Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Predictable chronic mild stress improves mood, hippocampal neurogenesis and memory

Molecular Psychiatry volume 16, pages 171–183 (2011)Cite this article

Subjects

Abstract

Maintenance of neurogenesis in adult hippocampus is important for functions such as mood and memory. As exposure to unpredictable chronic stress (UCS) results in decreased hippocampal neurogenesis, enhanced depressive- and anxiety-like behaviors, and memory dysfunction, it is believed that declined hippocampal neurogenesis mainly underlies the behavioral and cognitive abnormalities after UCS. However, the effects of predictable chronic mild stress (PCMS) such as the routine stress experienced in day-to-day life on functions such as mood, memory and hippocampal neurogenesis are unknown. Using FST and EPM tests on a prototype of adult rats, we demonstrate that PCMS (comprising 5 min of daily restraint stress for 28 days) decreases depressive- and anxiety-like behaviors for prolonged periods. Moreover, we illustrate that decreased depression and anxiety scores after PCMS are associated with ∼1.8-fold increase in the production and growth of new neurons in the hippocampus. Additionally, we found that PCMS leads to enhanced memory function in WMT as well as NORT. Collectively, these findings reveal that PCMS is beneficial to adult brain function, which is exemplified by increased hippocampal neurogenesis and improved mood and cognitive function.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  1. Kuhn HG, Dickinson-Anson H, Gage FH . Neurogenesis in the dentate gyrus of the adult rat: age-related decrease of neuronal progenitor proliferation. J Neurosci 1996; 16: 2027–2033.

    Article  CAS  Google Scholar 

  2. Eriksson PS, Perfilieva E, Bjork-Eriksson T, Alborn AM, Nordborg C, Peterson DA et al. Neurogenesis in the adult human hippocampus. Nat Med 1998; 4: 1313–1317.

    Article  CAS  Google Scholar 

  3. Gould E, Tanapat P, Hastings NB, Shors TJ . Neurogenesis in adulthood: a possible role in learning. Trends Cogn Sci 1999; 3: 186–192.

    Article  CAS  Google Scholar 

  4. Rao MS, Hattiangady B, Abdel-Rahman A, Stanley DP, Shetty AK . Newly born cells in the ageing dentate gyrus display normal migration, survival and neuronal fate choice but endure retarded early maturation. Eur J Neurosci 2005; 21: 464–476.

    Article  Google Scholar 

  5. Rao MS, Hattiangady B, Shetty AK . The window and mechanisms of major age-related decline in the production of new neurons within the dentate gyrus of the hippocampus. Aging Cell 2006; 5: 545–558.

    Article  CAS  Google Scholar 

  6. van Praag H, Schinder AF, Christie BR, Toni N, Palmer TD, Gage FH . Functional neurogenesis in the adult hippocampus. Nature 2002; 415: 1030–1034.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  8. Toni N, Laplagne DA, Zhao C, Lombardi G, Ribak CE, Gage FH et al. Neurons born in the adult dentate gyrus form functional synapses with target cells. Nat Neurosci 2008; 11: 901–907.

    Article  CAS  Google Scholar 

  9. Feng R, Rampon C, Tang YP, Shrom D, Jin J, Kyin M et al. Deficient neurogenesis in forebrain-specific presenilin-1 knockout mice is associated with reduced clearance of hippocampal memory traces. Neuron 2001; 32: 911–926.

    Article  CAS  Google Scholar 

  10. 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 

  11. 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 

  12. Drapeau E, Mayo W, Aurousseau C, Le Moal M, Piazza PV, Abrous DN . Spatial memory performances of aged rats in the water maze predict levels of hippocampal neurogenesis. Proc Natl Acad Sci USA 2003; 100: 14385–14390.

    Article  CAS  Google Scholar 

  13. 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 

  14. van Praag H, Shubert T, Zhao C, Gage FH . Exercise enhances learning and hippocampal neurogenesis in aged mice. J Neurosci 2005; 25: 8680–8685.

    Article  CAS  Google Scholar 

  15. Kee N, Teixeira CM, Wang AH, Frankland PW . Preferential incorporation of adult-generated granule cells into spatial memory networks in the dentate gyrus. Nat Neurosci 2007; 10: 355–362.

    Article  CAS  Google Scholar 

  16. Bizon JL, Lee HJ, Gallagher M . Neurogenesis in a rat model of age-related cognitive decline. Aging Cell 2004; 3: 227–234.

    Article  CAS  Google Scholar 

  17. Leuner B, Gould E, Shors TJ . Is there a link between adult neurogenesis and learning? Hippocampus 2006; 16: 216–224.

    Article  Google Scholar 

  18. Thomas RM, Hotsenpiller G, Peterson DA . Acute psychosocial stress reduces cell survival in adult hippocampal neurogenesis without altering proliferation. J Neurosci 2007; 27: 2734–2743.

    Article  CAS  Google Scholar 

  19. Pollak DD, Monje FJ, Zuckerman L, Denny CA, Drew MR, Kandel ER . An animal model of a behavioral intervention for depression. Neuron 2008; 60: 149–161.

    Article  CAS  Google Scholar 

  20. Revest JM, Dupret D, Koehl M, Funk-Reiter C, Grosjean N, Piazza PV et al. Adult hippocampal neurogenesis is involved in anxiety-related behaviors. Mol Psychiatry 2009; 14: 959–967.

    Article  Google Scholar 

  21. Taliaz D, Stall N, Dar DE, Zangen A . Knockdown of brain-derived neurotrophic factor in specific brain sites precipitates behaviors associated with depression and reduces neurogenesis. Mol Psychiatry 2009; e-pub ahead of print.

  22. Dupret D, Revest JM, Koehl M, Ichas F, De Giorgi F, Costet P et al. Spatial relational memory requires hippocampal adult neurogenesis. PLoS One 2008; 3: e1959.

    Article  Google Scholar 

  23. Imayoshi I, Sakamoto M, Ohtsuka T, Takao K, Miyakawa T, Yamaguchi M et al. Roles of continuous neurogenesis in the structural and functional integrity of the adult forebrain. Nat Neurosci 2008; 11: 1153–1161.

    Article  CAS  Google Scholar 

  24. Clelland CD, Choi M, Romberg C, Clemenson Jr GD, Fragniere A, Tyers P et al. A functional role for adult hippocampal neurogenesis in spatial pattern separation. Science 2009; 325: 210–213.

    Article  CAS  Google Scholar 

  25. Jessberger S, Clark RE, Broadbent NJ, Clemenson Jr GD, Consiglio A, Lie DC et al. Dentate gyrus-specific knockdown of adult neurogenesis impairs spatial and object recognition memory in adult rats. Learn Mem 2009; 16: 147–154.

    Article  Google Scholar 

  26. Vollmayr B, Mahlstedt MM, Henn FA . Neurogenesis and depression: what animal models tell us about the link. Eur Arch Psychiatry Clin Neurosci 2007; 257: 300–303.

    Article  Google Scholar 

  27. Kempermann G, Gage FH . Closer to neurogenesis in adult humans. Nat Med 1998; 4: 555–557.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  29. Montaron MF, Drapeau E, Dupret D, Kitchener P, Aurousseau C, Le Moal M et al. Lifelong corticosterone level determines age-related decline in neurogenesis and memory. Neurobiol Aging 2006; 27: 645–654.

    Article  CAS  Google Scholar 

  30. Hitoshi S, Maruta N, Higashi M, Kumar A, Kato N, Ikenaka K . Antidepressant drugs reverse the loss of adult neural stem cells following chronic stress. J Neurosci Res 2007; 85: 3574–3585.

    Article  CAS  Google Scholar 

  31. Li S, Wang C, Wang W, Dong H, Hou P, Tang Y . Chronic mild stress impairs cognition in mice: from brain homeostasis to behavior. Life Sci 2008; 82: 934–942.

    Article  CAS  Google Scholar 

  32. Liu Q, Yu J, Mao-Ying QL, Mi WL, Li B, Wang YQ et al. Repeated clomipramine treatment reversed the inhibition of cell proliferation in adult hippocampus induced by chronic unpredictable stress. Pharmacogenomics J 2008; 8: 375–383.

    Article  CAS  Google Scholar 

  33. Stambor Z . Stressed out nation. Monit Psychol 2006; 37: 28.

    Google Scholar 

  34. Joels M, Karst H, Alfarez D, Heine VM, Qin Y, van Riel E et al. Effects of chronic stress on structure and cell function in rat hippocampus and hypothalamus. Stress 2004; 7: 221–231.

    Article  CAS  Google Scholar 

  35. Heine VM, Zareno J, Maslam S, Joels M, Lucassen PJ . Chronic stress in the adult dentate gyrus reduces cell proliferation near the vasculature and VEGF and Flk-1 protein expression. Eur J Neurosci 2005; 21: 1304–1314.

    Article  Google Scholar 

  36. Galea LA, Wide JK, Barr AM . Estradiol alleviates depressive-like symptoms in a novel animal model of post-partum depression. Behav Brain Res 2001; 122: 1–9.

    Article  CAS  Google Scholar 

  37. Pellow S, Chopin P, File SE, Briley M . Validation of open:closed arm entries in an elevated plus-maze as a measure of anxiety in the rat. J Neurosci Methods 1985; 14: 149–167.

    Article  CAS  Google Scholar 

  38. Rao MS, Hattiangady B, Reddy DS, Shetty AK . Hippocampal neurodegeneration, spontaneous seizures, and mossy fiber sprouting in the F344 rat model of temporal lobe epilepsy. J Neurosci Res 2006; 83: 1088–1105.

    Article  CAS  Google Scholar 

  39. Abdel-Rahman A, Rao MS, Shetty AK . Nestin expression in hippocampal astrocytes after injury depends on the age of the hippocampus. Glia 2004; 47: 299–313.

    Article  Google Scholar 

  40. Hattiangady B, Rao MS, Shetty AK . Plasticity of hippocampal stem/progenitor cells to enhance neurogenesis in response to kainate-induced injury is lost by middle age. Aging Cell 2008; 7: 207–224.

    Article  CAS  Google Scholar 

  41. Rao MS, Shetty AK . 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.

    Article  Google Scholar 

  42. Kempermann G, Gast D, Kronenberg G, Yamaguchi M, Gage FH . Early determination and long-term persistence of adult-generated new neurons in the hippocampus of mice. Development 2003; 130: 391–399.

    CAS  Google Scholar 

  43. Morris R . Developments of a water-maze procedure for studying spatial learning in the rat. J Neurosci Methods 1984; 11: 47–60.

    Article  CAS  Google Scholar 

  44. Gourley SL, Kiraly DD, Howell JL, Olausson P, Taylor JR . Acute hippocampal brain-derived neurotrophic factor restores motivational and forced swim performance after corticosterone. Biol Psychiatry 2008; 64: 884–890.

    Article  CAS  Google Scholar 

  45. Wang SH, Zhang ZJ, Guo YJ, Teng GJ, Chen BA . Hippocampal neurogenesis and behavioural studies on adult ischemic rat response to chronic mild stress. Behav Brain Res 2008; 189: 9–16.

    Article  Google Scholar 

  46. Borcel E, Perez-Alvarez L, Herrero AI, Brionne T, Varea E, Berezin V et al. Chronic stress in adulthood followed by intermittent stress impairs spatial memory and the survival of newborn hippocampal cells in aging animals: prevention by FGL, a peptide mimetic of neural cell adhesion molecule. Behav Pharmacol 2008; 19: 41–49.

    Article  Google Scholar 

  47. Lucassen PJ, Heine VM, Muller MB, van der Beek EM, Wiegant VM, De Kloet ER et al. Stress, depression and hippocampal apoptosis. CNS Neurol Disord Drug Targets 2006; 5: 531–546.

    Article  Google Scholar 

  48. Pham K, Nacher J, Hof PR, McEwen BS . Repeated restraint stress suppresses neurogenesis and induces biphasic PSA-NCAM expression in the adult rat dentate gyrus. Eur J Neurosci 2003; 17: 879–886.

    Google Scholar 

  49. Becker S, Macqueen G, Wojtowicz JM . Computational modeling and empirical studies of hippocampal neurogenesis-dependent memory: effects of interference, stress and depression. Brain Res 2009; 1299: 45–54.

    Article  CAS  Google Scholar 

  50. Sahay A, Hen R . Hippocampal neurogenesis and depression. Novartis Found Symp 2008; 289: 152–160; discussion 160–154, 193–155.

    Article  CAS  Google Scholar 

  51. Boldrini M, Underwood MD, Hen R, Rosoklija GB, Dwork AJ, John Mann J et al. Antidepressants increase neural progenitor cells in the human hippocampus. Neuropsychopharmacology 2009; 34: 2376–2389.

    Article  CAS  Google Scholar 

  52. Ageta H, Murayama A, Migishima R, Kida S, Tsuchida K, Yokoyama M et al. Activin in the brain modulates anxiety-related behavior and adult neurogenesis. PLoS One 2008; 3: e1869.

    Article  Google Scholar 

  53. Bergami M, Rimondini R, Santi S, Blum R, Gotz M, Canossa M . Deletion of TrkB in adult progenitors alters newborn neuron integration into hippocampal circuits and increases anxiety-like behavior. Proc Natl Acad Sci USA 2008; 105: 15570–15575.

    Article  CAS  Google Scholar 

  54. Smith SM, Vale WW . The role of the hypothalamic–pituitary–adrenal axis in neuroendocrine responses to stress. Dialogues Clin Neurosci 2006; 8: 383–395.

    PubMed  PubMed Central  Google Scholar 

  55. Yuen EY, Liu W, Karatsoreos IN, Feng J, McEwen BS, Yan Z . Acute stress enhances glutamatergic transmission in prefrontal cortex and facilitates working memory. Proc Natl Acad Sci USA 2009; 106: 17552–17557.

    Article  Google Scholar 

  56. Joels M, Pu Z, Wiegert O, Oitzl MS, Krugers HJ . Learning under stress: how does it work? Trends Cogn Sci 2006; 10: 152–158.

    Article  Google Scholar 

  57. McEwen BS . The neurobiology of stress: from serendipity to clinical relevance. Brain Res 2000; 886: 172–189.

    Article  CAS  Google Scholar 

  58. Joels M, Krugers H, Karst H . Stress-induced changes in hippocampal function. Prog Brain Res 2008; 167: 3–15.

    Article  CAS  Google Scholar 

  59. Muscatell KA, Slavich GM, Monroe SM, Gotlib IH . Stressful life events, chronic difficulties, and the symptoms of clinical depression. J Nerv Ment Dis 2009; 197: 154–160.

    Article  Google Scholar 

  60. Gould E, Tanapat P, Rydel T, Hastings N . Regulation of hippocampal neurogenesis in adulthood. Biol Psychiatry 2000; 48: 715–720.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  62. Garcia A, Steiner B, Kronenberg G, Bick-Sander A, Kempermann G . Age-dependent expression of glucocorticoid and mineralocorticoid receptors on neural precursor cell populations in the adult murine hippocampus. Aging Cell 2004; 3: 363–371.

    Article  CAS  Google Scholar 

  63. Yu IT, Lee SH, Lee YS, Son H . Differential effects of corticosterone and dexamethasone on hippocampal neurogenesis in vitro. Biochem Biophys Res Commun 2004; 317: 484–490.

    Article  CAS  Google Scholar 

  64. Deisseroth K, Singla S, Toda H, Monje M, Palmer TD, Malenka RC . Excitation—neurogenesis coupling in adult neural stem/progenitor cells. Neuron 2004; 42: 535–552.

    Article  CAS  Google Scholar 

  65. Nakamichi N, Takarada T, Yoneda Y . Neurogenesis mediated by gamma-aminobutyric acid and glutamate signaling. J Pharmacol Sci 2009; 110: 133–149.

    Article  CAS  Google Scholar 

  66. Lupien SJ, Wilkinson CW, Briere S, Menard C, Ng Ying Kin NM, Nair NP . The modulatory effects of corticosteroids on cognition: studies in young human populations. Psychoneuroendocrinology 2002; 27: 401–416.

    Article  CAS  Google Scholar 

  67. Joels M . Corticosteroid effects in the brain: U-shape it. Trends Pharmacol Sci 2006; 27: 244–250.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  69. Molteni R, Calabrese F, Cattaneo A, Mancini M, Gennarelli M, Racagni G et al. Acute stress responsiveness of the neurotrophin BDNF in the rat hippocampus is modulated by chronic treatment with the antidepressant duloxetine. Neuropsychopharmacology 2009; 34: 1523–1532.

    Article  CAS  Google Scholar 

  70. Jin K, Sun Y, Xie L, Batteur S, Mao XO, Smelick C et al. Neurogenesis and aging: FGF-2 and HB-EGF restore neurogenesis in hippocampus and subventricular zone of aged mice. Aging Cell 2003; 2: 175–183.

    Article  CAS  Google Scholar 

  71. Lichtenwalner RJ, Forbes ME, Bennett SA, Lynch CD, Sonntag WE, Riddle DR . Intracerebroventricular infusion of insulin-like growth factor-I ameliorates the age-related decline in hippocampal neurogenesis. Neuroscience 2001; 107: 603–613.

    Article  CAS  Google Scholar 

  72. Lee J, Seroogy KB, Mattson MP . Dietary restriction enhances neurotrophin expression and neurogenesis in the hippocampus of adult mice. J Neurochem 2002; 80: 539–547.

    Article  CAS  Google Scholar 

  73. Decressac M, Prestoz L, Veran J, Cantereau A, Jaber M, Gaillard A . Neuropeptide Y stimulates proliferation, migration and differentiation of neural precursors from the subventricular zone in adult mice. Neurobiol Dis 2009; 34: 441–449.

    Article  CAS  Google Scholar 

  74. Howell OW, Silva S, Scharfman HE, Sosunov AA, Zaben M, Shatya A et al. Neuropeptide Y is important for basal and seizure-induced precursor cell proliferation in the hippocampus. Neurobiol Dis 2007; 26: 174–188.

    Article  CAS  Google Scholar 

  75. Lee JS, Jang DJ, Lee N, Ko HG, Kim H, Kim YS et al. Induction of neuronal vascular endothelial growth factor expression by cAMP in the dentate gyrus of the hippocampus is required for antidepressant-like behaviors. J Neurosci 2009; 29: 8493–8505.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by a Gulf War Research grant (to AKS) and a VA Merit Review Award (to AKS) from the Department of Veterans Affairs, and an R01 grant from the National Institute of Neurological Disorders and Stroke (NS 54780 to AKS).

Author information

Authors and Affiliations

  1. Medical Research & Surgery Services, Veterans Affairs Medical Center, Durham, NC, USA

    V K Parihar, B Hattiangady, R Kuruba, B Shuai & A K Shetty

  2. Department of Surgery, Division of Neurosurgery, Duke University Medical Center, Durham, NC, USA

    V K Parihar, B Hattiangady, R Kuruba, B Shuai & A K Shetty

Authors
  1. V K Parihar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. B Hattiangady
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. R Kuruba
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. B Shuai
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. A K Shetty
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A K Shetty.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Molecular Psychiatry website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Parihar, V., Hattiangady, B., Kuruba, R. et al. Predictable chronic mild stress improves mood, hippocampal neurogenesis and memory. Mol Psychiatry 16, 171–183 (2011). https://doi.org/10.1038/mp.2009.130

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/mp.2009.130

Keywords

This article is cited by

Search

Advanced search

Quick links