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.

Two subjects with Parkinson's disease who had long-term survival of transplanted fetal mesencephalic dopaminergic neurons (11-16 years) developed alpha-synuclein-positive Lewy bodies in grafted neurons. Our observation has key implications for understanding Parkinson's pathogenesis by providing the first evidence, to our knowledge, that the disease can propagate from host to graft cells. However, available data suggest that the majority of grafted cells are functionally unimpaired after a decade, and recipients can still experience long-term symptomatic relief.

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...

To model human neural-cell-fate specification and to provide cells for regenerative therapies, we have developed a method to generate human neural progenitors and neurons from human embryonic stem cells, which recapitulates human fetal brain development. Through the addition of a small molecule that activates canonical WNT signaling, we induced rapid and efficient dose-dependent specification of regionally defined neural progenitors ranging from telencephalic forebrain to posterior hindbrain fates. Ten days after initiation of differentiation, the progenitors could be transplanted to the adult rat striatum, where they formed neuron-rich and tumor-free grafts with maintained regional specification. Cells patterned toward a ventral midbrain (VM) identity generated a high proportion of authentic dopaminergic neurons after transplantation. The dopamine neurons showed morphology, projection pattern, and protein expression identical to that of human fetal VM cells grafted in parallel. VM-patterned but not forebrain-patterned neurons released dopamine and reversed motor deficits in an animal model of Parkinson's disease.