Differential Response of Ventral Midbrain and Striatal Progenitor Cells to Lesions of the Nigrostriatal Dopaminergic Projection

In response to injury, progenitor cells in the adult brain can proliferate and generate new neurons and/or glia, which may then participate in injury-induced compensatory processes. In this study, we explore the ability of young adult mice to generate new cells in response to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) lesions, which selectively kill nigrostriatal dopaminergic neurons. Using the thymidine analogue 5-bromo-2′-deoxyuridine (BrdU), we labeled dividing cells 3, 10, and 15 days after MPTP lesion. A robust proliferative response was seen specifically in the substantia nigra (SN) and the dorsal striatum 3 days postlesion; the response persisted 10–14 days. To explore the fate of proliferative cells, we administered BrdU 3 days postlesion and examined the phenotype of BrdU + cells at various times thereafter, using double immunolabeling. In the striatum, nearly all newly-generated cells rapidly differentiated into GFAP + astrocytes that participated in the injury-induced glial reaction. In the SN, however, reactive astroglia were not BrdU + . Some midbrain cells co-immunostained for BrdU and Mac-1, a microglial marker. However, most BrdU + cells in the SN failed to express markers for microglia, astroglia, oligodendroglia, or neurons, suggesting that they may remain as uncommitted progenitors. Thus, progenitors in the vicinity of the degenerating dopaminergic cell bodies respond differently to lesion than progenitors in the vicinity of the degenerating axon terminal. Although the putative midbrain progenitors appear uncommitted 22 days after their birth, it is possible that they may adopt neural or glial fates if allowed to survive longer, or if exposed to exogenous factors.