Effects of alcohol on neuronal cell migration

酒精对神经细胞迁移的影响

• 批准号: 6463408
• 负责人: Hitoshi Komuro
• 金额: $ 25.9万
• 依托单位: CLEVELAND CLINIC FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-05-01 至 2006-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6463408
• 关键词: NMDA receptors; calcium flux; calcium indicator; cell migration; cell morphology; cerebellum; confocal scanning microscopy; cytotoxicity; developmental neurobiology; drug administration rate /duration; embryo /fetus tissue /cell culture; embryo /fetus toxicology; excitatory aminoacid; fetal alcohol syndrome; fluorescent dye /probe; glycine; granule cell; ion channel blocker; laboratory mouse; magnesium; membrane potentials; potassium; sectioning; time resolved data

DESCRIPTION (provided by applicant): Maternal alcohol consumption during pregnancy can cause serious birth defects, of which fetal alcohol syndrome (FAS) is the most devastating. Recognized by characteristic craniofacial abnormalities and growth deficiency, this condition includes severe alcohol-induced damage to the developing brain. FAS children experience deficits in intellectual functioning; difficulties in learning, memory, problem solving, and attention; difficulties with mental health and social interactions. The long-term goal of present proposal is to elucidate the cellular and molecular mechanisms underlying alcohol-induced malformation of brain. Specially, we will focus on the effects of alcohol on neuronal cell migration in the developing brain, since many ectopic neurons are found in the brain of FAS patients, suggesting that alcohol exposure causes abnormal migration of immature neurons. To this end, we use cerebellum as a model system, because the effect of alcohol on brain growth is especially marked in the cerebellum. We will determine the effects of alcohol on the cerebellar granule cell migration. First, we will determine when, where and how alcohol alters the migration of cerebellar granule cells in a real-time manner with the use of acute cerebellar slice preparations and microexplant cultures. In particularly, we will examine a relationship between mounts and durations of alcohol administration and inhibition of cell movement. Second, we will determine whether changes in intracellular Ca2+ fluctuations and membrane potential of migrating granule cells are involved in alcohol-induced alteration of neuronal migration. Third, we will determine whether manipulations of intracellular Ca2+ fluctuations and membrane potentials by activating NMDA receptor or inhibiting K+ channel activity can overcome the alcohol-induced changes in cell migration. The fundamental mechanisms whereby ethanol administration leads to the disturbances of brain development have not been delineated definitively. Answers to the questions raised in this project will provide a new insight for understanding how prenatal and early postnatal exposure to alcohol causes malformation of brain.

描述（由申请人提供）：在 怀孕可能导致严重的先天缺陷，其中胎儿酒精综合症 （FAS）是最毁灭性的。以特征性的颅面认可 异常和生长不足，这种情况包括严重 酒精引起的大脑损害。 FAS儿童经历 智力功能的缺陷；学习，记忆，问题的困难 解决和注意；心理健康和社会的困难 互动。目前建议的长期目标是阐明 酒精引起的畸形的细胞和分子机制 脑。特别是，我们将专注于酒精对神经元细胞的影响 由于在发育中的大脑中迁移，因为在许多异位神经元中发现了许多异位神经元 FAS患者的大脑，表明酒精暴露会导致异常 未成熟神经元的迁移。为此，我们将小脑用作模型 系统，因为酒精对大脑生长的影响特别明显 小脑。 我们将确定酒精对小脑颗粒细胞的影响 迁移。首先，我们将确定酒精何时，何时和如何改变 小脑颗粒细胞以实时方式迁移 急性小脑切片制剂和微爆发培养物。特别是 我们将检查坐骑与酒精持续时间之间的关系 给药和抑制细胞运动。第二，我们将确定 细胞内Ca2+波动和膜电位的变化是否变化 迁移的颗粒细胞参与酒精诱导的神经元改变 迁移。第三，我们将确定细胞内Ca2+的操作是否 通过激活NMDA受体或抑制来波动和膜电位 K+通道活性可以克服酒精引起的细胞迁移变化。 乙醇给药的基本机制导致 大脑发育的干扰尚未确切地描述。 对该项目提出的问题的答案将为您提供新的见解 了解产后和早期暴露于酒精原因 大脑的畸形。