This grant proposes the first systematic study of the effects of prenatal exposure to alcohol on cortical ontogeny. Alcohol ingestion during pregnancy can cause a variety of developmental defects in the unborn child. These defects have been classified as the fetal alcohol syndrome (FAS). FAS represents a major health problem since alcohol has been cited as the most common teratogenic cause of mental deficiency in the Western World affecting as many as one to five people per thousand live births. Neurological abnormalities in children with FAS include hypotonia, delayed neuromuscular development, coordinative difficulties hypotonia, and deficiencies in fine motor skills. These signs strongly indicate maldevelopment of the central nervous system, and in particular motor areas of the cerebral cortex. Although detailed morphological studies in animal models are few, those structural developmental abnormalities in the cortex which have been reported implicate that motor-somatosensory cortex is affected. Thus, it is necessary to perform a controlled study on cortical development in experimental FAS. Development of the cortex encompasses four phases, proliferation, migration, differentiation, and death. Each phase will be examined in rat pups of females fed an ethanol diet during pregnancy and in control animals using a battery of qualitative and quantitative methods. Cell proliferation will be examined autoradiographically by determining the percentage of cells incorporating a radioactively labeled precursor of DNA, i.e., those cells actively involved in mitosis. Cell migration consists of two parts, the time when cells begin to migrate from the germinal zone and the rate of migration. Both will be assessed with autoradiography. Neuronal differentiation will be examined using morphometric light microscopy with Golgi preparations to describe the growth of cell bodies and dendrites and quantitative electron microscopy to trace cortical synaptogenesis. Cell death will be determined autoradiographically by calculating the diminution with time in the percentage of labeled cells. This study will provide insight into the mechanisms by which ethanol and other gestational toxins produce their teratogenic effects upon the developing nervous system. In addition, it should provide a controlled system with the effects of proposed treatments for fetal alcohol syndrome can be assessed.
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