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.

  • Review Article
  • Published:

Effects of stress throughout the lifespan on the brain, behaviour and cognition

Key Points

  • During stress there is activation of the hypothalamic-pituitary-adrenal (HPA) axis, culminating in the production of glucocorticoids. Glucocorticoids can easily access the brain, where they bind to receptors and influence the brain and behaviour.

  • Different outcomes result from exposure to stress at different periods of an individual's life.

  • Exposure to stress in the prenatal period leads to programming effects, as evidenced by increased reactivity to stress later in life and reduced hippocampal volume in adulthood.

  • Exposure to prenatal stress has been associated with learning impairments, enhanced sensitivity to drugs of abuse, and increases in anxiety and depression-related behaviours in adulthood.

  • Maternal separation is a potent stressor in the postnatal period, and it leads to increased secretion of glucocorticoids that can extend into adulthood. By contrast, exposure to severe abuse during infancy is associated with lower levels of glucocorticoids in both primates and humans.

  • Stress during adolescence has more important effects on the HPA axis than a similar stress exposure during adulthood. Moreover, the effects of stress during adolescence can incubate until adulthood, at which time they will become apparent.

  • The effects of stress exposure on the brain and behaviour in adulthood are similar to those that are observed in childhood and adolescence. However, unlike these latter effects, the former effects are reversible; that is, they usually disappear after cessation of the stressor.

  • In adulthood, chronic exposure to high levels of glucocorticoids has been associated with depressive disorder. By contrast, patients with post-traumatic stress disorder present lower levels of glucocorticoids.

  • The effects of stress during aging are associated with both memory impairments and reduced hippocampal volumes.

  • The life cycle model of stress explains why different disorders emerge in populations exposed to stress at different stages of their lives.

Abstract

Chronic exposure to stress hormones, whether it occurs during the prenatal period, infancy, childhood, adolescence, adulthood or aging, has an impact on brain structures involved in cognition and mental health. However, the specific effects on the brain, behaviour and cognition emerge as a function of the timing and the duration of the exposure, and some also depend on the interaction between gene effects and previous exposure to environmental adversity. Advances in animal and human studies have made it possible to synthesize these findings, and in this Review a model is developed to explain why different disorders emerge in individuals exposed to stress at different times in their lives.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1: The stress system.
Figure 2: The life cycle model of stress.

Similar content being viewed by others

References

  1. Barker, D. J. The foetal and infant origins of inequalities in health in Britain. J. Public Health Med. 13, 64–68 (1991).

    CAS  PubMed  Google Scholar 

  2. Cadet, R., Pradier, P., Dalle, M. & Delost, P. Effects of prenatal maternal stress on the pituitary adrenocortical reactivity in guinea-pig pups. J. Dev. Physiol. 8, 467–475 (1986).

    CAS  PubMed  Google Scholar 

  3. Dean, F. & Matthews, S. G. Maternal dexamethasone treatment in late gestation alters glucocorticoid and mineralocorticoid receptor mRNA in the fetal guinea pig brain. Brain Res. 846, 253–259 (1999).

    CAS  PubMed  Google Scholar 

  4. Seckl, J. R. Glucocorticoids, developmental 'programming' and the risk of affective dysfunction. Prog. Brain Res. 167, 17–34 (2008). A superb review that summarized prenatal work and linked it to clinical implications.

    CAS  PubMed  Google Scholar 

  5. Koehl, M. et al. Prenatal stress alters circadian activity of hypothalamo-pituitary-adrenal axis and hippocampal corticosteroid receptors in adult rats of both gender. J. Neurobiol. 40, 302–315 (1999).

    CAS  PubMed  Google Scholar 

  6. Barbazanges, A., Piazza, P. V., Le Moal, M. & Maccari, S. Maternal glucocorticoid secretion mediates long-term effects of prenatal stress. J. Neurosci. 16, 3943–3949 (1996).

    CAS  PubMed  Google Scholar 

  7. Meyer, J. S. Early adrenalectomy stimulates subsequent growth and development of the rat brain. Exp. Neurol. 82, 432–446 (1983).

    CAS  PubMed  Google Scholar 

  8. Weaver, I. C. et al. Epigenetic programming by maternal behavior. Nature Neurosci. 7, 847–854 (2004). The first paper to show that early experience has epigenetic effects, altering methylation patterns.

    CAS  PubMed  Google Scholar 

  9. Uno, H. et al. Brain damage induced by prenatal exposure to dexamethasone in fetal rhesus macaques. I. Hippocampus. Brain Res. Dev. Brain Res. 53, 157–167 (1990).

    CAS  PubMed  Google Scholar 

  10. Murmu, M. S. et al. Changes of spine density and dendritic complexity in the prefrontal cortex in offspring of mothers exposed to stress during pregnancy. Eur. J. Neurosci. 24, 1477–1487 (2006).

    PubMed  Google Scholar 

  11. Cratty, M. S., Ward, H. E., Johnson, E. A., Azzaro, A. J. & Birkle, D. L. Prenatal stress increases corticotropin-releasing factor (CRF) content and release in rat amygdala minces. Brain Res. 675, 297–302 (1995).

    CAS  PubMed  Google Scholar 

  12. Vallee, M. et al. Long-term effects of prenatal stress and postnatal handling on age-related glucocorticoid secretion and cognitive performance: a longitudinal study in the rat. Eur. J. Neurosci. 11, 2906–2916 (1999).

    CAS  PubMed  Google Scholar 

  13. Deminiere, J. M. et al. Increased locomotor response to novelty and propensity to intravenous amphetamine self-administration in adult offspring of stressed mothers. Brain Res. 586, 135–139 (1992).

    CAS  PubMed  Google Scholar 

  14. Vallee, M. et al. Prenatal stress induces high anxiety and postnatal handling induces low anxiety in adult offspring: correlation with stress-induced corticosterone secretion. J. Neurosci. 17, 2626–2636 (1997).

    CAS  PubMed  Google Scholar 

  15. Lemaire, V., Koehl, M., Le Moal, M. & Abrous, D. N. Prenatal stress produces learning deficits associated with an inhibition of neurogenesis in the hippocampus. Proc. Natl Acad. Sci. USA 97, 11032–11037 (2000).

    CAS  PubMed  Google Scholar 

  16. Piazza, P. V. & Le Moal, M. L. Pathophysiological basis of vulnerability to drug abuse: role of an interaction between stress, glucocorticoids, and dopaminergic neurons. Annu. Rev. Pharmacol. Toxicol. 36, 359–378 (1996).

    CAS  PubMed  Google Scholar 

  17. Kapoor, A., Petropoulos, S. & Matthews, S. G. Fetal programming of hypothalamic-pituitary-adrenal (HPA) axis function and behavior by synthetic glucocorticoids. Brain Res. Rev. 57, 586–595 (2008).

    CAS  PubMed  Google Scholar 

  18. Hedegaard, M., Henriksen, T. B., Sabroe, S. & Secher, N. J. Psychological distress in pregnancy and preterm delivery. BMJ 307, 234–239 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Orr, S. T. & Miller, C. A. Maternal depressive symptoms and the risk of poor pregnancy outcome. Review of the literature and preliminary findings. Epidemiol. Rev. 17, 165–171 (1995).

    CAS  PubMed  Google Scholar 

  20. Lyons-Ruth, K., Wolfe, R. & Lyubchik, A. Depression and the parenting of young children: making the case for early preventive mental health services. Harv. Rev. Psychiatry 8, 148–153 (2000).

    CAS  PubMed  Google Scholar 

  21. Gutteling, B. M., de Weerth, C. & Buitelaar, J. K. Prenatal stress and children's cortisol reaction to the first day of school. Psychoneuroendocrinology 30, 541–549 (2005).

    CAS  PubMed  Google Scholar 

  22. O'Connor, T. G. et al. Prenatal anxiety predicts individual differences in cortisol in pre-adolescent children. Biol. Psychiatry 58, 211–217 (2005).

    CAS  PubMed  Google Scholar 

  23. Glover, V. Maternal stress or anxiety in pregnancy and emotional development of the child. Br. J. Psychiatry 171, 105–106 (1997).

    CAS  PubMed  Google Scholar 

  24. Stott, D. H. Follow-up study from birth of the effects of prenatal stresses. Dev. Med. Child. Neurol. 15, 770–787 (1973).

    CAS  PubMed  Google Scholar 

  25. Trautman, P. D., Meyer-Bahlburg, H. F., Postelnek, J. & New, M. I. Effects of early prenatal dexamethasone on the cognitive and behavioral development of young children: results of a pilot study. Psychoneuroendocrinology 20, 439–449 (1995).

    CAS  PubMed  Google Scholar 

  26. Buss, C. et al. Maternal care modulates the relationship between prenatal risk and hippocampal volume in women but not in men. J. Neurosci. 27, 2592–2595 (2007).

    CAS  PubMed  Google Scholar 

  27. Levine, S. & Wiener, S. G. Psychoendocrine aspects of mother-infant relationships in nonhuman primates. Psychoneuroendocrinology 13, 143–154 (1988).

    CAS  PubMed  Google Scholar 

  28. Anisman, H., Zaharia, M. D., Meaney, M. J. & Merali, Z. Do early-life events permanently alter behavioral and hormonal responses to stressors? Int. J. Dev. Neurosci. 16, 149–164 (1998).

    CAS  PubMed  Google Scholar 

  29. Liu, D. et al. Maternal care, hippocampal glucocorticoid receptors, and hypothalamic-pituitary-adrenal responses to stress. Science 277, 1659–1662 (1997).

    CAS  PubMed  Google Scholar 

  30. Fenoglio, K. A., Brunson, K. L. & Baram, T. Z. Hippocampal neuroplasticity induced by early-life stress: functional and molecular aspects. Front. Neuroendocrinol. 27, 180–192 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Schulkin, J., Gold, P. W. & McEwen, B. S. Induction of corticotropin-releasing hormone gene expression by glucocorticoids: implication for understanding the states of fear and anxiety and allostatic load. Psychoneuroendocrinology 23, 219–243 (1998).

    CAS  PubMed  Google Scholar 

  32. de Kloet, E. R. & Oitzl, M. S. Who cares for a stressed brain? The mother, the kid or both? Neurobiol. Aging 24 (Suppl. 1), S61–S65; discussion S67–S68 (2003).

    PubMed  Google Scholar 

  33. Sanchez, M. M. et al. Alterations in diurnal cortisol rhythm and acoustic startle response in nonhuman primates with adverse rearing. Biol. Psychiatry 57, 373–381 (2005).

    CAS  PubMed  Google Scholar 

  34. Coplan, J. D. et al. Persistent elevations of cerebrospinal fluid concentrations of corticotropin-releasing factor in adult nonhuman primates exposed to early-life stressors: implications for the pathophysiology of mood and anxiety disorders. Proc. Natl Acad. Sci. USA 93, 1619–1623 (1996).

    CAS  PubMed  Google Scholar 

  35. Sanchez, M. M. The impact of early adverse care on HPA axis development: nonhuman primate models. Horm. Behav. 50, 623–631 (2006).

    PubMed  Google Scholar 

  36. Rosenblum, L. A. et al. Differing concentrations of corticotropin-releasing factor and oxytocin in the cerebrospinal fluid of bonnet and pigtail macaques. Psychoneuroendocrinology 27, 651–660 (2002).

    CAS  PubMed  Google Scholar 

  37. Siegel, S. J. et al. Effects of social deprivation in prepubescent rhesus monkeys: immunohistochemical analysis of the neurofilament protein triplet in the hippocampal formation. Brain Res. 619, 299–305 (1993).

    CAS  PubMed  Google Scholar 

  38. Sanchez, M. M., Ladd, C. O. & Plotsky, P. M. Early adverse experience as a developmental risk factor for later psychopathology: evidence from rodent and primate models. Dev. Psychopathol. 13, 419–449 (2001).

    CAS  PubMed  Google Scholar 

  39. Gunnar, M. R. & Donzella, B. Social regulation of the cortisol levels in early human development. Psychoneuroendocrinology 27, 199–220 (2002).

    CAS  PubMed  Google Scholar 

  40. Geoffroy, M. C., Cote, S. M., Parent, S. & Seguin, J. R. Daycare attendance, stress, and mental health. Can. J. Psychiatry 51, 607–615 (2006).

    PubMed  Google Scholar 

  41. NICHD Early Child Care Research Network. Early child care and children's development prior to school entry: results from the NICHD Study of Early Child Care. Am. Educ. Res. J. 39, 133–164 (2002).

  42. Albers, E. M., Riksen-Walraven, J. M., Sweep, F. C. & de Weerth, C. Maternal behavior predicts infant cortisol recovery from a mild everyday stressor. J. Child. Psychol. Psychiatry 49, 97–103 (2008).

    PubMed  Google Scholar 

  43. Lupien, S. J., King, S., Meaney, M. J. & McEwen, B. S. Child's stress hormone levels correlate with mother's socioeconomic status and depressive state. Biol. Psychiatry 48, 976–980 (2000).

    CAS  PubMed  Google Scholar 

  44. Halligan, S. L., Herbert, J., Goodyer, I. & Murray, L. Disturbances in morning cortisol secretion in association with maternal postnatal depression predict subsequent depressive symptomatology in adolescents. Biol. Psychiatry 62, 40–46 (2007). Provided some of the first evidence that adverse early life experiences in humans, in this case rearing by a mother suffering from post-partum depression, are associated with heightened HPA activity years later, and that the HPA axis hyperactivity mediates the association between early risk exposure and later psychiatric symptoms.

    CAS  PubMed  Google Scholar 

  45. Jones, N. A., Field, T. & Davalos, M. Right frontal EEG asymmetry and lack of empathy in preschool children of depressed mothers. Child. Psychiatry Hum. Dev. 30, 189–204 (2000).

    CAS  PubMed  Google Scholar 

  46. Fries, E., Hesse, J., Hellhammer, J. & Hellhammer, D. H. A new view on hypocortisolism. Psychoneuroendocrinology 30, 1010–1016 (2005).

    CAS  PubMed  Google Scholar 

  47. Yehuda, R., Yang, R. K., Buchsbaum, M. S. & Golier, J. A. Alterations in cortisol negative feedback inhibition as examined using the ACTH response to cortisol administration in PTSD. Psychoneuroendocrinology 31, 447–451 (2006).

    CAS  PubMed  Google Scholar 

  48. Gunnar, M. R. & Quevedo, K. M. Early care experiences and HPA axis regulation in children: a mechanism for later trauma vulnerability. Prog. Brain Res. 167, 137–149 (2008).

    PubMed  PubMed Central  Google Scholar 

  49. McGowan, P. O. et al. Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse. Nature Neurosci. 12, 342–348 (2009). This study examined epigenetic differences in a neuron-specific glucocorticoid receptor (NR3C1) promoter between post-mortem hippocampus obtained from suicide victims with a history of childhood abuse and hippocampus from either suicide victims with no childhood abuse or controls. It found decreased levels of glucocorticoid receptor mRNA, as well as mRNA transcripts bearing the glucocorticoid receptor 1F splice variant and increased cytosine methylation of an NR3C1 promoter in suicide victims with early abuse.

    CAS  PubMed  Google Scholar 

  50. McCormick, C. M. & Mathews, I. Z. HPA function in adolescence: role of sex hormones in its regulation and the enduring consequences of exposure to stressors. Pharmacol. Biochem. Behav. 86, 220–233 (2007). A very good review on the acute and chronic effects of stress during adolescence.

    CAS  PubMed  Google Scholar 

  51. O'Donnell, S., Noseworthy, M. D., Levine, B. & Dennis, M. Cortical thickness of the frontopolar area in typically developing children and adolescents. Neuroimage 24, 948–954 (2005).

    PubMed  Google Scholar 

  52. Vazquez, D. M. & Akil, H. Pituitary-adrenal response to ether vapor in the weanling animal: characterization of the inhibitory effect of glucocorticoids on adrenocorticotropin secretion. Pediatr. Res. 34, 646–653 (1993).

    CAS  PubMed  Google Scholar 

  53. Goldman, L., Winget, C., Hollingshead, G. W. & Levine, S. Postweaning development of negative feedback in the pituitary-adrenal system of the rat. Neuroendocrinology 12, 199–211 (1973).

    CAS  PubMed  Google Scholar 

  54. Girotti, M. et al. Habituation to repeated restraint stress is associated with lack of stress-induced c-fos expression in primary sensory processing areas of the rat brain. Neuroscience 138, 1067–1081 (2006).

    CAS  PubMed  Google Scholar 

  55. Romeo, R. D. et al. Stress history and pubertal development interact to shape hypothalamic-pituitary-adrenal axis plasticity. Endocrinology 147, 1664–1674 (2006).

    CAS  PubMed  Google Scholar 

  56. Avital, A. & Richter-Levin, G. Exposure to juvenile stress exacerbates the behavioural consequences of exposure to stress in the adult rat. Int. J. Neuropsychopharmacol. 8, 163–173 (2005).

    PubMed  Google Scholar 

  57. Lee, P. R., Brady, D. & Koenig, J. I. Corticosterone alters N-methyl-D-aspartate receptor subunit mRNA expression before puberty. Brain Res. Mol. Brain Res. 115, 55–62 (2003).

    CAS  PubMed  Google Scholar 

  58. Isgor, C., Kabbaj, M., Akil, H. & Watson, S. J. Delayed effects of chronic variable stress during peripubertal-juvenile period on hippocampal morphology and on cognitive and stress axis functions in rats. Hippocampus 14, 636–648 (2004). One of the first papers to show protracted effects of adolescent stress on adulthood stress reactivity in rodents.

    PubMed  Google Scholar 

  59. Tsoory, M. & Richter-Levin, G. Learning under stress in the adult rat is differentially affected by 'juvenile' or 'adolescent' stress. Int. J. Neuropsychopharmacol. 9, 713–728 (2006).

    PubMed  Google Scholar 

  60. Kabbaj, M., Isgor, C., Watson, S. J. & Akil, H. Stress during adolescence alters behavioral sensitization to amphetamine. Neuroscience 113, 395–400 (2002).

    CAS  PubMed  Google Scholar 

  61. McCormick, C. M., Robarts, D., Gleason, E. & Kelsey, J. E. Stress during adolescence enhances locomotor sensitization to nicotine in adulthood in female, but not male, rats. Horm. Behav. 46, 458–466 (2004).

    CAS  PubMed  Google Scholar 

  62. Gunnar, M. R., Wewerka, S., Frenn, K., Long, J. D. & Griggs, C. Developmental changes in hypothalamus-pituitary-adrenal activity over the transition to adolescence: normative changes and associations with puberty. Dev. Psychopathol. 21, 69–85 (2009).

    PubMed  PubMed Central  Google Scholar 

  63. Giedd, J. N. et al. Quantitative magnetic resonance imaging of human brain development: ages 4–18. Cereb. Cortex 6, 551–560 (1996).

    CAS  PubMed  Google Scholar 

  64. Perlman, W. R., Webster, M. J., Herman, M. M., Kleinman, J. E. & Weickert, C. S. Age-related differences in glucocorticoid receptor mRNA levels in the human brain. Neurobiol. Aging 28, 447–458 (2007).

    CAS  PubMed  Google Scholar 

  65. Dahl, R. E. Adolescent brain development: a period of vulnerabilities and opportunities. Keynote address. Ann. NY Acad. Sci. 1021, 1–22 (2004).

    PubMed  Google Scholar 

  66. Paus, T., Keshavan, M. & Giedd, J. N. Why do many psychiatric disorders emerge during adolescence? Nature Rev. Neurosci. 9, 947–957 (2008). A very interesting review on the state of research into why adolescents have a greater vulnerability to mental health disorders.

    CAS  Google Scholar 

  67. Evans, G. W. & English, K. The environment of poverty: multiple stressor exposure, psychophysiological stress, and socioemotional adjustment. Child Dev. 73, 1238–1248 (2002).

    PubMed  Google Scholar 

  68. Andersen, S. L. & Teicher, M. H. Stress, sensitive periods and maturational events in adolescent depression. Trends Neurosci. 31, 183–191 (2008).

    CAS  PubMed  Google Scholar 

  69. De Bellis, M. D. et al. A. E. Bennett Research Award. Developmental traumatology. Part II: brain development. Biol. Psychiatry 45, 1271–1284 (1999). One of the first clear demonstrations that, in children who were physically healthy at birth, severe abuse in the early years of life is associated with reduced brain volume. The reduction correlates negatively with the age of onset and positively with the duration of the maltreatment.

    CAS  PubMed  Google Scholar 

  70. Cohen, R. A. et al. Early life stress and morphometry of the adult anterior cingulate cortex and caudate nuclei. Biol. Psychiatry 59, 975–982 (2006).

    PubMed  Google Scholar 

  71. Diamond, D. M., Bennett, M. C., Fleshner, M. & Rose, G. M. Inverted-U relationship between the level of peripheral corticosterone and the magnitude of hippocampal primed burst potentiation. Hippocampus 2, 421–430 (1992).

    CAS  PubMed  Google Scholar 

  72. Vouimba, R. M., Yaniv, D. & Richter-Levin, G. Glucocorticoid receptors and β-adrenoceptors in basolateral amygdala modulate synaptic plasticity in hippocampal dentate gyrus, but not in area CA1. Neuropharmacology 52, 244–252 (2007).

    CAS  PubMed  Google Scholar 

  73. Roozendaal, B., Brunson, K. L., Holloway, B. L., McGaugh, J. L. & Baram, T. Z. Involvement of stress-released corticotropin-releasing hormone in the basolateral amygdala in regulating memory consolidation. Proc. Natl Acad. Sci. USA 99, 13908–13913 (2002).

    CAS  PubMed  Google Scholar 

  74. Magarinos, A. M. & McEwen, B. S. Stress-induced atrophy of apical dendrites of hippocampal CA3c neurons: involvement of glucocorticoid secretion and excitatory amino acid receptors. Neuroscience 69, 89–98 (1995).

    CAS  PubMed  Google Scholar 

  75. Conrad, C. D., LeDoux, J. E., Magarinos, A. M. & McEwen, B. S. Repeated restraint stress facilitates fear conditioning independently of causing hippocampal CA3 dendritic atrophy. Behav. Neurosci. 113, 902–913 (1999).

    CAS  PubMed  Google Scholar 

  76. Gould, E., McEwen, B. S., Tanapat, P., Galea, L. A. & Fuchs, E. Neurogenesis in the dentate gyrus of the adult tree shrew is regulated by psychosocial stress and NMDA receptor activation. J. Neurosci. 17, 2492–2498 (1997).

    CAS  PubMed  Google Scholar 

  77. McEwen, B. S. Effects of adverse experiences for brain structure and function. Biol. Psychiatry 48, 721–731 (2000).

    CAS  PubMed  Google Scholar 

  78. Pham, K., Nacher, J., Hof, P. R. & McEwen, B. S. Repeated restraint stress suppresses neurogenesis and induces biphasic PSA-NCAM expression in the adult rat dentate gyrus. Eur. J. Neurosci. 17, 879–886 (2003).

    PubMed  Google Scholar 

  79. McEwen, B. S. Plasticity of the hippocampus: adaptation to chronic stress and allostatic load. Ann. NY Acad. Sci. 933, 265–277 (2001).

    CAS  PubMed  Google Scholar 

  80. Luine, V., Villegas, M., Martinez, C. & McEwen, B. S. Repeated stress causes reversible impairments of spatial memory performance. Brain Res. 639, 167–170 (1994).

    CAS  PubMed  Google Scholar 

  81. Joels, M., Karst, H., Krugers, H. J. & Lucassen, P. J. Chronic stress: implications for neuronal morphology, function and neurogenesis. Front. Neuroendocrinol. 28, 72–96 (2007).

    PubMed  Google Scholar 

  82. Izquierdo, A., Wellman, C. L. & Holmes, A. Brief uncontrollable stress causes dendritic retraction in infralimbic cortex and resistance to fear extinction in mice. J. Neurosci. 26, 5733–5738 (2006).

    CAS  PubMed  Google Scholar 

  83. Shansky, R. M., Hamo, C., Hof, P. R., McEwen, B. S. & Morrison, J. H. Stress-induced dendritic remodeling in the prefrontal cortex is circuit specific. Cereb. Cortex 4 Feb 2009 (doi:10.1093/cercor/bhp003).

    PubMed  Google Scholar 

  84. Cerqueira, J. J. et al. Corticosteroid status influences the volume of the rat cingulate cortex - a magnetic resonance imaging study. J. Psychiatr. Res. 39, 451–460 (2005).

    CAS  PubMed  Google Scholar 

  85. Mitra, R., Jadhav, S., McEwen, B. S., Vyas, A. & Chattarji, S. Stress duration modulates the spatiotemporal patterns of spine formation in the basolateral amygdala. Proc. Natl Acad. Sci. USA 102, 9371–9376 (2005).

    CAS  PubMed  Google Scholar 

  86. Mitra, R. & Sapolsky, R. M. Acute corticosterone treatment is sufficient to induce anxiety and amygdaloid dendritic hypertrophy. Proc. Natl Acad. Sci. USA 105, 5573–5578 (2008). This interesting study addressed endocrine effects on the brain, with a focus on the amygdala and anxiety (rather than on hippocampus and memory). Of note, a single dose of glucocorticoids was sufficient to induce changes in amygdala structure 10 days later, which might be useful to model in animals PTSD.

    CAS  PubMed  Google Scholar 

  87. Lupien, S. J. & McEwen, B. S. The acute effects of corticosteroids on cognition: integration of animal and human model studies. Brain Res. Brain Res. Rev. 24, 1–27 (1997).

    CAS  PubMed  Google Scholar 

  88. Roozendaal, B. Glucocorticoids and the regulation of memory consolidation. Psychoneuroendocrinology 25, 213–238 (2000).

    CAS  PubMed  Google Scholar 

  89. Lupien, S. J. et al. Stress hormones and human memory function across the lifespan. Psychoneuroendocrinology 30, 225–242 (2005).

    CAS  PubMed  Google Scholar 

  90. Lupien, S. J. et al. Hippocampal volume is as variable in young as in older adults: implications for the notion of hippocampal atrophy in humans. Neuroimage 34, 479–485 (2007). This study showed that 25% of young adults present hippocampal volumes as small as those of older adults. The presence of small hippocampal volumes in healthy young individuals supports the vulnerability hypothesis.

    CAS  PubMed  Google Scholar 

  91. Pruessner, J. C., Lord, C., Meaney, M. & Lupien, S. Effects of self-esteem on age-related changes in cognition and the regulation of the hypothalamic-pituitary-adrenal axis. Ann. NY Acad. Sci. 1032, 186–194 (2004).

    PubMed  Google Scholar 

  92. Pruessner, J. C. et al. Self-esteem, locus of control, hippocampal volume, and cortisol regulation in young and old adulthood. Neuroimage 28, 815–826 (2005).

    PubMed  Google Scholar 

  93. Burke, H. M., Davis, M. C., Otte, C. & Mohr, D. C. Depression and cortisol responses to psychological stress: a meta-analysis. Psychoneuroendocrinology 30, 846–856 (2005).

    CAS  PubMed  Google Scholar 

  94. Yehuda, R., Golier, J. A. & Kaufman, S. Circadian rhythm of salivary cortisol in Holocaust survivors with and without PTSD. Am. J. Psychiatry 162, 998–1000 (2005).

    PubMed  Google Scholar 

  95. Meewisse, M. L., Reitsma, J. B., de Vries, G. J., Gersons, B. P. & Olff, M. Cortisol and post-traumatic stress disorder in adults: systematic review and meta-analysis. Br. J. Psychiatry 191, 387–392 (2007). This paper presented the first meta-analysis of cortisol findings in PTSD, to elucidate the determinants of hypocortisolism and resolve the inconsistency in findings.

    PubMed  Google Scholar 

  96. Heim, C. et al. Pituitary-adrenal and autonomic responses to stress in women after sexual and physical abuse in childhood. JAMA 284, 592–597 (2000).

    CAS  Google Scholar 

  97. Heim, C., Mletzko, T., Purselle, D., Musselman, D. L. & Nemeroff, C. B. The dexamethasone/corticotropin-releasing factor test in men with major depression: role of childhood trauma. Biol. Psychiatry 63, 398–405 (2008).

    CAS  PubMed  Google Scholar 

  98. Carpenter, L. L. et al. Cerebrospinal fluid corticotropin-releasing factor and perceived early-life stress in depressed patients and healthy control subjects. Neuropsychopharmacology 29, 777–784 (2004).

    CAS  PubMed  Google Scholar 

  99. Heim, C., Newport, D. J., Mletzko, T., Miller, A. H. & Nemeroff, C. B. The link between childhood trauma and depression: insights from HPA axis studies in humans. Psychoneuroendocrinology 33, 693–710 (2008). A crucially important review which documents that the disturbances in the HPA axis that are observed in many adults with depression may be specific to those who experienced trauma or maltreatment in childhood.

    CAS  PubMed  Google Scholar 

  100. Videbech, P. & Ravnkilde, B. Hippocampal volume and depression: a meta-analysis of MRI studies. Am. J. Psychiatry 161, 1957–1966 (2004).

    PubMed  Google Scholar 

  101. Smith, M. E. Bilateral hippocampal volume reduction in adults with post-traumatic stress disorder: a meta-analysis of structural MRI studies. Hippocampus 15, 798–807 (2005).

    PubMed  Google Scholar 

  102. Vythilingam, M. et al. Childhood trauma associated with smaller hippocampal volume in women with major depression. Am. J. Psychiatry 159, 2072–2080 (2002).

    PubMed  PubMed Central  Google Scholar 

  103. Gilbertson, M. W. et al. Smaller hippocampal volume predicts pathologic vulnerability to psychological trauma. Nature Neurosci. 5, 1242–1247 (2002). The first paper to study whether the reduced hippocampal volume observed in PTSD patients is due to the disorder, to trauma exposure or to a pre-existing factor.

    CAS  PubMed  Google Scholar 

  104. Issa, A. M., Rowe, W., Gauthier, S. & Meaney, M. J. Hypothalamic-pituitary-adrenal activity in aged, cognitively impaired and cognitively unimpaired rats. J. Neurosci. 10, 3247–3254 (1990).

    CAS  PubMed  Google Scholar 

  105. Landfield, P. W., Waymire, J. C. & Lynch, G. Hippocampal aging and adrenocorticoids: quantitative correlations. Science 202, 1098–1102 (1978).

    CAS  PubMed  Google Scholar 

  106. Landfield, P. W., Baskin, R. K. & Pitler, T. A. Brain aging correlates: retardation by hormonal-pharmacological treatments. Science 214, 581–584 (1981). The first study to show that chronic exposure to high levels of glucocorticoids in rodents is associated with memory impairments and reduced hippocampal volume.

    CAS  PubMed  Google Scholar 

  107. Landfield, P. W., Blalock, E. M., Chen, K. C. & Porter, N. M. A new glucocorticoid hypothesis of brain aging: implications for Alzheimer's disease. Curr. Alzheimer Res. 4, 205–212 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Kulstad, J. J. et al. Effects of chronic glucocorticoid administration on insulin-degrading enzyme and amyloid-β peptide in the aged macaque. J. Neuropathol. Exp. Neurol. 64, 139–146 (2005).

    CAS  PubMed  Google Scholar 

  109. Sapolsky, R. M., Krey, L. C. & McEwen, B. S. The neuroendocrinology of stress and aging: the glucocorticoid cascade hypothesis. Endocr. Rev. 7, 284–301 (1986). The first paper to present the glucocorticoid cascade hypothesis, now referred to as the neurotoxicity hypothesis.

    CAS  PubMed  Google Scholar 

  110. Lowy, M. T., Wittenberg, L. & Yamamoto, B. K. Effect of acute stress on hippocampal glutamate levels and spectrin proteolysis in young and aged rats. J. Neurochem. 65, 268–274 (1995).

    CAS  PubMed  Google Scholar 

  111. Raskind, M. A., Peskind, E. R. & Wilkinson, C. W. Hypothalamic-pituitary-adrenal axis regulation and human aging. Ann. NY Acad. Sci. 746, 327–335 (1994).

    CAS  PubMed  Google Scholar 

  112. Lupien, S. J. et al. Cortisol levels during human aging predict hippocampal atrophy and memory deficits. Nature Neurosci. 1, 69–73 (1998).

    CAS  PubMed  Google Scholar 

  113. Giubilei, F. et al. Altered circadian cortisol secretion in Alzheimer's disease: clinical and neuroradiological aspects. J. Neurosci. Res. 66, 262–265 (2001).

    CAS  PubMed  Google Scholar 

  114. Aisen, P. S. et al. A randomized controlled trial of prednisone in Alzheimer's disease. Alzheimer's Disease Cooperative Study. Neurology 54, 588–593 (2000).

    CAS  PubMed  Google Scholar 

  115. Dai, J., Buijs, R. & Swaab, D. Glucocorticoid hormone (cortisol) affects axonal transport in human cortex neurons but shows resistance in Alzheimer's disease. Br. J. Pharmacol. 143, 606–610 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Chen, Y., Dube, C. M., Rice, C. J. & Baram, T. Z. Rapid loss of dendritic spines after stress involves derangement of spine dynamics by corticotropin-releasing hormone. J. Neurosci. 28, 2903–2911 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Charney, D. S. & Manji, H. K. Life stress, genes, and depression: multiple pathways lead to increased risk and new opportunities for intervention. Sci. STKE 2004, re5 (2004).

  118. Maercker, A., Michael, T., Fehm, L., Becker, E. S. & Margraf, J. Age of traumatisation as a predictor of post-traumatic stress disorder or major depression in young women. Br. J. Psychiatry 184, 482–487 (2004).

    PubMed  Google Scholar 

  119. Teicher, M. H., Tomoda, A. & Andersen, S. L. Neurobiological consequences of early stress and childhood maltreatment: are results from human and animal studies comparable? Ann. NY Acad. Sci. 1071, 313–323 (2006).

    PubMed  Google Scholar 

  120. Hall, F. S. Social deprivation of neonatal, adolescent, and adult rats has distinct neurochemical and behavioral consequences. Crit. Rev. Neurobiol. 12, 129–162 (1998).

    CAS  PubMed  Google Scholar 

  121. Andersen, S. L. Trajectories of brain development: point of vulnerability or window of opportunity? Neurosci. Biobehav. Rev. 27, 3–18 (2003). A superb review paper which suggested that trauma at different time points during early development might be associated with different outcomes, depending on the brain structure that was affected at the time of exposure to adversity.

    PubMed  Google Scholar 

  122. Widom, C. S., DuMont, K. & Czaja, S. J. A prospective investigation of major depressive disorder and comorbidity in abused and neglected children grown up. Arch. Gen. Psychiatry 64, 49–56 (2007).

    PubMed  Google Scholar 

  123. Clayton, N. S. & Krebs, J. R. Hippocampal growth and attrition in birds affected by experience. Proc. Natl Acad. Sci. USA 91, 7410–7414 (1994).

    CAS  PubMed  Google Scholar 

  124. Kudielka, B. M., Buske-Kirschbaum, A., Hellhammer, D. H. & Kirschbaum, C. HPA axis responses to laboratory psychosocial stress in healthy elderly adults, younger adults, and children: impact of age and gender. Psychoneuroendocrinology 29, 83–98 (2004).

    CAS  PubMed  Google Scholar 

  125. Kessler, R. C. Epidemiology of women and depression. J. Affect. Disord. 74, 5–13 (2003).

    PubMed  Google Scholar 

  126. Harlow, B. L., Cohen, L. S., Otto, M. W., Spiegelman, D. & Cramer, D. W. Early life menstrual characteristics and pregnancy experiences among women with and without major depression: the Harvard study of moods and cycles. J. Affect. Disord. 79, 167–176 (2004).

    PubMed  Google Scholar 

  127. Zabin, L. S., Emerson, M. R. & Rowland, D. L. Childhood sexual abuse and early menarche: the direction of their relationship and its implications. J. Adolesc. Health 36, 393–400 (2005).

    PubMed  Google Scholar 

  128. Jones, K. C. & de Voogt, P. Persistent organic pollutants (POPs): state of the science. Environ. Pollut. 100, 209–221 (1999).

    CAS  PubMed  Google Scholar 

  129. Centers for Disease Control and Prevention. Second National Report on Human Exposure to Environmental Chemicals. (CDC, Atlanta, Georgia, 2003).

  130. Daston, G. P., Cook, J. C. & Kavlock, R. J. Uncertainties for endocrine disrupters: our view on progress. Toxicol. Sci. 74, 245–252 (2003).

    CAS  PubMed  Google Scholar 

  131. Gump, B. B. et al. Low-level prenatal and postnatal blood lead exposure and adrenocortical responses to acute stress in children. Environ. Health Perspect. 116, 249–255 (2008).

    CAS  PubMed  Google Scholar 

  132. Denham, M. et al. Relationship of lead, mercury, mirex, dichlorodiphenyldichloroethylene, hexachlorobenzene, and polychlorinated biphenyls to timing of menarche among Akwesasne Mohawk girls. Pediatrics 115, e127–e134 (2005).

    PubMed  Google Scholar 

  133. Turek, F. W. From circadian rhythms to clock genes in depression. Int. Clin. Psychopharmacol. 22 (Suppl. 2), S1–S8 (2007).

    PubMed  Google Scholar 

  134. Lamarche, L. J. & De Koninck, J. Sleep disturbance in adults with posttraumatic stress disorder: a review. J. Clin. Psychiatry 68, 1257–1270 (2007).

    PubMed  Google Scholar 

  135. Antoch, M. P. et al. Functional identification of the mouse circadian Clock gene by transgenic BAC rescue. Cell 89, 655–667 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Yakovlev, P. L. & Lecours, A. R. in Regional Development of the Brain in Early Life (ed. Minkowski, A.) 3–70 (Blackwell, Oxford, 1967).

    Google Scholar 

  137. Pruessner, J. C. et al. Volumetry of hippocampus and amygdala with high-resolution MRI and three-dimensional analysis software: minimizing the discrepancies between laboratories. Cereb. Cortex 10, 433–442 (2000).

    CAS  PubMed  Google Scholar 

  138. Tisserand, D. J. et al. Regional frontal cortical volumes decrease differentially in aging: an MRI study to compare volumetric approaches and voxel-based morphometry. Neuroimage 17, 657–669 (2002).

    PubMed  Google Scholar 

  139. Insel, T. R., Battaglia, G., Fairbanks, D. W. & De Souza, E. B. The ontogeny of brain receptors for corticotropin-releasing factor and the development of their functional association with adenylate cyclase. J. Neurosci. 8, 4151–4158 (1988).

    CAS  PubMed  Google Scholar 

  140. Levine, S. The ontogeny of the hypothalamic-pituitary-adrenal axis. The influence of maternal factors. Ann. NY Acad. Sci. 746, 275–288; discussion 289–293 (1994).

    CAS  PubMed  Google Scholar 

  141. Gunnar, M. R. & Cheatham, C. L. Brain and behavior interfaces: stress and the developing brain. Infant Ment. Health J. 24, 195–211 (2003). A superb paper that summarized the effects of stress during development and how this knowledge can be used to develop effective interventions.

    Google Scholar 

  142. LeDoux, J. E. The emotional brain: The mysterious underpinnings of emotional life (Simon & Schuster, New York, 1996).

    Google Scholar 

Download references

Acknowledgements

Sonia Lupien holds a Research Chair on Gender and Mental Health by the Canadian Institutes of Health Research.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Sonia J. Lupien.

Related links

Related links

FURTHER INFORMATION

Sonia J. Lupien's homepage

Glossary

Programming

When an environmental factor that acts during a sensitive developmental period affects the structure and function of tissues, leading to effects that persist throughout life.

Mineralocorticoid receptor

A receptor that is activated by mineralocorticoids, such as aldosterone and deoxycorticosterone, as well as glucocorticoids, such as cortisol and cortisone. It also responds to progestins.

Glucocorticoid receptor

A receptor that is activated by cortisol, corticosterone and other glucocorticoids and is expressed in almost every cell in the body. It regulates genes controlling development, metabolism and the immune response.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lupien, S., McEwen, B., Gunnar, M. et al. Effects of stress throughout the lifespan on the brain, behaviour and cognition. Nat Rev Neurosci 10, 434–445 (2009). https://doi.org/10.1038/nrn2639

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrn2639

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing