Adult-generated neurons born during chronic social stress are uniquely adapted to respond to subsequent chronic social stress


Chronic stress is a recognized risk factor for psychiatric and psychological disorders and a potent modulator of adult neurogenesis. Numerous studies have shown that during stress, neurogenesis decreases; however, during the recovery from the stress, neurogenesis increases. Despite the increased number of neurons born after stress, it is unknown if the function and morphology of those neurons are altered. Here we asked whether neurons in adult mice, born during the final 5 days of chronic social stress and matured during recovery from chronic social stress, are similar to neurons born with no stress conditions from a quantitative, functional and morphological perspective, and whether those neurons are uniquely adapted to respond to a subsequent stressful challenge. We observed an increased number of newborn neurons incorporated in the dentate gyrus of the hippocampus during the 10-week post-stress recovery phase. Interestingly, those new neurons were more responsive to subsequent chronic stress, as they showed more of a stress-induced decrease in spine density and branching nodes than in neurons born during a non-stress period. Our results replicate findings that the neuronal survival and incorporation of neurons in the adult dentate gyrus increases after chronic stress and suggest that such neurons are uniquely adapted in the response to future social stressors. This finding provides a potential mechanism for some of the long-term hippocampal effects of stress.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1
Fig. 2
Fig. 3


  1. 1.

    Gage FH. Mammalian neural stem cells. Science. 2000;287:1433–8.

    CAS  Article  Google Scholar 

  2. 2.

    Van Praag H, Schinder AF, Christie BR, Toni N, Palmer TD, Gage FH. Functional neurogenesis in the adult hippocampus. Nature. 2002;415:1030–4.

    Article  Google Scholar 

  3. 3.

    Zhao C, Teng EM, Summers RG Jr, Ming GL, Gage FH. Distinct morphological stages of dentate granule neuron maturation in the adult mouse hippocampus. J Neurosci. 2006;26:3–11.

    CAS  Article  Google Scholar 

  4. 4.

    Ge S, Yang CH, Hsu KS, Ming GL, Song H. A critical period for enhanced synaptic plasticity in newly generated neurons of the adult brain. Neuron. 2007;54:559–66.

    CAS  Article  Google Scholar 

  5. 5.

    Toni N, Teng EM, Bushong EA, Aimone JB, Zhao C, Consiglio A, et al. Synapse formation on neurons born in the adult hippocampus. Nat Neurosci. 2007;10:727–34.

    CAS  Article  Google Scholar 

  6. 6.

    Deng W, Saxe MD, Gallina IS, Gage FH. Adult-born hippocampal dentate granule cells undergoing maturation modulate learning and memory in the brain. J Neurosci. 2009;29:13532–42.

    CAS  Article  Google Scholar 

  7. 7.

    Nakashiba T, Cushman JD, Pelkey KA, Renaudineau S, Buhl DL, McHugh TJ, et al. Young dentate granule cells mediate pattern separation, whereas old granule cells facilitate pattern completion. Cell. 2012;149:188–201.

    CAS  Article  Google Scholar 

  8. 8.

    Sahay A, Scobie KN, Hill AS, O’Carroll CM, Kheirbek MA, Burghardt NS, et al. Increasing adult hippocampal neurogenesis is sufficient to improve pattern separation. Nature. 2011;472:466–70.

    CAS  Article  Google Scholar 

  9. 9.

    Bruel-Jungerman E, Rampon C, Laroche S. Adult hippocampal neurogenesis, synaptic plasticity and memory: facts and hypotheses. Rev Neurosci. 2007;18:93–114.

    CAS  Article  Google Scholar 

  10. 10.

    Aimone JB, Li Y, Lee SW, Clemenson GD, Deng W, Gage FH. Regulation and function of adult neurogenesis: from genes to cognition. Physiol Rev. 2014;94:991–1026.

    CAS  Article  Google Scholar 

  11. 11.

    de Quervain DJ, Roozendaal B, McGaugh JL. Stress and glucocorticoids impair retrieval of long-term spatial memory. Nature. 1998;394:787–90.

    Article  Google Scholar 

  12. 12.

    Lucassen PJ, Meerlo P, Naylor AS, van Dam AM, Dayer AG, Fuchs E, et al. Regulation of adult neurogenesis by stress, sleep disruption, exercise and inflammation: Implications for depression and antidepressant action. Eur Neuropsychopharmacol. 2010;20:1–17.

    CAS  Article  Google Scholar 

  13. 13.

    Schoenfeld TJ, Gould E. Differential effects of stress and glucocorticoids on adult neurogenesis. Curr Top Behav Neurosci. 2013;15:139–64.

    CAS  Article  Google Scholar 

  14. 14.

    Egeland M, Zunszain PA, Pariante CM. Molecular mechanisms in the regulation of adult neurogenesis during stress. Nat Rev Neurosci. 2015;16:189–200.

    CAS  Article  Google Scholar 

  15. 15.

    Opendak M, Gould E. Adult neurogenesis: a substrate for experience-dependent change. Trends Cogn Sci. 2015;19:151–61.

    Article  Google Scholar 

  16. 16.

    Schoenfeld TJ, Gould E. Stress, stress hormones, and adult neurogenesis. Exp Neurol. 2012;233:12–21.

    CAS  Article  Google Scholar 

  17. 17.

    Lagace DC, Donovan MH, DeCarolis NA, Farnbauch LA, Malhotra S, Berton O, et al. Adult hippocampal neurogenesis is functionally important for stress-induced social avoidance. Proc Natl Acad Sci USA. 2010;107:4436–41.

    CAS  Article  Google Scholar 

  18. 18.

    McCormick CM, Thomas CM, Sheridan CS, Nixon F, Flynn JA, Mathews IZ. Social instability stress in adolescent male rats alters hippocampal neurogenesis and produces deficits in spatial location memory in adulthood. Hippocampus. 2012;22:1300–12.

    Article  Google Scholar 

  19. 19.

    Snyder JS, Glover LR, Sanzone KM, Kamhi JF, Cameron HA. The effects of exercise and stress on the survival and maturation of adult-generated granule cells. Hippocampus. 2009;19:898–906.

    CAS  Article  Google Scholar 

  20. 20.

    Gray JD, Rubin TG, Hunter RG, McEwen BS. Hippocampal gene expression changes underlying stress sensitization and recovery. Mol Psychiatry. 2014;19:1171–8.

    CAS  Article  Google Scholar 

  21. 21.

    Wang K, Xiang XH, He F, Lin LB, Zhang R, Ping XJ, et al. Transcriptome profiling analysis reveals region-distinctive changes of gene expression in the CNS in response to different moderate restraint stress. J Neurochem. 2010;113:1436–46.

    CAS  PubMed  Google Scholar 

  22. 22.

    Goldwater DS, Pavlides C, Hunter RG, Bloss EB, Hof PR, McEwen BS, et al. Structural and functional alterations to rat medial prefrontal cortex following chronic restraint stress and recovery. Neuroscience. 2009;164:798–808.

    CAS  Article  Google Scholar 

  23. 23.

    Czeh B, Welt T, Fischer AK, Erhardt A, Schmitt W, Muller MB, et al. Chronic psychosocial stress and concomitant repetitive transcranial magnetic stimulation: effects on stress hormone levels and adult hippocampal neurogenesis. Biol Psychiatry. 2002;52:1057–65.

    CAS  Article  Google Scholar 

  24. 24.

    Lee KJ, Kim SJ, Kim SW, Choi SH, Shin YC, Park SH, et al. Chronic mild stress decreases survival, but not proliferation, of new-born cells in adult rat hippocampus. Exp Mol Med. 2006;38:44–54.

    CAS  Article  Google Scholar 

  25. 25.

    Lyons DM, Buckmaster PS, Lee AG, Wu C, Mitra R, Duffey LM, et al. Stress coping stimulates hippocampal neurogenesis in adult monkeys. Proc Natl Acad Sci USA. 2010;107:14823–7.

    CAS  Article  Google Scholar 

  26. 26.

    Toth E, Gersner R, Wilf-Yarkoni A, Raizel H, Dar DE, Richter-Levin G, et al. Age-dependent effects of chronic stress on brain plasticity and depressive behavior. J Neurochem. 2008;107:522–32.

    CAS  Article  Google Scholar 

  27. 27.

    Oomen CA, Girardi CE, Cahyadi R, Verbeek EC, Krugers H, Joels M, et al. Opposite effects of early maternal deprivation on neurogenesis in male versus female rats. PloS One. 2009;4:e3675.

    Article  Google Scholar 

  28. 28.

    Barha CK, Brummelte S, Lieblich SE, Galea LA. Chronic restraint stress in adolescence differentially influences hypothalamic-pituitary-adrenal axis function and adult hippocampal neurogenesis in male and female rats. Hippocampus. 2011;21:1216–27.

    CAS  Article  Google Scholar 

  29. 29.

    Kudryavtseva NN, Bakshtanovskaya IV, Koryakina LA. Social model of depression in mice of C57BL/6J strain. Pharmacol Biochem Behav. 1991;38:315–20.

    CAS  Article  Google Scholar 

  30. 30.

    Vegas O, Beitia G, Sanchez-Martin JR, Arregi A, Azpiroz A. Behavioral and neurochemical responses in mice bearing tumors submitted to social stress. Behav Brain Res. 2004;155:125–34.

    CAS  Article  Google Scholar 

  31. 31.

    Vorhees CV, Williams MT. Morris water maze: procedures for assessing spatial and related forms of learning and memory. Nat Protoc. 2006;1:848–58.

    Article  Google Scholar 

  32. 32.

    Fabel K, Wolf SA, Ehninger D, Babu H, Leal-Galicia P, Kempermann G. Additive effects of physical exercise and environmental enrichment on adult hippocampal neurogenesis in mice. Front Neurosci. 2009;3:50.

    PubMed  PubMed Central  Google Scholar 

  33. 33.

    Kempermann G, Kuhn HG, Gage FH. More hippocampal neurons in adult mice living in an enriched environment. Nature. 1997;386:493–5.

    CAS  Article  Google Scholar 

  34. 34.

    Leuner B, Mendolia-Loffredo S, Kozorovitskiy Y, Samburg D, Gould E, Shors TJ. Learning enhances the survival of new neurons beyond the time when the hippocampus is required for memory. J Neurosci. 2004;24:7477–81.

    CAS  Article  Google Scholar 

  35. 35.

    Schloesser RJ, Lehmann M, Martinowich K, Manji HK, Herkenham M. Environmental enrichment requires adult neurogenesis to facilitate the recovery from psychosocial stress. Mol Psychiatry. 2010;15:1152–63.

    CAS  Article  Google Scholar 

  36. 36.

    Mandyam CD, Harburg GC, Eisch AJ. Determination of key aspects of precursor cell proliferation, cell cycle length and kinetics in the adult mouse subgranular zone. Neuroscience. 2007;146:108–22.

    CAS  Article  Google Scholar 

  37. 37.

    Armario A, Lopez-Calderon A, Jolin T, Balasch J. Response of anterior pituitary hormones to chronic stress. The specificity of adaptation. Neurosci Biobehav Rev. 1986;10:245–50.

    CAS  Article  Google Scholar 

  38. 38.

    Babb JA, Masini CV, Day HE, Campeau S. Habituation of hypothalamic-pituitary-adrenocortical axis hormones to repeated homotypic stress and subsequent heterotypic stressor exposure in male and female rats. Stress. 2014;17:224–34.

    CAS  Article  Google Scholar 

  39. 39.

    Grissom N, Bhatnagar S. Habituation to repeated stress: get used to it. Neurobiol Learn Mem. 2009;92:215–24.

    Article  Google Scholar 

  40. 40.

    Folkman S, Lazarus RS. An analysis of coping in a middle-aged community sample. J Health Soc Behav. 1980;21:219–39.

    CAS  Article  Google Scholar 

  41. 41.

    Wood SK, Walker HE, Valentino RJ, Bhatnagar S. Individual differences in reactivity to social stress predict susceptibility and resilience to a depressive phenotype: role of corticotropin-releasing factor. Endocrinology. 2010;151:1795–805.

    CAS  Article  Google Scholar 

  42. 42.

    Kempermann G, Chesler EJ, Lu L, Williams RW, Gage FH. Natural variation and genetic covariance in adult hippocampal neurogenesis. Proc Natl Acad Sci USA. 2006;103:780–5.

    CAS  Article  Google Scholar 

  43. 43.

    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;10:355–62.

    CAS  Article  Google Scholar 

  44. 44.

    Buwalda B, Kole MH, Veenema AH, Huininga M, de Boer SF, Korte SM, et al. Long-term effects of social stress on brain and behavior: a focus on hippocampal functioning. Neurosci Biobehav Rev. 2005;29:83–97.

    Article  Google Scholar 

  45. 45.

    Conrad CD. A critical review of chronic stress effects on spatial learning and memory. Prog Neuropsychopharmacol Biol Psychiatry. 2010;34:742–55.

    Article  Google Scholar 

  46. 46.

    Hoffman AN, Krigbaum A, Ortiz JB, Mika A, Hutchinson KM, Bimonte-Nelson HA, et al. Recovery after chronic stress within spatial reference and working memory domains: correspondence with hippocampal morphology. Eur J Neurosci. 2011;34:1023–30.

    CAS  Article  Google Scholar 

  47. 47.

    Shors TJ. Stressful experience and learning across the lifespan. Annu Rev Psychol. 2006;57:55–85.

    Article  Google Scholar 

  48. 48.

    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;97:253–66.

    CAS  Article  Google Scholar 

  49. 49.

    Drapeau E, Montaron MF, Aguerre S, Abrous DN. Learning-induced survival of new neurons depends on the cognitive status of aged rats. J Neurosci. 2007;27:6037–44.

    CAS  Article  Google Scholar 

  50. 50.

    Akers KG, Martinez-Canabal A, Restivo L, Yiu AP, De Cristofaro A, Hsiang HL, et al Hippocampal neurogenesis regulates forgetting during adulthood and infancy. Science. 2014;344:598–602.

    CAS  Article  Google Scholar 

  51. 51.

    Alfarez DN, Joels M, Krugers HJ. Chronic unpredictable stress impairs long-term potentiation in rat hippocampal CA1 area and dentate gyrus in vitro. Eur J Neurosci. 2003;17:1928–34.

    Article  Google Scholar 

  52. 52.

    McEwen BS. Stress and hippocampal plasticity. Annu Rev Neurosci. 1999;22:105–22.

    CAS  Article  Google Scholar 

  53. 53.

    McEwen BS, Eiland L, Hunter RG, Miller MM. Stress and anxiety: structural plasticity and epigenetic regulation as a consequence of stress. Neuropharmacology. 2012;62:3–12.

    CAS  Article  Google Scholar 

  54. 54.

    McKittrick CR, Magarinos AM, Blanchard DC, Blanchard RJ, McEwen BS, Sakai RR. Chronic social stress reduces dendritic arbors in CA3 of hippocampus and decreases binding to serotonin transporter sites. Synapse. 2000;36:85–94.

    CAS  Article  Google Scholar 

  55. 55.

    Pavlides C, Nivon LG, McEwen BS. Effects of chronic stress on hippocampal long-term potentiation. Hippocampus. 2002;12:245–57.

    Article  Google Scholar 

  56. 56.

    Vyas A, Mitra R, Shankaranarayana Rao BS, Chattarji S. Chronic stress induces contrasting patterns of dendritic remodeling in hippocampal and amygdaloid neurons. J Neurosci. 2002;22:6810–8.

    CAS  Article  Google Scholar 

  57. 57.

    Magarinos AM, McEwen BS, Flugge G, Fuchs E. Chronic psychosocial stress causes apical dendritic atrophy of hippocampal CA3 pyramidal neurons in subordinate tree shrews. J Neurosci. 1996;16:3534–40.

    CAS  Article  Google Scholar 

  58. 58.

    Arendt T, Stieler J, Strijkstra AM, Hut RA, Rudiger J, Van der Zee EA, et al. Reversible paired helical filament-like phosphorylation of tau is an adaptive process associated with neuronal plasticity in hibernating animals. J Neurosci. 2003;23:6972–81.

    CAS  Article  Google Scholar 

  59. 59.

    Conrad CD, LeDoux JE, Magarinos AM, McEwen BS. Repeated restraint stress facilitates fear conditioning independently of causing hippocampal CA3 dendritic atrophy. Behav Neurosci. 1999;113:902–13.

    CAS  Article  Google Scholar 

  60. 60.

    Alvarez VA, Sabatini BL. Anatomical and physiological plasticity of dendritic spines. Annu Rev Neurosci. 2007;30:79–97.

    CAS  Article  Google Scholar 

  61. 61.

    Alves ND, Correia JS, Patricio P, Mateus-Pinheiro A, Machado-Santos AR, Loureiro-Campos E, et al. Adult hippocampal neuroplasticity triggers susceptibility to recurrent depression. Transl Psychiatry. 2017;7:e1058.

    CAS  Article  Google Scholar 

  62. 62.

    Snyder JS, Soumier A, Brewer M, Pickel J, Cameron HA. Adult hippocampal neurogenesis buffers stress responses and depressive behaviour. Nature. 2011;476:458–61.

    CAS  Article  Google Scholar 

  63. 63.

    Miller GE, Chen E, Parker KJ. Psychological stress in childhood and susceptibility to the chronic diseases of aging: moving toward a model of behavioral and biological mechanisms. Psychol Bull. 2011;137:959–97.

    Article  Google Scholar 

  64. 64.

    Shonkoff JP, Boyce WT, McEwen BS. Neuroscience, molecular biology, and the childhood roots of health disparities: building a new framework for health promotion and disease prevention. JAMA. 2009;301:2252–9.

    CAS  Article  Google Scholar 

  65. 65.

    Van den Bergh BR, Van Calster B, Smits T, Van Huffel S, Lagae L. Antenatal maternal anxiety is related to HPA-axis dysregulation and self-reported depressive symptoms in adolescence: a prospective study on the fetal origins of depressed mood. Neuropsychopharmacology. 2008;33:536–45.

    Article  Google Scholar 

Download references


We thank Dr. Andrew K. Evans for valuable discussion. This work was supported by Marie Curie n-273487 (GCs-CNS-IS) awarded to Z.DM. and NIH R01MH085911 awarded to T.D.P.

Author information



Corresponding author

Correspondence to Zurine De Miguel.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

De Miguel, Z., Haditsch, U., Palmer, T.D. et al. Adult-generated neurons born during chronic social stress are uniquely adapted to respond to subsequent chronic social stress. Mol Psychiatry 24, 1178–1188 (2019).

Download citation

Further reading