Dopaminergic Substantia Nigra Neurons Project Topographically Organized to the Subventricular Zone and Stimulate Precursor Cell Proliferation in Aged Primates

Abstract

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-2Јdeoxyuridine) 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 ϩ (proliferating cell nuclear antigen-positive) proliferating cells (Ϫ44%) and PSA-NCAM ϩ (polysialylated neural cell adhesion moleculepositive) neuroblasts (Ϫ59%) 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.

Dopamine D3Receptor Agonist Delivery to a Model of Parkinson's Disease Restores the Nigrostriatal Pathway and Improves Locomotor Behavior

“…Thus, observations in humans would be consistent with the data reported here and further highlight their relevance to PD. Indeed, dopaminergic modulation of forebrain precursor proliferation is not restricted to rodents but has also been identified in monkeys (Freundlieb et al, 2006) and humans (Höglinger et al, 2004), suggesting that pharmacological manipulation of precursor cell proliferation by small-molecule receptor agonists could represent an exciting means of using endogenous neural progenitor cells to repair the damaged PD brain.…”

Can endocrine disruptors influence neuroplasticity in the aging brain?

“…Since then, a series of publications (e.g., Van Kampen et al, 2005 ) has confirmed the potency of dopamine as a stimulator of precursor cell proliferation in the rodent SVZ. Even more convincing, research by Freundlieb et al (2006) in aged primates has demonstrated a subventricular dopaminergic projection system from the substantia nigra pars compacta to the SVZ that suggests the possibility of using endogenous neural precursor cells to treat aged primates like ourselves. In these animal studies, a significant portion of the new neurons are integrated into the striatum.…”

“…Their argument is countered by a variety of sources. One comes from experiments in nonhuman primates, such as noted above in Freundlieb et al (2006). Several other experimenters have offered evidence from nonhuman primates.…”

1980-2011: Parkinson's Disease and Advance in Stem Cell Research

“…The SVZ, one of the two neurogenic zones region located in the lateral wall of the ventricles that maintains the largest pool of proliferating cells in the mature mammalian CNS, receives organized projections from the SNc. These efferent projections can influence precursor cell proliferation in both adult animal (Baker et al, 2004;O'Keeffe et al, 2009a) and primate models (Freundlieb et al, 2006), probably through dopamine-induced release of Epidermal Growth Factor in the SVZ (O'Keeffe et al, 2009b). Dopaminergic denervation within SVZ causes a reduced rate of neural precursor mitosis and abridged neuronal maturation in the long term, a phenomenon common among PD patients (Hoglinger et al, 2004) and toxininduced animal models of PD (Aponso et al, 2008;He et al, 2006;He et al, 2008;Winner et al, 2009;Winner et al, 2006).…”