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神经元的一种新形式。 可塑性与某些形式的依赖于大脑的学习有关。我们最近的研究表明， 成年齿状回内新颗粒神经元的产生在暴露于中等剂量的 乙醇在整个妊娠期。虽然一些研究已经证明了急性乙醇对 成年海马体和培养的分离干细胞中的神经发生（Crews和尼克松，2003; He等， 2005;尼克松和克鲁斯，2004），我们的研究是第一个证明胎儿酒精暴露（FAE） 导致小鼠成年海马神经发生的持续缺陷（Choi等，2005年）。有趣的是，这些 只有当成年FAE小鼠受到行为攻击时，神经原性缺陷才变得明显。为 例如，当暴露于丰富的生活条件数周时，对照小鼠显示出2倍的增加， 在海马神经发生中，而FAE小鼠的反应没有增加神经源性反应。 因为我们发现齿状颗粒下区的祖细胞池的大小没有差异， 我们的研究表明，随着祖细胞增殖速率的改变， 成年齿状核内的神经元在丰富的环境条件下。目前，我们的研究主要集中在 了解FAE小鼠这种受损神经原性反应的机制基础。 我们的总体假设是，对丰富环境的神经原性反应受损是由于 成体神经干细胞自身的内在缺陷和/或由于持续存在的微环境变化 在神经原生态位中。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是否导致成体神经干细胞的内在缺陷？为了解决这个问题， 我们将比较分离自成人FAE与成人FAE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是否会造成在大气层内持续存在的微环境扰动？ 成年海马体的神经原生态位为了解决这个问题，我们将比较血管 FAE与对照小鼠中成年颗粒下区/齿状门区域内的密度和小胶质细胞特性， 因为这些成分部分调节对丰富环境的神经原性反应。

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.