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.
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