Behavioral and fMRI Studies

项目2 在上一个资助期，我们证明了GDNF的可编程泵输送促进了 非人灵长类动物模型运动和黑质纹状体多巴胺(DA)功能的改善 帕金森氏病(PD)。在拟议的研究中，项目2将使用行为和功能磁力 磁共振成像(FMRI)方法确定进一步增强GDNF在运动和运动中作用的条件 DA在MPTP损伤的恒河猴中发挥作用，这是最能模拟人类帕金森状态的。在……里面 结合项目1和项目3，项目2将确定壳核和黑质联合输送GDNF， 通过可编程泵和实质内导管，将产生更好的行为恢复 黑质纹状体途径比单部位壳核分娩更有效。项目2还将调查是否慢性， 实质内注射GDNF将更完全地恢复MPTP损伤的运动和DA功能 与严重受损的动物相比，表现出较轻但稳定的帕金森症的动物。在项目2中， 动物将用阿朴吗啡和左旋多巴/卡比多巴进行量化表征，在GDNF治疗前后 行政管理。为此，我们将使用各种行为测量，包括：1)自动 用于分析全身运动的视频跟踪系统，2)自动手检索任务 评估精细的手/粗略的手臂动作，以及3)用于评估的非人灵长类分级标准 帕金森病的行为特征：运动迟缓、僵硬、姿势、平衡、震颤。除了……之外 行为测试，项目2将使用fMRI技术非侵入性地同时测量 阿朴吗啡诱导的血氧水平依赖(BOLD)改变对基底节功能的警示 恒河猴GDNF给药前后。总体而言，这些研究应该有助于 改善慢性GDNF治疗对黑质纹状体DA系统影响的机制理解 在非人类灵长类动物中的研究以及帕金森病治疗的改进方法。

PROJECT 2 During the last funding period, we demonstrated that programmable pump delivery of GDNF promotes improvements in motor and nigrostriatal dopamine (DA)functions in nonhuman primate models of Parkinson's disease (PD). In the proposed studies, Project 2 will use behavioral and functional magnetic resonance imaging (fMRI) methods to determine conditions to further enhance GDNF actions on motor arid DA functions in MPTP-lesioned rhesus monkeys, which best simulate the human parkinsonian state. In conjunction with Projects 1 & 3, Project 2 will determine if combined putamenal and nigral delivery of GDNF, via programmable pumps and intraparenchymal catheters, will produce better behavioral recovery of the nigrostriatal pathway than single-site putamenal delivery alone. Project 2 will also investigate if chronic, intraparenchymal delivery of GDNF will more completely, restore motor and DA functions in MPTP-lesioned animals expressing milder, but stable parkinsonism versus severely impaired animals. In Project 2, the animals will be quantitatively characterized with apomorphine and levodopa/carbidopa, pre- and post-GDNF administration. To this end, we will use a variety of behavioral measurements, including: 1) an automated video-tracking system for analyzing whole body movements, 2) an automated hand-retrieval task for evaluating fine hand/coarse arm movements, and 3) a nonhuman primate rating scale for evaluating behavioral features characteristic of PD: bradykinesia, rigidity, posture, balance and tremor. In addition to behavioral testing, Project 2 will use fMRI techniques to noninvasively and simultaneously measure apomorphine-evoked blood oxygen level-dependent (BOLD) changes in basal ganglia functions of alert rhesus monkeys, pre- and post-GDNF administration. Collectively, these studies should contribute to an improved mechanistic understanding of the effects of chronic GDNF treatment on the nigrostriatal DA system in nonhuman primates and improved approaches for the treatment of PD.