Aberrant Adult Neurogenesis in the Subventricular Zone-Rostral Migratory Stream-Olfactory Bulb System Following Subchronic Manganese Exposure

Abstract Adult neurogenesisoccurs in brain subventricular zone(SVZ). Our recent data reveal an elevated proliferation of BrdU(+) cells in SVZ following subchronic manganese (Mn) exposure in rats. This study was designed to distinguish Mn effect on the critical stage of adult neurogenesis, i.e., proliferation, migration, survival and differentiation from the SVZ via the rostral migratory stream(RMS) to the olfactory bulb (OB). Adult rats received a single ip-dose of BrdU at the end of 4-wk Mn exposure to label proliferating cells. Immunostaining and cell-counting showed a 48% increase of BrdU(+) cells in Mn-exposed SVZ than in controls (p<0.05). These BrdU(+) cells were identified as a mixed population of mainly GFAP(+) type-B neural stem cells with Nestin(+) type-C transit progenitor cells, DCX(+) migratory neuroblastsand Iba1(+) microglial cells. Another group of adult rats received 3 daily ip-injections of BrdU followed by subchronic Mn exposure. By 4-wk post BrdU labeling, most of the surviving BrdU(+) cells in the OB were differentiated into NeuN(+) matured neurons. However, survival rates of BrdU/ NeuN/ DAPItriple-labeled cells in OB were 33% and 64% in Mn-exposed and control animals, respectively (p<0.01). Infusion of Cu directly into the lateral ventriclesignificantly decreased the cell proliferation in the SVZ. Taken together, these results suggest that Mn exposure initially enhances the cell proliferation in adult SVZ mainly by increasing type-B cells. In the OB, however, Mn exposure significantly reduces the surviving adult-born cells and markedly inhibits their differentiation into mature neurons, resulting in an overall decreased adult neurogenesisin the OB.