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显著影响。然而，表观遗传对成瘾表型的潜在影响仍不清楚。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的发展，以描绘遗传表型导致的可卡因的自我管理。我们发现，虽然有可卡因经验的母鼠（BCocSired）的雄性后代与对照母鼠（BSalSired）的后代相比，获得可卡因自我给药的时间延迟，维持时间减少，但雌性后代在获得可卡因自我给药方面没有差异。这些新颖的结果表明，可卡因经验丰富的男性后代对可卡因的抵抗力增强了。本应用概述的具体目的将评估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的实验旨在评估表观遗传和行为机制，通过父本可卡因自我给药可能影响其后代的行为。在具体目标2中，我们将评估自我服用可卡因的雄性大鼠的后代（F1）和大后代（F2）对可卡因和食物自我给药的获得性。特异性目的3关注内侧前额叶皮层脑源性神经营养因子在F1和F2 CocSired大鼠可卡因自我给药获得中的潜在作用。本应用程序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。我们的研究发现，相对于BSalSired大鼠，BCocSired大鼠的可卡因自我给药减少，这一发现是强有力的，对人类健康具有重要意义。下一步是确定这种表型背后的细胞和分子机制。本应用程序中描述的实验将使用最先进的细胞，分子和行为方法来i)检查表观遗传和行为机制，从而将可卡因相关信息从后代传递给后代，ii)确定遗传的可卡因抗性表型是否跨代，iii)评估可能构成与可卡因自我给药相关的父系遗传表型的特定神经元机制。

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. PUBLIC HEALTH RELEVANCE: A growing body of evidence indicates that environmental information can be inherited, which suggests that changes in the mammalian germline can act as a trans-generational carrier of environmental information. Here, we describe a rat model developed in order to delineate heritable behavioral characteristics resulting from the self-administration of cocaine. Our results suggest that cocaine experienced sires confer a resistance to cocaine reinforcement in their male offspring. The experiments described in this application will use state-of- the-art cellular, molecular and behavioral methodologies to examine the mechanisms whereby cocaine- associated information can be transmitted from sires to offspring and assess specific neuronal changes that may underlie this paternally transmitted phenotype associated with cocaine self-administration.