Abstract
Reports of continuous genesis and turnover of neurons in the adult primate association neocortex — the site of the highest cognitive functions — have generated great excitement. Here, I review the available evidence, and question the scientific basis of this claim.
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References
Leblond, C. P. Classification of cell populations on the basis of their proliferative behavior. Natl Cancer Inst. Monogr. 14, 119–150 (1964).
Jacobson, M. Developmental Neurobiology (Plenum, New York, 1991).
Gage, F. H. Mammalian neural stem cells. Science 287, 1433–1438 (2000).
Rakic, P. Young neurons for old brains? Nature Neurosci. 1, 643–645 (1998).
Gould, E., Reeves, A. J., Graziano, M. S. & Gross, C. G. Neurogenesis in the neocortex of adult primates. Science 286, 548–552 (1999).
Shankle, W. R. et al. Evidence for a postnatal doubling of neuron number in the developing human cerebral cortex between 15 months and 6 years. J. Theor. Biol. 191, 115–140 (1998).
Blakeslee, S. A decade of discovery yields a shock about the brain. New York Times F1, F4 (4 January 2000).
Rakic, P. Kinetics of proliferation and latency between final cell division and onset of differentiation of cerebellar stellate and basket neurons. J. Comp. Neurol. 147, 523–546 (1973).
Rakic, P. Neurons in the monkey visual cortex: systematic relation between time of origin and eventual disposition. Science 183, 425–427 (1974).
Rakic, P. Genesis of the dorsal lateral geniculate nucleus in the rhesus monkey: site and time of origin, kinetics of proliferation, routes of migration and pattern of distribution of neurons. J. Comp. Neurol. 176, 23–52 (1977).
Rakic, P. & Nowakowski, R. S. Time of origin of neurons in the hippocampal region of the rhesus monkey. J. Comp. Neurol. 196, 99–124 (1981).
Levitt, P. & Rakic, P. The time of genesis, embryonic origin and differentiation of the brainstem monoamine neurons in the rhesus monkey. Brain Res. 256, 35–57 (1982).
Rakic, P. Early developmental events: cell lineages, acquisitions of neuronal positions, and areal and laminar development. Neurosci. Res. Program Bull. 20, 439–451 (1982).
Kordower, J. H. & Rakic, P. Neurogenesis of the magnocellular basal nuclei in the rhesus monkey. J. Comp. Neurol. 291, 637–653 (1990).
LaVail, M. M., Rapaport, D. H. & Rakic, P. Cytogenesis in the monkey retina. J. Comp. Neurol. 309, 86–114 (1991).
Schwartz, M. L., Rakic, P. & Goldman-Rakic, P. S. Early phenotype expression of cortical neurons: evidence that a subclass of migrating neurons have callosal axons. Proc Natl Acad Sci U S A 88, 1354–1358 (1991).
Kordower, J. H., Piecinski, P. & Rakic, P. Neurogenesis of the amygdalar complex in the rhesus monkey. Brain Res. Dev. Brain Res. 68, 9–15 (1992).
Granger, B., LeSurd, A. M., Rakic, P. & Bourgeois, J.-P. Tempo of neurogenesis and synaptogenesis in the primate cingulate mesocortex: comparison with the neocortex. J. Comp. Neurol. 360, 363–376 (1995).
Rakic, P. Limits of neurogenesis in primates. Science 227, 1054–1056 (1985).
Eckenhoff, M. E. & Rakic, P. Nature of the proliferative cells in the hippocampal dentate gyrus during the life span of the rhesus monkey. J. Neurosci. 8, 2729–2747 (1988).
Rakic, P. Mode of cell migration to the superficial layers of fetal monkey neocortex. J. Comp. Neurol. 145, 61–84 (1972).
Zecevic, N. & Rakic, P. Development of layer I neurons in the primate cerebral cortex J. Neurosci. 21, 5607–5619 (2001).
Levitt, P., Cooper, M. L. & Rakic, P. Coexistence of neuronal and glial precursor cells in the cerebral ventricular zone of the fetal monkey: an ultrastructural immunoperoxidase analysis. J. Neurosci. 1, 27–39 (1981).
Yakovlev, P. I. & LeCours, A. R. in Regional Development of the Brain in Early Life (ed. Minkowski, A.) 3–70 (Blackwell, Oxford, 1967).
Angevine, J. B. Jr & Sidman, R. L. Autoradiographic study of cell migration during histogenesis of cerebral cortex in the mouse. Nature 192, 766–768 (1961).
Berry, M. & Rogers, A. W. The migration of neuroblasts in the developing cortex. J. Anat. 99, 691–709 (1965).
Hicks, S. P. & D'Amato, C. J. Cell migrations to the isocortex in the rat. Anat. Rec. 160, 619–634 (1968).
Caviness, V. S. Jr & Sidman, R. L. Time of origin of corresponding cell classes in the cerebral cortex of normal and reeler mutant mice: an autoradiographic analysis. J. Comp. Neurol. 148, 141–152 (1973).
Smart, I. H. M. & Smart, M. Growth patterns in the lateral wall of the mouse telencephalon. I. Autoradiographic studies of the histogenesis of the isocortex and adjacent areas. J. Anat. 134, 273–298 (1982).
Luskin, M. B. & Shatz, C. J. Neurogenesis of the cat's primary visual cortex. J. Comp. Neurol. 242, 611–631 (1985).
Jackson, C. A., Peduzzi, J. D. & Hickey, T. L. Visual-cortex development in the ferret. 1. Genesis and migration of visual cortical-neurons. J. Neurosci. 9, 1242–1253 (1989).
Takahashi, T., Nowakowski, R. S. & Caviness, V. S. The leaving or Q fraction of the murine cerebral proliferative epithelium: a general model of neocortical neuronogenesis. J. Neurosci. 16, 6183–6196 (1996).
Nowakowski, R. S. & Hayes, N. L. New neurons: extraordinary evidence or extraordinary conclusion? Science 288, 771a (2000).
Gould, E., Vail, N., Wagers, M. & Gross, C. G. Adult-generated hippocampal and neocortical neurons in macaques have a transient existence. Proc Natl Acad Sci U S A 98, 10910–10917 (2001).
Kornack, D. R. & Rakic, P. Cell proliferation without neurogenesis in adult primate neocortex. Science 294, 2127–2130 (2001).
Kornack, D. R. & Rakic, P. Generation and migration of new olfactory neurons in adult primates. Proc. Natl Acad. Sci. USA 98, 4752–4757 (2001).
Mares, V. & Bruckner, G. Postnatal formation of non-neuronal cells in the rat occipital cerebrum: an autoradiographic study of the time and space pattern of cell division. J. Comp. Neurol. 177, 519–528 (1978).
Korr, H., Schilling, D., Schultze, B. & Maurer, W. Autoradiographic studies of glial proliferation in different areas of the brain of the 14-day-old rat. Cell Tissue Kinet. 16, 393–413 (1983).
McDermott, K. W. G. & Lantos, P. L. Cell proliferation in the subependymal layer of the postnatal marmoset, Callithrix jacchus. Brain Res. Dev. Brain Res. 57, 269–277 (1990).
Lewis, P. D. Mitotic activity in the primate subependymal layer and the genesis of the gliomas. Nature 217, 974–975 (1968).
Rakic, P. DNA synthesis and cell division in the adult primate brain. Ann. NY Acad. Sci. 457, 193–211 (1985).
Luskin, M. B. Restricted proliferation and migration of postnatally generated neurons derived from the forebrain subventricular zone. Neuron 11, 173–189 (1993).
Lois, C. & Alvarez-Buylla, A. Long-distance neuronal migration in the adult mammalian brain. Science 264, 1145–1148 (1994).
Rakic, P. & Kornack D. R. Constraints on neurogenesis in adult primate brain: an evolutionary advantage? Restor. Neurol. 6, 257–266 (1993).
Kuhn, H. G., Winkler, J., Kempermann, G., Thal, L. J. & Gage, F. H. Epidermal growth factor and fibroblast growth factor-2 have different effects on neural progenitors in the adult rat brain. J. Neurosci. 17, 5820–5829 (1997).
Magavi, S. S., Leavitt, B. R. & Macklis, J. D. Induction of neurogenesis in the neocortex of adult mice. Nature 405, 951–955 (2000).
Kornack, D. R. & Rakic, P. Continuation of neurogenesis in the hippocampus of the adult macaque monkey. Proc. Natl Acad. Sci. USA 96, 5768–5773 (1999).
Nowakowski, R. S., Lewin, S. B. & Miller, M. W. Bromodeoxyuridine immunohistochemical determination of the lengths of the cell cycle and the DNA-synthetic phase for an anatomically defined population. J. Neurocytol. 18, 311–318 (1989).
Rakic, P. Adult neurogenesis in mammals: an identity crisis. J. Neurosci. (in the press).
Angevine, J. B. Jr. Time of neuron origin in the hippocampal region. An autoradiographic study in the mouse. Exp. Neurol. (Suppl.) 2, 1–70 (1965).
Yang, Y., Geldmacher, D. S. & Herrup, K. DNA replication precedes neuronal cell death in Alzheimer's disease. J. Neurosci. 15, 2661–2668 (2001). | PubMed |
Neve, R., McPhie, D. L. & Chen, Y. Alzheimer's disease: a dysfunction of the amyloid precursor protein. Brain Res. 886, 54–66 (2000).
Katchanov, J. et al. Mild cerebral ischemia induces loss of cyclin-dependent kinase inhibitors and activation of cell cycle machinery before delayed neuronal cell death. J. Neurosci. 21, 5045–5053 (2001).
Copani, A. et al. Activation of cell cycle-associated proteins in neuronal death: a mandatory or dispensable path. Trends Neurosci. 24, 25–31 (2001).
Anatskaya. O. V., Vinogradov, A. E. & Kudryavtsev, B. N. Hepatocyte polyploidy and metabolism/life-history traits: hypotheses testing. J. Theor. Biol. 168, 191–199 (1994).
Pieper, A. A. et al. Poly ADP-ribosylation basally activated by DNA strand breaks reflects glutamate–nitric oxide neurotransmission. Proc. Natl Acad. Sci. USA 97, 1845–1850 (2000).
Ino, H. & Chiba, T. Expression of proliferating cell nuclear antigen (PCNA) in the adult and developing mouse nervous system. Brain Res. Mol. Brain Res. 78, 163–174 (2000).
Deloulme, J. C. et al. Expression of the neuron-specific enolase gene by rat oligodendroglial cells during their differentiation. J. Neurochem. 66, 936–945 (1996).
Sensenbrenner, M., Lucas, J. C. & Deloulme, J. C. Expression of two neuronal markers, growth-associated protein 43 and neuron-specific enolase, in rat glial cells. J. Mol. Med. 75, 653–663 (1997).
Ricard, D. et al. Isolation and expression pattern of human Unc-33-like phosphoprotein 6/collapsin response mediator protein 5 (Ulip6/CRMP5): coexistence with Ulip2/CRMP2 in Sema3A-sensitive oligodendrocytes J. Neurosci. 21, 7203–7214 (2001).
Parker, J. R. et al. Antineuronal nuclei immunohistochemical staining patterns in childhood ependymomas. J. Child Neurol. 16, 548–552 (2001).
Lu, D. et al. Adult bone marrow stromal cells administered intravenously to rats after traumatic brain injury migrate into brain and improve neurological outcome. Neuroreport 12, 559–563 (2001).
Brazelton, T. R., Rossi, F. M., Keshet, G. I. & Blau, H. M. From marrow to brain: expression of neuronal phenotypes in adult mice. Science 290, 1775–1779 (2000).
Woodbury, D., Schwarz, E. J., Prockop, D. J. & Black, I. B. Adult rat and human bone marrow stromal cells differentiate into neurons. J. Neurosci. Res. 61, 364–370 (2000).
Korr, H. & Schmitz, C. Facts and fictions regarding post-natal neurogenesis in the developing human cerebral cortex. J. Theor. Biol. 200, 291–297 (1999).
Kakita, A. & Goldman, J. E. Patterns and dynamics of SVZ cell migration in the postnatal forebrain: monitoring living progenitors in slice preparations. Neuron 23, 461–472 (1999).
Nacher, J., Rosell, D. R. & McEwen, B. S. Widespread expression of rat collapsin response-mediated protein 4 in the telencephalon and other areas of the adult rat central nervous system. J. Comp. Neurol. 424, 628–639 (2000).
Nishiyama, A., Chang, A. & Trapp, B. D. NG2+ glial cells: a novel glial cell population in the adult brain. J. Neuropathol. Exp. Neurol. 58, 1113–1124 (1999).
Chan, A., Nishiyama, A., Peterson, J., Prineas, J. & Trapp, B. D. NG2-positive oligodendrocyte progenitor cells in adult human brain and multiple sclerosis lesions. J. Neurosci. 17, 6404–6412 (2000).
Kirsche, W. Ueber postembryonale matrixzonen im Gehirn verschiedener Vertebraten und deren Beziehung zur Hirnbauplanlehre. Z. Mikrosk. Anat. Forsch. 77, 313–406 (1967).
Meyer, R. L. Evidence from thymidine labeling for continuing growth of retina and tectum in juvenile goldfish. Exp. Neurol. 59, 99–111 (1978).
Goldman, S. A. & Nottebohm, F. Neuronal production, migration and differentiation in a vocal control nucleus of the adult female canary brain. Proc. Natl Acad. Sci. USA 80, 2390–2394 (1983).
Kuhn, H. G., Dickinson-Anson, H. & Gage, F. H. Neurogenesis in the dentate gyrus of the adult rat: age-related decrease of neuronal progenitor proliferation. J. Neurosci. 16, 2027–2033 (1996).
Gross, C. G. Neurogenesis in the adult brain: death of the dogma. Nature Rev. Neurosci. 1, 67–73 (2000).
Altman, J. Are neurons formed in the brains of adult mammals? Science 135, 1127–1128 (1962).
Acknowledgements
I am grateful to A. Alvarez-Buylla, V. Caviness, F. H. Gage, P. S. Goldman-Rakic, K. Herrup, D. R. Kornack, P. R. Levitt, E. Markakis, J. H. Morrison, E. Mugnaini, R. S. Nowakowski, D. Purves, N. Sestan and D. A. Steindler for their discussion and comments on the manuscript.
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Rakic, P. Neurogenesis in adult primate neocortex: an evaluation of the evidence. Nat Rev Neurosci 3, 65–71 (2002). https://doi.org/10.1038/nrn700
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DOI: https://doi.org/10.1038/nrn700
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