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: 8442214
• 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/8442214
• 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）是一种全身神经毒素，通常用于产生至少从蛋白酶Nigra Pars Compacta（SNPC）到Caudate/putamen（CPU）的Dopamine（DA）输入的部分损失。这也改变了谷氨酸的输入到CPU和黑质Nigra（SN）。 MPTP之后，CPU中的基础细胞外谷氨酸水平降低，SN的增加。将谷氨酸受体激动剂注射到CPU中导致帕金森氏症，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起重要作用。 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关键作用，并且在急性MPTP处理的小鼠中跑步机运动后部分逆转。在最后一次剂量MPTP后1天开始，强迫跑步机运动导致SN和CPU中DA神经元和标记的部分恢复，并改善了步态/身体活动。但是，由于SNPC中DA神经元的50％损失，该亚急性模型受到限制。我们通过每周在4周内增加了MPTP的剂量来增加DA损失和运动功能障碍的新渐进模型。 MPTP 4周后​​，SNPC中DA神经元的62％降低与PD患者报道的相似。 渐进性MPTP治疗后，CPU中神经末端谷氨酸免疫金的密度有所增加，这表明谷氨酸的积累和释放的降低。 我们还发现MPTP诱导的CPU（VGLUT 1，EAAC1，GLAST）和SN（VGLUT 1/2，EAAC1，GLAST，GLT-1）内的几个谷氨酸转运蛋白标记的变化将与vivo Microdia in In In vivo Microdiaia s Melecs seals seals s ressems s race cpu。此外，跑步机 在天真小鼠中运动会导致CPU细胞外谷氨酸的降低。 该项目的总体目标是确定在（即干预）或随后（即恢复）MPTP逐渐剂量的跑步机和自愿跑步车轮运动对CPU/SNPC内谷氨酸的改变以及年轻小鼠和年龄小鼠中谷氨酸的变化的影响。该提案的总体假设是，运动后将增加MPTP对CPU谷氨酸的影响，但会在SN中进行运动，从而导致运动功能的恢复和CPU/SNPC中DA标记的部分恢复。与年龄较大的小鼠相比，在跑步机与跑步轮运动和年轻小鼠相比，谷氨酸和DA标记的这些变化将在更大程度上发生运动功能。该提案的具体目的是1。）！确定强迫跑步机和自愿跑步轮运动的效果，从渐进式MPTP施用（即干预）开始2周，并继续进行2周的MPTP，并进行4周的锻炼，对谷氨酸和DA标记在CPU/SN和运动型中的锻炼，并在年轻效果中效果，并确定型号的效果，并确定型号的效果。从持续运动进行4周，在CPU/SN的谷氨酸和DA标记上进行渐进式MPTP启动后4周，在年轻和年龄小鼠中的运动功能以及3.）确定是否会在胎面运动中增加CPU谷氨酸水平，并在SNPC和运动功能中增加da神经元的恢复。为了模仿跑步机运动的影响，在MPTP处理过程中，SN将阻塞谷氨酸受体。