NUTRITIONAL COPPER STATUS AND THE NERVOUS SYSTEM

我们之前的研究表明，不足的铜(铜) 在围产期发育对中枢神经系统有重大影响 导致严重的长期神经化学和行为后果。这个 这项研究的广泛的长期目标是确定神经化学作用 对于铜，这将导致更好地理解难以捉摸的机制 铜缺乏的神经病理。我们正在对啮齿动物进行的研究表明 铜缺乏可引起特定的局部神经化学改变。 包括铜水平、儿茶酚胺库的变化以及酶活性的变化 铜酶。我们的研究还表明，脑内铜的恢复 围产期缺陷即使不是不可能，也可能是困难的。更重要的是，我们 已经能够证明至少有一种感觉-运动功能，声学 惊吓，在铜重复摄入的大鼠身上发生了微妙的变化，即使在几个月后 营养补充。这一聚焦的具体目标 多学科项目既是描述性的，也是基于机制的。目标1： 首先，我们希望确定临界时间段和膳食铜水平 对于永久性行为改变和神经病理学的表现是必要的。 为了实现这些目标，将使用SpragueDawley进行实验 老鼠。膳食中铜的缺乏会在围产期发育和 哺乳期后调查发育中的营养相关反应 神经系统。在所有情况下，缺铜或补铜的大鼠将 与铜充足的对照动物相比。目标2：第二，我们将确定 脑发育障碍的治疗机制(S)。具体地说，我们将测试 大脑去甲肾上腺素过低是导致大脑改变的假说 发育(髓鞘过少和突触发育延迟)和听觉改变 将L-3，4-二羟基苯丝氨酸(L-DOPS)的研究纳入 绕过依赖铜的酶--多巴胺-β-单加氧酶。生化和 将使用行为终端。目标3：第三，我们将确定 神经元病理学机制(S)。这些实验是基于 脑部改变导致坏死和细胞凋亡的假说 线粒体功能。我们将研究分离的线粒体并测试特定的 与细胞凋亡和坏死机制相关的假说。总而言之， 这些目标的实现将使我们更好地理解 由于未能积累铜，因此铜和的分子机制是相关的 在大脑发育过程中可能会导致永久性的改变 神经传递、异常行为和认知能力减弱。

Our previous research demonstrates that insufficient copper (Cu) during perinatal development has a major impact on the central nervous system leading to severe long-term neurochemical and behavioral consequences. The broad long-range goal of this research is to identify the neurochemical roles for Cu which will lead to a better understanding of the elusive mechanisms of Cu deficient neuropathology. Our ongoing research in rodents demonstrates that there are selected regional neurochemical alterations induced by Cu deficiency including changes in Cu levels, catecholamine pools, and altered activity of cuproenzymes. Our research also suggests that restoration of brain Cu following perinatal deficiency may be difficult, if not impossible. More importantly, we have been able to show that at least one sensory-motor function, acoustic startle, is exquisitely altered in Cu-repleted rats even after months of nutritional supplementation. The specific aims of this focused multidisciplinary project are both descriptive and mechanism based. AIM 1: Firstly, we wish to establish the critical time period and dietary Cu level necessary for expression of permanent behavior alterations and neuropathology. To accomplish these goals, experiments will be conducted using Sprague Dawley rats. Dietary Cu deficiency will be produced during perinatal development and post lactation to investigate nutrition-related responses in the developing nervous system. In all cases, the Cu-deficient or Cu-repleted rats will be compared to Cu-adequate control animals. AIM 2: Secondly, we will identify the mechanism(s) for impaired brain development. Specifically, we will test the hypothesis that low brain norepinephrine is responsible for the altered brain development (hypomyelination and delayed synaptogenesis) and altered auditory startle by including studies with L-3,4-dihydroxyphenylserine (L-DOPS) to bypass the Cu-dependent enzyme dopamine-beta-monooxygenase. Biochemical and behavioral endpoints will be employed. AIM 3: Thirdly, we will identify the mechanism(s) for neuronal pathology. These experiments are based on the hypothesis that necrosis and apoptosis are driven by alterations in brain mitochondrial function. We will study isolated mitochondria and test specific hypotheses related to mechanisms of apoptosis and necrosis. Collectively, accomplishment of these aims will lead to a better understanding of the molecular mechanisms of Cu and are relevant because failure to accumulate Cu during brain development may lead to permanent alterations in neurotransmission, abnormal behavior, and diminished cognitive capacity.