Cholinergic Neuron Degeneration in Mn Neurotoxicity

锰神经毒性中的胆碱能神经元变性

• 批准号: 9906056
• 负责人: Tomas R Guilarte
• 金额: $ 32.96万
• 依托单位: FLORIDA INTERNATIONAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9906056
• 关键词: Advanced Development; Aerosols; Affect; Alzheimer' s Disease; Amygdaloid structure; Amyloid beta-Protein; Animals; Attention; Autoradiography; Basal Ganglia; Behavioral; Brain; Brain region; Brain-Derived Neurotrophic Factor; Carrier Proteins; Cell Count; Cell Nucleus; Cerebral cortex; Choline O-Acetyltransferase; Chronic; Clinical; Cognition; Compulsive Behavior; Corpus striatum structure; Development; Dopamine; Dopaminergic Agents; Emotions; Equilibrium; Exposure to; Functional disorder; Future; Gait; Goals; Hippocampus (Brain); Human; Immunohistochemistry; Impairment; Injury; Interneurons; Laboratories; Lead; Ligands; Locomotion; Macaca fascicularis; Manganese; Measures; Mediating; Methods; Molecular; Motor Activity; Nerve Degeneration; Nerve Growth Factors; Neurodegenerative Disorders; Neurologic Dysfunctions; Neurologic Effect; Neuronal Injury; Neurons; Nucleus Accumbens; Occupational; Paired-Associate Learning; Parkinsonian Disorders; Pharmacotherapy; Physiology; Population; Posture; Presynaptic Terminals; Public Health; Quantitative Autoradiography; Refractory; Research; Resolution; Role; Short-Term Memory; Source; Stains; Structure; System; Thalamic structure; Treatment Efficacy; United States; Varicosity; Work; acetylcholine transporter; alpha synuclein; axonal degeneration; axonopathy; basal forebrain; basal forebrain cholinergic neurons; base; cholinergic; cholinergic neuron; cohort; dopaminergic neuron; drinking water; executive function; experience; exposed human population; frontal lobe; in vivo; insight; motor control; nervous system disorder; neuroimaging; neuron loss; neuronal cell body; neuropathology; neurotoxic; neurotoxicity; neurotrophic factor; nonhuman primate; novel; particle; putamen; vesamicol

4.2. Project Summary (Abstract): The long-term goal of the proposed research is to understand the role of the cholinergic system in manganese (Mn)-induced neurological dysfunction. Today, millions of welders, smelters, and miners in the United States (US) and throughout the world are chronically exposed to Mn- containing fumes, aerosols, and particles on a regular basis. Furthermore, drinking water with naturally high Mn concentrations is now recognized as an important source of chronic Mn exposure to large segments of the population in the US and globally. Therefore, the number of humans that are potentially exposed to neurotoxic levels of Mn worldwide are much larger than previously recognized, making it a public health problem of global proportion. Exposure to contemporary levels of Mn results in impairments in working memory and executive function and produces deficits in fine motor control and postural stability. These neurological effects of chronic Mn exposure are likely to have a pathophysiology that involves multiple neuronal systems. Previous studies from our laboratory have shown that chronic exposure to moderate levels of Mn in non-human primates produces dysfunction of nigrostriatal dopaminergic (DAergic) neurons by inhibiting striatal dopamine release. We now find a marked loss of striatal cholinergic interneurons (ChI) and these findings challenge the current dogma of Mn-induced pathophysiology from a solely DAergic perspective to one in which there is disruption of the DAergic-Cholinergic balance in the basal ganglia. Cholinergic neurons are important in the physiology of cognition, emotion, compulsive behavior, locomotion, and gait, domains that are affected in Mn-induced neurological dysfunction. Here, we also provide initial evidence that chronic Mn exposure in non-human primates results in an apparent basal forebrain cholinergic neuron loss or injury similar to what is found in Alzheimer's disease and other neurodegenerative disorders. Thus, we propose to rigorously characterize the effect of chronic Mn exposure on choline acetyltransferase (ChAT)-positive cholinergic neurons in the caudate/putamen/nucleus accumbens as well as in the basal forebrain and pedunculopontine nucleus in the non-human primate brain (specific aim 1). These studies will use rigorous unbiased stereological cell counting and soma size determination methods. We will also determine the effect of chronic Mn exposure on vesicular acetylcholine transporter (vAChT) in cholinergic axon terminals and varicosities (specific aim 2) to assess if chronic Mn exposure produces cholinergic neuron axonopathy. Finally, we will examine the role of neurotrophic factors on the Mn-induced loss of cholinergic neurons (specific aim 3) by measuring concentrations of Brain-Derived Neurotrophic Factor and Nerve Growth Factor in relevant brain regions. The proposed studies will provide a more precise mechanistic understanding of Mn-induced pathophysiology that can lead to the development of cholinergic- and/or neurotrophic factor- based therapies for the treatment of Mn-induced neurological dysfunction.

4.2.项目摘要(摘要)：拟议研究的长期目标是了解 锰致神经功能障碍中的胆碱能系统。今天，数以百万计的焊工， 美国和世界各地的冶炼厂和矿工长期暴露在锰氧化物中。 定期含有烟雾、气雾剂和颗粒的。此外，饮用天然高含量的水 锰浓度现在被认为是慢性接触锰的一个重要来源。 美国和全球的人口。因此，可能暴露于神经毒性的人类数量 世界范围内的锰水平比以前认识到的要大得多，使其成为全球公共卫生问题。 比例。暴露于当代水平的锰会导致工作记忆和执行能力的损害 并在精细运动控制和姿势稳定性方面产生缺陷。慢性精神疾病的这些神经影响 接触锰可能具有涉及多个神经系统的病理生理学。以前的研究 我们实验室的研究表明，在非人类灵长类动物中，长期接触中等水平的锰 通过抑制纹状体多巴胺的释放，导致黑质纹状体多巴胺能神经元功能障碍。 我们现在发现纹状体胆碱能中间神经元(CHI)显著丧失，这些发现挑战了目前 锰诱导的病理生理学教条--从单纯的DAR角度到存在干扰的观点 基底节的胆碱能平衡。 胆碱能神经元在认知、情绪、强迫行为、运动、 步态，在锰诱导的神经功能障碍中受到影响的区域。在这里，我们还提供了首字母 非人灵长类动物慢性锰暴露导致基底前脑胆碱能明显增加的证据 神经元丢失或损伤，类似于阿尔茨海默病和其他神经退行性疾病。 因此，我们建议严格表征慢性锰暴露对胆碱乙酰转移酶的影响。 (ChAT)阳性胆碱能神经元在尾状核/壳核/伏隔核以及基底核 非人灵长类动物脑内的前脑和桥小脚核(特定目标1)。这些研究将 使用严格的、无偏的体细胞计数和胞体大小测定方法。我们还将 慢性锰暴露对胆碱能轴突囊泡乙酰胆碱转运体的影响 评估慢性锰暴露是否产生胆碱能神经元的终末和静脉曲张(特定目标2) 轴突病症。最后，我们将研究神经营养因子在锰诱导的胆碱能丧失中的作用。 测定脑源性神经营养因子浓度和神经生长的神经元(特异靶3) 相关大脑区域的因素。拟议的研究将提供更精确的机械性理解。 可导致胆碱能和/或神经营养因子发展的锰诱导的病理生理- 治疗锰致神经功能障碍的基础疗法。

项目成果

Behavioral and neurochemical studies of inherited manganese-induced dystonia-parkinsonism in Slc39a14-knockout mice.

• DOI: 10.1016/j.nbd.2021.105467
• 发表时间: 2021-10
• 期刊: Neurobiology of disease
• 影响因子: 6.1
• 作者: Rodichkin AN;Edler MK;McGlothan JL;Guilarte TR
• 通讯作者: Guilarte TR

Hereditary Disorders of Manganese Metabolism: Pathophysiology of Childhood-Onset Dystonia-Parkinsonism in SLC39A14 Mutation Carriers and Genetic Animal Models.

锰代谢的遗传疾病：SLC39A14突变携带者和遗传动物模型中儿童期肌张力障碍 - 肌张力肌的病理生理。

• DOI: 10.3390/ijms232112833
• 发表时间: 2022-10-24
• 期刊: International journal of molecular sciences
• 影响因子: 5.6

Pathophysiological studies of aging Slc39a14 knockout mice to assess the progression of Manganese-Induced Dystonia-Parkinsonism.

• DOI: 10.1016/j.neuro.2022.09.005
• 发表时间: 2022-09
• 期刊: Neurotoxicology
• 影响因子: 3.4
• 作者: Alexander N. Rodichkin;Melissa K. Edler;J. McGlothan;T. Guilarte