In the adult brain, new neurons are continuously generated in the subventricular zone and dentate gyrus, but it is unknown whether these neurons can replace those lost following damage or disease. Here we show that stroke, caused by transient middle cerebral artery occlusion in adult rats, leads to a marked increase of cell proliferation in the subventricular zone. Stroke-generated new neurons, as well as neuroblasts probably already formed before the insult, migrate into the severely damaged area of the striatum, where they express markers of developing and mature, striatal medium-sized spiny neurons. Thus, stroke induces differentiation of new neurons into the phenotype of most of the neurons destroyed by the ischemic lesion. Here we show that the adult brain has the capacity for self-repair after insults causing extensive neuronal death. If the new neurons are functional and their formation can be stimulated, a novel therapeutic strategy might be developed for stroke in humans.

New hippocampal neurons are continuously generated in the adult brain. Here, we demonstrate that lipopolysaccharide-induced inflammation, which gives rise to microglia activation in the area where the new neurons are born, strongly impairs basal hippocampal neurogenesis in rats. The increased neurogenesis triggered by a brain insult is also attenuated if it is associated with microglia activation caused by tissue damage or lipopolysaccharide infusion. The impaired neurogenesis in inflammation is restored by systemic administration of minocycline, which inhibits microglia activation. Our data raise the possibility that suppression of hippocampal neurogenesis by activated microglia contributes to cognitive dysfunction in aging, dementia, epilepsy, and other conditions leading to brain inflammation. In the adult mammalian brain, neural progenitor cells located in the subgranular zone (SGZ) of the dentate gyrus (DG) generate thousands of new neurons each day (1). These neurons develop the morphological and functional properties of dentate granule cells and become integrated into existing neuronal circuitries (2). The role of neurogenesis for hippocampal function is still unclear, but some experimental evidence suggests its involvement in memory formation (3) and mood regulation (4). Impairment of hippocampal neurogenesis may be linked to the cognitive decline in aging, Alzheimer's disease (AD), and major depression (5-7).Brain inflammation probably plays an important role in the pathogenesis of chronic neurodegenerative disorders like AD and ParkinsonЈs disease (8, 9). Neurodegeneration caused by inflammation involves activation of the brain's resident immune cells, the microglia, which produce a large number of proinflammatory factors (10-12). Also, acute brain insults, e.g., stroke and status epilepticus (SE), are linked to inflammation (13,14), which contributes to the propagation of the neuropathological events (9, 15). These insults trigger increased neurogenesis in the SGZ (16)(17)(18)(19). After severe SE, there is an 80% loss of newly formed dentate neurons (20), which raises the possibility that the associated inflammatory response is deleterious for hippocampal neurogenesis.Here, we show that the microglia activation associated with inflammation impairs both basal and insult-induced hippocampal neurogenesis. We find that systemic administration of the tetracycline derivative minocycline, which specifically inhibits microglia activation, is an effective treatment to restore neurogenesis suppressed by inflammation. Materials and MethodsSurgery and Induction of SE. Male Sprague-Dawley rats were implanted with a stimulating͞recording electrode into the right ventral hippocampus [coordinates: 4.8 mm caudal and 5.2 mm lateral to bregma, 6.3 mm ventral to dura, and toothbar at Ϫ3.3 mm (21)] under pentobarbital or halothane anesthesia. In 37 animals, a brain infusion cannula (Alzet, Palo Alto, CA) was also placed intracortically on the right side of the brain (2 mm caudal and 1.2 mm lateral to bregma and 2.6 mm ve...

Recent progress shows that neurons suitable for transplantation can be generated from stem cells in culture, and that the adult brain produces new neurons from its own stem cells in response to injury. These findings raise hope for the development of stem cell therapies in human neurodegenerative disorders. Before clinical trials are initiated, we need to know much more about how to control stem cell proliferation and differentiation into specific phenotypes, induce their integration into existing neural and synaptic circuits, and optimize functional recovery in animal models closely resembling the human disease.

Neural stem cells in the subventricular zone of adult rodents produce new striatal neurons that may replace those that have died after stroke; however, the neurogenic response has been considered acute and transient, yielding only small numbers of neurons. In contrast, we show herein that striatal neuroblasts are generated without decline at least for 4 months after stroke in adult rats. Neuroblasts formed early or late after stroke either differentiate into mature neurons, which survive for several months, or die through caspasemediated apoptosis. The directed migration of the new neurons toward the ischemic damage is regulated by stromal cell-derived factor-1␣ and its receptor CXCR4. These results show that endogenous neural stem cells continuously supply the injured adult brain with new neurons, which suggests novel self-repair strategies to improve recovery after stroke. STEM CELLS 2006;24:739 -747

No abstract

Many common neurological disorders, such as Parkinson's disease, stroke and multiple sclerosis, are caused by a loss of neurons and glial cells. In recent years, neurons and glia have been generated successfully from stem cells in culture, fueling efforts to develop stem-cell-based transplantation therapies for human patients. More recently, efforts have been extended to stimulating the formation and preventing the death of neurons and glial cells produced by endogenous stem cells within the adult central nervous system. The next step is to translate these exciting advances from the laboratory into clinically useful therapies.

Neuronal apoptosis was observed in the rat dentate gyrus in two experimental models of human limbic epilepsy. Five hours after one hippocampal kindling stimulation, a marked increase of in situ terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling (TUNEL) of fragmented DNA was observed in nuclei located within and on the hilar border of the granule cell layer and in the polymorphic region. Forty kindling stimulations with 5-min interval produced higher numbers of labeled nuclei compared with one stimulation. The increase of TUNEL-positive nuclei was prevented by the protein synthesis inhibitor cycloheximide but not affected by the N-methyl-D-aspartate receptor antagonist MK-801. Kainic acidinduced seizures lead to a pattern of labeling in the hippocampal formation identical to that evoked by kindling. A large proportion of cells displaying TUNEL-positive nuclei was doublelabeled by the neuron-specific antigen NeuN, demonstrating the neuronal identity of apoptotic cells. Either 1 or 40 kindling stimulations also gave rise to a marked increase of the number of cells double-labeled with the mitotic marker bromodeoxyuridine and NeuN in the subgranular zone and on the hilar border of the dentate granule cell layer. The present data show that single and intermittent, brief seizures induce both apoptotic death and proliferation of dentate gyrus neurons. We hypothesize that these processes, occurring early during epileptogenesis, are primary events in the development of hippocampal pathology in animals and possibly also in patients suffering from temporal lobe epilepsy.

Stem cell-based approaches have received much hype as potential treatments for neurodegenerative disorders. Indeed, transplantation of stem cells or their derivatives in animal models of neurodegenerative diseases can improve function by replacing the lost neurons and glial cells and by mediating remyelination, trophic actions, and modulation of inflammation. Endogenous neural stem cells are also potential therapeutic targets because they produce neurons and glial cells in response to injury and could be affected by the degenerative process. As we discuss here, however, significant hurdles remain before these findings can be responsibly translated to novel therapies. In particular, we need to better understand the mechanisms of action of stem cells after transplantation and learn how to control stem cell proliferation, survival, migration, and differentiation in the pathological environment.