The principal long term goal of this research will be to determine if iron deficiency leads to functional changes in dopamine metabolism with a resultant impact on behavior This study will establish if a relationship does exist between regional brain iron content during iron deficiency, dopamine dysfunction, and behavioral alterations. Moreover, this will be examined within he context of iron deficiency during late lactation verses iron deficiency post weaning. An estimated 2.5 billion humans suffer from the effects of too little iron in their diet; when this occurs during early development deficits in cognition and behavioral development frequently occur. Thus an understanding of the developmental timing and aspects of the neurobiologic mechanisms seem critical. We have recently established in a post weaning rat that iron is rapidly lost from the brain and can be rapidly restored with refeeding. Iron is not lost or restored equally to all parts of the brain during depletion and repletion. In the striatum, there is a greater than 30 percent loss in iron and greater than 50 percent rise in extra-cellular dopamine (DA). Both are rapidly normalized with iron therapy. Specifically, we propose to: 1)identify alterations in in vivo dopamine kinetics in a key dopaminergic pathway of the rat, 2) determine if regional brain iron deficiency alters the release and re-uptake of DA in synaptosomes from caudate-putamen and to determine if the number of functioning transporter mRNA for these transporters are altered, 3) determine if t o kinds of DA related behaviors (exploration of their environment and """"""""anxiety"""""""") are affected by poor iron status, and 4) determine if developmental timing of inadequate iron levels (pre-weaning verses post weaning) is important in mediating these effects. The hypothesis being tested is that ID during late lactation (PND10-21) will have a greater impact on DA biology and behavior than when ID is imposed post-weaning. We also will determine if this effect is irreversible with later iron therapy. The expected results of these experiments will demonstrate that DA clearance from the inter-neuronal space is attenuated by iron deficiency in ventral midbrain due to decreased amounts of functioning of the DA transporter. This elevation in DA in turn leads to decreased exploratory behavior of the environment and """"""""arousal"""""""" of the iron deficient individual. We expect these studies to lay the groundwork for future cellular studies of direct effects of local brain iron on neurotransmitter functioning, brain organization, and cellular adaptation to nutrient deficiencies with implications for cognitive and behavioral development. The significance of this work is that it investigates a biologic basis for understanding the behavioral alterations frequently observed in the hundreds of thousands of iron deficient children around the world.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS035088-03
Application #
6139525
Study Section
Nutrition Study Section (NTN)
Program Officer
Edwards, Emmeline
Project Start
1998-01-01
Project End
2002-09-29
Budget Start
2000-01-01
Budget End
2002-09-29
Support Year
3
Fiscal Year
2000
Total Cost
$187,796
Indirect Cost
Name
Pennsylvania State University
Department
Nutrition
Type
Schools of Allied Health Profes
DUNS #
City
University Park
State
PA
Country
United States
Zip Code
16802
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Wiesinger, Jason A; Buwen, James P; Cifelli, Christopher J et al. (2007) Down-regulation of dopamine transporter by iron chelation in vitro is mediated by altered trafficking, not synthesis. J Neurochem 100:167-79
Beard, John L; Unger, Erica L; Bianco, Laura E et al. (2007) Early postnatal iron repletion overcomes lasting effects of gestational iron deficiency in rats. J Nutr 137:1176-82
Unger, Erica L; Beard, John L; Jones, Byron C (2007) Iron regulation in C57BLI6 and DBA/2 mice subjected to iron overload. Nutr Neurosci 10:89-95
Jones, Byron C; Beard, John L; Gibson, Jennifer N et al. (2007) Systems genetic analysis of peripheral iron parameters in the mouse. Am J Physiol Regul Integr Comp Physiol 293:R116-24

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