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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Self-citation
Chronic Psychosocial Stress Causes Apical Dendritic Atrophy of Hippocampal CA3 Pyramidal Neurons in Subordinate Tree Shrews
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BREMNER J, IN PRESS BIOL PSYCHI .
GURVITS T, IN PRESS BIOL PSYCHI .
STARKMAN M, COMMUNICATION .

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Background
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“Psychologic stress compromises hippocampal function, which is involved in learning and memory [7] and is an important”
Background
Mixed Symptoms and Syndromes of Anxiety and Depression: Diagnostic, Prognostic, and Etiologic Issues
Barbee, J. G. (1998) · Annals of Clinical Psychiatry · doi:10.1023/a:1026198512361 · Cited by 60
“As one might suspect, recent research into the neurobiological basis of each of the anxiety disorders has tended to be far more divergent than convergent—examples include the focus on orbitofrontal/cingulate cortex and head of the caudate nucleus in OCD (98), the role of the amygdala and locus coeruleus in panic (99),…”
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Information Processing Bias in Post-traumatic Stress Disorder
Weber, D. L. (2008) · The Open Neuroimaging Journal · doi:10.2174/1874440000802010029 · Cited by 66
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Hippocampal volume in borderline personality disorder with and without comorbid posttraumatic stress disorder: A meta-analysis
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“This pattern of results is logical, as both conditions are associated with prolonged activation of the HPA Axis and exposure to glucocorticoids [15,16].”
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Altered behavioural response to acute stress in mice lacking cellular prion protein
Nico, P. B. C., de Paris, F., Vinadé, E. R., Amaral, O. B., Rockenbach, I. C., Soares, B. L., Guarnieri, R., Wichert‐Ana, L., Calvo, F., Walz, R., et al. (2005) · Behavioural Brain Research · doi:10.1016/j.bbr.2005.02.003 · Cited by 60
Caffeic Acid Phenethyl Ester (CAPE): Biosynthesis, Derivatives and Formulations with Neuroprotective Activities
Pérez, R., Burgos, V., Marín, V., Camins, A., Olloquequi, J., González‐Chavarría, I., Ulrich, H., Wyneken, Ú., Luarte, A., Ortíz, L., et al. (2023) · Antioxidants · doi:10.3390/antiox12081500 · Cited by 58
The Electroconvulsive Therapy Controversy: Evidence and Ethics
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Incorporating hypothalamic–pituitary–adrenal axis measures into preventive interventions for adolescent depression: Are we there yet?
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“Experimental animal models have demonstrated that continually heightened cortisol levels may over time contribute to hippocampal damage (Sapolsky, 1996), helping explain cognitive and memory deficits, and findings of reduced hippocampal volume in MDD (Bremner, 2000).”
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Social function in boys with cleft lip and palate: Relationship to ventral frontal cortex morphology
Boes, A. D., Murko, V., Wood, J. L., Langbehn, D. R., Canady, J. W., Richman, L. C., & Nopoulos, P. (2007) · Behavioural Brain Research · doi:10.1016/j.bbr.2007.04.009 · Cited by 60
“One mechanism that may mediate such structural changes is elevated corticosteroid levels, which have been shown to cause neuronal atrophy and decreased neurogenesis [16, 33,62].”
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Alterations in cognitive flexibility in a rat model of post-traumatic stress disorder
George, S. A., Rodriguez-Santiago, M., Riley, J., Abelson, J. L., Floresco, S., & Liberzon, I. (2015) · Behavioural Brain Research · doi:10.1016/j.bbr.2015.02.051 · Cited by 58
Single Aggressive Interactions Increase Urinary Glucocorticoid Levels in Wild Male Chimpanzees
Wittig, R. M., Crockford, C., Weltring, A., Deschner, T., & Zuberbühler, K. (2015) · PLoS ONE · doi:10.1371/journal.pone.0118695 · Cited by 57
“Social stress is often caused by a lack of control and predictability, such as the exclusion from food or other resources, or the threat of recurring aggression [6, 11].”
BackgroundInfluential
Role of Glia in Stress-Induced Enhancement and Impairment of Memory
Pearson-Leary, J., Osborne, D. M., & McNay, E. C. (2016) · Frontiers in Integrative Neuroscience · doi:10.3389/fnint.2015.00063 · Cited by 60
“…with results including cognitive deficits, hippocampal atrophy, metabolic dysfunction, and central insulin resistance (Sapolsky et al., 1985; Sapolsky, 1996; Willi et al., 2002; Joëls et al., 2004; Stranahan et al., 2008; Karatsoreos et al., 2010; Yun et al., 2010; Ye et al., 2011; Reagan,…”
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All Approaches to Preventing or Reversing Effects of Stress are Not the Same
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Plasma Membrane Calcium Pump Isoform 1 Gene Expression Is Repressed by Corticosterone and Stress in Rat Hippocampus
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“…and rapidly repressed by GCs. Characterization of the PMCA1 promoter region and 59 untranslated region will yield important insight into regulation of this gene by GCs. Elevated GCs compromise the ability of neural cells to withstand stresses such as ischemia or seizures (Sapolsky, 1996a,b).”
Background
Astrocyte control of glutamatergic activity: Downstream effects on serotonergic function and emotional behavior
Fullana, M. N., Gasull-Camós, J., Tarrés-Gatius, M., Castañé, A., Bortolozzi, A. A., & Artigas, F. (2019) · Neuropharmacology · doi:10.1016/j.neuropharm.2019.107914 · Cited by 58
Fecal corticosterone, body mass, and caching rates of Carolina chickadees (Poecile carolinensis) from disturbed and undisturbed sites
Lucas, J. R., Freeberg, T. M., Egbert, J. R., & Schwabl, H. G. (2006) · Hormones and Behavior · doi:10.1016/j.yhbeh.2005.12.012 · Cited by 57
“These effects could in turn be detrimental for a population's survival (see Sapolsky, 1996; Wingfield et al., 1997).”
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Retrograde episodic memory and emotion: A perspective from patients with dissociative amnesia
Reinhold, N., & Markowitsch, H. J. (2009) · Neuropsychologia · doi:10.1016/j.neuropsychologia.2009.01.037 · Cited by 59
“The effects of stressful and traumatic life events on cognitive and mnestic functions are especially apparent in patients with posttraumatic stress disorder (PTSD) (Sapolsky, 1994, 1996a, 1996b) and can even be seen in their offspring (Federenko et al., 2006; Yehuda, Blair, Labinsky, & Bierer, 2007).”
Influential
Relationships between Self‐Rating of Recovery from Work and Morning Salivary Cortisol
Gustafsson, K., Lindfors, P., Aronsson, G., & Lundberg, U. (2008) · Journal of Occupational Health · doi:10.1539/joh.50.24 · Cited by 57
Steroid dementia: An overlooked diagnosis?
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Dexamethasone Enhances Oxidative Stress-Induced Cell Death in Murine Neural Stem Cells
Mutsaers, H. A. M., & Tofighi, R. (2012) · Neurotoxicity Research · doi:10.1007/s12640-012-9308-9 · Cited by 57
The Prevalence of Posttraumatic Stress Disorder in an Adolescent Inpatient Unit
Koltek, M., Wilkes, T. C., & Atkinson, M. J. (1998) · The Canadian Journal of Psychiatry · doi:10.1177/070674379804300107 · Cited by 58
Stress associated with caregiving: An examination of the stress process model among Kenyan Luo elders
Ice, G. H., Sadruddin, A. F. A., Vagedes, A., Yogo, J., & Juma, E. A. (2012) · Social Science & Medicine · doi:10.1016/j.socscimed.2012.02.018 · Cited by 56
“Physiologically, stress increases cortisol, catecholamines and blood pressure, which, if sustained for a long enough period, can increase the risk of cardiovascular disease, weight gain, impaired immune response, impaired glucose tolerance and other negative health outcomes (Bjorntorp & Rosmond, 2000; McEwen, 2001, 20…”
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Antidepressant Administration Modulates Neural Stem Cell Survival and Serotoninergic Differentiation Through Bcl-2
Chen, S., Kao, C.-L., Chang, Y., Yen, C.-J., Shui, J.-W., Chien, C.-S., Chen, I.-L., Tsai, T., Ku, H., & Chiou, S. (2007) · Current Neurovascular Research · doi:10.2174/156720207779940707 · Cited by 56
“The recent observations supported that antidepressant drugs increase the production of serotoninergic neurotransmitter and they play a critical role in the initiation of neurogenesis in the hippocampus.”
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Chronic Unpredictable Mild Stress Induces Loss of GABA Inhibition in Corticotrophin-Releasing Hormone-Expressing Neurons through NKCC1 Upregulation
Gao, Y., Zhou, J., Zhu, Y. F., Kosten, T. A., & Li, D. (2016) · Neuroendocrinology · doi:10.1159/000446114 · Cited by 57
Preventing and treating PTSD-like memory by trauma contextualization
Abed, A. S. A., Ducourneau, E., Bouarab, C., Sellami, A., Marighetto, A., & Desmedt, A. (2020) · Nature Communications · doi:10.1038/s41467-020-18002-w · Cited by 63
CELLULAR MECHANISMS IN THE VULNERABILITY TO DEPRESSION AND RESPONSE TO ANTIDEPRESSANTS
Shelton, R. C. (2000) · Psychiatric Clinics of North America · doi:10.1016/s0193-953x(05)70193-3 · Cited by 55
New Insights into Glucocorticoid and Mineralocorticoid Signaling: Lessons from Gene Targeting
Reichardt, H. M., Tronche, F., Berger, S. M., Kellendonk, C., & Schütz, G. (1999) · Advances in pharmacology · doi:10.1016/s1054-3589(08)60108-8 · Cited by 56
The Brain, Homeostasis, and Health: Balancing Demands of the Internal and External Milieu
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Genetic and environmental factors interact to influence anxiety
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Social Competitiveness and Plasticity of Neuroendocrine Function in Old Age: Influence of Neonatal Novelty Exposure and Maternal Care Reliability
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“Because high levels of circulating stress hormones are known to result in reduced synaptic plasticity [69] as well as brain atrophy and cognitive dysfunction [70-72], less stress hormone release in response to familiar stressors may ultimately promote greater brain”
Correlation of ERα/ERβ expression with dendritic and behavioural changes in CUMS mice
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Worsening of Post-Traumatic Stress Disorder Symptoms with Cognitive Decline: Case Series
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Long-term effects of adverse childhood experiences - Actual evidence and needs for research/ Früher Streß und Langzeitfolgen für die Gesundheit - Wissenschaftlicher Erkenntnisstand und Forschungsdesiderate
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Mechanisms of Dendritic Maturation
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“High levels of glucocorticoids have been demonstrated to decrease dendritic length and the complexity of pyramidal cells in the adult hippocampus (111), thus being considered a stress effect on dendritic structure (107,108).”
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Fetal Growth And Programming Of The Hypothalamic–Pituitary–Adrenal Axis
Phillips, D. I. (2001) · Clinical and Experimental Pharmacology and Physiology · doi:10.1046/j.1440-1681.2001.03558.x · Cited by 54
“Glucocorticoids have been shown to endanger hippocampal neurons such that combination of a metabolic insult (such as hypoglycaemia) with altered glucocorticoids leads to neuron death.(18,19) This would result in decreased glucocorticoid feedback at the levels of the hippocampus.”
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Efficacy of ECT in Chronic, Severe, Antidepressant- and CBT-Refractory PTSD: An Open, Prospective Study
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Corticosteroids limit microglial activation occurring during acute stress
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“These effects were mimicked by chronic administration of high-doses of corticosterone (CORT) in non-stressed rats (Sapolsky et al., 1985; Sapolsky, 1996).”
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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