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The mood-improving actions of antidepressants do not depend on neurogenesis but are associated with neuronal remodeling

Molecular Psychiatry volume 14, pages 764–773 (2009)Cite this article

Abstract

The mechanisms underlying the initiation/onset of, and the recovery from, depression are still largely unknown; views that neurogenesis in the hippocampus may be important for the pathogenesis and amelioration of depressive symptoms have gained currency over the years although the original evidence has been challenged. In this study, an unpredictable chronic mild stress protocol was used to induce a depressive-like phenotype in rats. In the last 2 weeks of stress exposure, animals were treated with the antidepressants fluoxetine, imipramine, CP 156,526 or SSR 1494515, alone or combined with methylazoxymethanol, a cytostatic agent used to arrest neurogenesis. We found that antidepressants retain their therapeutic efficacy in reducing both measured indices of depression-like behavior (learned helplessness and anhedonia), even when neurogenesis is blocked. Instead, our experiments suggest re-establishment of neuronal plasticity (dendritic remodeling and synaptic contacts) in the hippocampus and prefrontal cortex, rather than neurogenesis, as the basis for the restoration of behavioral homeostasis by antidepressants.

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References

  1. Castrén E . Is mood chemistry? Nat Rev Neurosci 2005; 6: 241–246.

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  3. Berton O, Nestler EJ . New approaches to antidepressant drug discovery: beyond monoamines. Nat Rev Neurosci 2006; 7: 137–151.

    Article  CAS  Google Scholar 

  4. Gould E . How widespread is adult neurogenesis in mammals? Nat Rev Neurosci 2007; 8: 481–488.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  6. Manganas LN, Zhang X, Li Y, Hazel RD, Smith SD, Wagshul ME et al. Magnetic resonance spectroscopy identifies neural progenitor cells in the live human brain. Science 2007; 318: 980–985.

    Article  CAS  Google Scholar 

  7. Shors TJ, Townsend DA, Zhao M, Kozorovitskiy Y, Gould E . Neurogenesis may relate to some but not all types of hippocampal-dependent learning. Hippocampus 2002; 12: 578–584.

    Article  Google Scholar 

  8. Malberg JE, Eisch AJ, Nestler EJ, Duman RS . Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J Neurosci 2000; 20: 9104–9110.

    Article  CAS  Google Scholar 

  9. Czéh B, Michaelis T, Watanabe T, Frahm J, de Biurrun G, van Kampen M et al. Stress-induced changes in cerebral metabolites, hippocampal volume, and cell proliferation are prevented by antidepressant treatment with tianeptine. Proc Natl Acad Sci USA 2001; 98: 12796–12801.

    Article  Google Scholar 

  10. Sairanen M, Lucas G, Ernfors P, Castrén M, Castrén E . Brain-derived neurotrophic factor and antidepressant drugs have different but coordinated effects on neuronal turnover, proliferation, and survival in the adult dentate gyrus. J Neurosci 2005; 25: 1089–1094.

    Article  CAS  Google Scholar 

  11. Airan RD, Meltzer LA, Roy M, Gong Y, Chen H, Deisseroth K . High-speed imaging reveals neurophysiological links to behavior in an animal model of depression. Science 2007; 317: 819–823.

    Article  CAS  Google Scholar 

  12. Vollmayr B, Simonis C, Weber S, Gass P, Henn F . Reduced cell proliferation in the dentate gyrus is not correlated with the development of learned helplessness. Biol Psychiatry 2003; 54: 1035–1040.

    Article  Google Scholar 

  13. Reif A, Fritzen S, Finger M, Strobel A, Lauer M, Schmitt A et al. Neural stem cell proliferation is decreased in schizophrenia, but not in depression. Mol Psychiatry 2006; 11: 514–522.

    Article  CAS  Google Scholar 

  14. Sapolsky RM . Is impaired neurogenesis relevant to the affective symptoms of depression? Biol Psychiatry 2004; 56: 137–139.

    Article  Google Scholar 

  15. David DJ, Klemenhagen KC, Holick KA, Saxe MD, Mendez I, Santarelli L et al. Efficacy of the MCHR1 antagonist N-[3-(1-{[4-(3,4-difluorophenoxy)phenyl]methyl}(4-piperidyl))-4-methylphenyl]-2-methylpropanamide (SNAP 94847) in mouse models of anxiety and depression following acute and chronic administration is independent of hippocampal neurogenesis. J Pharmacol Exp Ther 2007; 321: 237–248.

    Article  CAS  Google Scholar 

  16. Holick KA, Lee DC, Hen R, Dulawa SC . Behavioral effects of chronic fluoxetine in BALB/cJ mice do not require adult hippocampal neurogenesis or the serotonin 1A receptor. Neuropsychopharmacology 2008; 33: 406–417.

    Article  CAS  Google Scholar 

  17. Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S et al. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 2003; 301: 805–809.

    Article  CAS  Google Scholar 

  18. Gould E, McEwen BS, Tanapat P, Galea LA, Fuchs E . 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.

    Article  CAS  Google Scholar 

  19. Sousa N, Lukoyanov NV, Madeira MD, Almeida OF, Paula-Barbosa MM . Reorganization of the morphology of hippocampal neurites and synapses after stress-induced damage correlates with behavioral improvement. Neuroscience 2000; 97: 253–266.

    Article  CAS  Google Scholar 

  20. Radley JJ, Sisti HM, Hao J, Rocher AB, McCall T, Hof PR et al. Chronic behavioral stress induces apical dendritic reorganization in pyramidal neurons of the medial prefrontal cortex. Neuroscience 2004; 125: 1–6.

    Article  CAS  Google Scholar 

  21. Cook SC, Wellman CL . Chronic stress alters dendritic morphology in rat medial prefrontal cortex. J Neurobiol 2004; 60: 236–248.

    Article  Google Scholar 

  22. Cerqueira JJ, Mailliet F, Almeida OF, Jay TM, Sousa N . The prefrontal cortex as a key target of the maladaptive response to stress. J Neurosci 2007; 27: 2781–2787.

    Article  CAS  Google Scholar 

  23. Colla M, Kronenberg G, Deuschle M, Meichel K, Hagen T, Bohrer M et al. Hippocampal volume reduction and HPA-system activity in major depression. J Psychiatr Res 2007; 41: 553–560.

    Article  Google Scholar 

  24. Sairanen M, O'Leary OF, Knuuttila JE, Castrén E . Chronic antidepressant treatment selectively increases expression of plasticity-related proteins in the hippocampus and medial prefrontal cortex of the rat. Neuroscience 2007; 144: 368–374.

    Article  CAS  Google Scholar 

  25. Willner P . Chronic mild stress (CMS) revisited: consistency and behavioural-neurobiological concordance in the effects of CMS. Neuropsychobiology 2005; 52: 90–110.

    Article  CAS  Google Scholar 

  26. Dupret D, Montaron MF, Drapeau E, Aurousseau C, Le Moal M, Piazza PV et al. Methylazoxymethanol acetate does not fully block cell genesis in the young and aged dentate gyrus. Eur J Neurosci 2005; 22: 778–783.

    Article  Google Scholar 

  27. Shors TJ, Miesegaes G, Beylin A, Zhao M, Rydel T, Gould E . Neurogenesis in the adult is involved in the formation of trace memories. Nature 2001; 410: 372–376.

    Article  CAS  Google Scholar 

  28. Bruel-Jungerman E, Laroche S, Rampon C . New neurons in the dentate gyrus are involved in the expression of enhanced long-term memory following environmental enrichment. Eur J Neurosci 2005; 21: 513–521.

    Article  Google Scholar 

  29. Bekris S, Antoniou K, Daskas S, Papadopoulou-Daifoti Z . Behavioural and neurochemical effects induced by chronic mild stress applied to two different rat strains. Behav Brain Res 2005; 161: 45–59.

    Article  CAS  Google Scholar 

  30. Bodnoff SR, Suranyi-Cadotte B, Aitken DH, Quirion R, Meaney MJ . The effects of chronic antidepressant treatment in an animal model of anxiety. Psychopharmacology (Berl) 1998; 95: 298–302.

    Google Scholar 

  31. Kee N, Sivalingam S, Boonstra R, Wojtowicz JM . The utility of Ki-67 and BrdU as proliferative markers of adult neurogenesis. J Neurosci Methods 2002; 115: 97–105.

    Article  CAS  Google Scholar 

  32. Gibb R, Kolb B . A method for vibratome sectioning of Golgi-Cox stained whole rat brain. J Neurosci Methods 1998; 79: 1–4.

    Article  CAS  Google Scholar 

  33. Glaser EM, Van der Loos H . Analysis of thick brain sections by obverse-reverse computer microscopy: application of a new, high clarity Golgi-Nissl stain. J Neurosci Methods 1981; 4: 117–125.

    Article  CAS  Google Scholar 

  34. Harris KM, Jensen FE, Tsao B . Three-dimensional structure of dendritic spines and synapses in rat hippocampus (CA1) at postnatal day 15 and adult ages: implications for the maturation of synaptic physiology and long-term potentiation. J Neurosci 1992; 12: 2685–26705.

    Article  CAS  Google Scholar 

  35. Li Y, Luikart BW, Birnbaum S, Chen J, Kwon CH, Kernie SG et al. TrkB regulates hippocampal neurogenesis and governs sensitivity to antidepressive treatment. Neuron 2008; 59: 399–412.

    Article  CAS  Google Scholar 

  36. Nutt DJ . Overview of diagnosis and drug treatments of anxiety disorders. CNS Spectr 2005; 10: 49–56.

    Article  Google Scholar 

  37. Zhang CL, Zou Y, He W, Gage FH, Evans RM . A role for adult TLX-positive neural stem cells in learning and behaviour. Nature 2008; 451: 1004–1007.

    Article  CAS  Google Scholar 

  38. Rocher C, Spedding M, Munoz C, Jay TM . Acute stress-induced changes in hippocampal/prefrontal circuits in rats: effects of antidepressants. Cereb Cortex 2004; 14: 224–229.

    Article  Google Scholar 

  39. Lavretsky H, Roybal DJ, Ballmaier M, Toga AW, Kumar A . Antidepressant exposure may protect against decrement in frontal gray matter volumes in geriatric depression. J Clin Psychiatry 2005; 66: 964–967.

    Article  Google Scholar 

  40. Sheline YI, Gado MH, Kraemer HC . Untreated depression and hippocampal volume loss. Am J Psychiatry 2003; 160: 1516–1518.

    Article  Google Scholar 

  41. Maya Vetencourt JF, Sale A, Viegi A, Baroncelli L, De Pasquale R, O′Leary OF et al. The antidepressant fluoxetine restores plasticity in the adult visual cortex. Science 2008; 320: 385–388.

    Article  CAS  Google Scholar 

  42. Bonfati L . PSA-NCAM in mammalian structural plasticity and neurogenesis. Prog Neurobiol 2006; 80: 129–164.

    Article  Google Scholar 

  43. Dalva MB, McClelland AC, Kayser MS . Cell adhesion molecules: signalling functions at the synapse. Nat Rev Neurosci 2007; 8: 206–220.

    Article  CAS  Google Scholar 

  44. Doetsch F, García-Verdugo JM, Alvarez-Buylla A . Cellular composition and three-dimensional organization of the subventricular germinal zone in the adult mammalian brain. J Neurosci 1997; 17: 5046–5061.

    Article  CAS  Google Scholar 

  45. Varea E, Blasco-Ibáñez JM, Gómez-Climent MA, Castillo-Gómez E, Crespo C, Martínez-Guijarro FJ et al. Chronic fluoxetine treatment increases the expression of PSA-NCAM in the medial prefrontal cortex. Neuropsychopharmacology 2007; 32: 803–812.

    Article  CAS  Google Scholar 

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Acknowledgements

This project used compound(s) provided by the National Cancer Institute's Chemical Carcinogen Reference Standards Repository (operated under contract N02-CB-07008 by Midwest Research Institute; MAM), Sanofi-Synthelabo (SSR 149415) and Pfizer (CP 156,526). The authors' work was supported by the Portuguese Foundation for Science and Technology (FCT) (PTDC/SAU-NEU/72699/2006). The authors declare that they have no conflicts of interest.

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Authors and Affiliations

  1. Life and Health Science Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal

    J M Bessa, D Ferreira, I Melo, F Marques, J J Cerqueira, J A Palha & N Sousa

  2. Neuroadaptations Group, Max-Planck Institute for Psychiatry, Munich, Germany

    O F X Almeida

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  1. J M Bessa
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  2. D Ferreira
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Correspondence to N Sousa.

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Bessa, J., 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 14, 764–773 (2009). https://doi.org/10.1038/mp.2008.119

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