Mechanisms and therapies for the neurobehavioral deficits from early Mn exposure

项目摘要 在儿童/青少年中进行的研究将发育环境锰（Mn）暴露与 注意力不集中、冲动、多动症、对立行为和精细运动缺陷，尽管这些研究 由于其横截面设计和对混淆的有限控制， Mn导致了这些缺陷。我们最近的研究表明，发育中的锰暴露导致持久的 注意力、冲动控制和精细运动功能的缺陷，提供了支持 人类研究我们对长期口服哌甲酯（利他林）治疗的潜在益处的初步研究 研究表明，研究的一个剂量减轻了锰诱导的冲动控制和精细运动功能障碍，但 Mn动物的注意力表现受损。我们建议根据这些发现来阐明 神经机制潜在的持久的注意力，冲动控制，和精细运动功能障碍引起的 锰暴露的发展，并测试潜在的治疗干预措施（哌甲酯，胍法辛），在我们的 建立了儿童期锰暴露的啮齿动物模型。我们可检验的假设是1）口头MPH和/或 胍法辛治疗将减轻持续的精细运动，注意力和冲动控制缺陷引起的 发育锰暴露;和2）锰暴露引起的这些持久的缺陷是由于锰暴露水平的变化， 前额叶皮层-纹状体通路中的儿茶酚胺能系统蛋白。我们将测试这些假设，通过 以下目标：目标1将（i）确定临床相关的MPH治疗方案，用于治疗 注意力，冲动控制和精细运动功能，通过确定MPH的剂量反应关系， 雄性和雌性对照动物与Mn动物，以及（ii）确定DA D1、D2和α 2A肾上腺素受体的参与 在Mn缺乏和MPH的治疗效果中，使用选择性受体拮抗剂的给药 在行为测试中。目的2将使用PET神经成像和定量免疫组织化学进一步研究 阐明与注意力/冲动控制/精细运动有关的儿茶酚胺能系统蛋白的变化 Mn赤字，以及这些措施与注意力/冲动控制/精细运动结果的关联。目的 3将检验胍法辛消除由Mn产生的注意力/冲动控制缺陷的假设。这些 研究将是第一个确定潜在有效的治疗/预防注意力和 共病精细运动缺陷由于发育锰暴露，并阐明其神经机制。

Project Summary Studies in children/adolescents have linked developmental environmental manganese (Mn) exposure to inattention, impulsivity, hyperactivity, oppositional behaviors, and fine motor deficits, though these studies are limited by their cross-sectional designs and limited control of confounding that make it impossible to demonstrate that Mn causes these deficits. Our recent studies have shown that developmental Mn exposure causes lasting deficits in attention, impulse control, and fine motor function, providing the first causal evidence supporting the human studies. Our initial studies of the potential benefits of chronic oral methylphenidate (Ritalin) treatment revealed that the one dose studied alleviated the Mn-induced impulse control and fine motor dysfunctions, but impaired attentional performance in the Mn animals. We propose to build upon these findings to elucidate the neural mechanisms underlying the lasting attentional, impulse control, and fine motor dysfunction caused by developmental Mn exposure, and test potential therapeutic interventions (methylphenidate, guanfacine), in our established rodent model of childhood Mn exposure. Our testable hypotheses are 1) Oral MPH and/or guanfacine treatment will alleviate the lasting fine motor, attention and impulse control deficits caused by developmental Mn exposure; and 2) These lasting deficits caused by Mn exposure are due to changes levels of catecholaminergic system proteins in the pre-frontal cortex - striatal pathway. We will test these hypotheses via the following aims: Aim 1 will (i) Identify a clinically-relevant therapeutic regimen of MPH for the Mn deficits in attention, impulse control, and fine motor function by determining the dose-response relationship with MPH in male and female control vs Mn animals, and (ii) Determine involvement of DA D1, D2, and α2A adrenoreceptors in the Mn deficits and in the therapeutic efficacy of MPH, using administration of selective receptor antagonists during behavioral testing. Aim 2 will use PET neuroimaging and quantitative immunohistochemistry to further elucidate changes in catecholaminergic system proteins implicated in the attention/impulse control/fine motor Mn deficits, and the association of these measures with the attention/impulse control/fine motor outcomes. Aim 3 will test the hypotheses that guanfacine alleviates the attention/impulse control deficits produced by Mn. These studies will be the first to identify potentially efficacious therapies for the treatment/prevention of attentional and co-morbid fine motor deficits due to developmental Mn exposure, and to elucidate their neural mechanisms.