Alcohol consumption during pregnancy puts the fetus at risk for mental retardation and severe damage to the central nervous system (CNS). However, the severity of effects in the fetal alcohol syndrome are quite variable across individuals. Clinical observations and limited animal studies indicate that genetic differences among individuals can influence the severity of fetal alcohol effects. The proposed research will investigate the contributions of genetic differences to individual differences in susceptibility to alcohol-induced CNS damage during development. The long range objective is to identify factors influenced by genetic variation which can lead to differences in susceptibility to fetal alcohol effects on brain growth and structure and on behavior. The experimental approach will compare the susceptibility of rats from eight different inbred strains (those used in forming the NIH heterogeneous stock of rats for pharmacogenetic research) to effects of exposure to alcohol during the brain growth spurt, the period of most rapid brain growth. This period of brain development, which occurs postnatally in the first two weeks of life in rats, is roughly equivalent to that of the human third trimester. Exposure to alcohol during postnatal days 4-10 in randomly bred Sprague- Dawley rats has severe and enduring effects on brain growth and behavior. We will use artificial rearing procedures during this period to deliver controlled doses of alcohol in a nutritionally adequate diet to pups of the eight strains to characterize their susceptibility to fetal alcohol effects. There are four specific aims: 1) to identify those inbred strains which are most (and least) susceptible to restriction of brain growth and to determine the role of differences in blood alcohol concentrations in accounting for the strain differences in brain growth; 2) to determine whether strains differ both in terms of risks related to pharmacokinetic differences and in susceptibility of the brain independent of factors controlling blood alcohol concentration; 3) to examine the two most susceptible and most resistant strains identified on the basis of brain growth restriction for differences in neuron loss and neuromorphological changes in the hippocampal formation; 4) to test the identified strains for differences in behavioral impairments on tasks sensitive to hippocampal dysfunction. The proposed research will establish the contribution of genetic differences to variation in brain growth restriction, structural damage to the hippocampus and related behavioral impairments following alcohol exposure during the brain growth spurt.
