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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要甲基苯丙胺（meth）是一种强效成瘾性精神兴奋剂，能够造成神经元损伤。我的导师格雷夫斯博士最近的研究发现，冰毒会增加轴突中的线粒体压力黑质致密部 (SNc) 多巴胺 (DA) 神经元由细胞质 DA 的 MAO 代谢产生。初步研究表明，蓝斑 (LC) 去甲肾上腺素 (NE) 神经元的轴突具有类似的作用。使用 Graves 博士最近的研究发现 28 天的冰毒给药模式会导致 SNc DA 神经元退化 MAO 的药理学抑制具有神经保护作用。试点研究同样表明慢性甲基诱导的 LC 变性可通过 MAO 抑制而减弱。这些数据表明轴突 MAO- 依赖性线粒体应激导致慢性甲基化引起的退化。总体目标是该提案旨在确定变性的进展和表现，无论是神经元（而不是神经元）星形细胞）MAO 酶是退化所必需的，并且慢性的行为后果甲基诱导的 SNc 和 LC 变性。我的中心假设是，慢性冰毒会诱发神经元 MAO 依赖性 SNc 和 LC 变性的死亡模式导致认知障碍和将在以下目标中进行测试：目标 1：确定慢性冰毒是否会产生 SNc 的死亡模式和 LC 变性。冰毒会增加轴突，但不会增加体细胞 MAO 依赖性线粒体应激，并且 MAO 抑制可防止慢性甲基苯丙胺诱导的 SNc 和 LC 变性；这些数据表明 MAO 依赖性轴突线粒体应激会导致退化。因此，我假设长期吸食冰毒会产生 SNc 和 LC 变性的死亡模式，其中轴突损失先于体细胞损失。目标 2：确定神经元 MAO 是否是慢性甲基苯丙胺诱导的 SNc 和 LC 变性所必需的。研究表明系统性 MAO 抑制可防止慢性甲基苯丙胺诱导的 SNc 和 LC 变性，但 MAO 酶会表达在神经元和星形胶质细胞中。鉴于冰毒会增加 SNc 和 LC 轴突中的线粒体应激，我假设神经元 MAO 是退化所必需的。目标 3：确定慢性病的行为后果甲基诱导的 SNc 和 LC 变性。 SNc 变性和 LC 病变与损伤相关分别用于新物体识别和情境相关的恐惧条件反射实验；我因此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、无偏见的体视学来检验我的假设神经元和轴突变性评估、行为分析以及遗传和药理学 MAO 酶的抑制。测试我的假设将为我提供出色的技术和概念作为研究科学家接受培训。完成拟议的目标将提高我们对慢性甲基苯丙胺的神经退行性后果，扩展儿茶酚胺能变性的知识并为涉及类似退化的疾病的研究提供价值。