Prenatal Alcohol and Adult Hippocampal Neurogenesis

产前酒精与成人海马神经发生

• 批准号: 8460781
• 负责人: ANDREA M ALLAN
• 金额: $ 32.06万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-05 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8460781
• 关键词: Address; Adult; Alcohols; Attenuated; Behavioral; Blood alcohol level measurement; Brain; Brain region; Child; Clinical; Cognitive; Data; Defect; Depressive disorder; Development; Dose; Dysmorphology; Environment; Ethanol; Exposure to; FOS gene; Face; Female; Fetal Alcohol Exposure; Fetal Alcohol Spectrum Disorder; Fetal Alcohol Syndrome; Genetic; Glutamates; Goals; Growth; Growth Factor; Hippocampus (Brain); Immediate-Early Genes; Impairment; In Vitro; Label; Learning; Light; Link; Maps; Mediating; Memory; Mental Retardation; Mitotic; Mothers; Mus; Neuronal Differentiation; Neurons; Newborn Infant; Pattern; Phenotype; Pregnancy; Preparation; Production; Proliferating; Saccharin; Slice; Stem cells; Synapses; Tamoxifen; Teratogens; Testing; Time; Training; Transgenic Mice; alcohol consumption during pregnancy; alcohol exposure; alcohol measurement; base; dentate gyrus; design; disability; drinking; gamma-Aminobutyric Acid; granule cell; in vivo; irradiation; mouse model; nerve stem cell; nestin protein; neurogenesis; neuron development; newborn neuron; novel; offspring; prenatal; prenatal exposure; progenitor; public health relevance; relating to nervous system; research study; response; self-renewal; stem

DESCRIPTION (provided by applicant): The overall goal of this proposal is to elucidate the mechanisms by which prenatal exposure to moderate doses of alcohol results in long-lasting impairment of enrichment-mediated adult hippocampal neurogenesis, and to link this deficit with impairment of hippocampal-dependent learning in our mouse model of fetal alcohol spectrum disorder (FASD). FASD mice display impaired cognitive ability in hippocampal-dependent learning tasks and show signs of depressive disorder. FASD mice also display persistent deficits in adult hippocampal neurogenesis, which become apparent when the mice are behaviorally challenged by exposure to enriched environment. In this proposal, experiments are designed to determine whether the mechanisms underlying the FASD phenotype include impaired neuronal differentiation and maturation of neural stem cells in adult hippocampus, and diminished incorporation of adult-generated dentate granule cells into spatial memory networks. To test this, we will utilize a novel conditional and inducible nestin- CreERT2:YFP transgenic mouse which allows non-invasive labeling of large numbers of adult neural stem cells and their progeny. FASD and Sacc (control) mice will be generated in the nestin-CreERT2:YFP strain and utilized to address the following Specific Aims. Specific Aim 1 To determine whether prenatal ethanol exposure impairs neuronal differentiation and maturation of adult hippocampal neural stem cells. The nestin-CreERT2:YFP strain will be used to fate map and characterize neuronal differentiation of neural stem cells in adult hippocampus of FASD and Sacc (control) mice in vivo (SA1.1) and following isolation of adult NSCs in vitro (SA1.2). Specific Aim 2: To determine whether prenatal exposure to alcohol impairs synaptic maturation and plasticity of adult-born dentate granule cells (DGCs). Tamoxifen will be used to birthdate and YFP label newborn DGCs for electrophysiological recordings in adult hippocampal slice preparations from FASD and Sacc nestin-CreERT2:YFP mice. Using this approach, we will test the hypotheses that prenatal alcohol exposure disrupts the maturation of GABA- and glutamate-mediated currents (SA2.1) and attenuates LTP plasticity in adult born DGCs (SA2.2). Specific Aim 3: To determine whether prenatal ethanol exposure impairs the ability of newly- generated DGCs to preferentially incorporate into spatial memory networks. We will determine whether preferential activation of newborn neurons is attenuated in adult hippocampus of FASD mice during recall of a spatial memory task, as assessed by immediate early gene (c-fos) expression nestin-CreERT2:YFP mice.

描述(由申请人提供)：这项建议的总体目标是阐明产前暴露于中等剂量的酒精导致浓缩介导的成年海马神经发生的长期损害的机制，并将这种缺陷与我们的胎儿酒精谱障碍(FASD)小鼠模型的海马区依赖学习障碍联系起来。FASD小鼠在海马区依赖的学习任务中表现出认知能力受损，并表现出抑郁障碍的迹象。FASD小鼠在成年海马神经发生方面也表现出持续性缺陷，当小鼠暴露在丰富的环境中受到行为挑战时，这一点变得明显。在这项建议中，实验旨在确定FASD表型的潜在机制是否包括成年海马神经干细胞分化和成熟受损，以及成人产生的齿状颗粒细胞加入空间记忆网络的减少。为了测试这一点，我们将利用一种新型的条件和可诱导的Nestin-CreERT2：YFP转基因小鼠，它允许对大量成年神经干细胞及其后代进行非侵入性标记。FASD和Sacc(对照)小鼠将在Nestin-CreERT2：YFP品系中产生，并用于解决以下特定目的。具体目的1确定孕期酒精暴露是否损害成年海马神经干细胞的神经元分化和成熟。Nestin-CreERT2：YFP品系将用于FASD和Sacc(对照)小鼠成年海马神经干细胞在体内(SA1.1)和成年NSCs体外分离(SA1.2)的命运图谱和神经干细胞分化的特征。特定目的2：确定产前酒精暴露是否损害成年出生的齿状颗粒细胞(DGC)的突触成熟和可塑性。他莫昔芬将用于出生日期和YFP标记新生DGC，用于FASD和Sacc Nestin-CreERT2：YFP小鼠的成年海马片的电生理记录。使用这种方法，我们将检验以下假设：产前酒精暴露扰乱成年出生的DGC中GABA和谷氨酸介导的电流(SA2.1)的成熟，并减弱LTP的可塑性(SA2.2)。具体目标3：确定产前酒精暴露是否损害新生成的DGC优先整合到空间记忆网络的能力。我们将确定在空间记忆任务的回忆过程中，FASD小鼠成年海马区新生神经元的优先激活是否减弱，这是通过立即早期基因(c-fos)表达Nestin-CreERT2：YFP小鼠来评估的。