Cited by 1,306Stress Responses and CortisolMemory and Neural MechanismsNeuroscience and Neuropharmacology Research

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Why Stress Is Bad for Your Brain

Sapolsky, Robert M.·1996·Science

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Abstract

Several recent studies of humans correlate stress with atrophy of the hippocampus, an area of the brain required for memory and cognition. In his Perspective, Sapolsky argues that the underlying causal agent may be glucocorticoids secreted in abnormally high amounts under stressful conditions.

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Crossref · 10.1126/science.273.5276.749

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Physiological functions of glucocorticoids in stress and their relation to pharmacological actions
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Hippocampal damage associated with prolonged glucocorticoid exposure in primates
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Effect of Neonatal Handling on Age-Related Impairments Associated with the Hippocampus
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Self-citation
Chronic Psychosocial Stress Causes Apical Dendritic Atrophy of Hippocampal CA3 Pyramidal Neurons in Subordinate Tree Shrews
Magariños, A. M., McEwen, B. S., Flügge, G., & Fuchs, E. (1996) · The Journal of Neuroscience · doi:10.1523/jneurosci.16-10-03534.1996 · Cited by 864
Hippocampal formation volume, memory dysfunction, and cortisol levels in patients with Cushing's syndrome
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Hippocampal damage associated with prolonged and fatal stress in primates
Uno, H., Tarara, R., Else, J., Suleman, M., & Sapolsky, R. (1989) · The Journal of Neuroscience · doi:10.1523/jneurosci.09-05-01705.1989 · Cited by 728
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“Although chronic stress can be harmful (Sapolsky, 1996), relatively minor adversity is for the brain a necessary prerequisite for developing resilience to later challenges and as part of healthy development (Dhabhar andMcEwen, 1996;Macrı́ et al., 2009).”
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Eagle, A. L., & Perrine, S. A. (2013) · Drug and Alcohol Dependence · doi:10.1016/j.drugalcdep.2013.04.001 · Cited by 19
“Indeed, numerous studies have found that other types of stressors, both acute and chronic, can enhance psychostimulant sensitization (Kikusui et al., 2005; Nikulina et al., 1998; Prasad et al., 1995; Sapolsky, 1996).”
Background
The Everyday Stress Resilience Hypothesis: A Reparatory Sensitivity and the Development of Coping and Resilience
Tronick, E., & DiCorcia, J. A. (2015) · Children Australia · doi:10.1017/cha.2015.11 · Cited by 18
“…were more likely to have elevated resting cortisol levels (Bugental, Martorell, & Barraza, 2003), a maladaptive response indicative of a CHILDREN AUSTRALIA 131 hyper-responsive HPA axis (Dickerson & Kemeny, 2004; Hellhammer, Wüst, & Kudielka, 2009; Lovallo & Thomas, 2000; Sapolsky, 1996).”
Background
Systematic review of in-vivo neuro magnetic resonance spectroscopy for the assessment of posttraumatic stress disorder
Quadrelli, S., Mountford, C. E., & Ramadan, S. A. (2018) · Psychiatry Research Neuroimaging · doi:10.1016/j.pscychresns.2018.07.001 · Cited by 19
Protective Effects of Colomast®, a New Formulation of Adelmidrol and Sodium Hyaluronate, in a Mouse Model of Acute Restraint Stress
D’Amico, R., Siracusa, R., Fusco, R., Cordaro, M., Genovese, T., Peritore, A. F., Gugliandolo, E., Crupi, R., Impellizzeri, D., Cuzzocrea, S., et al. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21218136 · Cited by 18
“Stress has negative effects on health and plays an important role in the predisposition to many physical illnesses [29,30].”
Background
The Hypothalamic-Pituitary-Adrenal System (HPA) and the Development of Aggressive, Antisocial, and Substance Abuse Disorders
McBurnett, K., King, J., & Scarpa, A. (2003) · Cambridge University Press eBooks · doi:10.1017/cbo9780511546365.015 · Cited by 17
A Biological Model for Delayed Recall of Childhood Abuse
Bremner, J. D. (2001) · Journal of Aggression Maltreatment & Trauma · doi:10.1300/j146v04n02_08 · Cited by 18
“Work from laboratories such as Sapolsky (1996) at Stanford University and McEwen et al. (1992) at Rockefeller University demonstrated that, in a variety of animal species, high levels of glucocorticoids (cortisol in man) seen in stress are associated with damage to the hippocampus.”
Background
Neurological complications of chemotherapy
Cherubini, G. B., & Platt, S. R. (2008) · Companion animal · doi:10.1111/j.2044-3862.2008.tb00291.x · Cited by 18
Disaster, Terrorism and Children
Joshi, P. T., & Lewin, S. M. (2004) · Psychiatric Annals · doi:10.3928/0048-5713-20040901-16 · Cited by 18
Biomarkers of Hippocampal Gene Expression in a Mouse Restraint Chronic Stress Model
Ubaldi, M., Ricciardelli, E., Pasqualini, L., Sannino, G., Soverchia, L., Ruggeri, B., Falcinelli, S., Renzi, A., Ludka, C., Ciccocioppo, R., et al. (2015) · Pharmacogenomics · doi:10.2217/pgs.15.3 · Cited by 19
Religion, Families, and Health
Ellison, C. G., Hummer, R. A., Bartkowski, J. P., Pearce, L., Alwin, D. F., Felson, J., Regnerus, M., King, V., Xu, X., Burdette, A. M., et al. (2020) · Rutgers University Press eBooks · doi:10.36019/9780813549453 · Cited by 18
Automatism and dissociation: Disturbances of consciousness and volition from a psychological perspective
McLeod, H. J., Byrne, M. K., & Aitken, R. (2004) · International Journal of Law and Psychiatry · doi:10.1016/j.ijlp.2004.06.007 · Cited by 18
“However, such distinctions may be somewhat arbitrary, as psychological trauma may trigger biological reactions that have direct effects on brain function (Joseph, 1999; Sapolsky, 1996).”
Background
Reduction but not cleavage of poly(ADP-ribose) polymerase during stress-mediated cell death in the rat hippocampus
Yun, S., Lee, D.-J., Kim, M., Jung, B., Kim, S. O., Sohn, N. W., & Lee, E. H. (2003) · Neuroreport · doi:10.1097/00001756-200305230-00006 · Cited by 18
Antenatal steroid therapy: Have we undervalued the risks?
Cavalieri, R. L., & Cohen, W. R. (2006) · The Journal of Maternal-Fetal & Neonatal Medicine · doi:10.1080/14767050600676075 · Cited by 18
“Mood disorders have been linked to hippocampal volume [36] and dexamethasoneinduced hippocampal injury [37].”
Background
Post-traumatic stress disorder and memory: prescient medicolegal testimony at the International War Crimes Tribunal?
Sparr, L. F., & Bremner, J. D. (2005) · PubMed · Cited by 18
c-jun mRNA expression in the hippocampal formation induced by restraint stress
de Oliveira, C. L., Guimarães, F. S., & Bel, E. A. D. (1997) · Brain Research · doi:10.1016/s0006-8993(96)01490-4 · Cited by 18
Do neonatal pain and stress program the brain's response to future stimuli?
Winberg, J. (1998) · Acta Paediatrica · doi:10.1111/j.1651-2227.1998.tb01735.x · Cited by 18
“Interestingly, with modern imaging techniques, it has been shown that stress or high cortisol levels diminish the volume of the hippocampus (12).”
Background
A Novel Ashwagandha (Withania somnifera) Formulation Mitigates Sleep Deprivation-Induced Cognitive Impairment and Oxidative Stress in a Rat Model
Er, B., Ozmen, B., Şahin, E., Orhan, C., Şahin, N., Morde, A. A., Padigaru, M., & Şahin, K. (2025) · Biomolecules · doi:10.3390/biom15050710 · Cited by 18
“SD is closely linked to the activation of the hypothalamic–pituitary–adrenal (HPA) axis, leading to elevated levels of corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH), which can interfere with memory consolidation [6,7].”
Maladaptive Neuroplasticity Under Stress: Insights into Neuronal and Synaptic Changes in the Prefrontal Cortex
Ren, B., Yuan, Q., Cha, S., Liu, S.-Y. M., Zhang, J., & Guo, G. (2025) · Molecular Neurobiology · doi:10.1007/s12035-025-05152-5 · Cited by 21
“…molecular mechanisms of stress on neurogenesis and synaptic plasticity, emphasizing the pivotal role of glutamate and its receptors, such as N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, in stress-shaped synapse ([44, 45], reviewed in [46]).”
Neurobiological Formulations: Integrating Clinical and Biological Psychiatry
Posner, J. E., Stewart, J. W., & Rieder, R. (2007) · Academic Psychiatry · doi:10.1176/appi.ap.31.6.479 · Cited by 17
Mathematical modeling the neuroregulation of blood pressure using a cognitive top-down approach
Ewing, G. W. (2010) · North American Journal of Medical Sciences · doi:10.4297/najms.2010.2341 · Cited by 17
“• the measurement of blood pressure [79],”
The neurobiology of brain recovery from traumatic stress: A longitudinal DTI study
Meng, L., Chen, Y., Xu, X. Y., Chen, T., Lui, S., Huang, X., Sweeney, J. A., Li, K., & Gong, Q. (2017) · Journal of Affective Disorders · doi:10.1016/j.jad.2017.08.075 · Cited by 19
A case of lightning injury with delayed-onset psychiatric and cognitive symptoms
Reisner, A. D. (2006) · Brain Injury · doi:10.1080/02699050600832007 · Cited by 17
“This damage or dysfunction may result from over-stimulation of glutamate (an excitatory amino acid, EAA) receptors in the hippocampus and may be partially mediated by stress-induced glucocorticoid hormones [16, 18, 19].”
Background
Hormonal and Behavioural Abnormalities Induced by Stressin utero: an Animal Model for Depression
Maccari, S., Darnaudéry, M., & Reeth, O. V. (2001) · Stress · doi:10.3109/10253890109035016 · Cited by 17
“, 1992), and may result from a stress component (Sapolsky, 1996; Rosenwasser and Wirz-Justice, 1997).”
Background
Children’s Vocal Properties as Mobilizers of Stress-Related Physiological Responses in Adults
Lin, E. K., Bugental, D. B., Turek, V. F., Martorell, G. A., & Olster, D. H. (2002) · Personality and Social Psychology Bulletin · doi:10.1177/0146167202286006 · Cited by 17
“This hormonal system is typically activated in response to stimulus events that are ambiguous, unpredictable, unexpected, and potentially important (Sapolsky, 1996).”
Background
Monoamines, BDNF, Dehydroepiandrosterone, DHEA-Sulfate, and Childhood Depression—An Animal Model Study
Malkesman, O., Asaf, T., Shbiro, L., Goldstein, A., Maayan, R., Weizman, A., Kinor, N., Okun, E., Sredni, B., Yadid, G., et al. (2009) · Advances in Pharmacological Sciences · doi:10.1155/2009/405107 · Cited by 17
“From the BDNF results it seems that prepubertal WKY rats exhibit lower levels of BDNF in the hippocampus (at least in one region-CA3) as has been found in several human studies [73] and animal studies [30], and in accordance with the BDNF theory of depression.”
Result
Molecular Biology of Behavior
Post, R. M. (1997) · Archives of General Psychiatry · doi:10.1001/archpsyc.1997.01830190025003 · Cited by 17
The effect of stress on the acute neurotoxicity of the organophosphate insecticide chlorpyrifos
Hancock, S. K., Ehrich, M. F., Hinckley, J., Pung, T., & Jortner, B. S. (2006) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2006.11.014 · Cited by 17

Authors: Sapolsky, R. M.
Affiliations: Stanford University (US)
Corresponding author: Sapolsky, Robert M.
ORCID: Sapolsky, Robert M.
Venue: Science
Publisher: American Association for the Advancement of Science (AAAS)
Published: 1996-08-09
Volume: 273
Issue: 5276
Pages: 749-750
ISSN: 0036-8075 (ISSN-L)
1095-9203
DOI: 10.1126/science.273.5276.749
OpenAlex: W1994048221
Cited by: 1,306
References: 12
Citations by year: 2026: 10 · 2025: 13 · 2024: 12 · 2023: 17 · 2022: 27 · 2021: 36 · 2020: 37 · 2019: 24 · 2018: 27 · 2017: 32 · 2016: 35 · 2015: 45 · 2014: 49 · 2013: 43 · 2012: 51
FWCI: 24.94
Type: journal article
Language: en
Open access: closed
Locations: Science (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords: stress, hippocampal atrophy, glucocorticoids, memory, cognition, neurodegeneration, stress hormones
MeSH terms: Animals, Atrophy, Brain, Cushing Syndrome, Depressive Disorder, Female, Glucocorticoids, Hippocampus, Humans, Magnetic Resonance Imaging, Male, Stress, Physiological, Stress Disorders, Post-Traumatic, Causality

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