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 胆碱能系统在锰（Mn）诱导的神经功能障碍中的作用今天，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于锰， 含有烟雾、气溶胶和颗粒物。此外，饮用水天然高 锰浓度现在被认为是慢性锰暴露的一个重要来源， 美国和全球的人口。因此，有可能接触到神经毒素的人数 世界范围内的锰水平比以前认识到的要高得多，使其成为全球性的公共卫生问题。 比例暴露于当代水平的锰导致工作记忆和执行能力的损害 功能，并产生精细运动控制和姿势稳定性的缺陷。这些慢性的神经影响 锰暴露可能具有涉及多个神经系统的病理生理学。以前的研究 来自我们实验室的研究表明，非人类灵长类动物长期暴露于中等水平的锰， 通过抑制纹状体多巴胺释放产生黑质纹状体多巴胺能（DA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）的明显损失，这些发现挑战了目前的研究结果。 锰诱导的病理生理学的教条，从一个单独的DA能的角度来看，其中有一个中断 基底神经节中的DA能-胆碱能平衡。 胆碱能神经元在认知、情感、强迫行为、运动， 和步态，在Mn诱导的神经功能障碍中受影响的领域。在这里，我们还提供初始 非人灵长类动物中慢性锰暴露导致明显的基底前脑胆碱能的证据 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中发现的情况。 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）阳性胆碱能神经元位于尾状核/壳核/丘脑底核以及基底核， 非人灵长类动物脑中的前脑和脚桥核（具体目标1）。这些研究将 使用严格的无偏体视学细胞计数和索马大小测定方法。我们还将 确定慢性锰暴露对胆碱能轴突中囊泡乙酰胆碱转运体（vAChT）的影响 终末和静脉曲张（具体目的2），以评估慢性Mn暴露是否产生胆碱能神经元 轴突病最后，我们将研究神经营养因子在锰诱导的胆碱能神经元丢失中的作用。 通过测量脑源性神经营养因子和神经生长的浓度， 相关脑区的因素。拟议的研究将提供一个更精确的机制的理解 锰诱导的病理生理学，可导致胆碱能和/或神经营养因子的发展， 用于治疗Mn诱导的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