ALCOHOL AND BRAIN DEVELOPMENT

酒精与大脑发育

• 批准号: 2046549
• 负责人: JAMES R WEST
• 金额: $ 17.13万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-09-29 至 1999-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2046549
• 关键词: cell population study; dosage; embryo /fetus toxicology; ethanol; fetal alcohol syndrome; gestational age; laboratory rat; morphology; neurochemistry; neurogenesis; neurons

The overall purpose of this proposal is to determine whether there are critical periods during which the developing brain is expressly vulnerable to alcohol exposure. The first hypothesis to be tested is that the developing brain is vulnerable to alcohol-induced damage as a consequence of the timing of the alcohol exposure; this is the hypothesis of temporal vulnerability. A second major hypothesis to be addressed is that specific regions of the fetal brain are differentially vulnerable to alcohol exposure; this is the hypothesis of regional vulnerability. The proposal is divided into two series of experiments. The objective of the first series will be document dose-dependent fetal alcohol-induced alterations in regional volume and neuronal loss in selected brain regions across major periods of prenatal development in the rat: the first trimester equivalent (embryonic days E1-E10), the second trimester equivalent (E11-E21), and the combined first and second trimesters equivalent (E1-E21). once we have identified the temporal risks to the fetal brain from alcohol exposure on a trimester basis, we will narrow the focus of our temporal vulnerability hypothesis. The second series of experiments will address a third hypothesis that is closely related to the first one; that alcohol exposure interferes with neurogenesis (i.e., the specific period when the neurons are generated) preventing the acquisition of a normal complement of neurons at this particular stage of their development. All of the hypotheses in this proposal are intimately linked to an important postulate: the severity of a deficit is a function of the peak blood alcohol concentration (BAC) to which the fetus is exposed. Therefore, to optimize control over the peak BACs, a gastric intubation technique will be used to administer daily doses of alcohol that will produce low, medium, or high BACs. In order to accomplish the goals stated above, it is necessary to use dependent variables that are appropriate for comparisons across all brain regions. Thus, state-of-the-art three-dimensional stereological methods will be used to determine any alterations in regional volumes and in neuronal numbers in seven important brain regions including the cerebellum, hippocampus, locus coeruleus, substantia nigra, ventrolateral thalamus, entorhinal cortex, and the septum. Taken together, the results from these experiments will facilitate the formulation of tentative conclusions regarding temporal vulnerability of developing neurons to alcohol exposure. From an experimental point of view, information concerning temporal windows and regional differences in vulnerability of the developing brain to alcohol exposure will contribute significantly to the formulation of research strategies directed toward discovering the mechanism(s) underlying fetal alcohol-induced brain damage. Equally important from a clinical perspective, knowledge of critical periods during development, when the brain is especially vulnerable to damage from alcohol exposure, will be beneficial for counseling patients about risks to the fetus from alcohol consumption during pregnancy and the advantages of cessation of drinking at particular stages of pregnancy.

该提案的总体目的是确定是否存在 发育大脑明确的关键时期 容易暴露酒精。要检验的第一个假设是 发育中的大脑容易受到酒精引起的损害 酒精暴露时间的结果；这是假设 时间脆弱性。要解决的第二个主要假设是 胎儿大脑的特定区域差异很大 暴露酒精；这是区域脆弱性的假设。 该提案分为两个系列实验。目的 第一个系列将是依赖剂量的胎儿酒精诱导的文档 部分大脑的区域体积和神经元丧失的改变 大鼠主要产前发展的地区地区： 孕期等效（胚胎天E1-E10），孕期 等效（E11-E21），以及联合的第一和第二三个 等效（E1-E21）。一旦我们确定了暂时的风险 孕期酒精暴露的胎儿大脑，我们将狭窄 我们时间脆弱性假设的重点。第二系列 实验将解决与 第一个；酒精暴露会干扰神经发生（即 产生神经元的特定时期） 在此特定阶段获得正常的神经元补体 他们的发展。该提议中的所有假设都是 与一个重要的假设密切相关：赤字的严重性 是血液酒精浓度（BAC）的函数 胎儿暴露了。因此，为了优化对峰值BAC的控制 胃插管技术将用于每日剂量 酒精会产生低，中或高的BAC。为了 完成上述目标，有必要使用依赖 适用于所有大脑区域进行比较的变量。 因此，最先进的三维立体方法将是 用于确定区域体积和神经元的任何改变 包括小脑在内的七个重要大脑区域中的数字， 海马，位于二元的基因座，黑质，腹外侧丘脑， 内河皮层和隔膜。综上所述，这些结果 实验将促进暂定结论的制定 关于发展神经元对酒精的时间脆弱性 接触。从实验的角度来看，有关的信息 时间窗口和区域差异 向酒精暴露开发大脑将对 针对发现的研究策略的制定 胎儿酒精引起的脑损伤的机制。同样 从临床角度来看，重要时期的知识很重要 在开发过程中，大脑特别容易受到损害 从酒精暴露中，将对患者咨询有关 怀孕期间饮酒的风险和 在特定妊娠阶段停止饮酒的优势。