ALCOHOL AND BRAIN DEVELOPMENT

本提案的总体目的是确定是否存在 发育中的大脑明显 易受酒精影响第一个要检验的假设是， 发育中的大脑很容易受到酒精引起的损伤， 酒精暴露时间的后果;这是假设 暂时的脆弱性。第二个要解决的主要假设是 胎儿大脑中的特定区域 酒精暴露;这是区域脆弱性假设。 该提案分为两个系列的实验。的目标 第一个系列将记录剂量依赖性胎儿酒精诱导 在选定的大脑中局部体积和神经元损失的改变 大鼠产前发育主要时期的区域： 第一个三个月当量（胚胎日E1-E10），第二个三个月 相当于（E11-E21），以及合并的第一和第二孕期 等同物（E1-E21）。一旦我们确定了时间风险， 胎儿大脑在三个月的基础上从酒精暴露，我们将缩小 我们时间脆弱性假设的焦点第二系列 实验将解决第三个假设，这是密切相关的， 第一个;酒精暴露干扰神经发生（即， 神经元产生的特定时期）， 在这个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 与一个重要的假设密切相关：赤字的严重程度 是血液酒精浓度峰值（BAC）的函数， 胎儿暴露。因此，为了优化对峰值BAC的控制， 胃插管技术将用于给予每日剂量的 酒精会产生低，中，或高BAC。为了 为了实现上述目标，必须使用依赖 这些变量适用于所有大脑区域的比较。 因此，最先进的三维体视学方法将是 用于确定局部体积和神经元的任何变化 包括小脑在内的七个重要脑区的数字， 海马、蓝斑、黑质、丘脑腹外侧区、 内嗅皮层和隔膜。综合起来，这些结果 实验将有助于初步结论的形成 关于发育中的神经元对酒精的暂时脆弱性 exposure.从实验的角度来看，关于 脆弱性的时间窗口和区域差异 发育中的大脑暴露于酒精将大大有助于 制定研究战略，旨在发现 胎儿酒精性脑损伤的潜在机制。同样 从临床角度来看，重要的是，关键时期的知识 在发育过程中，大脑特别容易受到损伤， 从酒精暴露，将是有益的咨询病人， 怀孕期间饮酒对胎儿的风险， 在怀孕的特定阶段停止饮酒的好处。

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.