Developmental determinants of sensitivity and resistance to stress
Abstract
The purpose of this paper is two fold. First, to revisit the issue of the definition of stress and to highlight the difficulties with the contemporary definitions and, second, to review the literature on the influence of early experiences on the endocrine stress responses and behavior in rodents, sub-human primates and humans. Early experiences, usually involving some manipulation that results in disruption of the mother-infant relationship, have been shown to have long-term influences on the behavioral and endocrine responses to stress. In the rodent, brief periods of separation result in an attenuated adrenal response to stress (reduced secretion of corticosterone). In contrast, longer periods of separation result in an exaggerated response and several behavioral anomalies i.e. increased alcohol consumption, increased startle response etc. However, the effects of disruptions of the mother-infant relationships in primates reveal a pattern of behavioral disturbance but little influence on the endocrine response. Brief maternal separations result in a blunted cortisol response in juvenile squirrel monkeys. The long-term effects of early experiences in humans are very difficult to interpret. It is not possible to determine the length and severity of the experiences, and when in development the experiences were imposed on the child. Despite these limitations, there is a general consensus that adverse early experiences contribute to adult psychopathology.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The stress response system is highly plastic, particularly in response to early experience.
“The SRS is highly plastic, especially in response to early experience”
From The Adaptive Calibration Model of stress responsivity (2011) · cites this paper as Levine, 2005
Cites
The concept of allostasis in biology and biomedicine
McEwen, B. S., & Wingfield, J. C. (2003) · Hormones and Behavior · doi:10.1016/s0018-506x(02)00024-7 · Cited by 3,302 · see citing works
Liu, D., Diorio, J., Tannenbaum, B., Caldji, C., Francis, D., Freedman, A., Sharma, S., Pearson, D., Plotsky, P. M., & Meaney, M. J. (1997) · Science · doi:10.1126/science.277.5332.1659 · Cited by 3,170 · see citing works
Heim, C. (2000) · JAMA · doi:10.1001/jama.284.5.592 · Cited by 1,968 · see citing works
Plotsky, P. M., & Meaney, M. J. (1993) · Molecular Brain Research · doi:10.1016/0169-328x(93)90189-v · Cited by 1,638 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Chronic stress, drug use, and vulnerability to addiction
Sinha, R. (2008) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1441.030 · Cited by 1,904 · see citing works
Miller, G. E., Chen, E., & Parker, K. J. (2011) · Psychological Bulletin · doi:10.1037/a0024768 · Cited by 1,785 · see citing works
Stress revisited: a critical evaluation of the stress concept
Koolhaas, J. M., Bartolomucci, A., Buwalda, B., de Boer, S. F., Flügge, G., Korte, S. M., Meerlo, P., Murison, R., Olivier, B., Palanza, P., et al. (2011) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2011.02.003 · Cited by 1,626 · see citing works
The Adaptive Calibration Model of stress responsivity
Del Giudice, M., Ellis, B. J., & Shirtcliff, E. A. (2011) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2010.11.007 · Cited by 1,373 · see citing works
Antenatal maternal stress and long‐term effects on child neurodevelopment: how and why?
Talge, N. M., Neal, C., Glover, V., & the Early Stress, T. R. A. P. S. N. F. A. N. E. O. C. A. A. M. H. (2007) · Journal of Child Psychology and Psychiatry · doi:10.1111/j.1469-7610.2006.01714.x · Cited by 1,349 · see citing works
Dynamic DNA methylation programs persistent adverse effects of early-life stress
Murgatroyd, C., Patchev, A. V., Wu, Y., Micale, V., Bockmühl, Y., Fischer, D., Holsboer, F., Wotjak, C. T., Almeida, O. F. X., & Spengler, D. (2009) · Nature Neuroscience · doi:10.1038/nn.2436 · Cited by 1,162 · see citing works
Miller, G. E., Chen, E., Fok, A. K., Walker, H., Lim, A., Nicholls, E. F., Cole, S., & Kobor, M. S. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0902971106 · Cited by 822 · see citing works
Feldman, R., Granat, A., Pariente, C., Kanety, H., Kuint, J., & Gilboa-Schechtman, E. (2009) · Journal of the American Academy of Child & Adolescent Psychiatry · doi:10.1097/chi.0b013e3181b21651 · Cited by 747 · see citing works
Hostinar, C. E., Sullivan, R. M., & Gunnar, M. R. (2014) · Psychological Bulletin · doi:10.1037/a0032671 · Cited by 739 · see citing works
Feldman, R., Rosenthal, Z., & Eidelman, A. I. (2014) · Biological Psychiatry · doi:10.1016/j.biopsych.2013.08.012 · Cited by 632 · see citing works
Daskalakis, N. P., Bagot, R. C., Parker, K. J., Vinkers, C. H., & de Kloet, E. R. (2013) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2013.06.008 · Cited by 579 · see citing works
Touch attenuates infants' physiological reactivity to stress
Feldman, R., Singer, M., & Zagoory, O. (2010) · Developmental Science · doi:10.1111/j.1467-7687.2009.00890.x · Cited by 436 · see citing works
Van den Bergh, B. R. H., Van Calster, B., Smits, T., Van Huffel, S., & Lagae, L. (2008) · Neuropsychopharmacology · doi:10.1038/sj.npp.1301450 · Cited by 434 · see citing works
Maternal separation as a model of brain-gut axis dysfunction
O’Mahony, S. M., Hyland, N. P., Dinan, T. G., & Cryan, J. F. (2011) · Psychopharmacology · doi:10.1007/s00213-010-2010-9 · Cited by 415 · see citing works
Agorastos, A., Pervanidou, P., Chrousos, G. P., & Baker, D. G. (2019) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2019.00118 · Cited by 385 · see citing works
“This model underlines the extraordinary plasticity of the brain and suggests that “nothing is written in stone” (464).”
BackgroundGunnar, M. R., Frenn, K., Wewerka, S. S., & Van Ryzin, M. J. (2009) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2008.08.013 · Cited by 363 · see citing works
Mismatch or cumulative stress: Toward an integrated hypothesis of programming effects
Nederhof, E., & Schmidt, M. V. (2012) · Physiology & Behavior · doi:10.1016/j.physbeh.2011.12.008 · Cited by 363 · see citing works
Cicchetti, D., Rogosch, F. A., Gunnar, M. R., & Toth, S. L. (2010) · Child Development · doi:10.1111/j.1467-8624.2009.01393.x · Cited by 337 · see citing works
Feldman, R. (2015) · Development and Psychopathology · doi:10.1017/s0954579415000048 · Cited by 271 · see citing works
Tractenberg, S. G., Levandowski, M. L., de Azeredo, L. A., Orso, R., Roithmann, L. G., Hoffmann, E. S., Brenhouse, H., & Grassi-Oliveira, R. (2016) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2016.06.021 · Cited by 267 · see citing works
Burke, N. N., Finn, D. P., McGuire, B. E., & Roche, M. (2017) · Journal of Neuroscience Research · doi:10.1002/jnr.23802 · Cited by 268 · see citing works
Juster, R.-P., Bizik, G., Picard, M., Arsenault-Lapierre, G., Sindi, S., Trepanier, L., Marin, M.-F., Wan, N., Sekerovic, Z., Lord, C., et al. (2011) · Development and Psychopathology · doi:10.1017/s0954579411000289 · Cited by 268 · see citing works
Transcriptional modulation of the developing immune system by early life social adversity
Cole, S. W., Conti, G., Arevalo, J. M. G., Ruggiero, A. M., Heckman, J. J., & Suomi, S. J. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1218253109 · Cited by 207 · see citing works
kappa-Opioid receptor signaling and brain reward function
Bruijnzeel, A. W. (2009) · Brain Research Reviews · doi:10.1016/j.brainresrev.2009.09.008 · Cited by 214 · see citing works
Epigenetics and the regulation of stress vulnerability and resilience
Zannas, A. S., & West, A. E. (2014) · Neuroscience · doi:10.1016/j.neuroscience.2013.12.003 · Cited by 211 · see citing works
Moriceau, S., Shionoya, K., Jakubs, K., & Sullivan, R. M. (2009) · The Journal of Neuroscience · doi:10.1523/jneurosci.4106-09.2009 · Cited by 214 · see citing works
Ouellet-Morin, I., Wong, C. C. Y., Danese, A., Pariante, C. M., Papadopoulos, A. S., Mill, J., & Arseneault, L. (2013) · Psychological Medicine · doi:10.1017/s0033291712002784 · Cited by 207 · see citing works
Stead, J. D. H., Clinton, S., Neal, C., Schneider, J., Jama, A., Miller, S., Vazquez, D. M., Watson, S. J., & Akil, H. (2006) · Behavior Genetics · doi:10.1007/s10519-006-9058-7 · Cited by 209 · see citing works
Suri, D., Veenit, V., Sarkar, A., Thiagarajan, D., Kumar, A., Nestler, E. J., Galande, S., & Vaidya, V. A. (2013) · Biological Psychiatry · doi:10.1016/j.biopsych.2012.10.023 · Cited by 208 · see citing works
Stratified medicine for mental disorders
Schumann, G., Binder, E. B., Holte, A., de Kloet, E. R., Oedegaard, K. J., Robbins, T. W., Walker-Tilley, T. R., Bitter, I., Brown, V. J., Buitelaar, J., et al. (2014) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2013.09.010 · Cited by 186 · see citing works
Feldman, R. (2015) · Development and Psychopathology · doi:10.1017/s0954579415000656 · Cited by 181 · see citing works
Evolution and ontogeny of stress response to social challenges in the human child
FLINN, M. (2006) · Developmental Review · doi:10.1016/j.dr.2006.02.003 · Cited by 173 · see citing works
Cicchetti, D., & Rogosch, F. A. (2007) · Development and Psychopathology · doi:10.1017/s0954579407000399 · Cited by 168 · see citing works
Cicchetti, D., Rogosch, F. A., Toth, S. L., & Sturge-Apple, M. L. (2011) · Development and Psychopathology · doi:10.1017/s0954579411000307 · Cited by 168 · see citing works
Maternal separation with early weaning: A novel mouse model of early life neglect
George, E. D., Bordner, K. A., Elwafi, H. M., & Simen, A. A. (2010) · BMC Neuroscience · doi:10.1186/1471-2202-11-123 · Cited by 163 · see citing works
Parental depression and child outcomes–is marital conflict the missing link?
Hanington, L., Heron, J., Stein, A., & Ramchandani, P. (2012) · Child: Care, Health and Development · doi:10.1111/j.1365-2214.2011.01270.x · Cited by 160 · see citing works
Critical age windows for neurodevelopmental psychiatric disorders: evidence from animal models
Marco, E. M., Macrì, S., & Laviola, G. (2011) · Neurotoxicity Research · doi:10.1007/s12640-010-9205-z · Cited by 144 · see citing works
Early deprivation and home basal cortisol levels: a study of internationally adopted children
Kertes, D. A., Gunnar, M. R., Madsen, N. J., & Long, J. D. (2008) · Development and Psychopathology · doi:10.1017/s0954579408000230 · Cited by 121 · see citing works
Lifestyle and Chronic Pain across the Lifespan: An Inconvenient Truth?
Nijs, J., D'Hondt, E., Clarys, P., Deliens, T., Polli, A., Malfliet, A., Coppieters, I., Willaert, W., Tumkaya Yilmaz, S., Elma, Ö., et al. (2020) · PM&R · doi:10.1002/pmrj.12244 · Cited by 121 · see citing works
Cardiovascular health of Finnish war evacuees 60 years later
Alastalo, H., Räikkönen, K., Pesonen, A.-K., Osmond, C., Barker, D. J. P., Kajantie, E., Heinonen, K., Forsén, T. J., & Eriksson, J. G. (2009) · Annals of Medicine · doi:10.1080/07853890802301983 · Cited by 116 · see citing works
Childhood and later life stressors and increased inflammatory gene expression at older ages
Levine, M. E., Cole, S. W., Weir, D. R., & Crimmins, E. M. (2015) · Social Science & Medicine · doi:10.1016/j.socscimed.2015.01.030 · Cited by 106 · see citing works
Cirulli, F., Berry, A., Bonsignore, L. T., Capone, F., D’Andrea, I., Aloe, L., Branchi, I., & Alleva, E. (2010) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2010.02.008 · Cited by 105 · see citing works
Are behavioral effects of early experience mediated by oxytocin?
Bales, K. L., Boone, E., Epperson, P., Hoffman, G., & Carter, C. S. (2011) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2011.00024 · Cited by 99 · see citing works
Cellular and molecular mechanisms of hippocampal activation by acute stress are age-dependent
Chen, Y., Fenoglio, K. A., Dubé, C. M., Grigoriadis, D. E., & Baram, T. Z. (2006) · Molecular Psychiatry · doi:10.1038/sj.mp.4001863 · Cited by 98 · see citing works
Opendak, M., Gould, E., & Sullivan, R. (2017) · Developmental Cognitive Neuroscience · doi:10.1016/j.dcn.2017.02.002 · Cited by 94 · see citing works
Branchi, I., Karpova, N. N., D’Andrea, I., Castrén, E., & Alleva, E. (2011) · Neuroscience Letters · doi:10.1016/j.neulet.2011.03.038 · Cited by 87 · see citing works
Kofink, D., Boks, M. P. M., Timmers, H. T. M., & Kas, M. J. (2013) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2013.03.020 · Cited by 83 · see citing works
Kober, H., Brewer, J. A., Height, K. L., & Sinha, R. (2017) · NeuroImage · doi:10.1016/j.neuroimage.2016.09.042 · Cited by 75 · see citing works
Age of trauma onset and HPA axis dysregulation among trauma-exposed youth
Kuhlman, K. R., Vargas, I., Geiss, E. G., & Lopez‐Duran, N. L. (2015) · Journal of Traumatic Stress · doi:10.1002/jts.22054 · Cited by 75 · see citing works
Øines, E., Murison, R., Mrdalj, J., Grønli, J., & Milde, A. M. (2012) · Physiology & Behavior · doi:10.1016/j.physbeh.2011.11.024 · Cited by 66 · see citing works
Sevelinges, Y., Mouly, A.-M., Raineki, C., Moriceau, S., Forest, C., & Sullivan, R. M. (2011) · Developmental Cognitive Neuroscience · doi:10.1016/j.dcn.2010.07.005 · Cited by 56 · see citing works
Loria, A. S., Ho, D. H., & Pollock, J. S. (2014) · Acta Physiologica · doi:10.1111/apha.12189 · Cited by 53 · see citing works
“Overall, compelling data suggest that repeated exposure to adversity in early life programmes a ‘defensive’ phenotype, which displays a functional resistance to stress-induced responses (Levine 2005, Lyons et al. 2010).”
BackgroundGrowing pains and pleasures: how emotional learning guides development
Nelson, E. E., Lau, J. Y. F., & Jarcho, J. M. (2014) · Trends in Cognitive Sciences · doi:10.1016/j.tics.2013.11.003 · Cited by 48 · see citing works
Hamilton, K. R., Perry, M. E., Berger, S. S., & Grunberg, N. E. (2010) · Nicotine & Tobacco Research · doi:10.1093/ntr/ntq179 · Cited by 27 · see citing works
Kentrop, J., van der Tas, L., Loi, M., van IJzendoorn, M. H., Bakermans-Kranenburg, M. J., Joëls, M., & van der Veen, R. (2016) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2016.00122 · Cited by 16 · see citing works
- Authors
- Levine, S.
- Affiliations
- University of California, Davis (US)
- Corresponding author
- Levine, Seymour
- Venue
- Psychoneuroendocrinology
- Publisher
- Elsevier BV
- Published
- 2005-11
- Volume
- 30
- Issue
- 10
- Pages
- 939-946
- ISSN
- 0306-4530 (ISSN-L)
- OpenAlex
- W2003174307
- Cited by
- 574
- References
- 4
- Citations by year
- 2026: 15 · 2025: 11 · 2024: 7 · 2023: 11 · 2022: 23 · 2021: 33 · 2020: 27 · 2019: 32 · 2018: 21 · 2017: 27 · 2016: 34 · 2015: 29 · 2014: 40 · 2013: 40 · 2012: 32
- FWCI
- 11.39
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Psychoneuroendocrinology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r37mh045006-11)
- National Institute of Mental Health (MH 45006)
- National Institute of Child Health and Human Development
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD-0281)
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Social Sciences › Psychology › Clinical Psychology › Child Abuse and Trauma
- Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
- Keywords
- stress sensitivity, stress tolerance, childhood adversity, maternal separation, maternal deprivation, endocrine stress response, cortisol, corticosterone, startle response, alcohol consumption, behavioral anomalies, adult psychopathology, stress definition, rodents, squirrel monkey, primates
- MeSH terms
- Adult, Aging, Animals, Child, Child Abuse, Sexual, Female, Humans, Individuality, Male, Maternal Deprivation, Primates, Stress, Psychological
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
