The main goals of this consortium are to identify sources of variation in fetal alcohol spectrum disorder (FASD) phenotypes (facial dysmorphology, structural brain damage and neurobehavioral functional deficits), to advance understanding of structure-function relationships, to improve diagnosis and early identification of FASD, and to develop early interventions that may limit adverse outcomes in at-risk pregnancies. Animal models are essential to those goals. This project proposes a novel sheep model that is especially well suited for experimental translational studies of FASD. In utero brain development in sheep matches human brain development relatively well, and prenatal binge alcohol exposure in sheep produces brain and behavioral effects consistent with FASD. There are two long-term objectives for this project. The first is to use the sheep model to compare the effects of binge-like alcohol exposure during the period of brain development comparable to that of the human first trimester (1st-trimester mode/) with similar binge-like exposure that extends over the stages of brain development encompassing all three human trimesters (3-trimester model). These studies evaluate phenotypic measures used in the diagnosis of fetal alcohol syndrome-growth, facial dysmorphology, and brain and behavioral development-using methods derived explicitly from and collaboratively linked directly to approaches applied in the human components of the consortium. These studies test the general hypothesis that more pervasive effects on brain and neurobehavioral development will result from binge exposure that continues after the first trimester.
Aim 1 will evaluate growth, facial morphometry, and effects on in vivo brain regional volumes using structural magnetic resonance imaging.
Aim 2 will assess neurobehavioral outcomes using eyeblink classical conditioning and spatial working memory.
Aim 3 will assess neuroanatomical effects via neuronal counts in the cerebellum, hippocampal formation, and brainstem serotonin system. These studies are designed to inter-relate with and reciprocally inform four of the human projects [Facial Imaging (Foroud), Brain Imaging (Sowell), Neurobehavioral project (Mattson), and the Risk Factors/Nutrition project (Chambers)] and the two mouse basic science projects (Zhou;Sulik). The second objective (Aim 4) is to test the hypothesis that choline supplementation initiated periconceptually will attenuate the adverse effects of alcohol exposure in the 3-trimester sheep model. This study was designed with explicit and complementary collaboration with the choline-supplementation projects in rats [the basic science developmental project using rats (Thomas)] and in humans [Risk Factor/Nutrition project of Chambers/Keen]. This sheep model provides a unique opportunity to bridge the basic and clinical arms of the consortium more closely than has been achieved in the past.
