Adult Neurogenesis & Alcohol-Induced Learning Deficits

描述(申请人提供)：海马齿状回是成年后不断产生新神经元的区域。尽管成年海马区神经发生的作用仍然存在争议，但越来越多的证据表明，它与某些形式的海马区依赖学习的获得有关。基于这些发现，我们已经开始探索孕期酒精暴露的成年啮齿动物的学习障碍与神经发生之间的关系。在这些研究中，我们使用了胎儿酒精暴露(FAE)的小鼠模型，该模型基于自由选择，代表了FAE的中度酒精接触模型。FAE小鼠的成年后代表现出与FAE大鼠相似的学习缺陷，但FAE小鼠模型没有受到潜在的饮食和配对喂养效应的困扰。初步数据表明，在标准住房条件下，FAE不会损害基础神经发生，但会取消对丰富环境的神经发生反应。在这个探索性的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学习的神经源性反应，以及b)对行为挑战的神经源性反应的缓解是否由于FAE前体的内在缺陷和/或由于成年SGZ神经源性壁龛内的微环境变化。我们的初步研究表明，产前暴露可导致成年海马神经发生的持续性缺陷。由于学习障碍是儿童中最普遍和最普遍的胎儿酒精相关缺陷之一，在产前酒精暴露的动物模型中，似乎有必要进行进一步的研究，以了解这些缺陷的基础。

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.