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Central effects of stress hormones in health and disease: Understanding the protective and damaging effects of stress and stress mediators
Open accessAbstract
Stress begins in the brain and affects the brain, as well as the rest of the body. Acute stress responses promote adaptation and survival via responses of neural, cardiovascular, autonomic, immune and metabolic systems. Chronic stress can promote and exacerbate pathophysiology through the same systems that are dysregulated. The burden of chronic stress and accompanying changes in personal behaviors (smoking, eating too much, drinking, poor quality sleep; otherwise referred to as "lifestyle") is called allostatic overload. Brain regions such as hippocampus, prefrontal cortex and amygdala respond to acute and chronic stress and show changes in morphology and chemistry that are largely reversible if the chronic stress lasts for weeks. However, it is not clear whether prolonged stress for many months or years may have irreversible effects on the brain. The adaptive plasticity of chronic stress involves many mediators, including glucocorticoids, excitatory amino acids, endogenous factors such as brain neurotrophic factor (BDNF), polysialated neural cell adhesion molecule (PSA-NCAM) and tissue plasminogen activator (tPA). The role of this stress-induced remodeling of neural circuitry is discussed in relation to psychiatric illnesses, as well as chronic stress and the concept of top-down regulation of cognitive, autonomic and neuroendocrine function. This concept leads to a different way of regarding more holistic manipulations, such as physical activity and social support as an important complement to pharmaceutical therapy in treatment of the common phenomenon of being "stressed out". Policies of government and the private sector play an important role in this top-down view of minimizing the burden of chronic stress and related lifestyle (i.e. allostatic overload).
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TL;DR
This review argues that the brain is the central organ of the stress response and that acute stress mediators are protective/adaptive, whereas chronic or dysregulated allostasis produces “allostatic overload” that damages brain and body. It synthesizes evidence on stress-induced structural plasticity in hippocampus, prefrontal cortex, and amygdala, and discusses top-down behavioral and policy interventions.
Key findings
- Acute stress responses promote adaptation via neural, cardiovascular, autonomic, immune, and metabolic systems, but chronic stress can promote pathophysiology through the same systems; the cumulative burden plus behaviors such as poor sleep, smoking, overeating, drinking, and inactivity is termed allostatic overload.
- In hippocampus, chronic restraint stress causes retraction and simplification of CA3 dendrites, while repeated stress causes dendritic shortening in medial prefrontal cortex but dendritic growth in amygdala and orbitofrontal cortex; these changes are largely reversible if chronic stress lasts weeks, though it is unclear whether stress lasting months or years has irreversible brain effects.
- Adult rat dentate gyrus produces about 9,000 new neurons per day with a half-life of 28 days; the dentate gyrus–CA3 system gives roughly 600-fold amplification of excitation and 300-fold amplification of inhibition.
- Human findings cited include 12–13% smaller hippocampal volume in individuals with poor self-esteem and low internal locus of control, and lower allostatic load scores in people with 3 or more regular social contacts versus 0–2 contacts; a 12-month modest cortisol regimen did not cause outright neuronal loss in pigtail macaque hippocampus.
Methods
- Narrative review synthesizing animal and human studies on stress mediators, allostasis/allostatic load, and brain structural plasticity.
- Evidence includes rodent chronic stress and glucocorticoid studies, nonhuman primate cortisol studies, human neuroimaging, clinical studies of depression/Cushing’s disease/PTSD, and psychosocial studies.
- Main analysis is conceptual integration of allostasis, allostatic overload, and top-down regulation of cognitive, autonomic, and neuroendocrine function; no primary data or systematic meta-analysis are reported.
Limitations
- Stated: the interacting allostatic systems are non-linear and cannot all be measured simultaneously, so studies rely on only a few biomarkers and must interpret results with that non-linearity in mind.
- Stated: it is not clear whether prolonged stress for many months or years may have irreversible effects on the brain; mechanistic differences between chronic restraint stress and chronic corticosterone treatment remain to be determined, and BDNF mRNA findings after chronic restraint stress are contradictory.
- Evident from the text: as a narrative review, it does not report a systematic search strategy, quality appraisal, or meta-analytic synthesis, and much of the mechanistic evidence comes from animal models, limiting direct causal inference in humans.
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Claims the paper makes
100 Not checked yet · 21 Own interpretation
In the paper
“Cold and uncaring families produce long-lasting emotional problems in children (Repetti et al., 2002).”
What the sources say
- Not checked yetcites Repetti et al., 2002 source
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In the paper
“In contrast to these potentially maladaptive consequences, the same mediators are involved in the natural world in adaptation to environmental changes (McEwen and Wingfield, 2003).”
§ 1. Introduction > 1.2 Multiple mediators and multiple systems
What the sources say
- Not checked yetcites McEwen and Wingfield, 2003 source
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In the paper
“Parasympathetic activity also has anti-inflammatory effects (Thayer and Lane, 2000; Borovikova et al., 2000).”
§ 1. Introduction > 1.2 Multiple mediators and multiple systems
What the sources say
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In the paper
“on the other hand, chronic elevation of these same mediators - e.g. chronically increased heart rate and blood pressure – produce a chronic wear and tear on the cardiovascular system that can result, over time, in disorders such as stroke and heart attacks.”
§ 1. Introduction > 1.1 Defining stress, allostasis and allostatic load
What the sources say
- Not checked yetcites McEwen, 1998 source
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In the paper
“Different alleles of commonly occurring genes determine how individuals will respond to experiences.”
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Sleep deprivation produces an allostatic overload that can have deleterious consequences (McEwen, 2006; McEwen, 2007).”
§ 1. Introduction > 1.2 Multiple mediators and multiple systems
What the sources say
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In the paper
“In the case of the marsupial mouse, it is only the males that die after mating, due apparently to a response to mating that reduces the binding protein, corticosteroid binding globulin (CBG), for glucocorticoids and renders them much more active throughout the body (Cockburn and Lee, 1988).”
§ 1. Introduction > 1.3 Stress in the natural world
What the sources say
- Not checked yetcites Cockburn and Lee, 1988
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Early life physical and sexual abuse carry with it a life-long burden of behavioral and pathophysiological problems (Felitti et al., 1998; Heim and Nemeroff, 2001).”
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Yet, there are exceptions – pro-inflammatory effects of glucocorticoids that depend on dose and cell or tissue type (Dinkel et al., 2003; MacPherson et al., 2005).”
§ 1. Introduction > 1.2 Multiple mediators and multiple systems
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“The hippocampus expresses both Type I (mineralocorticoid, mineralocorticoid receptor) and Type II (glucocorticoid, glucocorticoid receptor) receptors”
§ 2. Central role of the brain > 2.1 Stress and glucocorticoid effects on the hippocampus
What the sources say
- Not checked yetcites Joels, 2006
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- Probably not a substantial claim. 15
- It may state two separate claims as one. 43
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Although glucocorticoids and catecholamines are the two defining hormones of the “fight or flight” stress response, there are many other mediators, such as pro- and anti-inflammatory cytokines and the parasympathetic nervous system, that are also involved in the adaptation to stressors, as well as in the negative impact of chronic stress, known in every day language as being “stressed out”.”
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The brain is the central organ of the stress response and determines what is stressful, as well as the behavioral and physiological responses to potential and actual stressors.”
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper may give no reason why it holds. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The adaptive plasticity of chronic stress involves many mediators, including glucocorticoids, excitatory amino acids, endogenous factors such as brain neurotrophic factor (BDNF), polysialated neural cell adhesion molecule (PSA-NCAM) and tissue plasminogen activator (tPA).”
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The brain is also a target of stress and it changes structurally and chemically in response to both acute and chronic stressors.”
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper may give no reason why it holds. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Chronic stress can promote and exacerbate pathophysiology through the same systems that are dysregulated.”
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Acute stress responses promote adaptation and survival via responses of neural, cardiovascular, autonomic, immune and metabolic systems.”
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Indeed, there are important differences in the effects of acute and chronic stress, as well as differences in the consequences of acute and chronic treatment with glucocorticoids.”
plaincorrelational- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Glucocorticoids play a role in these changes, but there are other mediators as well.”
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“on the one hand, the body responds to almost any sudden, unexpected event by releasing chemical mediators – e.g. catecholamines that increase heart rate and blood pressure – and help the individual cope with the situation”
§ 1. Introduction > 1.1 Defining stress, allostasis and allostatic load
What the sources say
- Not checked yetcites McEwen, 1998 source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Brain regions such as hippocampus, prefrontal cortex and amygdala respond to acute and chronic stress and show changes in morphology and chemistry that are largely reversible if the chronic stress lasts for weeks.”
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: unclear — It is unclear why the paper says it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Stress begins in the brain and affects the brain, as well as the rest of the body.”
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds. It may state two separate claims as one.
In the paper
“For example, the short form of the serotonin transporter is associated with a number of conditions such as alcoholism, and individuals who have this allele are more vulnerable to respond to stressful experiences by developing depressive illness (Caspi et al., 2003).”
What the sources say
- Not checked yetcites Caspi et al., 2003 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“There are enormous individual differences in the response to stress, based upon the experience of the individual early in life and in adult life.”
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“For example, uncertainty in the food supply for rhesus monkey mothers leads to increased emotionality in offspring and possibly an earlier onset of obesity and diabetes (Coplan et al., 2001).”
What the sources say
- Not checked yetcites Coplan et al., 2001 source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Regarding allostasis, in Spring, a sudden snowstorm is an acute stressor to birds and disrupts mating, and elevated cortisol is pivotal in directing the birds to suspend reproduction, to find a source of food and to relocate to a better mating site or at least to delay reproduction until the weather improves (Wingfield and Romero, 2000).”
§ 1. Introduction > 1.3 Stress in the natural world
What the sources say
- Not checked yetcites Wingfield and Romero, 2000
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In the paper
“Furthermore, in rodents, abuse of the young is associated with an attachment, rather than an avoidance, of the abusive mother, an effect that increases the chances that the infant can continue to obtain food and other support until weaning (Sullivan et al., 2000).”
What the sources say
- Not checked yetcites Sullivan et al., 2000 source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Hunger for comfort foods and increased caloric intake are one result, along with depressed mood and cognitive impairment (Dallman, 2003;McEwen, 2006).”
§ 1. Introduction > 1.2 Multiple mediators and multiple systems
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Whereas catecholamines can increase pro-inflammatory cytokine production, glucocorticoids are known to inhibit this production (Sapolsky et al., 2000).”
§ 1. Introduction > 1.2 Multiple mediators and multiple systems
What the sources say
- Not checked yetcites Sapolsky et al., 2000 source
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In the paper
“Effects of early maternal care are transmitted across generations by the subsequent behavior of the female offspring as they become mothers, and methylation of DNA on key genes appears to play a role in this epigenetic transmission (Weaver et al., 2004).”
What the sources say
- Not checked yetcites Weaver et al., 2004 source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“For allostatic load, bears preparing to hibernate for the winter eat large quantities of food and put on body fat to act as an energy source during the winter (Nelson, 1980).”
§ 1. Introduction > 1.3 Stress in the natural world
What the sources say
- Not checked yetcites Nelson, 1980
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In the paper
“What this non-linearity means is that when any one mediator is increased or decreased, there are compensatory changes in the other mediators that depend on time course and level of change of each of the mediators.”
§ 1. Introduction > 1.2 Multiple mediators and multiple systems
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In the paper
“The brain is the key organ of the stress response because it determines what is threatening and, therefore, potentially stressful, and also controls the behavioral and physiological responses, and resulting lifestyle, discussed earlier in this article, which are as important to development of allostatic load and overload as the stressful experiences themselves (Fig. 1).”
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“The effects include elevated evening cortisol, insulin and blood glucose, elevated blood pressure, reduced parasympathetic activity and elevated levels of proinflammatory cytokines, as well as the gut hormone, ghrelin, which increases appetite.”
§ 1. Introduction > 1.2 Multiple mediators and multiple systems
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Early life maternal care in rodents is a powerful determinant of life-long emotional reactivity and stress hormone reactivity and increases in both are associated with earlier cognitive decline and a shorter lifespan (Francis et al., 1999; Cavigelli and McClintock, 2003).”
What the sources say
- Not checked yetcites Francis et al., 1999 source
- Not checked yetcites Cavigelli and McClintock, 2003
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Regarding the mechanism of structural remodeling, adrenal steroids are important mediators of remodeling of hippocampal neurons during repeated stress, and exogenous adrenal steroids can also cause remodeling in the absence of an external stressor.”
§ 2. Central role of the brain > 2.1 Stress and glucocorticoid effects on the hippocampus
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Chronic restraint stress is known to reduce dentate gyrus proliferation whereas acute restraint does not have any measurable effect (Pham et al., 2003).”
§ 2. Central role of the brain > 2.1 Stress and glucocorticoid effects on the hippocampus
What the sources say
- Not checked yetcites Pham et al., 2003 source
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Emotional arousal for a rodent by being placed in a novel environment is required for adrenal steroids to enhance object recognition memory, that involves the hippocampus; the effects of adrenal steroids on this memory show an inverted U shaped dose response (Okuda et al., 2004).”
§ 2. Central role of the brain > 2.1 Stress and glucocorticoid effects on the hippocampus
What the sources say
- Not checked yetcites Okuda et al., 2004 source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“For neurogenesis in dentate gyrus, elevated glucocorticoid levels in an enriched environment or during physical activity are associated with increased neurogenesis and/or cell survival, even though there are other conditions in which glucocorticoids suppress neurogenesis (Mirescu and Gould, 2006).”
§ 2. Central role of the brain > 2.1 Stress and glucocorticoid effects on the hippocampus
What the sources say
- Not checked yetcites Mirescu and Gould, 2006 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Excitatory amino acids released by the mossy fiber pathway play a key role in the remodeling of the CA3 region of the hippocampus, and regulation of glutamate release by adrenal steroids may play an important role (McEwen, 1999).”
§ 2. Central role of the brain > 2.1 Stress and glucocorticoid effects on the hippocampus
What the sources say
- Not checked yetcites McEwen, 1999 source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“there is also adaptive structural plasticity, in that new neurons continue to be produced in the dentate gyrus throughout adult life, and CA3 pyramidal cells undergo a reversible remodeling of their dendrites in conditions such as hibernation and chronic stress (Popov et al., 1992; Popov and Bocharova, 1992; McEwen, 1999).”
§ 2. Central role of the brain > 2.1 Stress and glucocorticoid effects on the hippocampus
What the sources say
- Not checked yetcites Popov et al., 1992
- Not checked yetcites Popov and Bocharova, 1992
- Not checked yetcites McEwen, 1999 source
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In the paper
“these receptors mediate a biphasic response to adrenal steroids in the CA1 region although not in the dentate gyrus (Joels, 2006)”
§ 2. Central role of the brain > 2.1 Stress and glucocorticoid effects on the hippocampus
What the sources say
- Not checked yetcites Joels, 2006
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These studies indicate that only more prolonged treatment by higher glucocorticoid doses are able to impair performance on more demanding tasks involving hippocampal function and that they do so under conditions in which there is no neuronal loss but there are reductions in volume of hippocampal neuropil that may be due to loss of glia cells or reduction of dendritic length and branching.”
§ 2. Central role of the brain > 2.1 Stress and glucocorticoid effects on the hippocampus
hedgeddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“In childhood, individuals with an allele of the monoamine oxidase A gene are more vulnerable to abuse in childhood and more likely to themselves become abusers, and to show antisocial behaviors compared to individuals with another commonly occurring allele (Caspi et al., 2002).”
What the sources say
- Not checked yetcites Caspi et al., 2002 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“With respect to stress, certain types of acute stress and many chronic stressors suppress neurogenesis or cell survival in the dentate gyrus, and the mediators of these inhibitory effects include excitatory amino acids acting via NMDA receptors and endogenous opioids (Gould et al., 1997).”
§ 2. Central role of the brain > 2.1 Stress and glucocorticoid effects on the hippocampus
What the sources say
- Not checked yetcites Gould et al., 1997 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“BDNF +/− mice show a less branched dendritic tree and do not show a further reduction of CA3 dendrite length with chronic stress, whereas wild-type mice show reduced dendritic branching (Magarinos, McEwen, unpublished).”
§ 2. Central role of the brain > 2.3 Role of other modulators in structural remodeling
What the sources say
- Not checked yetcites Magarinos, McEwen, unpublished
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Neural cell adhesion molecule (NCAM) and its polysialated-NCAM (PSA-NCAM), as well as L1 are expressed in the dentate gyrus and CA3 region”
§ 2. Central role of the brain > 2.3 Role of other modulators in structural remodeling
What the sources say
- Not checked yetcites Sandi, 2004 source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“These effects occur in the medial and central amygdala and not in basolateral amygdala”
§ 2. Central role of the brain > 2.2 Prefrontal cortex and amygdala
What the sources say
- Not checked yetcites Matys et al., 2004 source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“and enhances amygdala-dependent unlearned fear and fear conditioning (Conrad et al., 1999)”
§ 2. Central role of the brain > 2.2 Prefrontal cortex and amygdala
What the sources say
- Not checked yetcites Conrad et al., 1999 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“a large number of reported rapid, non-genomic actions of adrenal steroids (Borski, 2000; Makara and Haller, 2001)”
§ 2. Central role of the brain > 2.1 Stress and glucocorticoid effects on the hippocampus
What the sources say
- Not checked yetcites Borski, 2000 source
- Not checked yetcites Makara and Haller, 2001
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“the discovery of adrenal steroid receptors that are G protein coupled in the amphibian brain (Orchinik et al., 1991)”
§ 2. Central role of the brain > 2.1 Stress and glucocorticoid effects on the hippocampus
What the sources say
- Not checked yetcites Orchinik et al., 1991 source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Tissue plasminogen activator (tPA) is an extracellular protease and signalling molecule that is released with neural activity and is required for chronic stress-induced loss of spines and NMDA receptor subunits on CA1 neurons (Pawlak et al., 2005).”
§ 2. Central role of the brain > 2.3 Role of other modulators in structural remodeling
What the sources say
- Not checked yetcites Pawlak et al., 2005 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“early life stress produces a delayed effect that reduces cognitive function and the number of CA3 neurons as well as decreased branching of hippocampal pyramidal neurons (Brunson et al., 2001; Brunson et al., 2005).”
§ 2. Central role of the brain > 2.3 Role of other modulators in structural remodeling
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“whereas CRF in the central amygdala is involved in control of behavioral and autonomic responses to stress, including the release to tPA that is an essential part of stress-induced anxiety and structural plasticity in the medial amygdala (Matys et al., 2004).”
§ 2. Central role of the brain > 2.3 Role of other modulators in structural remodeling
What the sources say
- Not checked yetcites Matys et al., 2004 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“BDNF and corticosteroids appear to oppose each other – with BDNF reversing reduced excitability in hippocampal neurons induced by stress levels of corticosterone (Hansson et al., 2006).”
§ 2. Central role of the brain > 2.3 Role of other modulators in structural remodeling
What the sources say
- Not checked yetcites Hansson et al., 2006 source
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“amygdala volume has been reported to increase in the first episode of depression, whereas hippocampal volume is not decreased (MacQueen et al., 2003; Frodl et al., 2003).”
§ 3. Translation to the human brain > 3.1 Depression, Cushing’s Disease and Anxiety Disorders
What the sources say
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“both mild cognitive impairment and Type 2, as well as Type 1, diabetes are recognized as risk factors for dementia (Ott et al., 1996; de Leon et al., 2001; Haan, 2006).”
§ 3. Translation to the human brain > 3.1 Depression, Cushing’s Disease and Anxiety Disorders
What the sources say
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“there are a variety of other anxiety-related disorders, such as post-traumatic stress disorder (PTSD) (Bremner, 2002) (Pitman, 2001) and borderline personality disorder (Driessen et al., 2000), in which atrophy of the hippocampus has been reported”
§ 3. Translation to the human brain > 3.1 Depression, Cushing’s Disease and Anxiety Disorders
What the sources say
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“businesses that encourage healthy lifestyle practices among their employees are likely to gain reduced health insurance costs and possibly a more loyal workforce (Aldana, 2001; Pelletier, 2001; Whitmer et al., 2003).”
What the sources say
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Because of the non-linearity of the systems of allostasis, the consequences of any drug treatment may be either to inhibit the beneficial effects of the systems in question or to perturb other systems that interact with it in a direction that promotes an unwanted side effect.”
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus basic education, housing, taxation, setting of a minimum wage, and addressing occupational health and safety and environmental pollution regulations are all likely to affect health via a myriad of mechanisms.”
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“poor self esteem has been shown to cause recurrent increases in cortisol levels during a repetition of a public speaking challenge in which those individuals with good self esteem are able to habituate, i.e., attenuate their cortisol response after the first speech (Kirschbaum et al., 1995).”
§ 3. Translation to the human brain > 3.2 Positive affect, self esteem and social support
What the sources say
- Not checked yetcites Kirschbaum et al., 1995 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Having a positive outlook on life and good self esteem appear to have long-lasting health consequences (Pressman and Cohen, 2005)”
§ 3. Translation to the human brain > 3.2 Positive affect, self esteem and social support
What the sources say
- Not checked yetcites Pressman and Cohen, 2005 source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper relies on this without support.
The amygdala and prefrontal cortex contain adrenal steroid receptors.
“Along with many other brain regions, the amygdala and prefrontal cortex also contain adrenal steroid receptors”
The paper relies on this without support.
Adrenocortical hormones enter the brain and produce a wide range of effects upon it.
“We now know that adrenocortical hormones enter the brain and produce a wide range of effects upon it.”
The paper relies on this without support.
Both major depression and Cushing’s disease are associated with chronic elevation of cortisol that results in gradual loss of minerals from bone and abdominal obesity.
“Both major depression and Cushing’s disease are associated with chronic elevation of cortisol that results in gradual loss of minerals from bone and abdominal obesity.”
The paper relies on this without support.
There are many useful pharmaceutical agents (sleeping pills, anxiolytics, beta blockers and antidepressants) that are used to counteract some of the problems associated with being stressed out.
“In fact, there are many useful pharmaceutical agents: sleeping pills, anxiolytics, beta blockers and antidepressants are all drugs that are used to counteract some of the problems associated with being stressed out.”
The paper relies on this without support.
Drugs that reduce oxidative stress or inflammation, block cholesterol synthesis or absorption and treat insulin resistance or chronic pain can help deal with the metabolic and neurologic consequences of being stressed out.
“Likewise, drugs that reduce oxidative stress or inflammation, block cholesterol synthesis or absorption and treat insulin resistance or chronic pain and can help deal with the metabolic and neurologic consequences of being stressed out.”
The paper relies on this without support.
Motivation and decision making and perseverance are all functions of the brain.
“Motivation and decision making and perseverance are all functions of the brain!”
The paper relies on this without support.
Animal studies of stress effects on brain structure are relevant to the human brain.
“Much of the impetus for studying the effects of stress on the structure of the human brain has come from the animal studies summarized thus far.”
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 source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Under chronic conditions, the relationship between HPA axis over-activity and disturbed sleep may be bidirectional as elevated evening cortisol levels are likely to disturb sleep.26,27”
From Effects of Insufficient Sleep on Pituitary–Adrenocortical Response to CRH Stimulation in Healthy Men (2017) · cites this paper as [27]
Experimental — accuracy not yet measuredIn the citing paper
“Inability to handle everyday stress leads to exacerbated physiological responses and is associated with the development and course of adverse long-term health outcomes, including a wide range of psychological disorders such as major depression, substance abuse, and anxiety disorders (Duffing et al., 2014;McEwen, 2008;Sinha, 2001).”
From Cortisol Response to Stress: The Role of Expectancy and Anticipatory Stress Regulation (2020) · cites this paper as McEwen, 2008
In the citing paper
“This modulation is achieved via the effect of glucocorticoid hormones and other components of the HPA axis [46-48, 50].”
From Predictive modeling of the hypothalamic-pituitary-adrenal (HPA) axis response to acute and chronic stress (2011) · cites this paper as [47]
In the citing paper
“chronic stress may alter receptor localization, rates of chemical reactions and transporting processes in different brain regions, such as the hippocampus, amygdala and prefrontal cortex [44-47]”
From Predictive modeling of the hypothalamic-pituitary-adrenal (HPA) axis response to acute and chronic stress (2011) · cites this paper as [47]
In the citing paper
“It is also well known that stress induces changes in the immune system function.”
From Predictive modeling of the hypothalamic-pituitary-adrenal (HPA) axis response to acute and chronic stress (2011) · cites this paper as [47]
In the citing paper
“Under certain conditions the allostasis, i.e. dynamic regulatory mechanisms may no longer be efficient, causing allostatic overload [28, 47].”
From Predictive modeling of the hypothalamic-pituitary-adrenal (HPA) axis response to acute and chronic stress (2011) · cites this paper as [47]
Citations
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Metadata
- Authors
- McEwen, B. S.
- Affiliations
- Rockefeller University (US)
- Corresponding author
- McEwen, Bruce S.
- ORCID
- McEwen, Bruce S.
- Venue
- European Journal of Pharmacology
- Publisher
- Elsevier BV
- Published
- 2008-04
- Volume
- 583
- Issue
- 2-3
- Pages
- 174-185
- ISSN
- 0014-2999 (ISSN-L)
- PMC
- PMC2474765
- OpenAlex
- W1969412681
- Semantic Scholar
- 4539d1634a572be94a61dd8b352135577b48fa33
- Cited by
- 1,864
- References
- 159
- Citations by year
- 2026: 69 · 2025: 85 · 2024: 90 · 2023: 90 · 2022: 111 · 2021: 119 · 2020: 139 · 2019: 110 · 2018: 116 · 2017: 115 · 2016: 123 · 2015: 94 · 2014: 102 · 2013: 95 · 2012: 118
- FWCI
- 7.09
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- European Journal of Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute of Mental Health (MH-41256, R37MH041256, P50MH058911, R01MH041256, 5-P50MH58911)
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- chronic stress, stress hormones, glucocorticoids, allostatic overload, hippocampus, prefrontal cortex, amygdala, neuroplasticity, brain-derived neurotrophic factor, PSA-NCAM, tissue plasminogen activator, excitatory amino acids, lifestyle habits, mental illness, top-down control, physical activity, social support, neuroendocrine function, autonomic function
- MeSH terms
- Animals, Mental Disorders, Brain, Glucocorticoids, Humans, Stress, Physiological, Allostasis
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.
A language model drew the claims from the paper on 2026-10-09, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-09 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
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 ›
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