Forebrain neurogenesis after focal Ischemic and traumatic brain injury

Abstract

Neural stem cells persist in the adult mammalian forebrain and are a potential source of neurons for repair after brain injury. The two main areas of persistent neurogenesis, the subventricular zone (SVZ)-olfactory bulb pathway and hippocampal dentate gyrus, are stimulated by brain insults such as stroke or trauma. Here we focus on the effects of focal cerebral ischemia on SVZ neural progenitor cells in experimental stroke, and the influence of mechanical injury on adult hippocampal neurogenesis in models of traumatic brain injury (TBI). Stroke potently stimulates forebrain SVZ cell proliferation and neurogenesis. SVZ neuroblasts are induced to migrate to the injured striatum, and to a lesser extent to the peri-infarct cortex. Controversy exists as to the types of neurons that are generated in the injured striatum, and whether adult-born neurons contribute to functional restoration remains uncertain. Advances in understanding the regulation of SVZ neurogenesis in general, and stroke-induced neurogenesis in particular, may lead to improved integration and survival of adult-born neurons at sites of injury. Dentate gyrus cell proliferation and neurogenesis similarly increase after experimental TBI. However, pre-existing neuroblasts in the dentate gyrus are vulnerable to traumatic insults, which appear to stimulate neural stem cells in the SGZ to proliferate and replace them, leading to increased numbers of new granule cells. Interventions that stimulate hippocampal neurogenesis appear to improve cognitive recovery after experimental TBI. Transgenic methods to conditionally label or ablate neural stem cells are beginning to further address critical questions regarding underlying mechanisms and functional significance of neurogenesis after stroke or TBI. Future therapies should be aimed at directing appropriate neuronal replacement after ischemic or traumatic injury while suppressing aberrant integration that may contribute to co-morbidities such as epilepsy or cognitive impairment.

Figures

Figure 1

Regions of persistent neurogenesis in the adult. A, The subventricular zone (SVZ)-olfactory bulb (OB) pathway. Radial glia-like neural stem cells in the SVZ give rise to rapidly dividing transit amplifying cells and then neuroblasts. All these cells are closely apposed in the SVZ niche that includes ependymal cells and endothelial cells (not shown). The SVZ-derived neuroblasts migrate tangentially to the bulb in neuronophilic chains via the rostral migratory stream (RMS). B, Stages of neurogenesis in the dentate subgranular zone (SGZ). GFP refers to reporter expression in a nestin-GFP mouse line. C, Section through the dentate granule cell layer of an adult nestin-GFP mouse showing GFP-expressing progenitors (green), doublecortin immunolabeled neuroblasts (DCX, red) and NeuN immunoreactive mature dentate granule cells (blue). The dentate hilus is at the very bottom of the image.

Figure 2

Stroke-induced neurogenesis. A, B, Doublecortin immunostaining at 14 days after tMCAO shows increased SVZ and striatal neurogenesis of the ipsilateral (il) hemisphere compared to contralateral (cl). The asterisks denote the lateral ventricle. C–E, Coronal sections of BrdU-immunoreactive olfactory neurons in the granular layer (GrO) of rats after tMCAO either ipsilateral (il, C) or contralateral (cl, D) to the infarct, or from a sham-operated control (E) at 28 days after surgery. (D) Quantification of GrO BrdU labeling shows significantly decreased BrdU-immunoreactivity il to the stroke after 28 days. *, p

Figure 3

YFP-expressing cells in the dentate gyrus following tamoxifen-mediated cre recombination in controls and after injury. In control animals, YFP-expressing progenitors and neurons remain confined to the most basal layers of the dentate gyrus (A). In the injured dentate gyrus both 2 and 6 months after tamoxifen injection followed by injury, there are stably incorporated neurons throughout the granular layer that exhibit extensive dendritic arborizations (B, C).