Neurogenesis and gliogenesis after focal brain ischemia. Modulation by enriched environment and exercise

Abstract

New neurons are formed from dividing neural stem cells in restricted areas in the adult mammalian brain: the dentate gyrus of the hippocampal formation (DG) and the forebrain subventricular zone (SVZ). New glia also form constitutively and seem to be important for neuronal function. This thesis investigated the effects of experimental stroke, postischemic environmental enrichment (EE) and voluntary exercise (VE) on neurogenesis and gliogenesis in the adult rat brain. A neocortical infarct was induced by distal ligation of the middle cerebral artery and rats were subsequently housed in standard environment, EE (larger cages and animal groups, introduction of novel objects) or in cages with running wheels. Sensorimotor functions were tested on a rotating rod and with the limb placement test. Bromodeoxyuridine was administered during the first postischemic week and the animals were sacrificed 1 or 5 weeks postsurgery. Cell proliferation, differentiation and survival were studied with immunohistochemistry and confocal microscopy. Cortical ischemia was found to increase proliferation of neural stem cells, neural progenitors and neuronal precursors in the SVZ and the DG. Migrating neuroblasts were recruited to the infarct from the SVZ but did not survive into maturity. VE attenuated the lesion-induced activation of the SVZ. In contrast, EE had enhancing effects on the SVZ. DG cell proliferation was increased after cortical ischemia without further effects by EE or VE. The majority of newborn cells in the DG became mature neurons but new astroglia were not similarly increased in standard housed stroke rats. EE increased DG astrogliogenesis and thus normalized the astrogliogenesis-to-neurogenesis ratio. In the postischemic neocortex, EE increased newborn reactive astroglia and also newborn NG2 positive polydendrocytes, often found closely apposed to neurons and exhibiting brain-derived neurotrophic factor immunoreactivity. Stroke EE rats had the best scores in behavior tests among lesioned rats. In conclusion, neocortical stroke activated the adult neurogenic niches. Isolated exercise activity early poststroke attenuated the lesion-induced SVZ activation. EE enhanced cell genesis in diverse regions of the postischemic brain which might be of importance for function improvement. Future efforts need to be focussed on providing the necessary instructive cues to promote functional neuronal replacement after stroke.