Iron deficiency (ID) is one of the most common nutrient deficiencies worldwide, affecting two billion people and up to 30% of all pregnant women and their offspring. It affects at least 3 major aspects of early brain development in the offspring. Fetal/neonatal ID has particularly profound effects on the developing hippocampus, the brain region responsible for recognition learning and memory. ID during late fetal and early postnatal life affects the genome, metabolome, structure, intracellular signaling pathways, electrophysiology and specific behavioral functions of the developing hippocampus. These deficits manifest while the infant or rodent pup is iron deficient and remain into adulthood in spite of iron repletion. In humans and dietary ID anemia (IDA) animal models, it is unclear whether structural and behavioral effects in the developing brain are due directly to a lack of iron interacting with important transcriptional, translational or post-translational processes or to indirect effects such as hypoxia due to anemia, stress or increased uptake of toxic divalent cations. We recently generated two non-anemic genetic mouse models by conditionally altering the expression of two iron uptake transport proteins in hippocampus area CA-1 in late gestation to directly assess iron's role in learning and memory. The hippocampus requires adequate energy and growth factors to differentiate normally. Fetal/neonatal ID alters the mammalian Target of Rapamycin (mTOR) pathway, an evolutionarily highly conserved signaling cascade that senses changes in neuronal nutritional, oxygen and growth factor signaling status and responds by adjusting protein translation and actin polymerization rates, which in turn determine neuronal structure and function. Iron plays a key, direct role in regulating mTOR activity through cytochromes and hypoxia inducible factor 1-alpha. The fundamental mechanisms by which neurons are dependent on iron for growth and development is not understood.
In Aim 1, we seek to use our unique models to test hypotheses about the fundamental mechanisms by which neuronal growth and development are dependent on iron's regulation of elements of the mTOR pathway. Early-life ID also alters regulation of growth factors mediating hippocampal plasticity and function in adulthood including Brain Derived Neurotrophic Factor (BDNF) and its downstream effectors. The mechanism of this long-term effect following early ID is not known but we hypothesize involves epigenetic mechanisms.
In aim 2, we will test whether epigenetic chromatin modifications of BDNF underlie the long-term plasticity loss following early IDA. Finally, since prompt iron treatment of early IDA in humans and rodents does not completely restore cognitive health, adjunct therapies in addition to iron may be needed.
In Aim 3, we capitalize on our understanding of the basic mechanisms of the short and long-term neuropathology to test whether choline treatment in addition to iron normalizes neuronal development and adult memory function.

Public Health Relevance

Iron deficiency (ID) is one of the most prevalent nutritional deficiencies in the world. ID in the late fetal and newborn period affects cognitive performance while babies and young animal models are iron deficient, but deficits persist long after complete treatment with iron. We propose to perform studies in iron deficient anemic rat pups and 2 genetic mouse models of ID. Successful completion of these studies will a) emphasize the need to identify and treat ID during pregnancy and early childhood, b) provide insights into how early life iron nutrition affects brain function across the lifespan and c) provide new interventions that are rapidly translatable to dietary and life-style recommendations in humans.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD029421-18
Application #
8450166
Study Section
Integrative Nutrition and Metabolic Processes Study Section (INMP)
Program Officer
Grave, Gilman D
Project Start
1994-12-01
Project End
2016-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
18
Fiscal Year
2013
Total Cost
$301,237
Indirect Cost
$80,819
Name
University of Minnesota Twin Cities
Department
Pediatrics
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Wachs, Theodore D; Georgieff, Michael; Cusick, Sarah et al. (2014) Issues in the timing of integrated early interventions: contributions from nutrition, neuroscience, and psychological research. Ann N Y Acad Sci 1308:89-106
Kennedy, Bruce C; Dimova, Jiva G; Siddappa, Asha J M et al. (2014) Prenatal choline supplementation ameliorates the long-term neurobehavioral effects of fetal-neonatal iron deficiency in rats. J Nutr 144:1858-65
Blegen, Mariah B; Kennedy, Bruce C; Thibert, Katie A et al. (2013) Multigenerational effects of fetal-neonatal iron deficiency on hippocampal BDNF signaling. Physiol Rep 1:e00096
Rao, Raghavendra; Ennis, Kathleen; Oz, Gulin et al. (2013) Metabolomic analysis of cerebrospinal fluid indicates iron deficiency compromises cerebral energy metabolism in the infant monkey. Neurochem Res 38:573-80
Tran, Phu V; Dakoji, Srikanth; Reise, Kathryn H et al. (2013) Fetal iron deficiency alters the proteome of adult rat hippocampal synaptosomes. Am J Physiol Regul Integr Comp Physiol 305:R1297-306
Pisansky, Marc T; Wickham, Robert J; Su, Jianjun et al. (2013) Iron deficiency with or without anemia impairs prepulse inhibition of the startle reflex. Hippocampus 23:952-62
Callahan, Liam S N; Thibert, Kathryn A; Wobken, Jane D et al. (2013) Early-life iron deficiency anemia alters the development and long-term expression of parvalbumin and perineuronal nets in the rat hippocampus. Dev Neurosci 35:427-36
Fretham, Stephanie J B; Carlson, Erik S; Georgieff, Michael K (2013) Neuronal-specific iron deficiency dysregulates mammalian target of rapamycin signaling during hippocampal development in nonanemic genetic mouse models. J Nutr 143:260-6
Monk, Catherine; Georgieff, Michael K; Osterholm, Erin A (2013) Research review: maternal prenatal distress and poor nutrition - mutually influencing risk factors affecting infant neurocognitive development. J Child Psychol Psychiatry 54:115-30
Tran, Phu V; Fretham, Stephanie J B; Wobken, Jane et al. (2012) Gestational-neonatal iron deficiency suppresses and iron treatment reactivates IGF signaling in developing rat hippocampus. Am J Physiol Endocrinol Metab 302:E316-24

Showing the most recent 10 out of 33 publications