Chronic methamphetamine-induced catecholaminergic degeneration and cognitive dysfunction

慢性甲基苯丙胺引起的儿茶酚胺能变性和认知功能障碍

• 批准号: 10464353
• 负责人: Alexander N Pilski
• 金额: $ 4.33万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-14 至 2025-01-13
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10464353
• 关键词: Astrocytes; Attenuated; Automobile Driving; Axon; Back; Behavioral; Biological Assay; CRISPR/Cas technology; Catecholamines; Chronic; Cytosol; Data; Deamination; Dependence; Disease; Dopamine; Enzymes; Functional disorder; Genetic; Goals; Immunofluorescence Immunologic; Impaired cognition; Impairment; Knock-out; Knowledge; Lead; Length; Lesion; Mentors; Metabolism; Methamphetamine; Mitochondria; Monoamine Oxidase; Morphology; Mus; Nerve Degeneration; Neurons; Neurosciences; Neurotransmitters; Norepinephrine; Pattern; Pharmacology; Pilot Projects; Population; Process; Proteins; Reactive Oxygen Species; Research; Saline; Scientist; Severities; Stimulant; Stress; Substantia nigra structure; Techniques; Testing; Training; Vesicle; axon injury; axonal degeneration; behavioral impairment; career; conditioned fear; dopaminergic neuron; genetic manipulation; improved; locus ceruleus structure; multidisciplinary; neuronal cell body; novel; object recognition; pars compacta; prevent; psychostimulant; vesicular monoamine transporter 2

PROJECT SUMMARY/ABSTRACT Methamphetamine (meth) is a powerfully addictive psychostimulant capable of causing neuronal damage. Recent studies by my mentor, Dr. Graves, found that meth increases mitochondrial stress in the axons of substantia nigra pars compacta (SNc) dopamine (DA) neurons resulting from MAO metabolism of cytosolic DA. Pilot studies showed similar effects in the axons of Locus coeruleus (LC) norepinephrine (NE) neurons. Using a 28-day meth administration paradigm, recent studies by Dr. Graves found degeneration of SNc DA neurons and that pharmacological inhibition of MAO was neuroprotective. Pilot studies similarly show chronic meth- induced LC degeneration that is attenuated by MAO inhibition. These data suggest that axonal MAO- dependent mitochondrial stress contributes to chronic meth-induced degeneration. The overarching goal of this proposal is to determine the progression and presentation of degeneration, whether neuronal (as opposed to astrocytic) MAO enzymes are necessary for degeneration, and the behavioral consequences of chronic meth-induced SNc and LC degeneration. My central hypothesis is that chronic meth induces a neuronal MAO-dependent dying-back pattern of SNc and LC degeneration resulting in cognitive impairment and will be tested in the following aims: Aim 1: Determine if chronic meth produces a dying-back pattern of SNc and LC degeneration. Meth increases axonal, but not somatic MAO-dependent mitochondrial stress, and MAO inhibition prevented chronic meth-induced SNc and LC degeneration; these data suggest that MAO-dependent axonal mitochondrial stress drives degeneration. I therefore hypothesize that chronic meth will produce a dying-back pattern of SNc and LC degeneration, where axonal loss precedes somatic loss. Aim 2: Determine if neuronal MAO is necessary for chronic meth-induced SNc and LC degeneration. Studies show systemic MAO inhibition prevented chronic meth-induced SNc and LC degeneration, but MAO enzymes are expressed in neurons and astrocytes. Given that meth increased mitochondrial stress in SNc and LC axons, I hypothesize that neuronal MAO is necessary for degeneration. Aim 3: Determine the behavioral consequences of chronic meth-induced SNc and LC degeneration. SNc degeneration and LC lesioning are associated with impairments in novel object recognition and context-associated fear conditioning assays, respectively; I therefore hypothesize that chronic meth-induced degeneration of the SNc and LC will lead to similar behavioral impairments. I will test my hypotheses by training in and using immunofluorescence, unbiased stereological assessment of neuronal and axonal degeneration, behavioral analysis, and both genetic and pharmacological inhibition of MAO enzymes. Testing my hypotheses will provide me with outstanding technical and conceptual training as a research scientist. Completion of proposed aims will improve our understanding of the neurodegenerative consequences of chronic meth, expanding knowledge of catecholaminergic degeneration and providing value to the study of disorders involving similar degeneration.

项目总结/摘要 甲基苯丙胺（冰毒）是一种强大的成瘾性精神兴奋剂，能够导致神经元损伤。 我的导师格雷夫斯博士最近的研究发现，冰毒会增加线粒体轴突的压力， 黑质腹侧部（SNc）多巴胺（DA）神经元由胞质DA的MAO代谢产生。 初步研究表明，在蓝斑（LC）去甲肾上腺素（NE）神经元的轴突中有类似的作用。使用 格雷夫斯博士最近的研究发现，在28天的冰毒给药模式下， 并且MAO的药理学抑制具有神经保护作用。试点研究同样显示，慢性冰毒- 诱导LC变性，通过MAO抑制减弱。这些数据表明，轴突毛泽东- 依赖性线粒体应激导致慢性甲硫氨酸诱导的变性。的首要目标 该建议是为了确定变性的进展和表现，无论是神经元的（相对于 到星形胶质细胞）单胺氧化酶是必要的退化，和行为后果的慢性 甲基诱导的SNc和LC变性。我的主要假设是慢性冰毒会诱导神经元 SNc和LC变性的MAO依赖性回退模式导致认知障碍， 将在以下目标中进行测试：目标1：确定慢性冰毒是否产生SNc的回退模式 和LC变性。甲基增加轴突，但不是体细胞单胺氧化酶依赖的线粒体应激， 抑制防止慢性甲基诱导的SNc和LC变性;这些数据表明， 轴突线粒体压力驱动退化。因此，我假设慢性冰毒会产生 SNc和LC变性的回退模式，其中轴突损失先于体细胞损失。目标2：确定 如果神经元MAO对于慢性甲基诱导的SNc和LC变性是必需的。研究表明，系统 单胺氧化酶抑制可防止慢性甲硫氨酸诱导的SNc和LC变性，但单胺氧化酶的表达 在神经元和星形胶质细胞中。鉴于冰毒增加了SNc和LC轴突的线粒体应激，我假设 神经元的单胺氧化酶是退化所必需的目的3：确定慢性行为后果 甲基诱导的SNc和LC变性。SNc变性和LC病变与损伤相关 在新的物体识别和上下文相关的恐惧条件反射试验，分别;因此，我 假设慢性甲基苯丙胺诱导的SNc和LC变性将导致类似的行为 损伤我将通过训练和使用免疫荧光，无偏体视学， 神经元和轴突变性评估、行为分析以及遗传和药理学 抑制MAO酶。测试我的假设将为我提供出色的技术和概念 作为一名研究科学家。完成拟议目标将提高我们对 慢性冰毒的神经退行性后果，扩大对儿茶酚胺能变性的认识 并为涉及类似变性的疾病的研究提供价值。