的。因此，哺乳动物生殖系中的表观遗传变化可以作为环境扰动的跨代载体。在这里，我们描述了一个大鼠模型，以描述可卡因自我给药导致的可遗传表型。我们发现，虽然有可卡因经验的雄性后代(BCocSired)比带轭生理盐水对照组(BSalSired)的后代延迟了可卡因的获得，并减少了对可卡因自我给药的维持，但雌性后代在获得可卡因自我给药方面没有差异。这些新的结果表明，有可卡因经验的雄性后代对可卡因强化具有抵抗力。在本申请中概述的具体目标将评估可能支持与可卡因自我给药相关的父系遗传表型的特定机制。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，父亲的可卡因自我给药可能会影响其后代的行为。在具体目标2中，我们将评估自服可卡因的雄性大鼠的子代(F1)和子代(F2)对可卡因的获得和食物自我管理。具体目标3集中于内侧前额叶皮质脑源性神经营养因子在F1和F2可卡因自我给药大鼠获得可卡因自我给药中的潜在作用。本申请中描述的初步数据是新颖的，并利用动物模型建立了成瘾相关表型的遗传。我们的发现是，相对于BSalSired大鼠，BCocSired大鼠的可卡因自我给药减少，这一发现是可靠的，对人类健康具有重大影响。下一步是确定这种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、分子和行为方法来检查表观遗传学和行为机制，从而使可卡因相关信息可以从父代传递给后代，ii)确定遗传的可卡因抗性表型是否是跨代的，以及iii)评估可能支持与可卡因自我给药相关的父系传递表型的特定神经机制。

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.