Seeing old friends from a different angle: Novel properties of hematopoietic growth factors in the healthy and diseased brain

Hippocampus

Volumn 22, Issue 5, 2012, Pages 1051-1057

  Diederich, Kai ^a   Schäbitz, Wolf Rüdiger ^a,b   Minnerup, Jens ^a  

^a UNIVERSITY OF MÜNSTER   (Germany)

^b EVANGELISCHES KRANKENHAUS   (Germany)

Author keywords

EPO; G CSF; Hippocampus; Learning and memory formation; Neurogenesis; TPO

Indexed keywords

CYCLIC AMP RESPONSIVE ELEMENT BINDING PROTEIN; ERYTHROPOIETIN; ERYTHROPOIETIN RECEPTOR; GRANULOCYTE COLONY STIMULATING FACTOR; GRANULOCYTE COLONY STIMULATING FACTOR RECEPTOR; HEMOPOIETIC GROWTH FACTOR; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; JANUS KINASE; MITOGEN ACTIVATED PROTEIN KINASE 1; MITOGEN ACTIVATED PROTEIN KINASE 3; MITOGEN ACTIVATED PROTEIN KINASE 7; PHOSPHATIDYLINOSITOL 3 KINASE; STAT PROTEIN; STAT3 PROTEIN; THROMBOPOIETIN;

ANGIOGENESIS; APOPTOSIS; ARTICLE; CAUDATE NUCLEUS; CELL ACTIVITY; CELL DIFFERENTIATION; CELL MATURATION; CELL PROLIFERATION; CELL SURVIVAL; CEREBELLUM; ENDOTHELIUM CELL; FIBROBLAST; FRONTAL CORTEX; HEMATOPOIETIC STEM CELL; HEMATOPOIETIC SYSTEM; HIPPOCAMPUS; HUMAN; HYPOTHALAMUS; INFLAMMATION; LEARNING; LONG TERM POTENTIATION; MEGAKARYOBLAST; MEMORY; MESOTHELIUM CELL; MONOCYTE; NERVE CELL; NERVOUS SYSTEM DEVELOPMENT; NONHUMAN; OCCIPITAL CORTEX; OLFACTORY BULB; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN FUNCTION; SIGNAL TRANSDUCTION; STEM CELL MOBILIZATION; SUBVENTRICULAR ZONE; TEMPORAL CORTEX;

ANIMALS; BRAIN; BRAIN DISEASES; ERYTHROPOIETIN; GRANULOCYTE COLONY-STIMULATING FACTOR; HEMATOPOIETIC CELL GROWTH FACTORS; HIPPOCAMPUS; HUMANS; MICE; NEURAL STEM CELLS; NEUROGENESIS; RATS; THROMBOPOIETIN;

EID: 84859710791     PISSN: 10509631     EISSN: 10981063     Source Type: Journal    
DOI: 10.1002/hipo.20904     Document Type: Article

References (88)

1. Adamcio B, Sargin D, Stradomska A, Medrihan L, Gertler C, Theis F, Zhang M, Muller M, Hassouna I, Hannke K, Sperling S, Radyushkin K, El Kordi A, Schulze L, Ronnenberg A, Wolf F, Brose N, Rhee JS, Zhang W, Ehrenreich H. 2008. Erythropoietin enhances hippocampal long-term potentiation and memory. BMC Biol 6: 37.
2. Arcasoy MO. 2008. The non-haematopoietic biological effects of erythropoietin. Br J Haematol 141: 14-31.
3. Avalos BR. 1996. Molecular analysis of the granulocyte colony-stimulating factor receptor. Blood 88: 761-777.
4. Bernaudin M, Marti HH, Roussel S, Divoux D, Nouvelot A, MacKenzie ET, Petit E. 1999. A potential role for erythropoietin in focal permanent cerebral ischemia in mice. J Cereb Blood Flow Metab 19: 643-651.
5. Boneberg EM, Hareng L, Gantner F, Wendel A, Hartung T. 2000. Human monocytes express functional receptors for granulocyte colony-stimulating factor that mediate suppression of monokines and interferon-gamma. Blood 95: 270-276.
6. Brines M, Cerami A. 2005. Emerging biological roles for erythropoietin in the nervous system. Nat Rev Neurosci 6: 484-494.
7. Brines M, Grasso G, Fiordaliso F, Sfacteria A, Ghezzi P, Fratelli M, Latini R, Xie QW, Smart J, Su-Rick CJ, Pobre E, Diaz D, Gomez D, Hand C, Coleman T, Cerami A. 2004. Erythropoietin mediates tissue protection through an erythropoietin and common beta-subunit heteroreceptor. Proc Natl Acad Sci USA 101: 14907-14912.
8. Brines ML, Ghezzi P, Keenan S, Agnello D, de Lanerolle NC, Cerami C, Itri LM, Cerami A. 2000. Erythropoietin crosses the blood-brain barrier to protect against experimental brain injury. Proc Natl Acad Sci USA 97: 10526-10531.
9. Byts N, Samoylenko A, Woldt H, Ehrenreich H, Siren AL. 2006. Cell type specific signalling by hematopoietic growth factors in neural cells. Neurochem Res 31: 1219-1230.
10. Byts N, Samoylenko A, Fasshauer T, Ivanisevic M, Hennighausen L, Ehrenreich H, Siren AL. 2008. Essential role for Stat5 in the neurotrophic but not in the neuroprotective effect of erythropoietin. Cell Death Differ 15: 783-792.
11. Cao XQ, Arai H, Ren YR, Oizumi H, Zhang N, Seike S, Furuya T, Yasuda T, Mizuno Y, Mochizuki H. 2006. Recombinant human granulocyte colony-stimulating factor protects against MPTP-induced dopaminergic cell death in mice by altering Bcl-2/Bax expression levels. J Neurochem 99: 861-867.
12. Chen ZY, Asavaritikrai P, Prchal JT, Noguchi CT. 2007. Endogenous erythropoietin signaling is required for normal neural progenitor cell proliferation. J Biol Chem 282: 25875-25883.
13. Dame C, Wolber EM, Freitag P, Hofmann D, Bartmann P, Fandrey J. 2003. Thrombopoietin gene expression in the developing human central nervous system. Brain Res Dev Brain Res 143: 217-223.
14. de Sauvage FJ, Hass PE, Spencer SD, Malloy BE, Gurney AL, Spencer SA, Darbonne WC, Henzel WJ, Wong SC, Kuang WJ. 1994. Stimulation of megakaryocytopoiesis and thrombopoiesis by the c-Mpl ligand. Nature 369: 533-538.
15. Diederich K, Schabitz WR, Kuhnert K, Hellstrom N, Sachser N, Schneider A, Kuhn HG, Knecht S. 2009a. Synergetic effects of granulocyte-colony stimulating factor and cognitive training on spatial learning and survival of newborn hippocampal neurons. PLoS ONE 4: e5303.
16. Diederich K, Sevimli S, Dorr H, Kosters E, Hoppen M, Lewejohann L, Klocke R, Minnerup J, Knecht S, Nikol S, Sachser N, Schneider A, Gorji A, Sommer C, Schabitz WR. 2009b. The role of granulocyte-colony stimulating factor (G-CSF) in the healthy brain: A characterization of G-CSF-deficient mice. J Neurosci 29: 11572-11581.
17. Digicaylioglu M, Bichet S, Marti HH, Wenger RH, Rivas LA, Bauer C, Gassmann M. 1995. Localization of specific erythropoietin binding sites in defined areas of the mouse brain. Proc Natl Acad Sci USA 92: 3717-3720.
18. Dupret D, Fabre A, Dobrossy MD, Panatier A, Rodriguez JJ, Lamarque S, Lemaire V, Oliet SH, Piazza PV, Abrous DN. 2007. Spatial learning depends on both the addition and removal of new hippocampal neurons. PLoS Biol 5: e214.
19. Ehrenreich H, Hasselblatt M, Knerlich F, von Ahsen N, Jacob S, Sperling S, Woldt H, Vehmeyer K, Nave KA, Siren AL. 2005. A hematopoietic growth factor, thrombopoietin, has a proapoptotic role in the brain. Proc Natl Acad Sci USA 102: 862-867.
20. Ehrenreich H, Weissenborn K, Prange H, Schneider D, Weimar C, Wartenberg K, Schellinger PD, Bohn M, Becker H, Wegrzyn M, Jahnig P, Herrmann M, Knauth M, Bahr M, Heide W, Wagner A, Schwab S, Reichmann H, Schwendemann G, Dengler R, Kastrup A, Bartels C. 2009. Recombinant human erythropoietin in the treatment of acute ischemic stroke. Stroke 40: e647-e656.
21. Epp JR, Spritzer MD, Galea LA. 2007. Hippocampus-dependent learning promotes survival of new neurons in the dentate gyrus at a specific time during cell maturation. Neuroscience 149: 273-285.
22. Fisher JW. 2003. Erythropoietin: Physiology and pharmacology update. Exp Biol Med (Maywood) 228: 1-14.
23. Ganser C, Papazoglou A, Just L, Nikkhah G. 2010. Neuroprotective effects of erythropoietin on 6-hydroxydopamine-treated ventral mesencephalic dopamine-rich cultures. Exp Cell Res 316: 737-746.
24. Geddis AE, Linden HM, Kaushansky K. 2002. Thrombopoietin: A pan-hematopoietic cytokine. Cytokine Growth Factor Rev 13: 61-73.
25. Gibson CL, Bath PM, Murphy SP. 2005. G-CSF reduces infarct volume and improves functional outcome after transient focal cerebral ischemia in mice. J Cereb Blood Flow Metab 25: 431-439.
26. Grunfeld JF, Barhum Y, Blondheim N, Rabey JM, Melamed E, Offen D. 2007. Erythropoietin delays disease onset in an amyotrophic lateral sclerosis model. Exp Neurol 204: 260-263.
27. Hengemihle JM, Abugo O, Rifkind J, Spangler E, Danon D, Ingram DK. 1996. Chronic treatment with human recombinant erythropoietin increases hematocrit and improves water maze performance in mice. Physiol Behav 59: 153-156.
28. Iwai M, Stetler RA, Xing J, Hu X, Gao Y, Zhang W, Chen J, Cao G. 2010. Enhanced oligodendrogenesis and recovery of neurological function by erythropoietin after neonatal hypoxic/ischemic brain injury. Stroke 41: 1032-1037.
29. Juul SE, Yachnis AT, Rojiani AM, Christensen RD. 1999. Immunohistochemical localization of erythropoietin and its receptor in the developing human brain. Pediatr Dev Pathol 2: 148-158.
30. Kaushansky K. 1995. Thrombopoietin: The primary regulator of platelet production. Blood 86: 419-431.
31. Kaushansky K. 2003. Thrombopoietin: A tool for understanding thrombopoiesis. J Thromb Haemost 1: 1587-1592.
32. Kaushansky K, Lin N, Adamson JW. 1988. Interleukin 1 stimulates fibroblasts to synthesize granulocyte-macrophage and granulocyte colony-stimulating factors. Mechanism for the hematopoietic response to inflammation. J Clin Invest 81: 92-97.
33. Knabe W, Knerlich F, Washausen S, Kietzmann T, Siren AL, Brunnett G, Kuhn HJ, Ehrenreich H. 2004. Expression patterns of erythropoietin and its receptor in the developing midbrain. Anat Embryol (Berl) 207: 503-512.
34. Koeffler HP, Gasson J, Ranyard J, Souza L, Shepard M, Munker R. 1987. Recombinant human TNF alpha stimulates production of granulocyte colony-stimulating factor. Blood 70: 55-59.
35. Komine-Kobayashi M, Zhang N, Liu M, Tanaka R, Hara H, Osaka A, Mochizuki H, Mizuno Y, Urabe T. 2006. Neuroprotective effect of recombinant human granulocyte colony-stimulating factor in transient focal ischemia of mice. J Cereb Blood Flow Metab 26: 402-413.
36. Koshimura K, Murakami Y, Sohmiya M, Tanaka J, Kato Y. 1999. Effects of erythropoietin on neuronal activity. J Neurochem 72: 2565-2572.
37. Li B, Pan H, Winkelmann JC, Dai W. 1996. Thrombopoietin and its alternatively spliced form are expressed in human amygdala and hippocampus. Blood 87: 5382-5384.
38. Liu C, Shen K, Liu Z, Noguchi CT. 1997. Regulated human erythropoietin receptor expression in mouse brain. J Biol Chem 272: 32395-32400.
39. Liu ZY, Chin K, Noguchi CT. 1994. Tissue specific expression of human erythropoietin receptor in transgenic mice. Dev Biol 166: 159-169.
40. Lok S, Kaushansky K, Holly RD, Kuijper JL, Lofton-Day CE, Oort PJ, Grant FJ, Heipel MD, Burkhead SK, Kramer JM. 1994. Cloning and expression of murine thrombopoietin cDNA and stimulation of platelet production in vivo. Nature 369: 565-568.
41. Marti HH. 2004. Erythropoietin and the hypoxic brain. J Exp Biol 207: 3233-3242.
42. Marti HH, Wenger RH, Rivas LA, Straumann U, Digicaylioglu M, Henn V, Yonekawa Y, Bauer C, Gassmann M. 1996. Erythropoietin gene expression in human, monkey and murine brain. Eur J Neurosci 8: 666-676.
43. Masuda S, Okano M, Yamagishi K, Nagao M, Ueda M, Sasaki R. 1994. A novel site of erythropoietin production. Oxygen-dependent production in cultured rat astrocytes. J Biol Chem 269: 19488-19493.
44. Meuer K, Pitzer C, Teismann P, Kruger C, Goricke B, Laage R, Lingor P, Peters K, Schlachetzki JC, Kobayashi K, Dietz GP, Weber D, Ferger B, Schabitz WR, Bach A, Schulz JB, Bahr M, Schneider A, Weishaupt JH. 2006. Granulocyte-colony stimulating factor is neuroprotective in a model of Parkinson's disease. J Neurochem 97: 675-686.
45. Minnerup J, Schabitz WR. 2009. Multifunctional actions of approved and candidate stroke drugs. Neurotherapeutics 6: 43-52.
46. Minnerup J, Heidrich J, Wellmann J, Rogalewski A, Schneider A, Schabitz WR. 2008. Meta-analysis of the efficacy of granulocyte-colony stimulating factor in animal models of focal cerebral ischemia. Stroke 39: 1855-1861.
47. Minnerup J, Heidrich J, Rogalewski A, Schabitz WR, Wellmann J. 2009. The efficacy of erythropoietin and its analogues in animal stroke models: A meta-analysis. Stroke 40: 3113-3120.
48. Miskowiak K, O'sullivan U, Harmer CJ. 2007. Erythropoietin enhances hippocampal response during memory retrieval in humans. J Neurosci 27: 2788-2792.
49. Mizuno K, Giese KP. 2005. Hippocampus-dependent memory formation: Do memory type-specific mechanisms exist? J Pharmacol Sci 98: 191-197.
50. Nagata S, Fukunaga R. 1991. Granulocyte colony-stimulating factor and its receptor. Prog Growth Factor Res 3: 131-141.
51. Nagata S, Tsuchiya M, Asano S, Kaziro Y, Yamazaki T, Yamamoto O, Hirata Y, Kubota N, Oheda M, Nomura H. 1986. Molecular cloning and expression of cDNA for human granulocyte colony-stimulating factor. Nature 319: 415-418.
52. Peters M, Mizuno K, Ris L, Angelo M, Godaux E, Giese KP. 2003. Loss of Ca2+/calmodulin kinase kinase beta affects the formation of some, but not all, types of hippocampus-dependent long-term memory. J Neurosci 23: 9752-9760.
53. Pickett JL, Theberge DC, Brown WS, Schweitzer SU, Nissenson AR. 1999. Normalizing hematocrit in dialysis patients improves brain function. Am J Kidney Dis 33: 1122-1130.
54. Pitzer C, Kruger C, Plaas C, Kirsch F, Dittgen T, Muller R, Laage R, Kastner S, Suess S, Spoelgen R, Henriques A, Ehrenreich H, Schabitz WR, Bach A, Schneider A. 2008. Granulocyte-colony stimulating factor improves outcome in a mouse model of amyotrophic lateral sclerosis. Brain 131: 3335-3347.
55. Popa-Wagner A, Stocker K, Balseanu AT, Rogalewski A, Diederich K, Minnerup J, Margaritescu C, Schabitz WR. 2010. Effects of granulocyte-colony stimulating factor after stroke in aged rats. Stroke 41: 1027-1031.
56. Samoylenko A, Byts N, Rajalingam K, von Ahsen N, Rapp UR, Ehrenreich H, Siren AL. 2008. Thrombopoietin inhibits nerve growth factor-induced neuronal differentiation and ERK signalling. Cell Signal 20: 154-162.
57. Sanchez PE, Fares RP, Risso JJ, Bonnet C, Bouvard S, Le Cavorsin M, Georges B, Moulin C, Belmeguenai A, Bodennec J, Morales A, Pequignot JM, Baulieu EE, Levine RA, Bezin L. 2009. Optimal neuroprotection by erythropoietin requires elevated expression of its receptor in neurons. Proc Natl Acad Sci USA 106: 9848-9853.
58. Sanchez-Ramos J, Song S, Sava V, Catlow B, Lin X, Mori T, Cao C, Arendash GW. 2009. Granulocyte colony stimulating factor decreases brain amyloid burden and reverses cognitive impairment in Alzheimer's mice. Neuroscience 163: 55-72.
59. Saxe MD, Battaglia F, Wang JW, Malleret G, David DJ, Monckton JE, Garcia AD, Sofroniew MV, Kandel ER, Santarelli L, Hen R, Drew MR. 2006. Ablation of hippocampal neurogenesis impairs contextual fear conditioning and synaptic plasticity in the dentate gyrus. Proc Natl Acad Sci USA 103: 17501-17506.
60. Schabitz WR, Schneider A. 2007. New targets for established proteins: exploring G-CSF for the treatment of stroke. Trends Pharmacol Sci 28: 157-161.
61. Schabitz WR, Kollmar R, Schwaninger M, Juettler E, Bardutzky J, Scholzke MN, Sommer C, Schwab S. 2003. Neuroprotective effect of granulocyte colony-stimulating factor after focal cerebral ischemia. Stroke 34: 745-751.
62. Schneider A, Kruger C, Steigleder T, Weber D, Pitzer C, Laage R, Aronowski J, Maurer MH, Gassler N, Mier W, Hasselblatt M, Kollmar R, Schwab S, Sommer C, Bach A, Kuhn HG, Schabitz WR. 2005a. The hematopoietic factor G-CSF is a neuronal ligand that counteracts programmed cell death and drives neurogenesis. J Clin Invest 115: 2083-2098.
63. Schneider A, Kuhn HG, Schabitz WR. 2005b. A role for G-CSF (granulocyte-colony stimulating factor) in the central nervous system. Cell Cycle 4: 1753-1757.
64. Sheridan WP, Morstyn G, Wolf M, Dodds A, Lusk J, Maher D, Layton JE, Green MD, Souza L, Fox RM. 1989. Granulocyte colony-stimulating factor and neutrophil recovery after high-dose chemotherapy and autologous bone marrow transplantation. Lancet 2: 891-895.
65. Sheridan WP, Begley CG, Juttner CA, Szer J, To LB, Maher D, McGrath KM, Morstyn G, Fox RM. 1992. Effect of peripheral-blood progenitor cells mobilised by filgrastim (G-CSF) on platelet recovery after high-dose chemotherapy. Lancet 339: 640-644.
66. Shingo T, Sorokan ST, Shimazaki T, Weiss S. 2001. Erythropoietin regulates the in vitro and in vivo production of neuronal progenitors by mammalian forebrain neural stem cells. J Neurosci 21: 9733-9743.
67. Siren AL, Knerlich F, Poser W, Gleiter CH, Bruck W, Ehrenreich H. 2001. Erythropoietin and erythropoietin receptor in human ischemic/hypoxic brain. Acta Neuropathol 101: 271-276.
68. Siren AL, Radyushkin K, Boretius S, Kammer D, Riechers CC, Natt O, Sargin D, Watanabe T, Sperling S, Michaelis T, Price J, Meyer B, Frahm J, Ehrenreich H. 2006. Global brain atrophy after unilateral parietal lesion and its prevention by erythropoietin. Brain 129: 480-489.
69. Siren AL, Fasshauer T, Bartels C, Ehrenreich H. 2009. Therapeutic potential of erythropoietin and its structural or functional variants in the nervous system. Neurotherapeutics 6: 108-127.
70. Snyder JS, Hong NS, McDonald RJ, Wojtowicz JM. 2005. A role for adult neurogenesis in spatial long-term memory. Neuroscience 130: 843-852.
71. Solaroglu I, Cahill J, Jadhav V, Zhang JH. 2006. A novel neuroprotectant granulocyte-colony stimulating factor. Stroke 37: 1123-1128.
72. Solaroglu I, Jadhav V, Zhang JH. 2007. Neuroprotective effect of granulocyte-colony stimulating factor. Front Biosci 12: 712-724.
73. Tan CC, Eckardt KU, Firth JD, Ratcliffe PJ. 1992. Feedback modulation of renal and hepatic erythropoietin mRNA in response to graded anemia and hypoxia. Am J Physiol 263: F474-F481.
74. Tsai KJ, Tsai YC, Shen CK. 2007. G-CSF rescues the memory impairment of animal models of Alzheimer's disease. J Exp Med 204: 1273-1280.
75. Tsai PT, Ohab JJ, Kertesz N, Groszer M, Matter C, Gao J, Liu X, Wu H, Carmichael ST. 2006. A critical role of erythropoietin receptor in neurogenesis and post-stroke recovery. J Neurosci 26: 1269-1274.
76. Vellenga E, Rambaldi A, Ernst TJ, Ostapovicz D, Griffin JD. 1988. Independent regulation of M-CSF and G-CSF gene expression in human monocytes. Blood 71: 1529-1532.
77. Verdonck O, Lahrech H, Francony G, Carle O, Farion R, van de LY, Remy C, Segebarth C, Payen JF. 2007. Erythropoietin protects from post-traumatic edema in the rat brain. J Cereb Blood Flow Metab 27: 1369-1376.
78. Viviani B, Bartesaghi S, Corsini E, Villa P, Ghezzi P, Garau A, Galli CL, Marinovich M. 2005. Erythropoietin protects primary hippocampal neurons increasing the expression of brain-derived neurotrophic factor. J Neurochem 93: 412-421.
79. Wang L, Zhang Z, Wang Y, Zhang R, Chopp M. 2004. Treatment of stroke with erythropoietin enhances neurogenesis and angiogenesis and improves neurological function in rats. Stroke 35: 1732-1737.
80. Watson FL, Heerssen HM, Bhattacharyya A, Klesse L, Lin MZ, Segal RA. 2001. Neurotrophins use the Erk5 pathway to mediate a retrograde survival response. Nat Neurosci 4: 981-988.
81. Weber A, Maier RF, Hoffmann U, Grips M, Hoppenz M, Aktas AG, Heinemann U, Obladen M, Schuchmann S. 2002. Erythropoietin improves synaptic transmission during and following ischemia in rat hippocampal slice cultures. Brain Res 958: 305-311.
82. Welte K, Platzer E, Lu L, Gabrilove JL, Levi E, Mertelsmann R, Moore MA. 1985. Purification and biochemical characterization of human pluripotent hematopoietic colony-stimulating factor. Proc Natl Acad Sci USA 82: 1526-1530.
83. Winocur G, Wojtowicz JM, Sekeres M, Snyder JS, Wang S. 2006. Inhibition of neurogenesis interferes with hippocampus-dependent memory function. Hippocampus 16: 296-304.
84. Wu Y, Shang Y, Sun S, Liang H, Liu R. 2007. Erythropoietin prevents PC12 cells from 1-methyl-4-phenylpyridinium ion-induced apoptosis via the Akt/GSK-3beta/caspase-3 mediated signaling pathway. Apoptosis 12: 1365-1375.
85. Youssoufian H, Longmore G, Neumann D, Yoshimura A, Lodish HF. 1993. Structure, function, and activation of the erythropoietin receptor. Blood 81: 2223-2236.
86. Zhang L, Chopp M, Zhang RL, Wang L, Zhang J, Wang Y, Toh Y, Santra M, Lu M, Zhang ZG. 2010. Erythropoietin amplifies stroke-induced oligodendrogenesis in the rat. PLoS ONE 5: e11016
87. Zsebo KM, Yuschenkoff VN, Schiffer S, Chang D, McCall E, Dinarello CA, Brown MA, Altrock B, Bagby GCJr. 1988. Vascular endothelial cells and granulopoiesis: interleukin-1 stimulates release of G-CSF and GM-CSF. Blood 71: 99-103.
88. Zhu DY, Lau L, Liu SH, Wei JS, Lu YM. 2004. Activation of cAMP-response-element-binding protein (CREB) after focal cerebral ischemia stimulates neurogenesis in the adult dentate gyrus. Proc Natl Acad Sci USA 101: 9453-9457.