MECHANISMS UNDERLYING CHOLINE ENHANCEMENT OF MEMORY

胆碱增强记忆的机制

• 批准号: 6098292
• 负责人: CHRISTINA L WILLIAMS
• 金额: $ 22.26万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-15 至 2000-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6098292
• 关键词: acetylcholine; acetylcholinesterase; aging; apolipoprotein E; behavior test; behavioral /social science research tag; choline; choline acetyltransferase; developmental neurobiology; dietary supplements; folate; genetically modified animals; hippocampus; immunocytochemistry; laboratory mouse; laboratory rat; memory; mother /embryo /fetus nutrition; neuroanatomy; neurochemistry; nutrient bioavailability; nutrition related tag; perinatal; phosphatidylcholines; space perception

Research from our laboratories has demonstrated that choline supplementation during perinatal development produces long-term facilitation of spatial memory, attention, and temporal processing, and inoculates against age-related memory decline, while deficiency of choline produces some deleterious effects. These long-lasting behavioral changes are accompanied by a complex pattern of changes in the neuroanatomy, neurochemistry, and neurophysiology of the septohippocampal system. The findings from several of the laboratories during the past funding period provide the foundation of the Aims of this Project. We have discovered that supplementation with folate, like choline , during the second half of pregnancy improve memory performance of the offspring. This finding is particularly important because the metabolism of choline and methyl-folate are closely interrelated. We propose to carefully characterize the nature of folate effects on memory and compare these effects to choline in order to determine if there might be a common mechanism underlying the effects of both these nutrients on memory function. As well, despite recommendations to supplement folate to women periconceptually to prevent neural tube defects, little is known about the long-term effects of folate during the latter half of pregnancy on brain or behavior. We aim to characterize the behavioral, neuroanatomical, and neurochemical effects of prenatal folate supplementation and deficiency. We have also determined that during choline supplementation to the dam's diet, the majority of choline ingested by the dam is converted to phospatidylcholine (PtdCho) and then delivered to the fetus. In addition, we have observed that a lipoprotein containing apolipoprotein E (apoE) can effectively deliver PtdCho to cells in vitro. We suggest that an apoE lipoprotein is responsible for delivery of PtdCho to brain cells in vivo. In addition, we have determined that apoE deficient mice have a selective deficit in working memory that can be detected in mice as young at 4-5 months of age. We hypothesize that apoE deficient mice may actually be suffering from choline insufficiency through life because they cannot effectively deliver PtdCho to brain cells. Thus, the second aim of our Project is to examine the behavioral neuroanatomical and biochemical consequences of prenatal or lifelong choline supplementation to apoE deficient mice in order to determine whether we can rescue them from these lifelong behavioral deficits.

我们实验室的研究表明，围产期发育期间补充胆碱可以长期促进空间记忆、注意力和时间处理，并预防与年龄相关的记忆衰退，而胆碱缺乏会产生一些有害影响。这些持久的行为变化伴随着隔海马系统的神经解剖学、神经化学和神经生理学的复杂模式变化。过去资助期间几个实验室的研究结果为本项目的目标奠定了基础。我们发现，在怀孕后半段补充叶酸（如胆碱）可以提高后代的记忆力。这一发现尤其重要，因为胆碱和甲基叶酸的代谢密切相关。我们建议仔细描述叶酸对记忆影响的性质，并将这些影响与胆碱进行比较，以确定这两种营养素对记忆功能的影响是否存在共同机制。此外，尽管建议女性在围孕期补充叶酸以预防神经管缺陷，但人们对怀孕后期叶酸对大脑或行为的长期影响知之甚少。我们的目标是描述产前叶酸补充和缺乏对行为、神经解剖学和神经化学的影响。我们还确定，在给母鼠饮食补充胆碱的过程中，母鼠摄入的大部分胆碱会转化为磷脂酰胆碱（PtdCho），然后输送给胎儿。此外，我们还观察到含有载脂蛋白E（apoE）的脂蛋白可以在体外有效地将PtdCho递送至细胞。我们认为 apoE 脂蛋白负责将 PtdCho 递送至体内脑细胞。此外，我们还确定，apoE 缺陷小鼠的工作记忆存在选择性缺陷，这种缺陷在 4-5 个月大的小鼠中就可以检测到。我们假设 apoE 缺陷小鼠实际上可能一生都患有胆碱不足，因为它们无法有效地将 PtdCho 传递到脑细胞。因此，我们项目的第二个目标是检查 apoE 缺陷小鼠产前或终生补充胆碱的行为神经解剖学和生化后果，以确定我们是否可以将它们从这些终生行为缺陷中拯救出来。