Glutamate, aging and enriched environment after dopamine loss

谷氨酸、衰老和多巴胺丢失后的富集环境

• 批准号: 8044988
• 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: 2010
• 资助国家: 美国
• 起止时间: 2010-10-01 至 2014-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8044988
• 关键词: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Address; Adult; Affect; Age; Age Reporting; Aging; Animal Disease Models; Animals; Area; Back; Basal Ganglia; Behavior; Behavioral; Caring; Cells; Clinical Research; Cognitive; Corpus striatum structure; Data; Dependence; Disease; Dopamine; Dose; Education; Electron Microscopy; Environment; Excitatory Amino Acid Antagonists; Exposure to; Funding; GLAST Protein; General Population; Glial Fibrillary Acidic Protein; Glutamate Receptor; Glutamate Transporter; Glutamates; Goals; Gold; Hour; Incidence; Individual; Investigation; Label; Lead; Locomotor Recovery; Measures; Medical center; Modeling; Motor; Motor Activity; Motor Neurons; Movement Disorders; Mus; Nerve; Neuroglia; Neurons; Neurotoxins; Output; Parkinson Disease; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Play; Population; Program Reviews; Proteins; Publications; Recovery; Reporting; Research; Research Priority; Research Project Grants; Rodent; Role; Staining method; Stains; Stroke; Substantia nigra structure; Synapses; Testing; Time; Tissues; Toxin; Traumatic Brain Injury; Tyrosine 3-Monooxygenase; Veterans; Western Blotting; age effect; aged; base; density; dopamine transporter; experience; extracellular; gamma-Aminobutyric Acid; locomotor deficit; mouse model; nervous system disorder; neurochemistry; neurorestoration; nigrostriatal pathway; older patient; pars compacta; partial recovery; restoration; trend

DESCRIPTION (provided by applicant): As observed in Parkinson's disease, loss of dopamine (DA) within the nigrostriatal pathway in rodents due to the neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), results in alterations in the glutamate input to the striatum and substantia nigra (SN). Following MPTP, there is a decrease in the basal glutamate levels in the striatum and an increase in the SN 56,84. Glutamate receptor antagonists decrease the locomotor deficits associated with the loss of striatal DA. Exposure of mice to an enriched environment (EE) for 2 months prior to the administration of MPTP results in a reduced loss of tyrosine hydroxylase (TH) immunolabeled neurons in the substantia nigra pars compacta (SN-PC) compared to the MPTP-treated animals exposed to the standard environment (SE) 6. We are the first to report that 1 week following subchronic MPTP, continuous exposure to an EE for the next 21 days, with continued MPTP administration, partially restores the loss of TH-labeled neurons in the SN-PC compared to the MPTP/SE group. This also results in improvement in motor function. In young mice, subchronic MPTP administration results in a 50% loss of TH-labeled neurons in the SN-PC and a 30% increase in their dependence upon a vertical support when rearing in a cylinder (ie wall assisted vs unassisted rears). In aged mice, subchronic MPTP results in a 45% loss of TH-labeled cells in the SN-PC and a nearly 60% increase in the number of wall-assisted vs unassisted rears. Comparing aged versus young mice, following exposure to an EE only, there is 1.) a 25% increase in the basal levels of extracellular striatal glutamate (~95% in young mice), 2.) no change in the density of nerve terminal glutamate immuno-gold labeling (25% decrease in young mice), 3.) no change in the striatal protein level for the glial protein, GFAP (65% increase in young mice), and 4.) a 29% increase in the protein levels for the glutamate transporter, GLT-1 (10% increase in young mice). There is a trend towards an increase in the dopamine transporter protein following an EE in both young and aged mice. Therefore, increased striatal glutamate may be a mechanism by which an EE reduces the loss of TH-labeled neurons in the SN-PC and promotes motor recovery. Another possible mechanism we will test is whether an EE is having an affect directly on glutamate and gamma-aminobutyric acid (GABA) synapses in the SN. The overall goal of this proposal is to investigate the effects of subchronic MPTP, age and exposure to an EE on alterations in glutamate in both the striatum and SN. GABA levels will also be measured in the SN. The overarching hypothesis of this proposal is that the effects of MPTP on striatal and SN glutamate will be partially reversed by exposure to an EE, leading to partial recovery of motor behavior, DA levels in the striatum and partial restoration of TH-labeled cells in the SN-PC. This reversal will occur in the aged mice, but it will be greater in younger compared to the aged mice. The specific aims of this proposal are to 1.) determine the effects of age (10 weeks vs 12 months) and dosing of the toxin on changes in striatal glutamate, TH-labeled cells in the SN-PC, and motor behavior after 1 week of subchronic administration of MPTP, followed by continuous exposure to an EE, 2.) determine the effect of subchronic MPTP-induced changes in striatal glutamate, TH-labeled cells in the SN- PC and motor behavior after exposure to an EE for either 2 or 6 hours/day, and 3.) determine the effects of subchronic administration of MPTP, followed by continuous exposure to an EE, on changes in both glutamate and GABA in the SN and motor behavior in young versus aged mice. We will further determine if blockade of SN glutamate receptors or increasing striatal glutamate following MPTP will both mimic the affect of exposure to an EE. PUBLIC HEALTH RELEVANCE: Investigation of movement disorders, especially Parkinson's disease, is a high priority research area within the Department of Veterans Affairs. Because of the high incidence of this disease in the general population over the age of 50 and the fact that the age of the veteran population is slowly increasing, this movement disorder is affecting more and more of our veterans. Since exposure to an enriched environment in at least non-Parkinsonian patients and in an animal model of this disease appears to be effective in terms of augmenting motor and cognitive behavior, this type of non-pharmacological approach needs further investigation. The results from this project have potentially wide implications of great significance to the population cared for by the Department of Veteran Affairs and by the fact that six Parkinson's Disease Research, Education and Care Centers (PADRECCs) currently are funded (one here at the Portland VA Medical Center), to carry out clinical research projects focusing on Parkinson's disease.

描述（由申请人提供）： 正如在帕金森病中观察到的那样，由于神经毒素 1-甲基-4-苯基-1,2,3,6-四氢吡啶 (MPTP)，啮齿类动物的黑质纹状体通路内多巴胺 (DA) 丢失，导致纹状体和黑质 (SN) 的谷氨酸输入发生变化。 MPTP 后，纹状体中的基础谷氨酸水平降低，SN 56,84 增加。谷氨酸受体拮抗剂可减少与纹状体 DA 丧失相关的运动缺陷。 与暴露于标准环境 (SE) 6 的 MPTP 治疗动物相比，在给予 MPTP 之前将小鼠暴露于富集环境 (EE) 2 个月，可减少黑质致密部 (SN-PC) 中酪氨酸羟化酶 (TH) 免疫标记神经元的损失6。我们是第一个报告亚慢性 MPTP 1 周后，持续暴露于 与 MPTP/SE 组相比，接下来 21 天的 EE 以及持续的 MPTP 给药可以部分恢复 SN-PC 中 TH 标记神经元的损失。这也导致运动功能的改善。在年轻小鼠中，亚慢性 MPTP 给药导致 SN-PC 中 TH 标记神经元损失 50%，并且在圆柱体中站立时（即壁辅助与无辅助后立），它们对垂直支撑的依赖性增加 30%。在老年小鼠中，亚慢性 MPTP 导致 SN-PC 中 TH 标记的细胞损失 45%，并且与无辅助的背部相比，墙壁辅助的背部数量增加了近 60%。比较老年小鼠与年轻小鼠，仅暴露于 EE 后，1.) 细胞外纹状体谷氨酸的基础水平增加 25%（年轻小鼠约为 95%），2.）神经末梢谷氨酸免疫金标记的密度没有变化（年轻小鼠减少 25%），3.）神经胶质蛋白 GFAP 的纹状体蛋白水平没有变化（增加 65%） 年轻小鼠中)，以及 4.) 谷氨酸转运蛋白 GLT-1 的蛋白质水平增加 29%（年轻小鼠中增加 10%）。在年轻和老年小鼠中，EE 后多巴胺转运蛋白都有增加的趋势。因此，增加纹状体谷氨酸可能是 EE 减少 SN-PC 中 TH 标记神经元损失并促进运动恢复的机制。我们将测试的另一个可能的机制是 EE 是否直接影响 SN 中的谷氨酸和γ-氨基丁酸 (GABA) 突触。 该提案的总体目标是研究亚慢性 MPTP、年龄和 EE 暴露对纹状体和 SN 谷氨酸变化的影响。 GABA 水平也将在 SN 中测量。该提议的总体假设是，MPTP 对纹状体和 SN 谷氨酸的影响将通过暴露于 EE 部分逆转，导致运动行为、纹状体中 DA 水平的部分恢复以及 SN-PC 中 TH 标记细胞的部分恢复。这种逆转会发生在老年小鼠身上，但与老年小鼠相比，年轻小鼠的逆转会更大。 该提案的具体目的是 1.) 确定年龄（10 周与 12 个月）和毒素剂量对纹状体谷氨酸、SN-PC 中 TH 标记细胞变化的影响，以及亚慢性施用 MPTP 1 周后运动行为的影响，然后持续暴露于 EE，2.) 确定亚慢性 MPTP 诱导的纹状体谷氨酸、SN-PC 中 TH 标记细胞变化的影响 每天暴露于 EE 2 或 6 小时后的 SN-PC 和运动行为，以及 3.) 确定亚慢性施用 MPTP，然后持续暴露于 EE，对年轻小鼠与老年小鼠 SN 中谷氨酸和 GABA 的变化以及运动行为的影响。我们将进一步确定 MPTP 后阻断 SN 谷氨酸受体或增加纹状体谷氨酸是否都会模拟暴露于 EE 的影响。 公共卫生相关性： 运动障碍的调查，特别是帕金森病，是退伍军人事务部的一个高度优先的研究领域。由于这种疾病在50岁以上的一般人群中发病率很高，而且退伍军人群体的年龄正在缓慢增加，这种运动障碍正在影响着我们越来越多的退伍军人。由于至少在非帕金森病患者和该疾病的动物模型中暴露于丰富的环境似乎在增强运动和认知行为方面是有效的，因此这种类型的非药物方法需要进一步研究。该项目的结果对退伍军人事务部所照顾的人群具有潜在的广泛影响，并且目前有六个帕金森病研究、教育和护理中心 (PADRECC) 得到资助（其中一个位于波特兰退伍军人管理局医疗中心），以开展专注于帕金森病的临床研究项目。