Why stress is bad for your brain

Sapolsky, Robert M.

doi:10.1126/science.273.5276.749

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

Why stress is bad for your brain

Sapolsky, Robert M.·1996·Science

DOI 10.1126/science.273.5276.749

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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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Cumulative exposure to high levels of cortisol over the lifetime is related to hippocampal atrophy.
“Cumulative exposure to high levels of cortisol over the lifetime is known to be related to hippocampal atrophy.”
From Self-esteem, locus of control, hippocampal volume, and cortisol regulation in young and old adulthood (2005) · cites this paper as Sapolsky, 1996
Stress can impair and damage specific brain structures via the action of neurotoxic glucocorticoids.
“Documented effects of stress include impairment and damage to specific brain structures via the action of neurotoxic glucocorticoids (Sapolsky, 1996;Watanabe et al., 1992;Woolley et al., 1990).”
From Self-esteem, locus of control, hippocampal volume, and cortisol regulation in young and old adulthood (2005) · cites this paper as Sapolsky, 1996

Physiological functions of glucocorticoids in stress and their relation to pharmacological actions
MUNCK, A., GUYRE, P. M., & HOLBROOK, N. J. (1984) · Endocrine Reviews · doi:10.1210/edrv-5-1-25 · Cited by 3,083 · see citing works
Hippocampal atrophy in recurrent major depression
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MRI-based measurement of hippocampal volume in patients with combat- related posttraumatic stress disorder
(1995) · American Journal of Psychiatry · doi:10.1176/ajp.152.7.973 · Cited by 1,610 · see citing works
Hippocampal damage associated with prolonged glucocorticoid exposure in primates
Sapolsky, R., Uno, H., Rebert, C., & Finch, C. (1990) · The Journal of Neuroscience · doi:10.1523/jneurosci.10-09-02897.1990 · Cited by 1,103 · see citing works
Effect of Neonatal Handling on Age-Related Impairments Associated with the Hippocampus
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Issa, A. M., Rowe, W. B., Gauthier, S. G., & Meaney, M. (1990) · Journal of Neuroscience · doi:10.1523/jneurosci.10-10-03247.1990 · Cited by 435 · see citing works
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Gurvits, T. V., Lasko, N. B., Schachter, S. C., Kuhne, A., Orr, S. P., & Pitman, R. K. (1993) · Journal of Neuropsychiatry · doi:10.1176/jnp.5.2.183 · Cited by 109 · see citing works
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Sapolsky, R. M. (1994) · Seminars in Neuroscience · doi:10.1006/smns.1994.1041 · Cited by 72 · see citing works

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Wingfield, J. C., & Romero, L. M. (2001) · Comprehensive physiology · doi:10.1002/cphy.cp070411 · Cited by 461 · see citing works
Decrease in cortisol reverses human hippocampal atrophy following treatment of Cushing’s disease
Starkman, M. N., Giordani, B., Gebarski, S. S., Berent, S., Schork, M. A., & Schteingart, D. E. (1999) · Biological Psychiatry · doi:10.1016/s0006-3223(99)00203-6 · Cited by 455 · see citing works
“The hippocampus as a target of glucocorticoid (GC)activity is an area of increasing scientific and clinical interest (Sapolsky 1996).”
Background
Cell aging in relation to stress arousal and cardiovascular disease risk factors
Epel, E. S., Lin, J., Wilhelm, F. H., Wolkowitz, O. M., Cawthon, R., Adler, N. E., Dolbier, C., Mendes, W. B., & Blackburn, E. H. (2006) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2005.08.011 · Cited by 450 · see citing works
“Glucocorticoids are linked to neuronal cell death (Sapolsky, 1996), in part through greater oxidative stress damage, by increasing intra-neuronal levels of glutamate and calcium and impairing antioxidant defenses (McIntosh and Sapolsky, 1996).”
Background
Dendritic Spines in Depression: What We Learned from Animal Models
Qiao, H., Li, M.-X., Xu, C. S., Chen, H.-B., An, S.-C., & Ma, X. (2016) · Neural Plasticity · doi:10.1155/2016/8056370 · Cited by 442 · see citing works
“The relationship between stress and psychiatric diseases has been well established for 20 years in the clinic [25, 26].”
Background
Measures of physiological stress: a transparent or opaque window into the status, management and conservation of species?
Dantzer, B., Fletcher, Q. E., Boonstra, R., & Sheriff, M. J. (2014) · Conservation Physiology · doi:10.1093/conphys/cou023 · Cited by 444 · see citing works
“For example, chronic stress can cause neuronal atrophy in key parts of the brain (Sapolsky, 1996), suppress the immune system (Dhabhar and McEwen, 1997; Korte et al.”
Background
The Potential Benefits of Mindfulness Training in Early Childhood: A Developmental Social Cognitive Neuroscience Perspective
Zelazo, P. D., & Lyons, K. E. (2012) · Child Development Perspectives · doi:10.1111/j.1750-8606.2012.00241.x · Cited by 446 · see citing works
“…attitude that may directly attenuate influences that interfere with reflection (such as cortisol/stress; e.g., Pechtel & Pizzagalli, 2010; Sapolsky, 1996) and amplify influences that promote it (such as dopamine/approach-oriented emotions such as Child Development Perspectives, Volume 0,…”
Background
Magnetic resonance imaging (MRI) measurement of hippocampal volume in posttraumatic stress disorder: a meta-analysis
Kitayama, N., Vaccarino, V., Kutner, M., Weiss, P., & Bremner, J. D. (2005) · Journal of Affective Disorders · doi:10.1016/j.jad.2005.05.014 · Cited by 423 · see citing works
“Studies in animals suggest that stress results in structural changes in the hippocampus (McEwen et al., 1992; Sapolsky, 1996).”
Background
Executive function and the promotion of social–emotional competence
Riggs, N. R., Jahromi, L. B., Razza, R. A., Dilworth‐Bart, J. E., & Mueller, U. (2006) · Journal of Applied Developmental Psychology · doi:10.1016/j.appdev.2006.04.002 · Cited by 421 · see citing works
“…in the structure and function of the brain (Beers & De Bellis, 2002; Cicchetti & Tucker, 1994; Dawson et al., 2001; De Bellis, Keshavan, Spencer, & Hall, 2000; Fishbein, 2001; Ito, Teicher, Glod, & Ackerman, 1998; McEwen, 1997; Sapolsky, 1996; Stein, Koverola, Hanna, Torchia, & McCarty, 1997).”
Is depression a risk factor for dementia or cognitive decline?
Jorm, A. F. (2000) · Gerontology · doi:10.1159/000022163 · Cited by 416 · see citing works
Early life influences on life-long patterns of behavior and health
McEwen, B. S. (2003) · Mental Retardation and Developmental Disabilities Research Reviews · doi:10.1002/mrdd.10074 · Cited by 418 · see citing works
Allostasis and Allostatic Load
McEwen, B. S., & Wingfield, J. C. (2007) · Elsevier eBooks · doi:10.1016/b978-012373947-6.00025-8 · Cited by 418 · see citing works
MR-based in vivo hippocampal volumetrics: 2. Findings in neuropsychiatric disorders
Geuze, E., Vermetten, E., & Bremner, J. D. (2005) · Molecular Psychiatry · doi:10.1038/sj.mp.4001579 · Cited by 412 · see citing works
Maternal prenatal cortisol and infant cognitive development: moderation by infant–mother attachment
Bergman, K., Sarkar, P., Glover, V., & O'Connor, T. G. (2010) · Biological Psychiatry · doi:10.1016/j.biopsych.2010.01.002 · Cited by 395 · see citing works
“Other evidence(25-26) that links cortisol exposure and impaired cognitive”
Antenatal Glucocorticoids and Programming of the Developing CNS
Matthews, S. G. (2000) · Pediatric Research · doi:10.1203/00006450-200003000-00003 · Cited by 400 · see citing works
Developing Sustainable Leaders Through Coaching and Compassion
Boyatzis, R. E., Smith, M. L., & Blaize, N. (2006) · Academy of Management Learning & Education · doi:10.5465/amle.2006.20388381 · Cited by 389 · see citing works
“neural tissue through normal neurogenesis (McEwen, 1998; Sapolsky, 1996; Sapolsky, 1999,”
Stress and development: Behavioral and biological consequences
Bremner, J., & Vermetten, E. (2001) · Development and Psychopathology · doi:10.1017/s0954579401003042 · Cited by 405 · see citing works
“(McEwen, 2000; Sapolsky, 1996, 2000; Sapolsky, Uno, Rebert, & Finch, 1990).”
Recurrent depressive symptoms and the incidence of dementia and mild cognitive impairment
Dotson, V. M., Beydoun, M. A., & Zonderman, A. B. (2010) · Neurology · doi:10.1212/wnl.0b013e3181e62124 · Cited by 385 · see citing works
Neonatal maternal separation reduces hippocampal mossy fiber density in adult Long Evans rats
Huot, R. L., Plotsky, P. M., Lenox, R. H., & McNamara, R. K. (2002) · Brain Research · doi:10.1016/s0006-8993(02)02985-2 · Cited by 383 · see citing works
“cortisol [12,13,54,85,89,90,97].”
BackgroundInfluential
Chronic widespread pain and fibromyalgia: what we know, and what we need to know
Clauw, D. J., & Crofford, L. J. (2003) · Best Practice & Research Clinical Rheumatology · doi:10.1016/s1521-6942(03)00035-4 · Cited by 379 · see citing works
Glutathione Depletion, Lipid Peroxidation and Mitochondrial Dysfunction Are Induced by Chronic Stress in Rat Brain
Madrigal, J. L. M. (2001) · Neuropsychopharmacology · doi:10.1016/s0893-133x(00)00208-6 · Cited by 381 · see citing works
Neurosteroids: Expression of Steroidogenic Enzymes and Regulation of Steroid Biosynthesis in the Central Nervous System
Mensah‐Nyagan, A. G., do Rego, J. L., Beaujean, D., Luu-The, V., Pelletier, G., & Vaudry, H. (1999) · Pharmacological Reviews · doi:10.1016/s0031-6997(24)01395-4 · Cited by 379 · see citing works
“Depending on their chemical nature and concentration, steroids can induce either protective or deleterious effects on nerve cells (Uno et al., 1989; Yu, 1989; Jones, 1993; Sapolsky, 1996; Green et al., 1997; Seckl, 1997; Kimonides et al., 1998).”
Child maltreatment and HPA axis dysregulation: relationship to major depressive disorder and post traumatic stress disorder in females
Shea, A., Walsh, C., MacMillan, H., & Steiner, M. (2005) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2004.07.001 · Cited by 378 · see citing works
“the potential negative effects of long-term exposure of glucorticoids on the brain (Sapolsky, 1996).”
Background
Repeated stress alters dendritic spine morphology in the rat medial prefrontal cortex
Radley, J. J., Rocher, A. B., Rodriguez, A., Ehlenberger, D. B., Dammann, M., McEwen, B. S., Morrison, J. H., Wearne, S. L., & Hof, P. R. (2007) · The Journal of Comparative Neurology · doi:10.1002/cne.21588 · Cited by 374 · see citing works
“…to play a critical role in the etiology of numerous psychiatric illnesses, such as depression, posttraumatic stress disorder, and anxiety (Sapolsky, 1996; Heim et al., 1997; McEwen, 1998; Newport and Nemeroff, 2000; Caspi et al., 2003), and in other instances it may precipitate the…”
Background
A systematic review and meta-analysis of magnetic resonance imaging measurement of structural volumes in posttraumatic stress disorder
O'Doherty, D. C. M., Chitty, K. M., Saddiqui, S., Bennett, M. R., & Lagopoulos, J. (2015) · Psychiatry Research: Neuroimaging · doi:10.1016/j.pscychresns.2015.01.002 · Cited by 375 · see citing works
“Animal studies on rodents (McEwen et al., 1992; Sunanda et al., 1995; Magarinos et al., 1996; Sapolsky, 1996; Gould et al., 1998; McEwen, 2000b; Stewart et al., 2005) and primates (Sapolsky et al.”
Background
Serotonergic vulnerability and depression: assumptions, experimental evidence and implications
Jans, L. A. W., Riedel, W. J., Markus, C. R., & Blokland, A. (2006) · Molecular Psychiatry · doi:10.1038/sj.mp.4001920 · Cited by 372 · see citing works
Increase in Urinary Cortisol Excretion and Memory Declines: MacArthur Studies of Successful Aging1
Seeman, T. E., McEwen, B. S., Singer, B. H., Albert, M., & Rowe, J. W. (1997) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.82.8.4173 · Cited by 372 · see citing works
Structural and functional plasticity of the human brain in posttraumatic stress disorder
Bremner, J. D., Elzinga, B. M., Schmahl, C. G., & Vermetten, E. H. G. J. M. (2007) · Progress in brain research · doi:10.1016/s0079-6123(07)67012-5 · Cited by 368 · see citing works
Neuroprotective effects of Ginkgo biloba extract
Ahlemeyer, B., & Krieglstein, J. (2003) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-003-3080-1 · Cited by 368 · see citing works
Evidence for Acquired Pregenual Anterior Cingulate Gray Matter Loss from a Twin Study of Combat-Related Posttraumatic Stress Disorder
Kasai, K., Yamasue, H., Gilbertson, M. W., Shenton, M. E., Rauch, S. L., & Pitman, R. K. (2007) · Biological Psychiatry · doi:10.1016/j.biopsych.2007.06.022 · Cited by 366 · see citing works
Hippocampal Volume in Patients With Alcohol Dependence
Agartz, I., Momenan, R., Rawlings, R. R., Kerich, M. J., & Hommer, D. W. (1999) · Archives of General Psychiatry · doi:10.1001/archpsyc.56.4.356 · Cited by 360 · see citing works
“The hippocampus is rich in glucocorticoid receptors and considered particularly vulnerable.(13) Thus, the human hippocampus may be more affected than other brain structures by alcohol’s neurotoxic effects.”
Background
Structural roles of acetylcholinesterase variants in biology and pathology
Grisaru, D., Sternfeld, M., Eldor, A., Glick, D., & Soreq, H. (1999) · European Journal of Biochemistry · doi:10.1046/j.1432-1327.1999.00693.x · Cited by 355 · see citing works
Diseases Among Men 20 Years After Exposure to Severe Stress
Boscarino, J. A. (1997) · Psychosomatic Medicine · doi:10.1097/00006842-199711000-00008 · Cited by 352 · see citing works
Fibromyalgia: an overview
Clauw, D. J. (2009) · The American Journal of Medicine · doi:10.1016/j.amjmed.2009.09.006 · Cited by 350 · see citing works
Early Intervention and the Development of Self-Regulation
Fonagy, P., & Target, M. (2002) · Psychoanalytic Inquiry · doi:10.1080/07351692209348990 · Cited by 350 · see citing works
Song as an honest signal of developmental stress in the zebra finch (Taeniopygia guttata)
Spencer, K. A., Buchanan, K. L., Goldsmith, A. R., & Catchpole, C. K. (2003) · Hormones and Behavior · doi:10.1016/s0018-506x(03)00124-7 · Cited by 345 · see citing works
Higher cortisol levels following exposure to traumatic reminders in abuse-related PTSD
Elzinga, B. M., Schmahl, C. G., Vermetten, E., van Dyck, R., & Bremner, J. D. (2003) · Neuropsychopharmacology · doi:10.1038/sj.npp.1300226 · Cited by 341 · see citing works
“Studies in animals show that high levels of GCs may have a long-term inhibitory effect on memory function with GC-mediated hippocampal toxicity and memory dysfunction with stress (McEwen et al, 1992; Sapolsky, 1996; Arbel et al, 1994; Conrad et al, 1996; Luine et al, 1994; Ohl et al, 2000).”
Background
Pathoetiological Model of Delirium: a Comprehensive Understanding of the Neurobiology of Delirium and an Evidence-Based Approach to Prevention and Treatment
Maldonado, J. R. (2008) · Critical Care Clinics · doi:10.1016/j.ccc.2008.06.004 · Cited by 338 · see citing works
“Finally, glucocorticoid excess may contribute to energy failure of neurons by inhibiting glucose transport into cells [173–176].”
Background

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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