Ramírez-Rodríguez G, Laguna-Chimal J, Vega-Rivera NM, Ortiz-López L, Méndez-Cuesta L, Estrada-Camarena EM, Babu H

Language: Spanish
References: 110
Page: 497-506
PDF size: 706.34 Kb.

ABSTRACT

New neuron formation in the adult brain extends our knowledge and incorporates a novel dimension about brain plasticity. Adult neurogenesis is a complex process regulated by different factors within the niche, where adult neural stem cells reside, proliferate and differentiate. Neural stem cell together with astrocytes and endothelial cells form the principle components of this complex niche. Other molecular factors that regulate adult neurogenesis are the neurotransmitters (GABA, glutamate, serotonin, dopamine); hormones (prolactin, growth hormone, estrogens and melatonin); growth factors (FGF, EGF, VEGF) and neurotrophins (BDNF, NT3). All of them regulate different aspects of the neurogenic process.
Behavioral regulators that influence new neuron formation in the adult brain include physical activity, complex stimulatory environment best known as enrichment environment, and social interaction. Voluntary physical activity with free access to the running wheel increases the number of proliferating cells, while the complex stimulatory environment provided by enriched environment preferentially influences survival of newborn cells. In addition, social interaction has a positive influence on the new neuron formation in the dentate gyrus (DG).
Although adult hippocampal neurogenesis is positively regulated by the aforementioned factors, there are different conditions with negative influence on this process. Some of these conditions are stress exposure and sleep deprivation. Both conditions are present in neuropsychiatric diseases such as depression, anxiety and schizophrenia. Thus, stress and sleep deprivation impair adult hippocampal neurogenesis.
Alteration of the neurogenic process following stress occurs due to the high levels of glucocorticoid receptors within the hippocampus and because exposure to stress causes the increase in glucocorticoid levels.
Preclinical studies have shown that exposure to different classes of stressors affect hippocampal neurogenesis. Prolonged exposure to stressors (chronic mild stress), predatory odor, foot shock, acute force swimming and psychosocial stress not only affect mature neuronal plasticity but also hippocampal neurogenesis.
Although there is information about the effects of stress on adult neurogenesis, the mechanism by which stress causes inhibition of hippocampal neurogenesis remains unclear. Recent work showed that exposure to stress increases the pro-inflammatory cytokine interleukin-1β (IL-1β) in several brain areas. Also, administration of IL-1β exerts stress-like effects including down-regulation of hippocampal brain derived neurotrophic factor (BDNF). Additionally, inhibition of the receptor for IL-1β prevents stress-like effects. Moreover, the suppression of cell proliferation is mediated by direct actions of IL-1β on IL-1RI receptors localized on precursor cells. These findings support that IL-1β is a critical mediator of the antineurogenic effect caused by acute and chronic stress. However, IL-1β is not the unique mediator of stress that could be involved in the alteration of adult hippocampal neurogenesis. Recently it was reported that the decrease in cell proliferation concomitantly occurs with an increase of IL6 and TNFα levels.
Preclinical studies have suggested that adult hippocampal neurogenesis is not a sole cause of depression or the sole mechanism of treatment efficacy, but it is likely an important contributor to this complex disorder. In order to revert the effects of stress on adult hippocampal neurogenesis, different therapies have been used, for example: electroconvulsive therapy (ECT), exercise, complex stimulatory environment and antidepressant drugs. Although the most rapid induction of neurogenesis is seen with ECT application, most studies have been done with antidepressant drugs. The effects of antidepressants are time-dependent as highest therapeutic effects are observed within the time course of weeks.
Different types of antidepressants (serotonin and norepinephrine reuptake inhibitors, monoamine oxidase inhibitors and atypical antidepressants) have been used to study their influence on the neurogenic process. Despite that serotonin reuptake inhibitors are the most prescribed treatments for major depression and that the therapeutic effects of antidepressants require chronic treatment, the mechanisms by which these drugs exert their effects on hippocampal neurogenesis are still unknown. Although serotonin reuptake inhibitors are very fast in increasing serotonin levels, the antidepressant action is delayed possibly because of the induction of structural or functional changes that possibly need longer time (2-4 weeks).
In this regard, one of the actions of antidepressants is the regulation of adult hippocampal neurogenesis, a process that is consistent with the delayed onset of therapeutic effects of antidepressants. Fluoxetine is one of the antidepressants more used to study its influence on adult neurogenesis. Fluoxetine targets amplifying neural progenitors by increasing the rate of symmetric divisions without altering the division of stem-like cells in the DG. Considering previous classification based on the temporal protein markers expression, the neural progenitors targeted by fluoxetine correspond to type 2a, 2b and type 3. In addition, the increase in new neurons caused by fluoxetine is due to the expansion of neural progenitors.
In addition to cell proliferation, the neurogenic process also involves a maturation step, which is associated with the expression of doublecortin, a protein that binds to microtubules and that is expressed along the cytoplasm of the cell. Further maturation of immature neurons such as dendrite maturation, is controlled independently of the regulation of precursor cell proliferation. Thus, micro-regulatory events influence the course of adult hippocampal neurogenesis. Here, fluoxetine also affects dendrite maturation and functional integration of new neurons. Chronic fluoxetine treatment modifies dendrite morphology increasing dendrite arborisation and favors synaptic plasticity of newborn granule cells. Also, chronic administration of fluoxetine causes behavioral improvement, an effect that was blocked when neurogenesis was ablated by X-ray irradiation.
Other important factor that influences the effect of antidepressants on adult neurogenesis is the genetic background. Then antidepressants induced behavioral improvement depending on the genetic background of the mouse strain used.
Preclinical studies in mice have revealed different actions of antidepressants on adult hippocampal neurogenesis. However, studies in humans are scarce and deserve greater attention to discover the correlation between preclinical and clinical studies. Recent work in human brains shows contradictory evidences about the regulation of neuronal development by antidepressants. These evidences are in the same line as recent published work in which it was demonstrated that the effects of ADs are age-dependent.
Altogether, multiple evidences indicate that antidepressants affect several aspects of the neurogenic process. Therefore, chronic treatment is necessary for the antidepressant-dependent regulation of adult hippocampal neurogenesis. In addition, it has been shown that antidepressants act through different pathways involving both neurogenesis-dependent and neurogenesis-independent actions.
Although there is an important increase in the adult hippocampal neurogenesis field, it is necessary to increase the number of studies performed in human beings to correlate the preclinical findings with clinical studies to address the role of adult neurogenesis in neuropsychiatric disorders.

REFERENCES

1. Altman J, Das GD. Autoradiographic and histological studies of postnatal neurogenesis. I. A longitudinal investigation of the kinetics, migration and transformation of cells incorporating tritiated thymidine in neonate rats, with special reference to postnatal neurogenesis in some brain regions. J Comp Neurol 1966;126:337-389.

2. Kempermann G, Jessberger S, Steiner B et al. Milestones of neuronal development in the adult hippocampus. Trends Neurosci 2004;27:447-452.

3. Lledo PM, Alonso M, Grubb MS. Adult neurogenesis and functional plasticity in neuronal circuits. Nat Rev Neurosci 2006;7:179-193.

4. Alvarez-Buylla A, Lim DA. For the long run: maintaining germinal niches in the adult brain. Neuron 2004;41:683-686.

5. Lim DA, Tramontin AD, Trevejo JM et al. Noggin antagonizes BMP signaling to create a niche for adult neurogenesis. Neuron 2000;28:713-726.

6. Palmer TD, Willhoite AR, Gage FH. Vascular niche for adult hippocampal neurogenesis. J Comp Neurol 2000;425:479-494.

7. Bolteus AJ, Bordey A. GABA release and uptake regulate neuronal precursor migration in the postnatal subventricular zone. J Neurosci 2004;24:7623-7631.

8. Bordey A. Adult neurogenesis: basic concepts of signaling. Cell Cycle 2006;5:722-728.

9. Borta A, Hoglinger GU. Dopamine and adult neurogenesis. J Neurochem 2007;100:587-595.

10. Lichtenwalner RJ, Forbes ME, Sonntag WE et al. Adult-onset deficiency in growth hormone and insulin-like growth factor-I decreases survival of dentate granule neurons: insights into the regulation of adult hippocampal neurogenesis. J Neurosci Res 2006;83:199-210.

11. Shingo T, Gregg C, Enwere E et al. Pregnancy-stimulated neurogenesis in the adult female forebrain mediated by prolactin. Science 2003; 299:117-120.

12. Ramirez-Rodriguez G, Klempin F, Babu H et al. Melatonin Modulates Cell Survival of New Neurons in the Hippocampus of Adult Mice. Neuropsychopharmacology 2009;34:2180-2190.

13. Abrous DN, Koehl M, Le Moal M. Adult neurogenesis: from precursors to network and physiology. Physiol Rev 2005;85:523-569.

14. van Praag H, Christie BR, Sejnowski TJ, Gage FH. Running enhances neurogenesis, learning, and long-term potentiation in mice. Proc Natl Acad Sci USA 1999;96:13427-13431.

15. 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.

16. Duman RS. Depression: a case of neuronal life and death? Biol Psychiatry 2004;56:140-145.

17. Eisch AJ. Adult neurogenesis: implications for psychiatry. Prog Brain Res 2002;138:315-342.

18. Revest JM, Dupret D, Koehl M et al. Adult hippocampal neurogenesis is involved in anxiety-related behaviors. Mol Psychiatry 2009;14:959-967.

19. Toro CT, Deakin JF. Adult neurogenesis and schizophrenia: a window on abnormal early brain development? Schizophr Res 2007;90:1-14.

20. Eriksson PS, Perfilieva E, Bjork-Eriksson T, et al. Neurogenesis in the adult human hippocampus. Nat Med 1998;4:1313-1317.

21. Garcia-Verdugo JM, Doetsch F, Wichterle H et al. Architecture and cell types of the adult subventricular zone: in search of the stem cells. J Neurobiol 1998;36:234-248.

22. Sanai N, Tramontin AD, 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.

23. Palmer TD, Takahashi J, Gage FH. The adult rat hippocampus contains primordial neural stem cells. Mol Cell Neurosci 1997;8:389-404.

24. Landgren H, Curtis MA. Locating and labeling neuronal stem cells in the brain. J Cell Physiol 2011;226:1-7.

25. Taupin P. BrdU immunohistochemistry for studying adult neurogenesis: Paradigms, pitfalls, limitations, and validation. Brain Res Rev 2007; 53:198-214.

26. Schmidt-Hieber C, Jonas P, Bischofberger J. Enhanced synaptic plasticity in newly generated granule cells of the adult hippocampus. Nature 2004;429:184-187.

27. van Praag H, Schinder AF, Christie BR et al. Functional neurogenesis in the adult hippocampus. Nature 2002;415:1030-1034.

28. Wang S, Scott BW, Wojtowicz JM. Heterogenous properties of dentate granule neurons in the adult rat. J Neurobiol 2000;42:248-257.

29. Geuze E, Vermetten E, Bremner JD. MR-based in vivo hippocampal volumetrics: 2. Findings in neuropsychiatric disorders. Mol Psychiatry 2005;10:160-184.

30. Lucassen PJ, Heine VM, Muller MB et al. Stress, depression and hippocampal apoptosis. CNS Neurol Disord Drug Targets 2006;5:531-546.

31. Pittenger C, Duman RS. Stress, depression, and neuroplasticity: a convergence of mechanisms. Neuropsychopharmacology 2008;33:88-109.

32. Malberg JE, Eisch AJ, Nestler EJ et al. Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J Neurosci 2000; 20:9104-9110.

33. Caspi A, Sugden K, Moffitt TE, Taylor A et al. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 2003;301:386-389.

34. Schoenfeld TJ, Gould E. Stress, hormones stress and adult neurogenesis. Exp Neurol 2011.doi:10.1016/jexpneurol.2011. 01.008.

35. Hill MN, Kambo JS, Sun JC et al. Endocannabinoids modulated stressinduced suppression of hippocampal cells proliferation and activation of defensive behaviours. Eur J Neurosci 2006;24:1845-1849.

36. Bain MJ, Dwyer SM, Rusak B. Restrain effect hippocampal cells proliferation differently in rats and mice. Neurosci Lett 2004;368:7-10.

37. Kambo JS, Galea LA. Activation levels of androgens influence risk assessment behavour but do not influence stress-induced suppression in hipocampal cell proliferation in adult male rats. Behav Brain Res 2006; 175:263-270.

38. Mirescu C, Peters JD, Gould E. Early life experience alters response of adult neurogenesis to stress. Nat Neurosci 2004;7:841-846.

39. Malberg JE, Duman RS. Cell proliferatioin in adult hippocampus is decreased by inescapable stress: reversal by fluoxetine treatment. Neuropsychopharmacology 2003;28:1562-1571.

40. Dagyté G, Crescente I, Postema F et al. Agomelatine reverses the decrease in hippocampal cell survival induced by chronic mild stress. Behav Brain Res 2011;218:121-128.

41. Snyder JS, Glover LR, Sanzone KM, et al. The effects of exercise and stress on the survival and maturation of adult-generated granule cells. Hippocampus 2009;19:898-906.

42. Lagace DC, Donovan MH, DeCarolis NA et al. Adult hippocamapal neurogénesis is functional important for stress-induced social avoidance. Proc Natl Acad Sci USA 2010;107: 4436-4441.

43. Toth E, Gersner R, Wilf-Yarkoni A et al. Age-dependent effect of chronic stress on brain plasticity and depressive behavior. J Neurochem 2008;107:522-532.

44. Czéh B, Müller-Keuker JI, Rygula R et al. Chronic social stress inhibits cell proliferation in the adult medial prefrontal cortex: hemispheric asymmetry and reversal by fluoxetine treatment. Neuropsychopharmacology 2007;32:1490-1503.

45. Jayatissa MN, Bisgaard C, Tingström A et al. Hippocampal cytogenesis correlates to escitalopram-mediated recovery in a chronic mild stress rat model of depression. Neuropsychopharmacology 2006;31:2395-2404.

46. Li S, Wang C, Wang W, et al. Chronic mild stress impairs cognition in mice: From brain homeostasis to behavior. Life Sci 2008;82:934-942.

47. Brummelte S, Galea LA. Chronic high corticosterone reduces neurogénesis in the dentate gyrus of adult male and female rats. Neuroscience 2010;168:680-690.

48. Schloesser RJ, Manji HK, Martinowich K. Supression of adult neurogénesis leads to an increased hypothalamo-pituitary-adrenal axis response. Neuroreport 2009;20:553-557.

49. Alonso R, Griebel G, Pavone G et al. Blockade of CRF(1) or V(1b) receptors reverses stress-induced suppression of neurogenesis in a mouse model of depression. Mol Psychiatry 2004;9:278-286.

50. Banasr M, Duman RS. Regulation of neurogenesis and gliogenesis by stress and antidepressant treatment. CNS Neurol Disord Drug Targets 2007;6:311-320.

51. Vollmayr B, Simonis C, Weber S et al. Reduced cell proliferation in the dentate gyrus is not correlated with the development of learned helplessness. Biol Psychiatry 2003;54:1035-1040.

52. Surget A, Saxe M, Leman S et al. Drug-dependent requirement of hippocampal neurogenesis in a model of depression and of antidepressant reversal. Biol Psychiatry 2008;64:293-301.

53. Gross M, Nakamura L, Pascual-Leone A et al. Has repetitive transcranial magnetic stimulation (rTMS) treatment for depression improved? A systematic review and meta-analysis comparing the recent vs. the earlier rTMS studies. Acta Psychiatr Scand 2007;116:165-173.

54. Czéh B, Welt T, Fischer AK et al. Chronic psychosocial stress and concomitant repetitive transcranial magnetic stimulation: effects on stress hormone levels and adult hippocampal neurogénesis. Biol Psychiatry 2002;52:1057-1065.

55. Ueyama E, Ukai S, Ogawa A et al. Chronic repetitive transcranial magnetic stimulation increases hippocampal neurogénesis in rats. Psychiatry Clin Neurosci 2011;65:77-81.

56. Duman RS, Malberg J, Nakagawa S. Regulation of adult neurogenesis by psychotropic drugs and stress. J Pharmacol Exp Ther 2001;299:401-407.

57. Barrientos RM, Sprunger DB, Campeau S et al. Brain-derived neurotrophic factor mRNA downregulation produced by social isolation is blocked by intrahippocampal interleukin-1 receptor antagonist. Neuroscience 2003;121:847-853.

58. Deak T, Bordner KA, McElderry NK et al. Stress-induced increases in hypothalamic IL-1: a systematic analysis of multiple stressor paradigms. Brain Res Bull 2005;64:541-556.

59. Nguyen KT, Deak T, Owens SM et al. Exposure to acute stress induces brain interleukin-1beta protein in the rat. J Neurosci 1998;18:2239-2246.

60. Koo JW, Duman RS. IL-1beta is an essential mediator of the antineurogenic and anhedonic effects of stress. Proc Natl Acad Sci USA 2008;105:751-756.

61. Duman RS, Monteggia LM. A neurotrophic for stress-related mood disorders. Biol Psychiatry 2006;59:1116-1127.

62. Murakami S, Imbe H, Morikawa Y, et al. Chronic stress, as well as acute stress, reduced BDNF mRNA expression in the rat hippocampus but less robustly. Neurosci Res 2005;53:129-139.

63. Rasmusson AM, Shi L, Duman R. Downregulation of BDNF mRNA in the hippocampus dentate gyrus after re-exposure to cues previously associated with footshock. Neuropsychopharmacology 2002;27:133-142.

64. Roceri M, Hendriks W, Racagni G et al. Early maternal deprivation reduces the expression of BDNF and NMDA receptor subunits in rat hippocampus. Mol Psychiatry 2002;7:609-616.

65. Tsankova NM, Berton O, Renthal W et al. Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action. Nat Neurosci 2006;9:519-525.

66. Dwivedi Y, Rizavi HS, Pandey GN. Antidepressants reverse corticosterone-mediated decrease in brain-derived neurptrophic factor expression: differential regulation of specific exons by antideprresants and cortiocsterone. Neuroscience 2006;139: 1017-1029.

67. Laifenfeld D, Karry R, Grauer E et al. Antidepressants and prolonged stress in rats modúlate CAM-L1, laminin, and pCREB, implicated in neuronal plasticity. Neurobiol Dis 2005; 2:432-441.

68. Smith MA, Makino S, Kvetnansky R et al. Stress and glucocorticoid affect the expression of brain derived neurotrophic factor and neurotrophin-3 mRNAs in the hippocampus. J Neurosci 1995;3:1768-1777.

69. Smith MA, Makino S, Altemus M et al. Stress and antidepressants differentially regulated neurotrophin 3 mRNA expression in the locus coeruleus. Proc Natl Acad Sci USA 1995; 19:8788-8792.

70. Bland ST, Tamlyn JP, Barrientos RM et al. Expression of fibroblast growth factor-2 and brain derived neurotrophic factor mRNA in the medial prefrontal cortex and hippocampus after uncontrollable or controllable stress. Neuroscience 2007; 144:1219-1228.

71. Molteni R, Fumagalli F, Magnaghi V et al. Modulation of fibroblast growth factor-2 by stress and corticosteroids: from developmental events to adult brain plasticity. Brain Res Rev 2001;37:249-258.

72. Datson NA, Morsink MC, Meijer OC et al. Central corticosteroids action: Search for gene targets. Eur J Pharmacol 2008;583:272-289.

73. Cameron HA, Tanapat P, Gould E. Adrenal steroids and N-methyl-Daspartate receptor activation regulate neurogénesis in the dentate gyrus of adult rats through a common pathway. Neuroscience 1998;82:349-354.

74. Gould E, McEwen BS, 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.

75. Cameron HA, McEwen BS, Gould E. Regulation of adult neurogenesis y excitatory imput and NMDA receptor activation in the dentate gyrus. J Neurosci 1995;15:4687-4692.

76. Eisch AJ, Cameron HA, Encinas JM et al. Adult neurogenesis, mental health, and mental illness: hope or hype? J Neurosci 2008;28:11785-11791.

77. Nakagawa S, Kim JE, Lee R et al. Localization of phosphorylated cAMP response element-binding protein in immature neurons of adult hippocampus. J Neurosci 2002;22:9868-9876.

78. Nakagawa S, Kim JE, 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.

79. Santarelli L, Saxe M, Gross C et al. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 2003;301: 805-809.

80. Li YF, Huang Y, Amsdell SL et al. Antidepressant-and anxiolytic-like effects of the phosphodiesterase-4 inhibitor rolipram on behavior depend on cyclic AMP response element binding protein-mediated neurogénesis in the hippocampus. Neuropsychopharmacology 2009;34:2404-2419.

81. Sasaki T, Kitagawa K, Omura-Matsuoka E et al. Survival of newborn hippocamapl neurons after ischemia. Stroke 2007;38: 1597-1605.

82. Sarainen M, Lucas G, Ernfors P et al. Brain derived neurotrophic factor and antidepressant drugs have different but coordinate effects on neuronal turnover, proliferation, and survival in the adult dentate gyrus. J Neurosci 2002;25:1089-1094.

83. Schiavon AP, Milani H, Romanini C et al. Imipramine enhances cell proliferation and decreases neurodegeneration in the hippocampus after transient global cerebral ischemia in rats. Neurosci Lett 2010;470:43-48.

84. Soumier A, Banasr M, Lortet S et al. Mechanisms contributing to the phase-dependent regulation of neurogénesis by the novel antidepressant, agomelatine, in the adult rat hippocampus. Neuropsychopharmacology 2009;34:2390-2403.

85. Banasr M, Soumier A, Hery M et al. Agomelatine, a new antidepressant, induces regional changes in hippocampal neurogenesis. Biol Psychiatry 2006;59:1087-1096.

86. Encinas JM, Vaahtokari A, Enikolopov G. Fluoxetine targets early progenitor cells in the adult brain. Proc Natl Acad Sci USA 2006;103:8233-8238.

87. Wang JW, David DJ, Monckton JE et al. Chronic fluoxetine stimulates maturation and synaptic plasticity of adult-born hippocampal granule cells. J Neurosci 2008;28:1374-1384.

88. 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.

89. Bessa JM, Ferreira D, Melo I et al. The mood-improving actions of antidepressants do not depend on neurogenesis but are associated with neuronal remodeling. Mol Psychiatry 2009;14:764-773, 39.

90. Kempermann G, Chesler EJ, Lu L et al. Natural variation and genetic covariance in adult hippocampal neurogenesis. Proc Natl Acad Sci USA 2006;103:780-785.

91. Meshi D, Drew MR, Saxe M et al. Hippocampal neurogenesis is not required for behavioral effects of environmental enrichment. Nat Neurosci 2006;9:729-731.

92. Warner-Schmidt JL, Duman RS. Hippocampal neurogenesis: opposing effects of stress and antidepressant treatment. Hippocampus 2006;16: 239-249.

93. Nibuya M, Morinobu S, Duman RS. Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments. J Neurosci 1995;15:7539-7547.

94. Russo-Neustadt AA, Beard RC, Huang YM, Cotman CW. Physical activity and antidepressant treatment potentiate the expression of specific brain-derived neurotrophic factor transcripts in the rat hippocampus. Neuroscience 2000;101:305-312.

95. Chen B, Dowlatshahi D, MacQueen GM et al. Increased hippocampal BDNF immunoreactivity in subjects treated with antidepressant medication. Biol Psychiatry 2001;50:260-265.

96. Saarelainen T, Hendolin P, Lucas G et al. Activation of the TrkB neurotrophin receptor is induced by antidepressant drugs and is required for antidepressant-induced behavioral effects. J Neurosci 2003;23:349-357.

97. Shirayama Y, Chen AC, Nakagawa S et al. Brain-derived neurotrophic factor produces antidepressant effects in behavioral models of depression. J Neurosci 2002;22:3251-3261.

98. Siuciak JA, Lewis DR, Wiegand SJ et al. Antidepressant-like effect of brain-derived neurotrophic factor (BDNF). Pharmacol Biochem Behav 1997;56:131-137.

99. Warner-Schmidt JL, Duman RS. VEGF as a potential target for therapeutic intervention in depression. Curr Opin Pharmacol 2008;8:14-819.

100. Warner-Schmidt JL, Duman RS. VEGF is an essential mediator of the neurogenic and behavioral actions of antidepressants. Proc Natl Acad Sci USA 2007;104:4647-4652.

101. Boldrini M, Arango V. Antidepressants, age, and neuroprogenitors. Neuropsychopharmacology 2010;35:351-352.

102. Lucassen PJ, Stumpel MW, Wang Q, Aronica E. Decreased numbers of progenitor cells but no response to antidepressant drugs in the hippocampus of elderly depressed patients. Neuropharmacology 2010;58:940-949.

103. Boldrini M, Underwood MD, Hen R et al. Antidepressants increase neural progenitor cells in the human hippocampus. Neuropsychopharmacology 2009;34:2376-2389.

104. Couillard-Despres S, Wuertinger C, Kandasamy M et al. Ageing abolishes the effects of fluoxetine on neurogenesis. Mol Psychiatry 2009;14:856-864.

105. Knoth R, Singec I, Ditter M et al. Murine features of neurogenesis in the human hippocampus across the lifespan from 0 to 100 years. PLoS One 2010;5:e8809.

106. Manganas LN, Zhang X, Li Y et al. Magnetic resonance spectroscopy identifies neural progenitor cells in the live human brain. Science 2007;318:980-985.

107. Romer B, Sartorius A, Inta D et al. Imaging new neurons in vivo: a pioneering tool to study the cellular biology of depression? Bioessays 2008;30:806-810.

108. Kempermann G, Krebs J, Fabel K. The contribution of failing adult hippocampal neurogenesis to psychiatric disorders. Curr Opin Psychiatry 2008;21:290-295.

109. Aimone JB, Wiles J, Gage FH. Potential role for adult neurogenesis in the encoding of time in new memories. Nat Neurosci 2006;9:723-727.

110. Becker S, Wojtowicz JM. A model of hippocampal neurogenesis in memory and mood disorders. Trends Cogn Sci 2007;11:70-76.