Embryo Transfer for the Study of Transgenerational Modifications in Morphine Sens

描述（由申请人提供）：许多研究表明，药物滥用的遗传性是由遗传和环境因素共同造成的。调控基因与环境相互作用的一种机制是表观遗传修饰。在这种情况下，术语表观遗传学是指DNA和组蛋白修饰，调节基因表达，并从母细胞传递到子细胞，或从亲本传递到子代，但不改变潜在的DNA序列。虽然表观遗传修饰可以从一代传递到下一代是很清楚的，但这些影响传递的机制还没有完全了解。最近的一些研究结果表明，母体环境，无论是产前还是产后，都可能在表观遗传转移中发挥关键作用。迄今为止，表观遗传学在家族性药物滥用模式中的作用尚未得到充分研究。我们开发了一种雌性大鼠青春期吗啡暴露的动物模型，以检查在这一独特的发育时期阿片类药物使用的长期后果。我们的研究结果表明，除了青春期暴露于吗啡的成年雌性大鼠的基因表达显著改变外，青春期暴露于吗啡的雌性大鼠的后代对吗啡的反应性增强。该模型的一个重要方面是，青春期接触吗啡的女性在交配前几周没有吸毒，因此没有直接在子宫内接触吗啡。本提案的目的是发展、完善和实施在青春期暴露于吗啡的女性的非手术胚胎移植。这项技术随后将被用于描述由这些基因在胚胎水平上的修饰直接介导的后代效应

DESCRIPTION (provided by applicant): Many studies demonstrate that the hereditary nature of drug abuse is due to both genetic and environmental factors. One mechanism regulating interactions between genes and the environment are epigenetic modifications. In this context, the term epigenetics refers to DNA and histone protein modifications that regulate gene expression and which are transmitted from a mother cell to a daughter cell, or from a parent to its progeny, but which do not change the underlying DNA sequence. While it is clear that epigenetic modifications can be passed from one generation to the next, the mechanisms involved in the transmission of these effects are not fully understood. Several recent findings indicate that the maternal environment, both pre- and postnatal, may play a critical role in epigenetic transfer. To date, the role of epigenetics in familial patterns of drug abuse has not been well-studied. We have developed an animal model of adolescent morphine exposure in female rats to examine the long-term consequences of opiate use during this unique developmental period. Our findings demonstrate that, in addition to significant alterations in gene expression in adult female rats exposed to morphine during adolescence, the offspring of adolescent-exposed females demonstrate enhanced responsiveness to morphine. One important aspect of this model is that adolescent morphine- exposed females are drug-free for several weeks prior to mating, and thus there is no direct in utero exposure. The purpose of this proposal is to develop, refine, and implement non-surgical embryo transfer in females exposed to morphine during adolescent development. This technique will then be used to delineate offspring effects that are directly mediated by modifications at the level of the embryo from those induced by alterations in the pre- and/or postnatal environment. The primary focus will be on transgenerational alterations in morphine sensitivity (behavioral and physiological) as these effects are well-characterized. Moreover, understanding how drug-induced alterations in morphine sensitivity may be passed from one generation to the next may help identify basic mechanisms underlying familial patterns of substance use.