Progressive dopamine loss:effect of exercise on striatal and nigral glutamate

进行性多巴胺丢失：运动对纹状体和黑质谷氨酸的影响

• 批准号: 8624514
• 负责人: Charles Kenneth Meshul
• 金额: --
• 依托单位: PORTLAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8624514
• 关键词: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Acute; Affect; Age; Agonist; Animal Disease Models; Animal Model; Area; Behavior; Caring; Carrier Proteins; Clinical Research; Corpus striatum structure; Development; Disease; Dopamine; Dose; Education; Effectiveness; Equilibrium; Excitatory Amino Acid Antagonists; Exercise; Functional disorder; Funding; GLAST Protein; Gait; General Population; Glutamate Receptor; Glutamate Transporter; Glutamates; Goals; Gold; Incidence; Individual; Infusion procedures; Injection of therapeutic agent; Intervention; Investigation; Label; Lead; Measures; Medical center; Microdialysis; Modeling; Motor; Motor Cortex; Movement; Movement Disorders; Mus; Nerve; Neurotoxins; Parkinson Disease; Parkinsonian Disorders; Pathway interactions; Patients; Physical activity; Play; Population; Proteins; Recovery; Reporting; Research; Research Priority; Research Project Grants; Role; Running; Substantia nigra structure; Synapses; Tyrosine 3-Monooxygenase; Veterans; aged; density; dopamine transporter; dopaminergic neuron; extracellular; immunoreactivity; improved; in vivo; motor control; motor function improvement; motor function recovery; pars compacta; partial recovery; postsynaptic; public health relevance; putamen; restoration

DESCRIPTION (provided by applicant): 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a systemic neurotoxin commonly used to produce partial loss of at least the dopamine (DA) input from the substantia nigra pars compacta (SNpc) to the caudate/putamen (CPu). This also alters the glutamate input to the CPu and substantia nigra (SN). Following MPTP, there is a decrease in the basal extracellular glutamate levels in the CPu and an increase in the SN. Injection of a glutamate receptor agonist into the CPu leads to parkinsonism, suggesting that glutamate synapses within at least the CPu play an important role in the development of the movement problems associated with PD. The imbalance between DA and glutamate within the CPu plays a critical role in the movement problems associated with PD and is partially reversed following treadmill exercise in acute MPTP treated mice. Forced treadmill exercise, starting 1 day after the last dose of subacute MPTP, resulted in partial recovery of DA neurons and markers in the SN and CPu, and improved gait/physical activity. However, this subacute model is limited due to a non-progressive 50% loss of DA neurons in the SNpc. We have developed a new progressive model of increased DA loss and motor dysfunction via weekly increased dosing of MPTP over 4 weeks. The 62% decrease in DA neurons in the SNpc after 4 weeks of MPTP is similar to that reported in patients with PD. There is an increase in the density of nerve terminal glutamate immuno-gold labeling in the CPu following progressive MPTP treatment, suggesting a buildup of glutamate and a decrease in release. We also find MPTP-induced changes in several glutamate transporter markers within the CPu (VGLUT 1, EAAC1, GLAST) and SN ( VGLUT 1/2, EAAC1, GLAST, GLT-1) that would be consistent with the decrease or increase in extracellular glutamate, respectively, as measured by in vivo microdialysis. In addition, treadmill exercise in naive mice results in a decrease in CPu extracellular glutamate. The overall goal of this project is to determine the effects of treadmill and voluntary running wheel exercise initiated during (i.e., intervention) or following (i.e., restoration) progressive dosing of MPTP on alterations in glutamate within the CPu/SNpc and motor function in both young and aged mice. The overarching hypothesis of this proposal is that the effects of MPTP on CPu glutamate will be augmented following exercise, but will be reversed by exercise in the SN, leading to recovery of motor function and partial restoration of DA markers in the CPu/SNpc. These changes in glutamate and DA markers, and motor function will occur to a greater extent following treadmill versus running wheel exercise and in younger compared to older mice. The specific aims of this proposal are to 1.)!determine the effect of forced treadmill versus voluntary running wheel exercise, beginning 2 weeks after the start of progressive MPTP administration (i.e., intervention) with continued MPTP for 2 more weeks and exercise for 4 weeks, on glutamate and DA markers in the CPu/SN, and motor function in both young and aged mice, 2.) determine the effect of forced treadmill versus voluntary running wheel exercise beginning 4 weeks after the start of progressive MPTP administration (i.e., restoration) with continued exercise for 4 weeks, on glutamate and DA markers in the CPu/SN, and motor function in both young and aged mice, and 3.) determine if increasing CPu glutamate levels during treadmill exercise will block the exercise-induced recovery of DA neurons in the SNpc and motor function following MPTP. To mimic the effect of treadmill exercise, glutamate receptors will be blocked in the SN during MPTP treatment.

描述（由申请人提供）： 1-甲基-4-苯基-1,2,3,6-四氢吡啶 (MPTP) 是一种全身性神经毒素，通常用于导致至少部分损失从黑质致密部 (SNpc) 到尾状核/壳核 (CPu) 的多巴胺 (DA) 输入。这也改变了 CPu 和黑质 (SN) 的谷氨酸输入。 MPTP 后，CPu 中的基础细胞外谷氨酸水平降低，SN 增加。将谷氨酸受体激动剂注射到 CPu 中会导致帕金森症，这表明至少 CPu 内的谷氨酸突触在与 PD 相关的运动问题的发展中发挥着重要作用。 CPu 内 DA 和谷氨酸之间的不平衡在与 PD 相关的运动问题中起着至关重要的作用，并且在急性 MPTP 治疗的小鼠中在跑步机运动后部分得到逆转。在最后一次亚急性 MPTP 剂量后 1 天开始进行强制跑步机锻炼，导致 SN 和 CPU 中的 DA 神经元和标记物部分恢复，并改善步态/身体活动。然而，由于 SNpc 中 DA 神经元非进行性损失 50%，这种亚急性模型受到限制。我们开发了一种新的渐进模型，通过在 4 周内每周增加 MPTP 剂量来增加 DA 损失和运动功能障碍。 MPTP 4 周后，SNpc 中 DA 神经元减少了 62%，与 PD 患者中报道的情况相似。 进行性 MPTP 治疗后，CPu 中神经末梢谷氨酸免疫金标记的密度增加，表明谷氨酸积累和释放减少。 我们还发现 MPTP 诱导的 CPu（VGLUT 1、EAAC1、GLAST）和 SN（VGLUT 1/2、EAAC1、GLAST、GLT-1）内的几种谷氨酸转运蛋白标记物发生变化，这些变化分别与细胞外谷氨酸的减少或增加一致，通过体内微透析测量。另外，跑步机 首次实验的小鼠进行运动会导致 CPu 细胞外谷氨酸减少。 该项目的总体目标是确定在 MPTP 渐进给药期间（即干预）或之后（即恢复）开始的跑步机和自愿跑轮运动对年轻和老年小鼠 CPu/SNpc 内谷氨酸和运动功能变化的影响。该提议的总体假设是，MPTP 对 CPu 谷氨酸的影响在运动后会增强，但会通过 SN 中的运动而逆转，从而导致运动功能恢复和 CPu/SNpc 中 DA 标记的部分恢复。与跑轮运动相比，在跑步机上进行运动后，谷氨酸和 DA 标记物以及运动功能的这些变化会更大程度地发生，并且与年长的小鼠相比，年轻的小鼠会发生更大程度的变化。该提案的具体目标是 1.)!确定强制跑步机与自愿跑轮运动的影响，从开始渐进性 MPTP 管理（即干预）开始 2 周开始，继续 MPTP 2 周以上并运动 4 周，对 CPu/SN 中的谷氨酸和 DA 标记以及年轻和老年小鼠运动功能的影响，2.) 确定强制跑步机与自愿跑轮运动的影响 开始渐进性 MPTP 给药（即恢复）后 4 周开始，持续运动 4 周，对年轻和老年小鼠的 CPu/SN 中的谷氨酸和 DA 标记物以及运动功能进行评估，以及 3.) 确定在跑步机运动期间增加 CPu 谷氨酸水平是否会阻止运动诱导的 SNpc 中的 DA 神经元和 MPTP 后运动功能的恢复。为了模拟跑步机运动的效果，MPTP 治疗期间将阻断 SN 中的谷氨酸受体。