The proposed project will 1) test the hypothesis that changes in neuromaturation observed in iron-deficient anemic infants are due to hypomyelination and 2) test a model of mechanisms explaining why iron-deficiency anemia in infancy is associated with poorer developmental outcome. Given the important role of iron in myelin formation and maintenance, impaired myelination is a promising explanation for recent evidence of immature neuromaturation in 6- month-olds with iron-deficiency anemia (slower Central Conduction Time, decreased vagal tone). The hypomyelination hypothesis (Aim 1) will be tested directly in a developmental rat model by examining vagal/optic nerve and regional brain myelination and indirectly in the child using auditory and visual evoked potentials and vagal tone measures from sleep studies. Annual neurophysiology evaluations will be conducted until children are 5 years of age to determine if the findings to date represent irregular progressions or arrests in neuromaturation (n=226, half initially anemic or nonanemic). The proposed model of the effects of early iron-deficiency anemia (Aim 2) postulates that hypomyelination and impaired dopaminergic function contribute to altered behavior in anemic infants, which interferes with their learning from the physical and social environment (functional isolation~) and makes them more vulnerable to the effects of environmental stressors, leading to poorer intellectual and motor development and more internalizing behaviors. Causal modeling techniques will be used to evaluate this model (n=1000 for testing the overall model; n=350 for exploring underlying mechanisms related to neuromaturation, dopaminergic function, and specific behavioral alterations). The proposed integration of a developmental animal model, related measures of CNS functioning and behavior in the child, and an overall model of explanatory mechanisms promises to be a major advance in understanding poorer developmental and behavioral outcome in early iron deficiency anemia, which affects 20-25% of the world~s babies and many poor or minority infants in the U.S.
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