Adulte Neurogenese im ZNS: Vom Labor zur Klinik?

Zusammenfassung

Seit einigen Jahren ist die adulte Neurogenese, also die Neubildung von Nervenzellen im erwachsenen Gehirn bei Säugetieren einschließlich des Menschen bekannt. So proliferieren in der subgranulären Zone des Gyrus dentatus des Hippocampus und in der subventrikulären Zone der Seitenventrikel adulte neuronale Stamm- bzw. Vorläuferzellen, welche Neuronen bilden, die funktionell in das bestehende Netzwerk integriert werden. Die funktionelle Relevanz der physiologischen adulten Neurogenese einerseits und die neu entdeckte potenzielle Möglichkeit einer zellulären Regeneration andererseits, weckte in den letzten Jahren das Interesse der grundlagenorientierten und klinischen Neurowissenschaftler. Es mehren sich so die Hinweise, dass sowohl eine gestörte hippokampale Neurogenese Teil des Pathomechanismus einiger neuropsychiatrischer Erkrankungen ist, als auch das neurogene Potenzial des erwachsenen Gehirns für regenerative Strategien bei neurodegenerativen Erkrankungen therapeutisch eingesetzt werden könnte. Dieser Artikel soll eine Übersicht über die neurobiologischen Grundlagen der adulten Neurogenese und deren Bedeutung bei der Entwicklung neuer Therapieverfahren neurologischer Erkrankungen geben.

Abstract

Two regions of the mammalian brain maintain the capability to generate new neurons throughout lifetime: Neuronal stem- and precursor cells proliferate in the subgranulare zone (SGZ) of the dentate gyrus in the hippocampus and in the subventricular zone (SVZ) of the lateral ventricles to give rise to new neurons that are functionally integrated into the neural network. The functional relevance of adult neurogenesis under physiological conditions on one hand, and the newly discovered potentiality of cellular regeneration in the diseased brain on the other hand, arouse the interest of fundamental and clinical neuroscientists. There is growing evidence that impaired adult neurogenesis is linked to the etiology of neuropsychiatric disorders (such as depression or Alzheimer's disease), as well as that the neurogenic potential may be used for the treatment of neurodegenerative diseases (such as Parkinson’s disease or stroke). This review summarizes the neurobiological bases of adult neurogenesis in their relevance for the future trend of novel therapeutic strategies.

Adulte Neurogenese - neurale Stammzellen - Hippocampus - Alzheimer'sche Erkrankung - idiopathisches Parkinson-Syndrom - zerebrale Ischämie - Epilepsie - Depression

adult neurogenesis - neural stem cells - Hippocampus - Alzheimer's disease - Parkinson's disease - cerebral ischemia - epilepsy - depression

Literatur

• 1 Ramon y Cajal S. Degeneration and Regeneration of the Nervous System. London, 1928: Oxford Univ. Press 1913
• 2 Altman J. Autoradiographic and histological studies of postnatal neurogenesis. IV. Cell proliferation and migration in the anterior forebrain, with special reference to persisting neurogenesis in the olfactory bulb.  J Comp Neurol. 1969;  137 433-457
• 3 Altman J, Das G D. Postnatal neurogenesis in the guinea-pig.  Nature. 1967;  214 1098-1101
• 4 Altman J, Das G D. Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats.  J Comp Neurol. 1965;  124 319-335
• 5 Kaplan M S, Hinds J W. Neurogenesis in the adult rat: electron microscopic analysis of light radioautographs.  Science. 1977;  197 1092-1094
• 6 Gage F H. Mammalian neural stem cells.  Science. 2000;  287 1433-1438
• 7 Gage F H. Neurogenesis in the adult brain.  J Neurosci. 2002;  22 612-613
• 8 Kempermann G, Kuhn H G, Gage F H. More hippocampal neurons in adult mice living in an enriched environment.  Nature. 1997;  386 493-495
• 9 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. 1996;  16 2027-2033
• 10 Alvarez-Buylla A, Lim D A. For the long run: maintaining germinal niches in the adult brain.  Neuron. 2004;  41 683-686
• 11 Temple S, Alvarez-Buylla A. Stem cells in the adult mammalian central nervous system.  Curr Opin Neurobiol. 1999;  9 135-141
• 12 Palmer T D, Markakis E A, Willhoite A R. et al . Fibroblast growth factor-2 activates a latent neurogenic program in neural stem cells from diverse regions of the adult CNS.  J Neurosci. 1999;  19 8487-8497
• 13 Hermann A, Maisel M, Wegner F. et al . Multipotent neural stem cells from the adult tegmentum with dopaminergic potential develop essential properties of functional neurons.  Stem Cells. 2006;  24 949-964
• 14 Palmer T D, Ray J, Gage F H. FGF-2-responsive neuronal progenitors reside in proliferative and quiescent regions of the adult rodent brain.  Mol Cell Neurosci. 1995;  6 474-486
• 15 Palmer T D, Willhoite A R, Gage F H. Vascular niche for adult hippocampal neurogenesis.  J Comp Neurol. 2000;  425 479-494
• 16 Carleton A, Petreanu L T, Lansford R. A. A-B, M. LP. Becoming a new neuron in the adult olfactory bulb.  Nat Neurosci. 2003;  6 507-518
• 17 Doetsch F, Garcia-Verdugo J M, Alvarez-Buylla A. Regeneration of a germinal layer in the adult mammalian brain.  Proc Natl Acad Sci USA. 1999;  96 11 619-11 624
• 18 Alvarez-Buylla A, Garcia-Verdugo J M, Tramontin A D. A unified hypothesis on the lineage of neural stem cells.  Nat Rev Neurosci. 2001;  2 287-293
• 19 Biebl M, Cooper C M, Winkler J. et al . Analysis of neurogenesis and programmed cell death reveals a self-renewing capacity in the adult rat brain.  Neurosci Lett. 2000;  291 17-20
• 20 Baker H, Liu N, Chun H S. et al . Phenotypic differentiation during migration of dopaminergic progenitor cells to the olfactory bulb.  J Neurosci. 2001;  21 8505-8513
• 21 Kosaka K, Hama K, Nagatsu I. et al . Postnatal development of neurons containing both catecholaminergic and GABAergic traits in the rat main olfactory bulb.  Brain Res. 1987;  403 355-360
• 22 McLean J H, Shipley M T. Postmitotic, postmigrational expression of tyrosine hydroxylase in olfactory bulb dopaminergic neurons.  J Neurosci. 1988;  8 3658-3669
• 23 Winner B, Cooper-Kuhn C M, Aigner R. et al . Long-term survival and cell death of newly generated neurons in the adult rat olfactory bulb.  Eur J Neurosci. 2002;  16 1681-1689
• 24 Seri B, Garcia-Verdugo J M, McEwen B S. et al . Astrocytes give rise to new neurons in the adult mammalian hippocampus.  J Neurosci. 2001;  21 7153-7160
• 25 Filippov V, Kronenberg G, Pivneva T. et al . Subpopulation of nestin-expressing progenitor cells in the adult murine hippocampus shows electrophysiological and morphological characteristics of astrocytes.  Mol Cell Neurosci. 2003;  23 373-382
• 26 Kempermann G, Jessberger S, Steiner B. et al . Milestones of neuronal development in the adult hippocampus.  Trends Neurosci. 2004;  27 447-452
• 27 Kronenberg G, Reuter K, Steiner B. et al . Subpopulations of proliferating cells of the adult hippocampus respond differently to physiologic neurogenic stimuli.  J Comp Neurol. 2003;  467 455-463
• 28 Steiner B, Kronenberg G, Jessberger S. et al . Differential regulation of gliogenesis in the context of adult hippocampal neurogenesis in mice.  Glia. 2004;  46 41-52
• 29 Tozuka Y, Fukuda S, Namba T. et al . GABAergic excitation promotes neuronal differentiation in adult hippocampal progenitor cells.  Neuron. 2005;  47 803-815
• 30 Wang L P, Kempermann G, Kettenmann H. A subpopulation of precursor cells in the mouse dentate gyrus receives synaptic GABAergic input.  Mol Cell Neurosci. 2005;  29 181-189
• 31 Plumpe T, Ehninger D, Steiner B. et al . Variability of doublecortin-associated dendrite maturation in adult hippocampal neurogenesis is independent of the regulation of precursor cell proliferation.  BMC Neurosci. 2006;  7 77
• 32 Rao M S, Shetty A K. Efficacy of doublecortin as a marker to analyse the absolute number and dendritic growth of newly generated neurons in the adult dentate gyrus.  Eur J Neurosci. 2004;  19 234-246
• 33 Brandt M D, Jessberger S, Steiner B. et al . Transient calretinin expression defines early postmitotic step of neuronal differentiation in adult hippocampal neurogenesis of mice.  Mol Cell Neurosci. 2003;  24 603-613
• 34 Hastings N B, Gould E. Rapid extension of axons into the CA3 region by adult-generated granule cells.  J Comp Neurol. 1999;  413 146-154
• 35 Zhao C, Teng E M, Summers Jr R G. et al . Distinct morphological stages of dentate granule neuron maturation in the adult mouse hippocampus.  J Neurosci. 2006;  26 3-11
• 36 Kuhn H G, Biebl M, Wilhelm D. et al . Increased generation of granule cells in adult Bcl-2-overexpressing mice: a role for cell death during continued hippocampal neurogenesis.  Eur J Neurosci. 2005;  22 1907-1915
• 37 Kempermann G, Gast D, Kronenberg G. et al . Early determination and long-term persistence of adult-generated new neurons in the hippocampus of mice.  Development. 2003;  130 391-399
• 38 Eriksson P S, Perfilieva E, Bjork-Eriksson T. et al . Neurogenesis in the adult human hippocampus.  Nat Med. 1998;  4 1313-1317
• 39 Curtis M A, Kam M, Nannmark U. et al . Human neuroblasts migrate to the olfactory bulb via a lateral ventricular extension.  Science. 2007;  315 1243-1249
• 40 Sanai N, Tramontin A D, Quinones-Hinojosa A. et al . Unique astrocyte ribbon in adult human brain contains neural stem cells but lacks chain migration.  Nature. 2004;  427 740-744
• 41 Bédard A, Parent A. Evidence of newly generated neurons in the human olfactory bulb.  Brain Res Dev Brain Res. 2004;  151 159-168
• 42 Liu Z, Martin L J. Olfactory bulb core is a rich source of neural progenitor and stem cells in adult rodent and human.  J Comp Neurol. 2003;  459 368-391
• 43 Sanai N, Berger M S, Garcia-Verdugo J M. et al . Comment on “Human neuroblasts migrate to the olfactory bulb via a lateral ventricular extension”.  Science. 2007;  318 393; author reply 393
• 44 Kukekov V G, Laywell E D, Suslov O. et al . Multipotent stem/progenitor cells with similar properties arise from two neurogenic regions of adult human brain.  Exp Neurol. 1999;  156 333-344
• 45 Roy N S, Benraiss A, Wang S. et al . Promoter-targeted selection and isolation of neural progenitor cells from the adult human ventricular zone.  J Neurosci Res. 2000;  59 321-331
• 46 Roy N S, Wang S, Jiang L. et al . In vitro neurogenesis by progenitor cells isolated from the adult human hippocampus.  Nat Med. 2000;  6 271-277
• 47 Hermann A, Maisel M, Liebau S. et al . Mesodermal cell types induce neurogenesis from adult human hippocampal progenitor cells.  J Neurochem. 2006;  98 629-640
• 48 Maisel M, Herr A, Milosevic J. et al . Transcription profiling of adult and fetal human neuroprogenitors identifies divergent paths to maintain the neuroprogenitor cell state.  Stem Cells. 2007;  25 1231-1240
• 49 Praag H van, Christie B R, Sejnowski T J. et al . Running enhances neurogenesis, learning, and long-term potentiation in mice.  Proc Natl Acad Sci U S A. 1999;  96 13 427-13 431
• 50 Brown J, Cooper-Kuhn C M, Kempermann G. et al . Enriched environment and physical activity stimulate hippocampal but not olfactory bulb neurogenesis.  Eur J Neurosci. 2003;  17 2042-2046
• 51 Rochefort C, Gheusi G, Vincent J D. et al . Enriched odor exposure increases the number of newborn neurons in the adult olfactory bulb and improves odor memory.  J Neurosci. 2002;  22 2679-2689
• 52 Praag H van, Kempermann G, Gage F H. Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus.  Nat Neurosci. 1999;  2 266-270
• 53 Carro E, Nunez A, Busiguina S. et al . Circulating insulin-like growth factor I mediates effects of exercise on the brain.  J Neurosci. 2000;  20 2926-2933
• 54 Fabel K, Tam B, Kaufer D. et al . VEGF is necessary for exercise-induced adult hippocampal neurogenesis.  Eur J Neurosci. 2003;  18 2803-2812
• 55 Cameron H A, Gould E. Adult neurogenesis is regulated by adrenal steroids in the dentate gyrus.  Neuroscience. 1994;  61 203-209
• 56 Gould E. The effects of adrenal steroids and excitatory input on neuronal birth and survival.  Ann N Y Acad Sci. 1994;  743 73-92
• 57 Gould E, McEwen B S, Tanapat P. et al . Neurogenesis in the dentate gyrus of the adult tree shrew is regulated by psychosocial stress and NMDA receptor activation.  J Neurosci. 1997;  17 2492-2498
• 58 Cameron H A, McKay R D. Restoring production of hippocampal neurons in old age.  Nat Neurosci. 1999;  2 894-897
• 59 Kempermann G, Kuhn H G, Gage F H. Experience-induced neurogenesis in the senescent dentate gyrus.  J Neurosci. 1998;  18 3206-3212
• 60 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. 1996;  16 2027-2033
• 61 Kempermann G, Gast D, Gage F H. Neuroplasticity in old age: sustained fivefold induction of hippocampal neurogenesis by long-term environmental enrichment.  Ann Neurol. 2002;  52 135-143
• 62 Kempermann G, Gage F H. Experience-dependent regulation of adult hippocampal neurogenesis: effects of long-term stimulation and stimulus withdrawal.  Hippocampus. 1999;  9 321-332
• 63 Jessberger S, Kempermann G. Adult-born hippocampal neurons mature into activity-dependent responsiveness.  Eur J Neurosci. 2003;  18 2707-2712
• 64 Magavi S S, Mitchell B D, Szentirmai O. et al . Adult-born and preexisting olfactory granule neurons undergo distinct experience-dependent modifications of their olfactory responses in vivo.  J Neurosci. 2005;  25 10 729-10 739
• 65 Praag H van, Schinder A F, Christie B R. et al . Functional neurogenesis in the adult hippocampus.  Nature. 2002;  415 1030-1034
• 66 Abraham W C, Mason S E, Demmer J. et al . Correlations between immediate early gene induction and the persistence of long-term potentiation.  Neuroscience. 1993;  56 717-727
• 67 Ben-Ari Y. Cell death and synaptic reorganizations produced by seizures.  Epilepsia. 2001;  42 Suppl 3 5-7
• 68 Shors T J, Miesegaes G, Beylin A. et al . Neurogenesis in the adult is involved in the formation of trace memories.  Nature. 2001;  410 372-376
• 69 Shors T J, Townsend D A, Zhao M. et al . Neurogenesis may relate to some but not all types of hippocampal-dependent learning.  Hippocampus. 2002;  12 578-584
• 70 Snyder J S, Hong N S, McDonald R J. et al . A role for adult neurogenesis in spatial long-term memory.  Neuroscience. 2005;  130 843-852
• 71 Kempermann G. Why new neurons? Possible functions for adult hippocampal neurogenesis.  J Neurosci. 2002;  22 635-638
• 72 Kempermann G. The neurogenic reserve hypothesis: what is adult hippocampal neurogenesis good for?.  Trends Neurosci. 2008;  31 163-169
• 73 Donovan M H, Yazdani U, Norris R D. et al . Decreased adult hippocampal neurogenesis in the PDAPP mouse model of Alzheimer's disease.  J Comp Neurol. 2006;  495 70-83
• 74 Haughey N J, Nath A, Chan S L. et al . Disruption of neurogenesis by amyloid beta-peptide, and perturbed neural progenitor cell homeostasis, in models of Alzheimer's disease.  J Neurochem. 2002;  83 1509-1524
• 75 Jin K, Peel A L, Mao X O. et al . Increased hippocampal neurogenesis in Alzheimer's disease.  Proc Natl Acad Sci U S A. 2004;  101 343-347
• 76 Jin K, Galvan V, Xie L. et al . Enhanced neurogenesis in Alzheimer 2004 s disease transgenic (PDGF-APPSw,Ind) mice.  Proc Natl Acad Sci U S A. 2004;  101 13 363-13 367
• 77 Zhang Y W, Xu H. Molecular and cellular mechanisms for Alzheimer's disease: understanding APP metabolism.  Curr Mol Med. 2007;  7 687-696
• 78 Chen G, Chen K S, Knox J. et al . A learning deficit related to age and beta-amyloid plaques in a mouse model of Alzheimer's disease.  Nature. 2000;  408 975-979
• 79 Nagy Z, Esiri M M, Smith A D. The cell division cycle and the pathophysiology of Alzheimer's disease.  Neuroscience. 1998;  87 731-739
• 80 Becker M, Lavie V, Solomon B. Stimulation of endogenous neurogenesis by anti-EFRH immunization in a transgenic mouse model of Alzheimer's disease.  Proc Natl Acad Sci U S A. 2007;  104 1691-1696
• 81 Rockenstein E, Mante M, Adame A. et al . Effects of Cerebrolysin on neurogenesis in an APP transgenic model of Alzheimer's disease.  Acta Neuropathol. 2007;  113 265-275
• 82 Costa D A, Cracchiolo J R, Bachstetter A D. et al . Enrichment improves cognition in AD mice by amyloid-related and unrelated mechanisms.  Neurobiol Aging. 2007;  28 831-844
• 83 Lazarov O, Robinson J, Tang Y P. et al . Environmental enrichment reduces Abeta levels and amyloid deposition in transgenic mice.  Cell. 2005;  120 701-713
• 84 Arendash G W, Garcia M F, Costa D A. et al . Environmental enrichment improves cognition in aged Alzheimer's transgenic mice despite stable beta-amyloid deposition.  Neuroreport. 2004;  15 1751-1754
• 85 Wolf S A, Kronenberg G, Lehmann K. et al . Cognitive and physical activity differently modulate disease progression in the amyloid precursor protein (APP)-23 model of Alzheimer's disease.  Biol Psychiatry. 2006;  60 1314-1323
• 86 Fratiglioni L, Wang H X. Brain reserve hypothesis in dementia.  J Alzheimers Dis. 2007;  12 11-22
• 87 Steiner B, Wolf S, Kempermann G. Adult neurogenesis and neurodegenerative disease.  Regen Med. 2006;  1 15-28
• 88 Jin K, Xie L, Mao X O. et al . Alzheimer's disease drugs promote neurogenesis.  Brain Res. 2006;  1085 183-188
• 89 Kaneko N, Okano H, Sawamoto K. Role of the cholinergic system in regulating survival of newborn neurons in the adult mouse dentate gyrus and olfactory bulb.  Genes Cells. 2006;  11 1145-1159
• 90 Zhao M, Momma S, Delfani K. et al . Evidence for neurogenesis in the adult mammalian substantia nigra.  Proc Natl Acad Sci U S A. 2003;  100 7925-7930
• 91 Kampen J M van, Eckman C B. Dopamine D3 receptor agonist delivery to a model of Parkinson's disease restores the nigrostriatal pathway and improves locomotor behavior.  J Neurosci. 2006;  26 7272-7280
• 92 Frielingsdorf H, Schwarz K, Brundin P. et al . No evidence for new dopaminergic neurons in the adult mammalian substantia nigra.  Proc Natl Acad Sci U S A. 2004;  101 10 177-10 182
• 93 Lie D C, Dziewczapolski G, Willhoite A R. et al . The adult substantia nigra contains progenitor cells with neurogenic potential.  J Neurosci. 2002;  22 6639-6649
• 94 Reimers D, Herranz A S, Diaz-Gil J J. et al . Intrastriatal infusion of liver growth factor stimulates dopamine terminal sprouting and partially restores motor function in 6-hydroxydopamine-lesioned rats.  J Histochem Cytochem. 2006;  54 457-465
• 95 Hoglinger G U, Breunig J J, Depboylu C. et al . The pRb/E2F cell-cycle pathway mediates cell death in Parkinson's disease.  Proc Natl Acad Sci U S A. 2007;  104 3585-3590
• 96 Mohapel P, Frielingsdorf H, Haggblad J. et al . Platelet-derived growth factor (PDGF-BB) and brain-derived neurotrophic factor (BDNF) induce striatal neurogenesis in adult rats with 6-hydroxydopamine lesions.  Neuroscience. 2005;  132 767-776
• 97 Cooper O, Isacson O. Intrastriatal transforming growth factor alpha delivery to a model of Parkinson's disease induces proliferation and migration of endogenous adult neural progenitor cells without differentiation into dopaminergic neurons.  J Neurosci. 2004;  24 8924-8931
• 98 Diaz J, Ridray S, Mignon V. et al . Selective expression of dopamine D3 receptor mRNA in proliferative zones during embryonic development of the rat brain.  J Neurosci. 1997;  17 4282-4292
• 99 Ohtani N, Goto T, Waeber C. et al . Dopamine modulates cell cycle in the lateral ganglionic eminence.  J Neurosci. 2003;  23 2840-2850
• 100 Höglinger G U, Rizk P, Muriel M P. et al . Dopamine depletion impairs precursor cell proliferation in Parkinson disease.  Nat Neurosci. 2004;  7 726-735
• 101 Freundlieb N, François C, Tandé D. et al . Dopaminergic substantia nigra neurons project topographically organized to the subventricular zone and stimulate precursor cell proliferation in aged primates.  J Neurosci. 2006;  26 2321-2325
• 102 Borta A, Hoglinger G U. Dopamine and adult neurogenesis.  J Neurochem. 2007;  100 587-595
• 103 Gould N F, Holmes M K, Fantie B D. et al . Performance on a virtual reality spatial memory navigation task in depressed patients.  Am J Psychiatry. 2007;  164 516-519
• 104 Campbell S, Marriott M, Nahmias C. et al . Lower hippocampal volume in patients suffering from depression: a meta-analysis.  Am J Psychiatry. 2004;  161 598-607
• 105 Videbech P, Ravnkilde B. Hippocampal volume and depression: a meta-analysis of MRI studies.  Am J Psychiatry. 2004;  161 1957-1966
• 106 MacQueen G M, Campbell S, McEwen B S. et al . Course of illness, hippocampal function, and hippocampal volume in major depression.  Proc Natl Acad Sci U S A. 2003;  100 1387-1392
• 107 Malberg J E, Eisch A J, Nestler E J. et al . Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus.  J Neurosci. 2000;  20 9104-9110
• 108 Czeh B, Michaelis T, Watanabe T. et al . Stress-induced changes in cerebral metabolites, hippocampal volume, and cell proliferation are prevented by antidepressant treatment with tianeptine.  Proc Natl Acad Sci U S A. 2001;  98 12 796-12 801
• 109 Santarelli L, Saxe M, Gross C. et al . Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants.  Science. 2003;  301 805-809
• 110 Duman R S, Monteggia L M. A neurotrophic model for stress-related mood disorders.  Biol Psychiatry. 2006;  59 1116-1127
• 111 Jiang W, Zhang Y, Xiao L. et al . Cannabinoids promote embryonic and adult hippocampus neurogenesis and produce anxiolytic- and antidepressant-like effects.  J Clin Invest. 2005;  115 3104-3116
• 112 Henn F A, Vollmayr B. Stress models of depression: forming genetically vulnerable strains.  Neurosci Biobehav Rev. 2005;  29 799-804
• 113 Vollmayr B, Mahlstedt M M, Henn F A. Neurogenesis and depression: what animal models tell us about the link.  Eur Arch Psychiatry Clin Neurosci. 2007;  257 300-303
• 114 Encinas J M, Vaahtokari A, Enikolopov G. Fluoxetine targets early progenitor cells in the adult brain.  Proc Natl Acad Sci U S A. 2006;  103 8233-8238
• 115 Nakagawa S, Kim J E, Lee R. et al . Localization of phosphorylated cAMP response element-binding protein in immature neurons of adult hippocampus.  J Neurosci. 2002;  22 9868-9876
• 116 Nakagawa S, Kim J E, Lee R. et al . Regulation of neurogenesis in adult mouse hippocampus by cAMP and the cAMP response element-binding protein.  J Neurosci. 2002;  22 3673-3682
• 117 Perera T D, Coplan J D, Lisanby S H. et al . Antidepressant-induced neurogenesis in the hippocampus of adult nonhuman primates.  J Neurosci. 2007;  27 4894-4901
• 118 Scott B W, Wojtowicz J M, Burnham W M. Neurogenesis in the dentate gyrus of the rat following electroconvulsive shock seizures.  Exp Neurol. 2000;  165 231-236
• 119 Guzman-Marin R, Bashir T, Suntsova N. et al . Hippocampal neurogenesis is reduced by sleep fragmentation in the adult rat.  Neuroscience. 2007;  148 325-333
• 120 Guzman-Marin R, Suntsova N, Methippara M. et al . Sleep deprivation suppresses neurogenesis in the adult hippocampus of rats.  Eur J Neurosci. 2005;  22 2111-2116
• 121 Grassi Zucconi G, Cipriani S, Balgkouranidou I. et al . “One night” sleep deprivation stimulates hippocampal neurogenesis.  Brain Res Bull. 2006;  69 375-381
• 122 McEwen B S. Glucocorticoids, depression, and mood disorders: structural remodeling in the brain.  Metabolism. 2005;  54 20-23
• 123 Czeh B, Lucassen P J. What causes the hippocampal volume decrease in depression? Are neurogenesis, glial changes and apoptosis implicated?.  Eur Arch Psychiatry Clin Neurosci. 2007;  257 250-260
• 124 Imai F, Suzuki H, Oda J. et al . Neuroprotective effect of exogenous microglia in global brain ischemia.  J Cereb Blood Flow Metab. 2007;  27 488-500
• 125 Liu J, Solway K, Messing R O. et al . Increased neurogenesis in the dentate gyrus after transient global ischemia in gerbils.  J Neurosci. 1998;  18 7768-7778
• 126 Takagi Y, Nozaki K, Takahashi J. et al . Proliferation of neuronal precursor cells in the dentate gyrus is accelerated after transient forebrain ischemia in mice.  Brain Res. 1999;  831 283-287
• 127 Tonchev A B, Yamashima T. Differential neurogenic potential of progenitor cells in dentate gyrus and CA1 sector of the postischemic adult monkey hippocampus.  Exp Neurol. 2006;  198 101-113
• 128 Yagita Y, Kitagawa K, Ohtsuki T. et al . Neurogenesis by progenitor cells in the ischemic adult rat hippocampus.  Stroke. 2001;  32 1890-1896
• 129 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. 2001;  14 10-18
• 130 Bendel O, Bueters T, Euler M von. et al . Reappearance of hippocampal CA1 neurons after ischemia is associated with recovery of learning and memory.  J Cereb Blood Flow Metab. 2005;  25 1586-1595
• 131 Ehninger D, Kempermann G. Regional effects of wheel running and environmental enrichment on cell genesis and microglia proliferation in the adult murine neocortex.  Cereb Cortex. 2003;  13 845-851
• 132 Gould E, Reeves A J, Graziano M S. et al . Neurogenesis in the neocortex of adult primates.  Science. 1999;  286 548-552
• 133 Kornack D R, Rakic P. Cell proliferation without neurogenesis in adult primate neocortex.  Science. 2001;  294 2127-2130
• 134 Nowakowski R S, Hayes N L. New neurons: extraordinary evidence or extraordinary conclusion?.  Science. 2000;  288 771
• 135 Arvidsson A, Collin T, Kirik D. et al . Neuronal replacement from endogenous precursors in the adult brain after stroke.  Nat Med. 2002;  8 963-970
• 136 Jin K, Minami M, Lan J Q. et al . Neurogenesis in dentate subgranular zone and rostral subventricular zone after focal cerebral ischemia in the rat.  Proc Natl Acad Sci U S A. 2001;  98 4710-4715
• 137 Zhang R, Zhang Z, Wang L. et al . Activated neural stem cells contribute to stroke-induced neurogenesis and neuroblast migration toward the infarct boundary in adult rats.  J Cereb Blood Flow Metab. 2004;  24 441-448
• 138 Zhang R L, LeTourneau Y, Gregg S R. et al . Neuroblast division during migration toward the ischemic striatum: a study of dynamic migratory and proliferative characteristics of neuroblasts from the subventricular zone.  J Neurosci. 2007;  27 3157-3162
• 139 Ehrenreich H, Hasselblatt M, Dembowski C. et al . Erythropoietin therapy for acute stroke is both safe and beneficial.  Mol Med. 2002;  8 495-505
• 140 Wang L, Zhang Z, Wang Y. et al . Treatment of stroke with erythropoietin enhances neurogenesis and angiogenesis and improves neurological function in rats.  Stroke. 2004;  35 1732-1737
• 141 Schabitz W R, Steigleder T, Cooper-Kuhn C M. et al . Intravenous brain-derived neurotrophic factor enhances poststroke sensorimotor recovery and stimulates neurogenesis.  Stroke. 2007;  38 2165-2172
• 142 Bengzon J, Kokaia Z, Elmer E. et al . Apoptosis and proliferation of dentate gyrus neurons after single and intermittent limbic seizures.  Proc Natl Acad Sci U S A. 1997;  94 10 432-10 437
• 143 Parent J M, Yu T W, Leibowitz R T. et al . Dentate granule cell neurogenesis is increased by seizures and contributes to aberrant network reorganization in the adult rat hippocampus.  J Neurosci. 1997;  17 3727-3738
• 144 Madsen T M, Treschow A, Bengzon J. et al . Increased neurogenesis in a model of electroconvulsive therapy.  Biol Psychiatry. 2000;  47 1043-1049
• 145 Nakagawa E, Aimi Y, Yasuhara O. et al . Enhancement of progenitor cell division in the dentate gyrus triggered by initial limbic seizures in rat models of epilepsy.  Epilepsia. 2000;  41 10-18
• 146 Parent J M, Janumpalli S, McNamara J O. et al . Increased dentate granule cell neurogenesis following amygdala kindling in the adult rat.  Neurosci Lett. 1998;  247 9-12
• 147 Helmstaedter C. Effects of chronic epilepsy on declarative memory systems.  Prog Brain Res. 2002;  135 439-453
• 148 Stafstrom C E, Chronopoulos A, Thurber S. et al . Age-dependent cognitive and behavioral deficits after kainic acid seizures.  Epilepsia. 1993;  34 420-432
• 149 Jessberger S, Romer B, Babu H. et al . Seizures induce proliferation and dispersion of doublecortin-positive hippocampal progenitor cells.  Exp Neurol. 2005;  196 342-351
• 150 Huttmann K, Sadgrove M, Wallraff A. et al . Seizures preferentially stimulate proliferation of radial glia-like astrocytes in the adult dentate gyrus: functional and immunocytochemical analysis.  Eur J Neurosci. 2003;  18 2769-2778
• 151 Houser C R. Morphological changes in the dentate gyrus in human temporal lobe epilepsy.  Epilepsy Res Suppl. 1992;  7 223-234
• 152 Shapiro L A, Korn M J, Ribak C E. Newly generated dentate granule cells from epileptic rats exhibit elongated hilar basal dendrites that align along GFAP-immunolabeled processes.  Neuroscience. 2005;  136 823-831
• 153 Scharfman H E, Goodman J H, Sollas A L. Granule-like neurons at the hilar/CA3 border after status epilepticus and their synchrony with area CA3 pyramidal cells: functional implications of seizure-induced neurogenesis.  J Neurosci. 2000;  20 6144-6158
• 154 Jakubs K, Nanobashvili A, Bonde S. et al . Environment matters: synaptic properties of neurons born in the epileptic adult brain develop to reduce excitability.  Neuron. 2006;  52 1047-1059
• 155 Jessberger S, Nakashima K, Clemenson Jr G D. et al . Epigenetic modulation of seizure-induced neurogenesis and cognitive decline.  J Neurosci. 2007;  27 5967-5975
• 156 Manganas L N, Zhang X, Li Y. et al . Magnetic resonance spectroscopy identifies neural progenitor cells in the live human brain.  Science. 2007;  318 980-985