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Neurobehavioral Impacts of Early Mn Exposures

早期接触锰对神经行为的影响

基本信息

批准号：
8628833
负责人：
DONALD R SMITH
金额：
$ 29.56万
依托单位：
UNIVERSITY OF CALIFORNIA SANTA CRUZ
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-06 至 2017-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8628833
关键词：
Address Affective Animal Model Animals Arousal Attention Attention deficit hyperactivity disorder Attentional deficit Behavior Behavioral Biological Biological Markers Biosensor Blood Brain Brain region Case Study Child Childhood Cognition Cognitive Cognitive deficits Consumption Control Animal Corpus striatum structure Coupled Data Development Diet Dietary Manganese Dorsal Dose Emotions Environment Epidemiologic Studies Epidemiology Exposure to Functional disorder Future GLAST Protein Glutamates Goals Guidelines Hair Health Health Policy Hippocampus (Brain)Human Immunohistochemistry Impaired cognition Impulsivity Infant Knowledge Learning Life Link Manganese Measures Memory Metals Methylphenidate Metric Microdialysis Molecular N-Methylaspartate Nature Neonatal Neurologic Oral Organ Pattern Pharmaceutical Preparations Plasma Play Prefrontal Cortex Principal Investigator Public Health Recording of previous events Reporting Research Risk Ritalin Rodent Rodent Model Role Severities Source Symptoms Synapses System Testing Therapeutic Time Tissues Tooth structure Toxic effect Uncertainty Urine Water Weaning base behavior test behavioral impairment bone cognitive function design dopamine transporter early life exposure executive function frontal lobe human data inattention indexing inhibitor/antagonist insight juvenile animal mature animal neonatal exposure neurobehavioral neurochemistry neuromechanism neurotoxicity neurotransmitter release nonhuman primate postnatal programs public health relevance receptor receptor binding receptor expression relating to nervous system response soy young adult

项目摘要

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.

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，证明显着的神经行为缺陷与环境和饮食中锰 (Mn) 暴露增加有关。然而，这些研究尚未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）的具体性质或潜在的神经化学改变的详细了解。目标 1 将使用锰神经毒性啮齿动物模型确定断奶前或出生后连续接触锰是否会导致年轻人神经行为缺陷。目标 II 将探讨断奶前或产后连续接触锰而引起认知缺陷的分子和神经化学机制。目标 III 将确定断奶前或出生后连续锰暴露与暴露生物标志物的关系，以及这些暴露生物标志物与神经行为和神经化学改变的相关程度。我们将测试以下总体假设：（1）新生儿锰暴露会导致认知（即学习、记忆、注意力和/或抑制控制）和情感（唤醒和/或情绪）功能各个方面的持久功能障碍，以及（2）这些变化与促进这些功能的大脑区域中多巴胺能和谷氨酸能系统的发育改变有关（即前额皮质、纹状体和海马体）。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，以便提供有关锰诱导的促进这些行为功能的系统变化的信息，并确定这些神经变化中的一种或多种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蛋白（DAT）抑制剂哌醋甲酯（利他林）的剂量反应关系，以及该药物是否减轻由于锰暴露引起的行为缺陷，直接测试因锰暴露引起的多巴胺能系统的改变是否在由此产生的行为缺陷中发挥作用。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生命早期接触锰水平所造成的神经系统后果的最全面的评估。这些知识将为公共卫生政策和指南提供有关儿童接触锰的适当水平的信息。