Alcohol and Development of the Prefrontal Cortex

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DESCRIPTION (provided by applicant): The developing brain is uniquely sensitive to insults, including ethanol. Although fetal brain development and alcohol toxicity have been extensively studied, early postnatal and adolescent stages of cerebral cortical brain development have not been extensively studied. "Critical periods" of unique high environment regulated plasticity occurs for many brain regions with the most studied being visual cortex. During these "critical periods of plasticity", developmental processes result in the formation of persisting synaptic and other cytoarchitecture and cellular function. Human alcohol abuse during adolescence and young adulthood is associated with an increased risk of alcoholism in adulthood. Thus the overall hypothesis is that alcohol abuse during post-natal periods of brain development will cause acute toxicity that results in persistent alterations to adult brain cortical cells and results in persistent changes in adult behavior and adult gross brain structure. This proposal will investigate the effects of ethanol exposure during distinct periods of early postnatal life and adolescence on cellular and synaptic architecture, behavior, and gross brain structure in adult animals. The frontal cortex will be targeted due to its late development and sensitivity to ethanol toxicity. The three specific aims of this project and their associated techniques are as follows: 1. to histochemically determine the effects of ethanol on post-natal days (PND) 7 and 14 as well as through adolescence (PND28-38) on cell death markers (activated caspase 3 and silver stain) just after treatment; and to examine adult frontal cortical structure following prenatal treatment using neuron specific markers for GABA interneurons and pyramidal cells; 2. to determine the effects of early postnatal and adolescent ethanol on adult behaviors, including tests of working memory, learning and reversal learning, prepulse inhibition, and anxiety; and 3. to determine the effects of ethanol during the early postnatal and adolescent periods on gross brain structure using Magnetic Resonance Imaging (MRI). Magnetic resonance imaging in humans has found continued development of cortical regions into the 3rd decade of life. Mouse brain development during this period has not been well studied, although neurochemical and behavioral studies have suggested similar courses of brain development between humans and mice; although the timing is clearly different. Using structural MRI we will test the effects of early postnatal and adolescent exposure of ethanol on adult brain regional volumes. Human adolescents commonly binge drink, and adolescent drinking is associated with increased risk of alcoholism. If it is established that the adolescent brain has unique vulnerability this could lead to increased prevention and treatment of adolescent binge drinking.