Adult Neurogenesis & Alcohol-Induced Learning Deficits

描述（由申请人提供）：海马体的齿状回是一个在整个成年生活中不断产生新神经元的区域。虽然成年海马神经发生的作用仍有争议，但越来越多的证据表明，它参与了某些形式的海马依赖性学习的获得。基于这些发现，我们已经开始探索产前乙醇暴露啮齿动物的成年后代的学习缺陷和神经发生之间的关系。在这些研究中，我们利用了一种基于自由选择的胎儿酒精暴露（FAE）小鼠模型，该模型代表了FAE的适度酒精接触模型。FAE小鼠的成年后代表现出与FAE大鼠相似的学习缺陷，但FAE小鼠模型不受潜在饮食和配对喂养效应的混淆。本提案中提供的初步数据表明，FAE在标准住房条件下不会损害基底神经发生，但会消除对丰富环境的神经原性反应。本探索性R21提案中概述的研究旨在确定a）FAE是否也损害对海马依赖性学习的神经原性反应，以及B）对行为挑战的神经原性反应的缓解是否是由于FAE祖细胞的内在缺陷和/或由于成年SGZ神经原性生态位内的微环境变化。我们的初步研究是最早证明产前暴露可导致成人海马神经发生持续性缺陷的研究之一。由于学习障碍是最普遍和最普遍的胎儿酒精相关的缺陷儿童，进一步的研究，以了解这些缺陷的基础上，产前乙醇暴露的动物模型似乎是必要的。

DESCRIPTION (provided by applicant): The denate gyrus of the hippocampus is an area where new neurons continue to be generated throughout adult life. Although the role of adult hippocampal neurogenesis is still debated, accumulating evidence suggests that it is involved in the acquisition of certain forms of hippocampal-dependent learning. Based on those findings, we have begun to explore the relationship between learning deficits and neurogenesis in adult offspring of prenatal ethanol exposed rodents. For these studies, we have utilized a mouse model of fetal alcohol exposure (FAE) that is based on free-choice and represents a moderate alcohol access model of FAE. Adult offspring of FAE mice display learning deficits similar to that of the FAE rat, but the FAE mouse model is not confounded by potential diet and pair feeding effects. Preliminary data presented in this proposal demonstrate that FAE does not impair basal neurogenesis under standard housing conditions, but abolishes the neurogenic response to enriched environment. Studies outlined in this exploratory R21 proposal are designed to determine a) whether FAE also impairs the neurogenic response to hippocampal-dependent learning, and b) whether mitigation of the neurogenic response to behavioral challenge is due to intrinsic defects of FAE progenitors and/or due to microenvironmental changes within the neurogenic niche of the adult SGZ. Our preliminary studies are among the first to demonstrate that prenatal exposures can result in persistent defects in adult hippocampal neurogenesis. Since learning disabilities are among the most prevalent and pervasive fetal alcohol-related defects in children, further studies to understand the basis of these deficits in animal models of prenatal ethanol exposure seems warranted.