IRON DEFICIENCY AND DOPAMINE

描述(申请人提供)：这项研究的主要长期目标是确定缺铁性贫血(IDA)在多大程度上会导致单胺类生物学的变化以及相关的行为变化。我们还将确定，尽管后来进行了铁剂治疗，但这种效果在开发过程中何时变得不可逆转。非常明显的是，早期缺铁会损害数百万儿童和婴儿的生物行为发育。先前资助的项目表明，断奶前和断奶后大脑缺铁会导致多巴胺代谢的戏剧性变化。我们发现多巴胺(DA)摄取、DA转运体(DAT)密度和DA(D_1和D_2)受体密度降低。补充铁只能将这些神经递质代谢指标中的一些恢复到正常水平。某些行为，如“探索”或“焦虑”，与尾状核和前额叶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(5-羟色胺、去甲肾上腺素和多巴胺)的代谢对脑铁缺乏敏感。我们现在假设，大脑缺铁会导致所有三个单胺系统的改变。具体目标1：使用短期和长期补充研究设计，证明断奶前大脑缺铁在多大程度上导致单胺代谢的不可逆变化。假说是，早期断奶前缺铁会导致神经元功能的显着变化，而这种变化在缺铁时是不可逆的。具体目标2：确定断奶前大脑缺铁改变运动和行为活动出现的程度。我们将通过统计模型确定特定行为与目标1中测量的单胺代谢变化相关的程度。具体目标3：确定缺铁影响Moneamine转运体和受体代谢的机制。这些细胞培养研究将检验这一假说，即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，这是通过调节GONE表达和蛋白质运输来实现的。将研究扩展到其他神经递质，将大大有助于我们了解缺铁对早期生命中大脑功能的影响。

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.