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

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

On neural plasticity, new neurons and the postischemic milieu: An integrated view on experimental rehabilitation

This review discusses actual and potential contributors to functional improvement after stroke injuries. Topics that will be covered are neuronal re-organization and sprouting, neural stem/progenitor cell,activation and neuronal replacement, as well as the neuronal milieu defined by glia, inflammatory cells and blood vessel supply. It is well established that different types of neuronal plasticity ultimately lead to post-stroke recovery. However, an untapped potential which only recently has started to be extensively explored is neuronal replacement through endogenous or exogenous resources. Major experimental efforts are needed to achieve progress in this burgeoning area. The review stresses the importance of applying neurodevelopmental principles as well as performing a characterization of the role of the postischemic milieu when studying adult brain neural stem/progenitor cells. Integrated and multifaceted experimentation, incorporating actual and possible poststroke function modulators, will be necessary in order to determine future strategies that will ultimately enable considerable progress in the field of neurorehabilitation. (c) 2006 Elsevier Inc. All rights reserved

Enriched environment after focal cortical ischemia enhances the generation of astroglia and NG2 positive polydendrocytes in adult rat neocortex

Environmental enrichment (EE) alleviates sensorimotor deficits after brain infarcts but the cellular correlates are not well-known. This study aimed to test the effects of postischemic EE on neocortical cell genesis. A neocortical infarct was caused by distal ligation of the middle cerebral artery in adult spontaneously hypertensive rats, subsequently housed in standard environment or EE. Bromodeoxyuridine (BrdU) was administered during the first postischemic week to label proliferating cells and BrdU incorporation was quantified 4 weeks later in the periinfarct, ipsilateral medial and contralateral cortex. Immunohistochemistry and confocal microscopy were used to analyze co-localization of BrdU with neuronal (calbindin D28k, calretinin, parvalbumin, glutamic acid decarboxylase, tyrosine hydroxylase), astrocytic (glial fibrillary acidic protein, glutamine synthetase, vimentin, nestin), microglia/macrophage (CD11b/Ox-42, CD68/ED-1), oligodendrocyte progenitor/polydendrocyte (NG2, platelet-derived growth factor alpha receptor) or mature oligodendrocyte (myelin basic protein) markers. BrdU positive cells were increased in all analyzed cortical regions in stroke EE rats compared with stroke standard environment rats. Newly bom cells in the periinfarct cortex were mostly reactive astroglia. Occasionally, BrdU positive cells in the periinfarct cortex that were negative for glial or microglia/macrophage markers coexpressed markers typical for interneurons but did not express appropriate functional markers. The majority of BrdU positive cells in intact cortical regions, ipsi- and contralaterally, were identified as NG2 positive polydendrocytes. Perineuronally situated newly born cells and polydendrocytes were found to be brain-derived neurotrophic factor immunoreactive. In conclusion, EE enhanced newborn glial scar astroglia and NG2+ polydendrocytes in the postischemic neocortex which might be beneficial for brain repair and poststroke plasticity. (c) 2005 Elsevier Inc. All rights reserved

Contribution of maternal oxygenic state to the effects of chronic postnatal hypoxia on mouse body and brain development

1-2% of live births are to very low birth weight, premature infants that often show a developmental trajectory plagued with neurological sequelae including ventriculomegaly and significant decreases in cortical volume. We are able to recapitulate these sequelae using a mouse model of hypoxia where early postnatal pups are exposed to chronic hypoxia for one week. However, because the timing of hypoxic exposure occurs so early in development, dams and pups are housed together in the hypoxic chamber, and therefore, dams are also subjected to the same hypoxic conditions as the pups. To understand the relative contribution of hypoxia directly on the pups as opposed to the indirect contribution mediated by the effects of hypoxia and potential alterations in the dam's care of the pups, we examined whether reducing the dams exposure to hypoxia may significantly increase pup outcomes on measures that we have found consistently changed immediately following chronic hypoxia exposure. To achieve this, we rotated dams between normoxic and hypoxic conditions, leaving the litters untouched in their respective conditions and compared gross anatomical measures of normoxic and hypoxic pups with non-rotating or rotating mothers. As we expected, hypoxic-rearing decreased pup body weight, brain weight and cortical volume. Reducing the dam's exposure to hypoxic conditions actually amplified the effects of hypoxia on body weight, such that hypoxic pups with rotating mothers showed significantly less growth. Interestingly, rotation o