Component 3: Cunningham & Allan

具体目标 成年齿状回内新神经元的产生代表了海马体的一种新形式 与某些形式的海马体依赖学习相关的可塑性。我们最近的研究表明 中等剂量暴露的小鼠齿状回内新颗粒神经元的产生受到损害 在整个怀孕过程中都是酒精。虽然有几项研究表明急性乙醇对人体健康的影响很强 成年海马区和培养中分离的干细胞中的神经发生(Crews和Nixon，2003；他等人， 2005；Nixon and Crews，2004)，我们的研究首次证明胎儿酒精暴露(FAE) 结果成年小鼠海马神经发生持续缺陷(Choi等人，2005年)。有趣的是，这些 神经源性缺陷只有在成年FAE小鼠受到行为挑战时才会变得明显。为 例如，当暴露在丰富的生活条件下几周时，对照组小鼠的体重增加了2倍 在海马神经发生中，而FAE小鼠的反应不增加神经性反应。 因为我们发现齿状颗粒下层的祖细胞池大小没有差别，也没有 祖细胞增殖率的变化，我们的研究表明新生的 在丰富的环境条件下，成体内的神经元呈齿状。目前，我们的研究主要集中在 了解FAE小鼠神经源性反应受损的机制基础。 我们的主要假设是，对丰富环境的神经原性反应受损是由于 成人神经干细胞本身的固有缺陷和/或由于持续的微环境变化 在神经源性的缝隙中。为了验证这一假设，我们提出了以下具体目标： 具体目标1：FAE是否会导致成人神经干细胞的内在缺陷？为了解决这个问题， 我们将比较从成体FAE中分离的神经干细胞的自我更新和分化特性。 体外对照小鼠。 具体目标2：FAE是否导致持续存在于 成年海马体的神经性生态位？为了解决这个问题，我们将比较血管 与对照组相比，FAE小鼠成体颗粒下带/齿状门区的密度和小胶质细胞特性 因为这些成分在一定程度上调节了对丰富环境的神经源性反应。

SPECIFIC AIMS The production of new neurons within the adult dentate gyrus represents a novel form of hippocampal plasticity associated with certain forms of hippocampal-dependent learning. Our recent studies suggest that the production of new granule neurons within the adult dentate gyrus is impaired in mice exposed to moderate ethanol throughout gestation. While several studies have demonstrated robust effects of acute ethanol on neurogenesis in the adult hippocampus and in isolated stem cells in culture (Crews and Nixon, 2003; He et al., 2005; Nixon and Crews, 2004), our studies were the first to demonstrate that fetal alcohol exposure (FAE) results in persistent deficits in adult hippocampal neurogenesis in mice (Choi et al., 2005). Interestingly, these neurogenic deficits only become apparent when the adult FAE mouse is behaviorally challenged. For example, when exposed for several weeks to enriched living conditions, control mice display a 2-fold increase in hippocampal neurogenesis, whereas FAE mice respond with no increase in the neurogenic response. Because we found no difference in the size of the progenitor pool in the dentate subgranular zone, nor any change in the rate of progenitor proliferation, our studies suggest impaired survival and integration of new neurons within the adult dentate under conditions of enriched environment. Currently, our studies are focused on understanding the mechanistic underpinnings of this impaired neurogenic response in FAE mice. Our overarching hypothesis is that the impaired neurogenic response to enriched environment is due to an intrinsic defect in the adult neural stem cells themselves and/or due to microenvironmental changes that persist within the neurogenic niche. To test this hypothesis, we propose the following Specific Aims: Specific Aim 1: Does FAE result in intrinsic defects in adult neural stem cells? To address this question, we will compare the self-renewal and differentiation properties of neural stem cells isolated from adult FAE vs. control mice in vitro. Specific Aim 2: Does FAE result in microenvironmental perturbations that persist within the neurogenic niche of the adult hippocampus? To address this question we will compare the vascular density and microglial properties within the adult subgranular zone/dentate hilus region in FAE vs. control mice, since these components regulate, in part, the neurogenic response to enriched environment.