Freundlieb Nils, François Chantal, Tandé Dominique, Oertel Wolfgang H, Hirsch Etienne C, Höglinger Günter U
Experimental Neurology, Philipps University, D-35033 Marburg, Germany.
J Neurosci. 2006 Feb 22;26(8):2321-5. doi: 10.1523/JNEUROSCI.4859-05.2006.
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.
成年灵长类动物脑室内下区含有能够产生新神经元的神经干细胞。因此，内源性神经发生可用于替代神经退行性疾病中丢失的神经元。然而，这需要精确了解体内干细胞增殖和分化的分子调控机制。在啮齿动物中已鉴定出几种调控因子，包括多巴胺，但在灵长类动物中尚未发现。因此，我们研究了非人类灵长类动物脑室内下区多巴胺能神经支配的起源和功能。对三只猕猴进行的追踪实验显示，从黑质致密部（SNpc）而非相邻的红核后区到脑室内下区存在一种按拓扑结构组织的投射：前内侧SNpc投射到前腹侧脑室内下区，后外侧SNpc投射到后背侧脑室内下区。对酪氨酸羟化酶和掺入增殖细胞DNA中的BrdU（5-溴-2'-脱氧尿苷）进行双重免疫标记显示，多巴胺能纤维接近脑室内下区的增殖细胞。我们研究了这种黑质-脑室内下投射对六只老年猕猴细胞增殖的影响，因为年轻成年灵长类动物和老年灵长类动物的神经发生速率不同，且神经退行性疾病主要影响老年人。三只猕猴接受MPTP（1-甲基-4-苯基-1,2,3,6-四氢吡啶）处理以减少脑室内下区的多巴胺能神经支配。在脑室内下区的去神经支配区域发现PCNA+（增殖细胞核抗原阳性）增殖细胞数量显著减少（-44%），PSA-NCAM(+)（多唾液酸神经细胞黏附分子阳性）神经母细胞数量显著减少（-59%），这表明完整的多巴胺能黑质-脑室内下神经支配对于老年灵长类动物持续的神经发生至关重要。
