Neurobehavioral Impacts of Early Mn Exposures

描述（由申请人提供）：儿童的流行病学和案例研究报告提供了令人信服的证据，证明显著的神经行为缺陷与环境和饮食中锰（Mn）暴露升高有关。然而，这些研究并没有建立锰暴露与神经行为缺陷之间的因果关系，也没有提供对认知缺陷（即学习、注意力、情绪等）或潜在神经化学改变的具体性质的详细了解。目的1将使用一种啮齿动物的锰神经毒性模型，确定断奶前或产后持续暴露于锰是否会导致年轻人的神经行为缺陷。目的II将探讨由断奶前或产后连续锰暴露引起的认知缺陷的分子和神经化学机制。目的III将确定断奶前或出生后持续的锰暴露与暴露的生物标志物之间的关系，以及这些暴露生物标志物与神经行为和神经化学改变相关的程度。我们将测试以下主要假设：(1)新生儿锰暴露导致认知（即学习、记忆、注意力和/或抑制控制）和情感（唤醒和/或情绪）功能的各个方面的持续功能障碍；(2)这些变化与大脑区域（即前额皮质、纹状体和海马体）中多巴胺能和谷氨酸能系统的发育改变有关。我们将通过微透析/生物传感器、受体结合和免疫组织化学在接受认知测试的同一动物中测量多巴胺能和谷氨酸能系统功能的细胞和神经化学参数，以提供有关mn诱导的服务于这些行为功能的系统变化的信息，并确定这些神经变化是否与行为缺陷相关。此外，我们将通过确定锰暴露是否改变多巴胺转运体（DAT）抑制剂哌甲酯（利他林）的剂量-反应关系，以及该药物是否减轻锰暴露导致的行为缺陷，直接测试锰暴露导致的多巴胺能系统改变是否在由此产生的行为缺陷中起作用。这些研究将是迄今为止对婴儿和儿童在其环境中可能遇到的早期暴露于锰水平的神经系统后果进行的最全面的评估。这一知识将为公共卫生政策和关于儿童适当锰暴露水平的指导方针提供信息。

DESCRIPTION (provided by applicant): Epidemiological and case study reports in children have provided compelling evidence for significant neurobehavioral deficits associated with elevated environmental and dietary manganese (Mn) exposure. However, these studies have not established a causal relationship between Mn exposure and neurobehavioral deficits, nor have they provided a detailed understanding of the specific nature of the cognitive deficits (i.e., learning, attention, emotionality, etc.), or underlying neurochemical alterations. Aim 1 will determine whether pre-weaning or continuous postnatal Mn exposure produces neurobehavioral deficits in young adults, using a rodent model of Mn neurotoxicity. Aim II will explore the molecular and neurochemical mechanisms underlying the cognitive deficits induced by pre-weaning or continuous postnatal Mn exposure. Aim III will determine the relationship of pre-weaning or continuous postnatal Mn exposures with biological markers of exposure, and the extent that these exposure biomarkers are associated with neurobehavioral and neurochemical alterations. We will test the overarching hypotheses that (1) neonatal Mn exposure causes lasting dysfunction in various aspects of cognitive (i.e., learning, memory, attention and/or inhibitory control) and affective (arousal and/or emotion) functioning, and (2) that these changes are linked to developmental alterations in dopaminergic and glutamatergic systems in brain regions which subserve these functions (i.e., the prefrontal cortex, striatum, and hippocampus). We will measure cellular and neurochemical parameters of dopaminergic and glutamatergic system function by microdialysis/biosensor, receptor binding, and immunohistochemistry in the same animals that underwent cognitive testing, in order to provide information about Mn-induced changes in systems that subserve these behavioral functions, and to determine whether one or more of these neural changes correlate with behavioral deficits. Further, we will directly test whether alteration of the dopaminergic system due to Mn exposure plays a role in the resulting behavioral deficits by determining whether Mn exposure alters the dose- response relationship of methylphenidate (Ritalin), a dopamine transporter (DAT) inhibitor, and whether the drug alleviates behavioral deficits due to Mn exposure. These studies will be the most comprehensive assessments to date on the neurological consequences of early life exposure to levels of manganese that infants and children are likely to encounter in their environment. This knowledge will inform public health policies and guidelines on suitable levels of Mn exposure to children.