Mechanisms and therapies for the neurobehavioral deficits from early Mn exposure

项目概要 对儿童/青少年的研究表明，发育环境中接触锰 (Mn) 与 注意力不集中、冲动、多动、对抗行为和精细运动缺陷，尽管这些研究表明 受限于它们的横截面设计和对混杂因素的有限控制，使得无法证明 锰导致了这些赤字。我们最近的研究表明，发育期接触锰会导致持久的 注意力、冲动控制和精细运动功能的缺陷，提供了第一个因果证据支持 人类研究。我们对长期口服哌醋甲酯（利他林）治疗潜在益处的初步研究 研究表明，所研究的一剂量可以缓解锰引起的冲动控制和精细运动功能障碍，但是 锰动物的注意力表现受损。我们建议以这些发现为基础来阐明 引起持久注意力、冲动控制和精细运动功能障碍的神经机制 发育性锰暴露，并测试潜在的治疗干预措施（哌醋甲酯、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) 口腔 MPH 和/或 胍法辛治疗将缓解由以下原因引起的持久精细运动、注意力和冲动控制缺陷 发育期锰暴露； 2) 锰暴露造成的这些持久缺陷是由于锰水平的变化 前额皮质-纹状体通路中的儿茶酚胺能系统蛋白。我们将通过以下方式测试这些假设 目标如下：目标 1 将 (i) 确定临床相关的 MPH 治疗方案，以治疗 Mn 缺乏症 通过确定 MPH 的剂量反应关系来评估注意力、冲动控制和精细运动功能 雄性和雌性对照与 Mn 动物的比较，以及 (ii) 确定 DA D1、D2 和 α2A 肾上腺素受体的参与情况 使用选择性受体拮抗剂治疗锰缺乏和 MPH 的治疗效果 在行为测试期间。目标 2 将使用 PET 神经影像和定量免疫组织化学来进一步 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 锰缺乏，以及这些措施与注意力/冲动控制/精细运动结果的关联。目标 3 将检验胍法辛减轻 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治疗/预防注意力和注意力障碍的潜在有效疗法的研究 由于发育期锰暴露导致的共病精细运动缺陷，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.