The purpose of the proposed FIRST project is to determine the effects of iron deficiency anemia (IDA) and iron treatment during brain development on brain iron concentration, regional brain iron localization, aspects of neurotransmission and behavioral/cognitive development in the rat. The rat model has been critical to understanding the effects of IDA on the developing central nervous system (CNS), since direct CNS studies have not been possible in infants. IDA during brain growth in the rat results in lower brain iron concentration and behavioral changes that are not normalized by iron treatment after the postnatal brain growth spurt. Functionally, IDA alters the dopaminergic system. Structurally, iron and its related proteins are most highly localized to oligodendrocytes and white matter in the brain, and IDA rats are hypomyelined. An unanswered question is whether these alterations could be corrected by earlier treatment. The focus of Study I is to refine the PI's developmental IDA rat model by defining the experimental conditions required to institute four periods of mild/moderate IDA and treatment during gestation and lactation. Maternal and pup hemoglobin levels and serum and liver iron concentrations will be determined. Study I will also determine the effect of this degree of anemia on pup brain and body growth and total non-heme iron concentrations during early development. Using the refined developmental IDA model, Study II will explore the effects of early IDA and treatment on several outcome measures. Regional brain iron localization patterns will be determined and compared for effects of time of IDA and treatment (Part A). Two aspects of neurotransmission will be studied during postnatal development and in adulthood and compared for effects of time of IDA and treatment: 1) neurotransmitter - regional caudate/putamen concentrations of dopamine, DOPAC and HVA (Part B); 2) myelinogenesis - luxol blue staining for gross estimation of time of myelin appearance and amount, and regional and cellular transferrin receptor, transferrin, and myelin basic protein localization (Part C). Part D of Study II includes functional measures related to myelination (emerging pup gross motor milestones). Part D also assesses the effect of early IDA on activity and circadian cycle and two measures of pups' cognitive/behavioral development: home orientation (postnatally) and a test of visual discrimination during later postnatal development and in adulthood. The results of this project will expand our knowledge about the importance of iron during neurodevelopment and may help guide approaches to the management of this common disorder of infancy, which affects 25% of the world's babies.
