The overall purposes of this program-project grant (PPG) are to understand how iron deficiency alters brain and behavior in early development and identify interventions that will correct or prevent ill effects in the shortand long-term. Up to 75% of women worldwide are anemic during pregnancy, with about half due to iron deficiency. In developing countries, 46-66% of children <4 years are anemic, again with half attributed to iron deficiency, and iron deficiency disproportionately affects poor and/or minority mothers and infants everywhere. Yet there are still important unanswered questions about the brain and behavior effects of early iron deficiency. In the next 5 years, the PPG will focus on 1) timing of iron deficiency in relation to different stages of brain development, 2) timing of iron repletion to ameliorate short-term effects and prevent longterm consequences for brain and behavior, and 3) in-depth study of short- and long-term effects and the processes that account for them. PPG involves 4 projects (1 human infant, 2 monkey, 1 rodent) supported by 3 cores (administrative, analytical, and statistical).The component projects and cores, with interdisciplinary collaboration among leading clinical and basic science researchers, are tightly linked conceptually and methodologically, designed so that each has a special but complementary role. Project I (human infant) will be a systematic investigation of brain and behavior effects of pre- v. postnatal v. combined pre- and postnatal iron deficiency in human infants and the timing of iron treatment. Project II (Davis monkey) will use an experimental model to pursue its novel finding that prenatal iron deprivation produced a behavioral profile of reduced inhibition and increased impulsivity, despite iron repletion. Project III (Madison monkey) will assess brain-behavior effects of combined pre- and postnatal iron deficiency in infants born to young mothers - a naturalistic model directly relevant to vulnerable human populations (developing countries, adolescent mothers). Project IV (developing rodent) will focus on the effectiveness of iron therapy at different times in brain development in preventing genomic, biochemical, structural, and behavioral alterations in adulthood. It will also consider the potential for neurotoxicity with too much iron following early iron deficiency. With close integration, all projects assess neural and behavioral development. Each uses innovative approaches to assess the brain (e.g., electrophysiology in Project I, PET with drug challenge in Project II, brain tissue in Project III, and regional genomics in Project IV). Individually, each project represents a substantial leap beyond previous research on early iron deficiency. Collectively, the program will make major contributions to understanding, treating, and preventing brain and behavior effects of iron deficiency, the world's most common single nutrient disorder.
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