ALCOHOL AND BRAIN DEVELOPMENT

酒精与大脑发育

• 批准号: 2046550
• 负责人: JAMES R WEST
• 金额: $ 17.5万
• 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/2046550
• 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.

这项提案的总体目的是确定是否有 大脑发育中的关键时期 易受酒精影响的。第一个要检验的假设是 发育中的大脑容易受到酒精引起的损害，因为 酒精暴露时间的后果；这是假设 时间上的脆弱性。需要解决的第二个主要假设是 胎儿大脑的特定区域具有不同的脆弱性 酒精暴露；这是区域脆弱性的假说。 该提案分为两个系列的实验。的目标是 第一个系列将记录剂量依赖的胎儿酒精诱导 部分脑内区域体积和神经元丢失的变化 大鼠出生前发育主要时期的区域： 相当于前三个月(胚胎第1-10天)，后三个月 相当于(E11-E21)，以及合并的第一和第二个三个月 等值(E1-E21)。一旦我们确定了 胎儿大脑因酒精暴露三个月为基础，我们将缩小 我们的时间脆弱性假说的焦点。第二个系列 实验将解决第三个假设，该假设与 第一个；酒精暴露会干扰神经发生(即， 神经元产生的特定时间段)防止 在这一特定阶段获得正常的神经元补充 他们的发展。该提案中的所有假设都是 与一个重要假设密切相关：赤字的严重性 是峰值血液酒精浓度(BAC)的函数 胎儿暴露在危险之中。因此，为了优化对峰值BAC的控制， 胃插管技术将被用来每天给药 会产生低、中或高BAC的酒精。为了 要实现上述目标，就必须使用依赖项 适合在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变化 包括小脑在内的七个重要大脑区域的数据， 海马体、蓝斑、黑质、丘脑腹外侧部、 内嗅皮层和隔膜。综上所述，这些结果 实验将有助于形成暂定结论。 关于发育中的神经元对酒精的时间脆弱性 曝光。从实验的角度来看，关于 时间窗口和区域差异的脆弱性 大脑暴露在酒精环境中将大大有助于 制定研究战略，旨在发现 胎儿酒精脑损伤的机制(S)。同样 从临床的角度来看，关键时期的知识很重要 在发育过程中，当大脑特别容易受到损害时 从酒精暴露中，将有益于咨询患者关于 怀孕期间饮酒对胎儿的风险以及 在怀孕的特定阶段停止饮酒的好处。