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The Journal of Neuroscience, February 22, 2006, 26(8):2321-2325; doi:10.1523/JNEUROSCI.4859-05.2006
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Brief Communication
Dopaminergic Substantia Nigra Neurons Project Topographically Organized to the Subventricular Zone and Stimulate Precursor Cell Proliferation in Aged Primates
Nils Freundlieb,1,2 * Chantal François,2 * Dominique Tandé,2 Wolfgang H. Oertel,1 Etienne C. Hirsch,2 andGünter U. Höglinger1 1Experimental Neurology, Philipps University, D-35033 Marburg, Germany, and 2Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 679, Experimental Neurology and Therapeutics, Hôpital de la Salpetrière, Université Pierre et Marie Curie Paris 6, F-75651 Paris, France
Correspondence should be addressed to Günter U. Höglinger, Experimental Neurology, Philipps University, D-35033 Marburg, Germany. Email: guenter.hoeglinger{at}med.uni-marburg.de
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.
Key words: nonhuman primate; aging; dopamine; adult neurogenesis; neural precursor cells; substantia nigra; Parkinson's disease
Received Nov. 11, 2005; revised Jan. 10, 2006; accepted Jan. 14, 2006.
Correspondence should be addressed to Günter U. Höglinger, Experimental Neurology, Philipps University, D-35033 Marburg, Germany. Email: guenter.hoeglinger{at}med.uni-marburg.de
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