BRAIN AGING--MOLECULAR EFFECTS OF PERINATAL NUTRITION

项目1的总体目标是确定参与由产前胆碱或叶酸的可用性和载脂蛋白E（apoE）基因型控制的脑重组的分子机制。我们已经发现，大鼠妊娠后半期胆碱的可用性导致脑中的生化，结构和电生理变化以及深刻的行为改变。一般来说，年轻成年和老年大鼠产前补充胆碱和改善性能相对于控制和产前缺陷的动物在测量记忆和注意力的任务。相比之下，产前缺陷动物在测量记忆和注意力的注意力任务中受到损害。相反，产前缺陷的动物在注意力任务中受损，但在记忆任务中有所改善。对数据进行的研究表明，产前胆碱的可用性可能会影响大脑中多种突触信号通路的发育。特别是产前胆碱的可用性改变海马的长期潜力，乙酰胆碱（ACh）营业额，磷脂酶D活性，神经生长因子信号的指数。我们将确定胎儿期胆碱和叶酸对发育、成年和衰老过程中大脑信号转导系统的影响。迄今为止进行的研究表明，产前胆碱的可用性改变了发育中大脑的有丝分裂和凋亡模式以及几种蛋白质的表达模式。这些数据与我们的假设一致，即产前必需营养素的可用性导致大脑组织的多种变化。我们建议确定的发展模式的表达的大脑基因使用杂交高密度寡核苷酸阵列和反向北方分析，然后通过原位杂交分析，从而确定的基因。叶酸和胆碱的代谢是高度相关的，因此，叶酸的可用性对乙酰胆碱在大脑中的营业额的影响将被检查。在脑内，胆碱可能通过一种机制在细胞间重新分布，该机制涉及载脂蛋白A介导的含胆碱脂质的转运。磷脂酰胆碱（PC）。我们将确定ApoE-/-小鼠的脑ACh周转是否改变。我们将调查的可能性，饮食胆碱将修改乙酰胆碱营业额叶酸缺乏和载脂蛋白E-/-动物。此外，我们建议，以确定是否含有载脂蛋白E的脂蛋白可以提供PC胆碱能神经元使用剔除培养模型。

The overall goal of Project 1 is to determine the molecular mechanisms involved in brain reorganization governed by prenatal availability of choline or folic acid and by apolipoprotein E (apoE) genotype. We have found that the availability of choline during the second half of gestation in rats causes biochemical, structural and electrophysiologic changes in brain as well as profound behavioral modifications.. In general, young adult and aged rats supplemented prenatally with choline and improved performance relative to control and prenatally-deficient animals in tasks measuring memory and attention. In contrast,, prenatally deficient animals were impaired in attentional tasks measuring memory and attention. In contrast, prenatally deficient animals were impaired in attentional tasks but somewhat improved in memory tasks. Studies performed to data indicated that prenatal availability of choline may affect the development of multiple synaptic signaling pathways in brain. Specifically prenatal choline availability modifies hippocampal long-term potential,.acetylcholine (ACh) turnover, phospholipase D activity, and indices of nerve growth factor signaling. We will determine the effects of prenatal choline availability and folate availability on signal transduction systems in brain during development, adulthood and aging. Studies performed to date show that prenatal availability of choline alters the patterns of mitosis and apoptosis in developing brain as well as patterns of expression of several proteins. These data are consistent with our hypothesis that prenatal availability of essential nutrients causes multiple changes in brain organization. We propose to determine the developmental patterns of expression of brain genes using hybridization to high density oligonucleotide arrays and reverse Northern analysis followed by in situ hybridization assays of thus identified genes. The metabolism of folate and choline are highly interrelated; therefore the effects of folate availability on ACh turnover in brain will be examined. Within the brain, choline may be redistribut4ed between cells by a mechanism involving apolipoprotein A-mediated transport of a choline- containing lipid. phosphatidylcholine (PC). We will determine if brain ACh turnover is altered in ApoE-/- mice. We will investigate the possibility that dietary choline will modify ACh turnover in folate deficient and ApoE-/- animals. In addition we propose to determine if apoE-containing lipoproteins can supply PC to cholinergic neurons using a cull culture model.