Intranigral Transplantation in Parkinsonian Monkeys

描述：（改编自研究者摘要）：近期研究 表明黑质（SN）中的多巴胺（DArgic）神经元 不仅在纹状体内的轴突末梢分泌多巴胺， 也通过它们的树突在SN网状部（SNr）内， SNr中的多巴胺可能在帕金森病的发展中起作用， 灵长类动物作为推论，黑质和纹状体多巴胺的恢复 输入可能会产生更好的功能恢复帕金森病比 恢复纹状体多巴胺的输入。因此，PI 建议检查结合DA神经元胎儿腹侧中脑的影响， (FVM)将细胞移植到SN和纹状体中的1-甲基-4-苯基-1， 2，3，6-四氢吡啶（MPTP）治疗的偏侧帕金森病（HP）猴和 将结果与纹状体中的FVM移植或单独的SN进行比较。动物 将由不了解类型的研究者定期评估 使用行为测试组合（BBT）进行移植。所有动物 接受颈动脉内MPTP注射治疗，以引起稳定的HP状态， 短期口服左旋多巴治疗，以验证对DArgic治疗的反应性 在随机分为4个相等的组（1-4）之前。微电极记录 神经元活动和磁共振成像（MRI）将用于指导 所有移植手术。在特定目标1（SA 1）中，第1组动物将 同时接受FVM移植到纹状体和SN中，组2 动物将接受纹状体FVM移植，第3组动物将接受FVM 移植到SN中，第4组动物将接受“对照”胎儿组织 移植到SN中。定期BBT评估和免疫化学评估 将使用组1-4中比较的移植动物中的每只来测试 联合纹状体和黑质FVM移植改善 帕金森症的程度大于纹状体FVM或黑质FVM移植 一个人在SA 2中，将在组织前和组织后获得神经元记录。 移植来自所有4组动物的SNr和丘脑底核 核（nucleus），并进行比较。这个实验将检验这样一个假设， 纹状体FVM移植将改变两个SNr神经元的放电模式， 而黑质FVM移植可改变神经元放电 仅在SNr中的模式。在SA 3中，将在体内测量多巴胺水平 在黑质FVM从SN移植前后使用微透析， 在第3组和第4组动物中，这个实验将检验这个假设 黑质FVM移植恢复了SN中的多巴胺含量， 影响脑内多巴胺含量。这三个实验客观上 评估恢复DA gic输入到SN中的作用， 恢复多巴胺能输入纹状体以改善帕金森病行为 在灵长类动物的标志，并将有助于了解SNr的作用， 灵长类帕金森病的病理生理学

DESCRIPTION: (Adapted from the Investigator's Abstract): Recent investigations indicate that dopaminergic (DArgic) neurons in the substantia nigra (SN) secrete dopamine not only in their axonal terminals within the striatum but also via their dendrites within the SN pars reticulata (SNr) and that loss of dopamine in the SNr may have a role in the development of parkinsonism in primates. As a corollary, restoration of both nigral and striatal dopamine inputs may produce better recovery of function in Parkinson's disease than restoration of dopamine inputs in the striatum alone. Therefore, the PI proposes to examine the effects of combined DArgic fetal ventral mesencephalic (FVM) cell transplantation into the SN and the striatum in 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-treated hemiparkinsonian (HP) monkeys and compare the results with FVM transplants in the striatum or SN alone. Animals will be periodically assessed by investigators blinded to the type of transplantation using a behavioral battery of tests (BBT). All animals will be treated with intracarotid MPTP injections to cause a stable HP state and briefly treated with oral levodopa to verify responsiveness to DArgic therapy prior to randomization into 4 equal groups (1-4). Microelectrode recordings of neuronal activity and magnetic resonance imaging (MRI) will be used to guide all transplantation procedures. In specific aim 1 (SA 1), group 1 animals will receive simultaneous FVM transplants into both striatum and the SN, group 2 animals will receive striatal FVM transplants, group 3 animals will receive FVM transplants into the SN and group 4 animals will receive "control" fetal tissue transplants into the SN. Periodic BBT assessments and immunochemical assessment of the transplanted animals compared across groups 1-4 will be used to test the hypothesis that combined striatal and nigral FVM transplants ameliorates parkinsonism to a greater extent than striatal FVM or nigral FVM transplants alone. In SA 2, neuronal recordings will be obtained before and after tissue transplantation from all 4 groups of animals from the SNr and the subthalamic nucleus (STN) and compared. This experiment will examine the hypothesis that striatal FVM transplantation will alter neuronal discharge patterns in both SNr and in the STN, while nigral FVM transplantation will alter neuronal discharge patterns in the SNr only. In SA 3, dopamine levels will be measured in vivo using microdialysis before and after nigral FVM transplantation from the SN and STN in group 3 and group 4 animals. This experiment will test the hypothesis that nigral FVM transplants restore dopamine content in the SN but do not effect dopamine content in the STN. These 3 experiments will objectively evaluate the role of restoring DArgic inputs into the SN in addition to restoring DArgic inputs into the striatum to ameliorate parkinsonian behavioral signs in primates and will help to understand the role of SNr in the pathophysiology of primate parkinsonism.