IRON DEFICIENCY AND DOPAMINE

描述（由申请人提供）：本研究的主要长期目标是确定生命早期缺铁性贫血（IDA）导致单胺生物学变化和相关行为变化的程度。我们还将确定在发展过程中，尽管后来进行了铁治疗，但这种效果何时变得不可逆转。非常清楚的是，生命早期缺铁会损害数百万幼儿和婴儿的生物行为发育。先前资助的项目表明，断奶前后脑铁缺乏会导致多巴胺代谢的剧烈变化。我们发现多巴胺（DA）摄取、DA转运体（DAT）密度以及DA （D1和D2）受体密度均有所下降。铁的补充只能使这些神经递质代谢指标中的一部分恢复正常。某些行为，如“探索”或“焦虑”与尾状核和前额皮质铁和多巴胺变量有关。最近的初步研究表明，所有中枢神经系统单胺（血清素、去甲肾上腺素和多巴胺）的代谢对脑铁缺乏很敏感。我们现在假设脑铁缺乏会导致所有三种单胺系统的改变。具体目标1：通过短期和长期补充研究设计，证明断奶前脑铁缺乏在多大程度上导致单胺代谢的不可逆变化。假设是早期断奶前缺铁会导致神经元功能的显著变化，而这种变化随着铁的补充是不可逆的。具体目标2：确定断奶前脑铁缺乏在多大程度上改变运动和行为活动的出现。我们将通过统计模型确定特定行为在多大程度上与Aim 1中测量的单胺代谢改变相关。特异性目的3：确定缺铁影响铁胺转运体和受体代谢的机制。这些细胞培养研究将验证神经元铁缺乏导致单胺转运体和潜在的单胺受体表达减少的假设，通过调节去表达和蛋白质运输。将研究扩展到其他神经递质将大大有助于我们了解早期缺铁对大脑功能的影响。

DESCRIPTION (provided by applicant): The principal long-term goal of this research is to determine the extent to which iron deficiency anemia (IDA)in early life leads to changes in monoamine biology with related changes in behavior. We will also determine when in development the effect becomes irreversible despite later iron therapy. It is abundantly clear that iron deficiency in early life impairs the biobehavioral development of millions of young children and infants. The previously funded project demonstrated that brain iron deficiency pro and post weaning results in dramatic changes in dopamine metabolism. We demonstrated decreases in dopamine (DA) uptake, DA transporter (DAT) density, and in DA (D1 and D2) receptor density. Iron repletion only restored some of these measures of neurotransmitter metabolism to normal. Certain behaviors, like "exploration" or "anxiety" were related to caudate and prefrontal cortex iron and dopamine variables. Recent pilot studies suggest that metabolism of all central nervous system monoamines (serotonin, norepinephrine, and dopamine) is sensitive to brain iron deficiency. We now hypothesize that brain iron deficiency results in alterations in all three monoamine systems. Specific Aim 1: To demonstrate the extent to which brain iron deficiency during preweaning results in irreversible changes in monoamine metabolism using both short and long term repletion research designs. The hypothesis is that early pre-weaning iron deficiency leads to significant changes in neuronal functioning that are irreversible with iron repletion. Specific Aim 2: To determine the extent to which brain iron deficiency during preweaning alters the emergence of motor and behavioral activities. We will determine the extent to which specific behaviors are related to the alterations in monoamine metabolism measured in Aim 1 through statistical models. Specific Aim 3: To determine the mechanism by which iron deficiency affects the metabolism of moneamine transporters and receptors. These cell culture studies will test the hypothesis that neuronal iron deficiency results in a decrease in the expression of monoamine transporters and potentially monoamine receptors through regulation of gone expression and protein trafficking. This expansion of study to other neurotransmitters will significantly contribute to our knowledge of the effects of iron deficiency on brain functioning in early life.