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（Mn）引起的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接触锰- 定期含有烟雾、气溶胶和颗粒。此外，饮用天然高浓度水 锰浓度现已被认为是大部分地区长期接触锰的重要来源。 美国和全球的人口。因此，可能接触神经毒性物质的人数 全球范围内的锰含量远高于之前认识的水平，使其成为全球公共卫生问题 部分。接触当代水平的锰会导致工作记忆和执行能力受损 功能并产生精细运动控制和姿势稳定性缺陷。这些慢性影响的神经系统 锰暴露可能具有涉及多个神经元系统的病理生理学。之前的研究 我们实验室的研究表明，非人类灵长类动物长期接触中等水平的锰 通过抑制纹状体多巴胺释放，导致黑质纹状体多巴胺能（DAergic）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）明显丧失，这些发现挑战了当前的研究 从单纯的 DAergic 角度到 Mn 诱导的病理生理学教条，其中存在破坏 基底神经节中的DAergic-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，这些领域受到锰引起的神经功能障碍的影响。在这里，我们还提供了初始 有证据表明，非人类灵长类动物长期接触锰会导致明显的基底前脑胆碱能 神经元损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 尾状核/壳核/伏核以及基底核中的 (ChAT) 阳性胆碱能神经元 非人类灵长类动物大脑中的前脑和桥脚核（具体目标 1）。这些研究将 使用严格无偏见的体视学细胞计数和体细胞大小测定方法。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蛋白（VAChT）的影响 末端和静脉曲张（具体目标 2）以评估慢性锰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对锰诱导的胆碱能丧失的作用。 通过测量脑源性神经营养因子和神经生长的浓度来观察神经元（具体目标 3） 相关大脑区域的因素。拟议的研究将提供更精确的机制理解 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 用于治疗锰引起的神经功能障碍的疗法。

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