Iron deficiency remains one of the foremost nutrient deficiencies in children in the world. Whereas over 40 studies have described the effects of postnatally acquired dietary iron deficiency on neurodevelopment, less attention has been paid to the immediate and long-term sequelae of fetal and neonatal brain iron deficiency. Fetal/neonatal iron deficiency occurs in three clinical conditions; severe maternal iron deficiency, intrauterine growth retardation (IUGR) and pregnancies complicated by diabetes mellitus. The former complicates 30-50% of pregnancies in the developing world. The latter two account for iron deficiency in 225,000 newborn infants per year in the US. Iron deficiency affects at least three major aspects of early brain development: energy metabolism, monoamine neurotransmitter homeostasis, and myelination. Our laboratory has focused on the former as it relates to the developing hippocampus; the major neural circuit that subserves explicit memory. Nutritional insults (e.g. iron deficiency) that affect early hippocampal development are likely to impair memory function. Our long term objectives are to understand the mechanisms by which late fetal and early postnatal iron deficiency alter the biochemistry, structure, cell signaling, and electrical output of the hippocampus and how this in turn alters hippocampally based memory behavior.
Our specific aims are to demonstrate that fetal/neonatal iron deficiency 1) causes abnormalities in recognition memory in human infants of diabetic mothers at birth and following iron repletion at 6, 12, 18 and 24 months as documented by event related potentials and behavioral tasks; and 2) alters hippocampal biochemistry, decreases dendritic arborization, neuronal cell-signaling kinase concentrations and long-term potentiation, and impairs hippocampally dependent trace conditioning in the rat while iron deficient and following iron repletion. In order to understand the specific effect of iron on the hippocampus, we will begin to identify potential transcriptional and post-transcriptional mechanisms by which iron regulates key hippocampal structural and functional proteins identified in specific aim 2.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD029421-12
Application #
7068653
Study Section
Special Emphasis Panel (ZRG1-EMNR-D (03))
Program Officer
Grave, Gilman D
Project Start
1994-12-01
Project End
2010-05-31
Budget Start
2006-06-01
Budget End
2007-05-31
Support Year
12
Fiscal Year
2006
Total Cost
$233,774
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Pediatrics
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Georgieff, Michael K; Tran, Phu V; Carlson, Erik S (2018) Atypical fetal development: Fetal alcohol syndrome, nutritional deprivation, teratogens, and risk for neurodevelopmental disorders and psychopathology. Dev Psychopathol 30:1063-1086
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Georgieff, Michael K; Ramel, Sara E; Cusick, Sarah E (2018) Nutritional influences on brain development. Acta Paediatr 107:1310-1321
Cusick, Sarah E; Georgieff, Michael K; Rao, Raghavendra (2018) Approaches for Reducing the Risk of Early-Life Iron Deficiency-Induced Brain Dysfunction in Children. Nutrients 10:
Condon, David E; Tran, Phu V; Lien, Yu-Chin et al. (2018) Defiant: (DMRs: easy, fast, identification and ANnoTation) identifies differentially Methylated regions from iron-deficient rat hippocampus. BMC Bioinformatics 19:31
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Cusick, Sarah E; Georgieff, Michael K (2016) The Role of Nutrition in Brain Development: The Golden Opportunity of the ""First 1000 Days"". J Pediatr 175:16-21
Zamora, Tara G; Guiang 3rd, Sixto F; Widness, John A et al. (2016) Iron is prioritized to red blood cells over the brain in phlebotomized anemic newborn lambs. Pediatr Res 79:922-8
Tran, Phu V; Kennedy, Bruce C; Pisansky, Marc T et al. (2016) Prenatal Choline Supplementation Diminishes Early-Life Iron Deficiency-Induced Reprogramming of Molecular Networks Associated with Behavioral Abnormalities in the Adult Rat Hippocampus. J Nutr 146:484-93

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