Dopaminergic substantia nigra neurons project topographically organized to the subventricular zone and stimulate precursor cell proliferation in aged primates
Dopaminergic substantia nigra neurons project topographically organized to the subventricular zone and stimulate precursor cell proliferation in aged primates
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DOI：
10.1523/jneurosci.4859-05.2006
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发表时间：
2006-02-22
影响因子：
5.3
通讯作者：
Höglinger, GU
中科院分区：
文献类型：
--
作者：
Freundlieb, N;François, C;Höglinger, GU
成年灵长类动物大脑的室下区含有可以产生新神经元的神经干细胞。因此，内源性神经发生可能用于替代神经退行性疾病中丢失的神经元。然而，这将需要对体内干细胞增殖和分化的分子调控的精确理解。包括多巴胺在内的几种调节因子在啮齿类动物中已被发现，但在灵长类动物中还没有发现。因此，我们研究了非人灵长类脑室下区多巴胺能神经支配的起源和功能。追踪实验在三只猕猴揭示了一个地形组织的投影从黑质pars aparta（SNPC），但不是相邻的retrorubral领域，脑室下区：前内侧SNPC项目的前腹侧脑室下区，后外侧SNPC的posterodoral脑室下区。酪氨酸羟化酶和BrdU（5-溴-2 '-脱氧尿苷）掺入增殖细胞DNA的双重免疫标记表明，多巴胺能纤维接近室管膜下区的增殖细胞。我们研究了这种黑质脑室下投射对6只老年猕猴细胞增殖的影响，因为年轻成年人和老年灵长类动物之间的神经发生率不同，而且神经退行性疾病主要影响老年人。用MPTP（1-甲基-4-苯基-1，2，3，6-四氢吡啶）处理三只猕猴，以减少室下区的多巴胺能神经支配。在室管膜下区的去神经支配区域中发现PCNA（+）（增殖细胞核抗原阳性）增殖细胞（-44%）和PSA-NCAM（+）（多唾液酸化神经细胞粘附分子阳性）成神经细胞（-59%）的数量显著减少，表明完整的多巴胺能黑质-室管膜下神经支配对于老年灵长类动物的持续神经发生至关重要。
The subventricular zone of the adult primate brain contains neural stem cells that can produce new neurons. Endogenous neurogenesis might therefore be used to replace lost neurons in neurodegenerative diseases. This would require, however, a precise understanding of the molecular regulation of stem cell proliferation and differentiation in vivo. Several regulatory factors, including dopamine, have been identified in rodents, but none in primates. We have, therefore, studied the origin and function of the dopaminergic innervation of the subventricular zone in nonhuman primates. Tracing experiments in three macaques revealed a topographically organized projection from the substantia nigra pars compacta (SNpc), but not the adjacent retrorubral field, to the subventricular zone: the anteromedial SNpc projects to the anteroventral subventricular zone, the posterolateral SNpc to the posterodorsal subventricular zone. Double immunolabeling for tyrosine hydroxylase and BrdU (5-bromo-2'-deoxyuridine) incorporated into the DNA of proliferating cells showed that dopaminergic fibers approach proliferating cells in the subventricular zone. We investigated the effect of this nigro-subventricular projection on cell proliferation in six aged macaques, because the rate of neurogenesis differs between young adult and aged primates and because neurodegenerative diseases mainly affect aged humans. Three macaques were treated with MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) to decrease dopaminergic innervation of the subventricular zone. A significant decrease in the number of PCNA(+) ( proliferating cell nuclear antigen-positive) proliferating cells ( - 44%) and PSA-NCAM(+) (polysialylated neural cell adhesion molecule-positive) neuroblasts ( - 59%) was found in the denervated regions of the subventricular zone, suggesting that an intact dopaminergic nigro-subventricular innervation is crucial for sustained neurogenesis in aged primates.