Notch1 signaling modulates neuronal progenitor activity in the subventricular zone in response to aging and focal ischemia

Abstract

Summary Neurogenesis diminishes with aging and ischemia‐induced neurogenesis also occurs, but reduced in aged brain. Currently, the cellular and molecular pathways mediating these effects remain largely unknown. Our previous study has shown that N otch1 signaling regulates neurogenesis in subventricular zone ( SVZ ) of young adult brain after focal ischemia, but whether a similar effect occurs in aged normal and ischemic animals is unknown. Here, we used normal and ischemic aged rat brains to investigate whether N otch1 signaling was involved in the reduction of neurogenesis in response to aging and modulates neurogenesis in aged brains after focal ischemia. By W estern blot, we found that N otch1 and J agged1 expression in the SVZ of aged brain was significantly reduced compared with young adult brain. Consistently, the activated form of N otch1 ( N otch intracellular domain; NICD ) expression was also declined. Immunohistochemistry confirmed that expression and activation of N otch1 signaling in the SVZ of aged brain were reduced. Double or triple immunostaining showed that that N otch1 was mainly expressed in doublecortin ( DCX )‐positive cells, whereas J agged1 was predominantly expressed in astroglial cells in the SVZ of normal aged rat brain. In addition, disruption or activation of N otch1 signaling altered the number of proliferating cells labeled by bromodeoxyuridine ( B rd U ) and DCX in the SVZ of aged brain. Moreover, ischemia‐induced cell proliferation in the SVZ of aged brain was enhanced by activating the Notch1 pathway and was suppressed by inhibiting the N otch1 signaling. Reduced infarct volume and improved motor deficits were also observed in N otch1 activator–treated aged ischemic rats. Our data suggest that Notch1 signaling modulates the SVZ neurogenesis in aged brain in normal and ischemic conditions.