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Neuronal replacement from endogenous precursors in the adult brain after stroke

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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.

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Figure 1: Stroke-induced neurogenesis in the adult striatum.
Figure 2: Ara-C treatment inhibits proliferation in SVZ and striatal neurogenesis after stroke.
Figure 3: Stroke-generated cells migrate from the subventricular zone into the ischemic lesion.
Figure 4: Stroke-generated cells express markers of developing striatal neurons.
Figure 5: Stroke-generated cells express markers of mature striatal medium-sized spiny neurons.

Change history

  • 23 August 2002

    Update panel b of Figure 1


  1. NOTE: In the AOP version of this article, in Fig. 1b a line of text was missing on the x axis. Below the second bar it should have read "MCAO intact" and below the third bar it should have read "MCAO total". This has been corrected in the HTML and PDF versions, and will appear correctly in a forthcoming print issue.


  1. Gage, F.H. Mammalian neural stem cells. Science 287, 1433–1438 (2000).

    Article  CAS  Google Scholar 

  2. Reynolds, B.A. & Weiss, S. Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science 255, 1707–1017 (1992).

    Article  CAS  Google Scholar 

  3. Parent, J.M. et al. Dentate granule cell neurogenesis is increased by seizures and contributes to aberrant network reorganization in the adult rat hippocampus. J. Neurosci. 17, 3727–3738 (1997).

    Article  CAS  Google Scholar 

  4. Bengzon, J. et al. Apoptosis and proliferation of dentate gyrus neurons after single and intermittent limbic seizures. Proc. Natl. Acad. Sci. USA 94, 10432–10437 (1997).

    Article  CAS  Google Scholar 

  5. Liu, J., Solway, K., Messing, R.O. & Sharp, F.R. Increased neurogenesis in the dentate gyrus after transient global ischemia in gerbils. J. Neurosci. 18, 7768–7778 (1998).

    Article  CAS  Google Scholar 

  6. Arvidsson, A., Kokaia, Z. & Lindvall, O. N-methyl-D-aspartate receptor-mediated increase of neurogenesis in adult rat dentate gyrus following stroke. Eur. J. Neurosci. 14, 10–18 (2001).

    Article  CAS  Google Scholar 

  7. Jin, K. et al. Neurogenesis in dentate subgranular zone and rostral subventricular zone after focal cerebral ischemia in the rat. Proc. Natl. Acad. Sci. USA 98, 4710–4715 (2001).

    Article  CAS  Google Scholar 

  8. Zhang, R.L., Zhang, Z.G., Zhang, L. & Chopp, M. Proliferation and differentiation of progenitor cells in the cortex and the subventricular zone in the adult rat after focal cerebral ischemia. Neuroscience 105, 33–41 (2001).

    Article  CAS  Google Scholar 

  9. Gu, W., Brännström, T. & Wester, P. Cortical neurogenesis in adult rats after reversible photothrombotic stroke. J. Cereb. Blood Flow Metab. 20, 1166–1173 (2000).

    Article  CAS  Google Scholar 

  10. Magavi, S.S., Leavitt, B.R. & Macklis, J.D. Induction of neurogenesis in the neocortex of adult mice. Nature 405, 951–955 (2000).

    Article  CAS  Google Scholar 

  11. Heimer, L., Zahm, D.S. & Alheid, G.F. Basal ganglia. in The Rat Nervous System (ed. Paxinos, G.) 579–628 (Academic, San Diego, 1995).

    Google Scholar 

  12. Davies, C.A., Loddick, S.A., Stroemer, R.P., Hunt, J. & Rothwell, N.J. An integrated analysis of the progression of cell responses induced by permanent focal middle cerebral artery occlusion in the rat. Exp. Neurol. 154, 199–212 (1998).

    Article  CAS  Google Scholar 

  13. Stoll, G., Jander, S. & Schroeter, M. Inflammation and glial responses in ischemic brain lesions. Prog. Neurobiol. 56, 149–171 (1998).

    Article  CAS  Google Scholar 

  14. Doetsch, F., Garcia-Verdugo, J.M. & Alvarez-Buylla, A. Regeneration of a germinal layer in the adult mammalian brain. Proc. Natl. Acad. Sci. USA 96, 11619–11624 (1999).

    Article  CAS  Google Scholar 

  15. Nacher, J., Crespo, C. & McEwen, B.S. Doublecortin expression in the adult rat telencephalon. Eur. J. Neurosci. 14, 629–644 (2001).

    Article  CAS  Google Scholar 

  16. Toresson, H., Parmar, M. & Campbell, K. Expression of Meis and Pbx genes and their protein products in the developing telencephalon: implications for regional differentiation. Mech. Dev. 94, 183–187 (2000).

    Article  CAS  Google Scholar 

  17. Marusich, M.F., Furneaux, H.M., Henion, P.D. & Weston, J.A. Hu neuronal proteins are expressed in proliferating neurogenic cells. J. Neurobiol. 25, 143–155 (1994).

    Article  CAS  Google Scholar 

  18. Barami, K., Iversen, K., Furneaux, H. & Goldman, S.A. Hu protein as an early marker of neuronal phenotypic differentiation by subependymal zone cells of the adult songbird forebrain. J. Neurobiol. 28, 82–101 (1995).

    Article  CAS  Google Scholar 

  19. Toresson, H., Mata de Urquiza, A., Fagerstrom, C., Perlmann, T. & Campbell, K. Retinoids are produced by glia in the lateral ganglionic eminence and regulate striatal neuron differentiation. Development 126, 1317–1326 (1999).

    CAS  PubMed  Google Scholar 

  20. Ouimet, C.C., Miller, P.E., Hemmings, H.C. Jr, Walaas, S.I. & Greengard, P. DARPP-32, a dopamine- and adenosine 3′:5′-monophosphate-regulated phosphoprotein enriched in dopamine-innervated brain regions. III. Immunocytochemical localization. J. Neurosci. 4, 111–124 (1984).

    Article  CAS  Google Scholar 

  21. Ouimet, C.C., Langley-Gullion, K.C. & Greengard, P. Quantitative immunocytochemistry of DARPP-32-expressing neurons in the rat caudatoputamen. Brain Res. 808, 8–12 (1998).

    Article  CAS  Google Scholar 

  22. Björklund, A. & Lindvall, O. Cell replacement therapies for central nervous system disorders. Nature Neurosci. 3, 537–544 (2000).

    Article  Google Scholar 

  23. Lois, C., Garcia-Verdugo, J.M. & Alvarez-Buylla, A. Chain migration of neuronal precursors. Science 271, 978–981 (1996).

    Article  CAS  Google Scholar 

  24. Wichterle, H., Garcia-Verdugo, J.M. & Alvarez-Buylla, A. Direct evidence for homotypic, glia-independent neuronal migration. Neuron 18, 779–791 (1997).

    Article  CAS  Google Scholar 

  25. Aboody, K.S. et al. Neural stem cells display extensive tropism for pathology in adult brain: evidence from intracranial gliomas. Proc. Natl. Acad. Sci. USA 97, 12846–12851 (2000).

    Article  CAS  Google Scholar 

  26. Veizovic, T., Beech, J.S., Stroemer, R.P., Watson, W.P. & Hodges, H. Resolution of stroke deficits following contralateral grafts of conditionally immortal neuroepithelial stem cells. Stroke 32, 1012–1019 (2001).

    Article  CAS  Google Scholar 

  27. Mason, H.A., Ito, S. & Corfas, G. Extracellular signals that regulate the tangential migration of olfactory bulb neuronal precursors: Inducers, inhibitors, and repellents. J. Neurosci. 21, 7654–7663 (2001).

    Article  CAS  Google Scholar 

  28. Benraiss, A., Chmielnicki, E., Lerner, K., Roh, D. & Goldman, S.A. Adenoviral brain-derived neurotrophic factor induces both neostriatal and olfactory neuronal recruitment from endogenous progenitor cells in the adult forebrain. J. Neurosci. 21, 6718–6731 (2001).

    Article  CAS  Google Scholar 

  29. Herrera, D.G., Garcia-Verdugo, J.M. & Alvarez-Buylla, A. Adult-derived neural precursors transplanted into multiple regions in the adult brain. Ann. Neurol. 46, 867–877 (1999).

    Article  CAS  Google Scholar 

  30. Ekdahl, C.T., Mohapel, P., Elmér, E. & Lindvall, O. Caspase inhibitors increase short-term survival of progenitor-cell progeny in the adult rat dentate gyrus following status epilepticus. Eur. J. Neurosci. 14, 937–945 (2001).

    Article  CAS  Google Scholar 

  31. Pencea, V., Bingaman, K.D., Wiegand, S.J. & Luskin, M.B. Infusion of brain-derived neurotrophic factor into the lateral ventricle of the adult rat leads to new neurons in the parenchyma of the striatum, septum, thalamus, and hypothalamus. J. Neurosci. 21, 6706–6717 (2001).

    Article  CAS  Google Scholar 

  32. Koizumi, J., Yoshida, Y., Nakazawa, T. & Ooneda, G. Experimental studies of ischemic brain edema. 1. A new experimental model of cerebral embolism in rats in which recirculation can be introduced in the ischemic area. Jpn. J. Stroke. 8, 1–8 (1986).

    Article  Google Scholar 

  33. Zhao, Q., Memezawa, H., Smith, M.L. & Siesjö, B.K. Hyperthermia complicates middle cerebral artery occlusion induced by an intraluminal filament. Brain Res. 649, 253–259 (1994).

    Article  CAS  Google Scholar 

  34. Kokaia, Z. et al. Regulation of brain-derived neurotrophic factor gene expression after transient middle cerebral artery occlusion with and without brain damage. Exp. Neurol. 136, 73–88 (1995).

    Article  CAS  Google Scholar 

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This work was supported by the Swedish Research Council, The Söderberg Foundation, Kock, Crafoord, and Elsa and Thorsten Segerfalk Foundations, the Swedish Stroke Foundation and the Swedish Association of Neurologically Disabled.

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Correspondence to Andreas Arvidsson.

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Arvidsson, A., Collin, T., Kirik, D. et al. Neuronal replacement from endogenous precursors in the adult brain after stroke. Nat Med 8, 963–970 (2002).

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