C H A P T E R

1
Stress, Definitions, Mechanisms, and Effects
Outlined: Lessons from Anxiety
G. Fink
Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia

O U T L I N E

Introduction 3 Amygdala: Pivotal Role in Fear, Memory, Attention,

and Anxiety 8
Stress Definitions 4
But Is the Stress Response “Nonspecific” as Proposed Conclusions and Relevance for Stress and Anxiety
by Hans Selye? 5 Management 8
Fear Versus Anxiety….What Are the Differences? 5 Glossary 9
Biological Response to Stress 6 Acknowledgments 9
Stress Neuroendocrinology Outlined 7
References 9
Central Neural Stress-Response Mechanisms 7

Abstract Numerous studies show that job stress is by far the

The present volume on concepts, cognition, emotion, and behav- major source of stress for American adults and that it
ior, is the first in this new Handbook series. The purpose of this first has escalated progressively over the past few decades.
chapter is to provide an outline of stress, stress definitions, the Increased levels of job stress as assessed by the perception
response to stress and neuroendocrine mechanisms involved,
and stress consequences such as anxiety and posttraumatic stress
of having little control but many demands have been
disorder. Study of the neurobiology of anxiety and related disor- demonstrated to be associated with increased rates of
ders has facilitated our understanding of the neural mechanisms heart attack, hypertension, obesity, addiction, anxiety,
that subserve stress and will therefore be underscored. depression, and other disorders. In New York, Los
Angeles, and other municipalities, the relationship
between job stress and heart attacks is recognized, so that
Now is the age of anxiety W.H. Auden any police officer who suffers a coronary event on or off
the job is assumed to have a work-related injury and is
compensated accordingly.
INTRODUCTION Stress is a highly personalized phenomenon that
varies between people depending on individual vulnera-
“Stress” has been dubbed the “Health Epidemic of the bility and resilience, and between different types of tasks.
21st Century” by the World Health Organization and is Thus one survey showed that having to complete paper
estimated to cost American businesses up to $300 billion work was more stressful for many police officers than
a year. The effect of stress on our emotional and physical the dangers associated with pursuing criminals. The
health can be devastating. In a recent US study, over 50% severity of job stress depends on the magnitude of the
of individuals felt stress negatively impacted work produc- demands that are being made and the individual’s sense
tivity. Between 1983 and 2009, stress levels increased by 10- of control or decision-making latitude for dealing with
30% among all demographic groups in the United States. the stress.

Stress: Concepts, Cognition, Emotion, and Behavior 3 Copyright © 2016 Elsevier Inc. All rights reserved.
[Link]
4 1. STRESS, DEFINITIONS, MECHANISMS, AND EFFECTS OUTLINED

Stress is, of course, not limited to the workplace. There functional brain imaging has enhanced our understand-
is vast literature on the possible role of stress in the cau- ing of the neurobiology of stress in the human.
sation and/or exacerbation of disease in most organ Here we provide an outline of stress with the focus on
systems of the body. Inextricably linked to anxiety, stress stress definitions, the response to stress, and neuroendo-
plays a pivotal role in mental disorders including crine and central neurobiological mechanisms involved,
phobias, major depression, and bipolar disorder.2–9 Stress and stress consequences, such as anxiety and PTSD.
and anxiety aggravate schizophrenia and people with The neurobiology of anxiety is underscored because it
schizophrenia often experience difficulties in coping with has heuristically facilitated our understanding of the
stress. Consequently, stress-inducing changes in lifestyle neural mechanisms that subserve stress.
patterns place a substantial burden on mental health.
Posttraumatic stress disorder (PTSD) is a special form KEY POINTS
of stress that affects more than 7 million people in the
• Stress is the (nonspecific) response of the body to
United States. In 1980, largely as a consequence of the
any demand.1
psychological trauma experienced by Vietnam War vet-
erans, PTSD was recognized as a disorder with specific • Stress consequences include anxiety, fear,
symptoms that could be reliably diagnosed and was, depression, and PTSD. In addition, stress has
therefore, added to the American Psychiatric Associa- adverse effects on other major mental disorders
tion’s Diagnostic and Statistical Manual of Mental Disorders such as bipolar disorder and schizophrenia.
(DSM). PTSD is recognized as a psychobiological mental • Stress also has adverse effects on the
disorder that can affect survivors of not only combat cardiovascular, including the cerebrovascular
experience in war and conflict, but also terrorist attacks, system and other organ systems of the body.
natural disasters, serious accidents, assault, rape trauma • Stressors are perceived and processed by the brain
syndrome, battered woman syndrome, child abuse which triggers the release of glucocorticoids (by
syndrome, or sudden and major emotional losses. PTSD way of the hypothalamic-pituitary-adrenocortical
is associated with epigenetic changes in the brain as well axis) and catecholamines (adrenaline and
as changes in brain function and structure. These changes noradrenaline) by way of the sympathetic-
provide clues to the origins and possible treatment, and adrenomedullary system (SAM).
prevention of PTSD. Stress, PTSD, and anxiety are linked
• The glucocorticoids and the catecholamines act
to fear, fear memory and extinction, phenomena that
synergistically to raise blood glucose levels (by
together with their neural circuitry and neurochemistry
triggering the release of glucose from the liver)
remain the subject of intense research. Notwithstanding
which facilitates the “flight or fight” response to
its links with anxiety, PTSD in the latest DSM-5 is now
stress, as does the ramp-up of cardiovascular
included in a new section/classification of trauma- and
output by the catecholamines. The rapid stress-
stressor-related disorders. This move of PTSD from its
induced release of the catecholamines also shunts
earlier classification in the DSM-IV as an anxiety disorder
blood from the skin and gut to the skeletal muscles.
is among several changes approved for PTSD that
heighten its profile as a disease entity that is increasingly • Central awareness of and response to stress, anxiety,
at the center of public as well as professional attention. and fear depends on extensive neural circuits that
Physiological and neurochemical approaches have involve, for example, the amygdala, thalamus,
elucidated the way in which stress is controlled by hypothalamus, brain stem nuclei such as the locus
two major neuroendocrine systems, the hypothalamic- coeruleus and the neocortex and limbic cortex.
pituitary-adrenal (HPA) axis and the sympathetic- • Our understanding of the neurobiology of stress
adrenomedullary (SAM) limb of the autonomic nervous has been enhanced by experimental, clinical, and
system (ANS). Our understanding of stress mechanisms human brain imaging studies of anxiety and other
in man and animals has benefited significantly from stress-related conditions.
several recent quantum leaps in technology and knowl-
edge. First, advances in molecular genetics (including
optogenetics and chemogenetics), sequencing of the
human genome and genomics10 have increased the rigor STRESS DEFINITIONS
and precision of our understanding of the molecular
neurobiology of stress and its effects on mental state, Stress has a different meaning for different people under
behavior, and somatic systems. Secondly, through different conditions. A working definition of stress that fits
genomics we are also beginning to understand the many human situations is a condition in which an individ-
genetic and epigenetic factors that play a role in suscep- ual is aroused and made anxious by an uncontrollable
tibility, vulnerability, and resilience to stress and the aversive challenge—for example, stuck in heavy traffic
various components of the stress response. Thirdly, on a motorway, a hostile employer, unpaid bills, or a

1. GENERAL CONCEPTS
 FEAR VERSUS ANXIETY….WHAT ARE THE DIFFERENCES? 5
predator. Stress leads to a feeling of fear and anxiety. ðSÞ ¼ E $ A $ U
Depending on the circumstances, the fear response can
lead to either fight or flight. The magnitude of the stress
and its physiological consequences are influenced by the
individual’s perception of their ability to cope with the But Is the Stress Response “Nonspecific”
stressor. as Proposed by Hans Selye?
Stress is difficult to define. As Hans Selye (the oft-
called “Father of stress”) opined, “Everyone knows what In a seminal paper, Pacak and Palkovits13 challenged
stress is, but nobody really knows.” Selye’s definition, Selye’s doctrine of nonspecificity of the stress response.
“Stress is the nonspecific response of the body to any They studied the similarities and differences between
demand,”1 is the most generic. This definition and Selye’s the neuroendocrine responses (“especially the sym-
stress-related concepts had several detractors which he pathoadrenal and the sympathoneuronal systems and
systematically rebutted.11 Other definitions are detailed the hypothalamo-pituitary-adrenocortical axis”) among
by Fink.3 Briefly, they include the following: five different stressors: immobilization, hemorrhage, cold
exposure, pain, or hypoglycemia. With the exception of
• “Perception of threat, with resulting anxiety immobilization stress, these stressors also differed in their
discomfort, emotional tension, and difficulty in intensities. Pacak and Palkovits found heterogeneity of
adjustment.” neuroendocrine responses to these stressors: each stressor
• “Stress occurs when environmental demands exceed had its own specific neurochemical “signature.” By exam-
one’s perception of the ability to cope.” ining changes of Fos immunoreactivity in various brain
• In the group situation, lack of structure or loss of regions upon exposure to different stressors, Pacak and
anchor “makes it difficult or impossible for the group Palkovits also investigated the central stressor-specific
to cope with the requirements of the situation. neuroendocrine pathways. In a separate study on the
Leadership is missing and required for coping with the aortic response to stress, Navarro-Oliveira et al.14 showed
demands of the situation.” that the SAM, but not the hypothalamic-pituitary-adrenal
• For the sociologist, it is social disequilibrium, that is, axis, participates in the adaptive responses of the aorta to
disturbances in the social structure within which stress.
people live. There is now substantial literature on the specificity of
• A purely biological definition is that stress is any stressors. Selye’s definition of stress holds but the term
stimulus that will activate (i) the HPA system, thereby “nonspecific” might be redundant. That is, Selye’s defini-
triggering the release of pituitary adrenocorticotropin tion of stress might now read “Stress is the response of the
(ACTH) and adrenal glucocorticoids and (ii) the SAM body to any demand.”
system with the consequent release of adrenaline and
noradrenaline.
• In their seminal review “The Stressed Hippocampus,
synaptic plasticity and lost memories,” Kim and
Diamond12 suggest a three-component definition of
FEAR VERSUS ANXIETY….WHAT
stress that can be applied broadly across species and
ARE THE DIFFERENCES?
paradigms. First, stress requires heightened
Stress is inextricably linked with fear and anxiety. Def-
excitability or arousal, which can be operationally
initions of fear and anxiety vary greatly, and to an extent
measured using electroencephalography, behavioral
depend on subjective assessment. Nonetheless, in their
(motor) activity, or neurochemical (adrenaline,
seminal review, “What is anxiety disorder?”, Craske
glucocorticoid) levels. Second, the experience must
and associates,15 using Barlow’s concepts, state; “anxiety
also be perceived as aversive. Third, there is lack of
is a future-oriented mood state associated with prepara-
control. Having control over an aversive experience
tion for possible, upcoming negative events; and fear is
has a profound mitigating influence on how stressful
an alarm response to present or imminent danger (real
the experience feels. The element of control (and
or perceived).” This view of human fear and anxiety
“predictability”) is the variable that ultimately
is comparable to that in animals. “That is, anxiety corre-
determines the magnitude of the stress experience and
sponds to an animal’s state during a potential predatory
the susceptibility of the individual to develop stress-
attack and fear corresponds to an animal’s state during
induced behavioral and physiological sequelae.
predator contact or imminent contact.”
Thus, the magnitude of neurocognitive stress (S)
Table 1 shows the prototypes of self-report symptoms
approximates to the product of:
of fear, anxiety, and depression. The symptoms that
• Excitability/arousal (E) represent prototypes of fear and anxiety lie at different
• Perceived aversiveness (A) places upon a continuum of responding. “Along such a
• Uncontrollability (U) continuum, symptoms of fear versus anxiety are likely

1. GENERAL CONCEPTS
6 1. STRESS, DEFINITIONS, MECHANISMS, AND EFFECTS OUTLINED

TABLE 1 Prototype of Self-Report Symptoms of Fear, Anxiety, reactions to stress, preventing those reactions from over-
and Depression shooting and themselves threatening homeostasis.”
Clustersa Munck’s hypothesis has retained its currency. Thus, for
example, Zhang et al.17 have reported that glucocorti-
Fear Anxiety Depression
coids inhibit lipopolysaccharide-induced myocardial
Response-systems inflammation. Munck’s theory does not necessarily con-
Verbal- Thoughts of Thoughts of Thoughts of flict with the fact that in the uninjured brain, basal or
subjective imminent threat future threat loss, failureb acutely elevated glucocorticoid levels increase synaptic
plasticity and facilitate hippocampal dependent cogni-
Somato- Sympathetic Muscle tension Energy lossb
visceral arousal tion whereas chronically elevated glucocorticoid levels
impair synaptic plasticity and cognition, decrease
Overt Escape Avoidance Withdrawalb
neurogenesis and spine density, and cause dendritic
motor
atrophy.7,18,19
a
While represented as prototypes, fear and anxiety may be better represented as points Glucocorticoid actions are mediated by two biochem-
along a continuum, with varying degrees of symptom overlap.
b
More specifically, these features represent lack of positive affect, as represented by the
ically distinct receptors which bind the same ligand (cor-
absence of thoughts of success, the absence of energy, and the absence of desire to be with tisol in humans, corticosterone in rodents), albeit with
other people. differing affinities. While glucocorticoid receptors (GRs)
Reproduced with permission from Craske MG, Rauch SL, Ursano R, Prenoveau J, Pine DS,
Zinbarg RE. Depression and Anxiety. John Wiley and Sons.
are ubiquitously distributed, the location of mineralocor-
ticoid receptors (MRs) is more discrete. However, both
receptors are expressed at particularly high levels in
to diverge and converge to varying degrees.” For further
limbic areas that are responsible for the modulation of
details, the reader is referred to Craske et al.15
the stress response.20 As compared with GR, MR have
a much greater affinity for cortisol/corticosterone and
are, therefore, highly occupied even under basal (stress-
BIOLOGICAL RESPONSE TO STRESS free) conditions.20 In contrast, GR become increasingly
occupied as circulating glucocorticoid levels rise in
The biological response to stress involves activation of response to stress. MR have been implicated in the
three major interrelated systems. First, the stressor is appraisal process and onset of the stress response, while
perceived by sensory systems of the brain, which evalu- GR are involved in the mobilization of energy substrates
ate and compare the stressful challenge with the existing and most stress-induced changes in behavior.
state and previous stress experience of the organism. The latter includes anxiety-like behavior and facili-
Second, on detection of a stressful challenge to homeo- tated learning and memory (in particular, consolidation
stasis, the brain activates the ANS which through the of memories). Long-term GR activation is associated with
SAM system triggers a rapid release of the catechol- deleterious effects on several cognitive functions.6,21–23
amines, noradrenaline, and adrenaline. The catechol- These deleterious effects have been correlated with neu-
amines increase cardiac output and blood pressure, roarchitectural changes in several brain regions, includ-
shunt blood from the skin and gut to skeletal muscle, ing the hippocampus, prefrontal cortex, and amygdala
and trigger the release of glucose from the liver into that are also implicated in modulating the negative feed-
the blood stream. Third, the brain simultaneously acti- back control within the HPA.23,24
vates the HPA axis which results in the release of adre- The amount of glucococorticoid available for cells is
nal glucocorticoids, cortisol in man and fish, and “micromanaged” by 11β-hydroxysteroid dehydrogenase
corticosterone in rodents. (HSD-11β) enzymes of which there are two isoforms.
Increased glucocorticoid levels enhance the organ- First, HSD11B1 which reduces cortisone to the active hor-
ism’s resistance and adaptation to stress. However, the mone cortisol that activates GRs. Second, HSD11B2
precise mechanisms of this defensive action of glucocor- which oxidizes cortisol to cortisone and prevents illicit
ticoids remain to be elucidated. Glucocorticoids act activation of the MR.25–29
synergistically with adrenaline to increase blood glucose, While elevated glucocorticoid levels characterize
thus ensuring energy supplies often needed to overcome stress, high levels of glucocorticoids per se do not mimic
the stress by facilitating fight or flight. Glucocorticoids are stress. Of the several central neurochemical neurotrans-
also potent inhibitors of the immune response and mitters involved in the stress response, attention has
inflammation, moderating the production of prostaglan- focused on the corticotropin releasing factor (CRF) pep-
dins and inflammatory cytokines. In a seminal review, tide family (and especially the urocortins) as possible
Munck and associates16 proposed “that stress-induced orchestrators of the stress response. For details of the
increases in glucocorticoid levels protect not against the CRF peptide family and their cognate receptors, readers
source of stress itself, but rather against the body's normal are referred to several reviews.4,30–34

1. GENERAL CONCEPTS
 BIOLOGICAL RESPONSE TO STRESS 7

Stress Neuroendocrinology Outlined block the ACTH response to CRF and inhibit the synthe-
sis of ACTH and its precursor, proopiomelanocortin. The
As mentioned above, stressors are perceived and limbic system of the brain, especially the hippocampus
processed by the sensory cortex which drives the hypo- and amygdala, also plays a role in glucocorticoid nega-
thalamus by several pathways that include the thalamus tive feedback.4,7,8,31,38,39,54
and the limbic forebrain and hindbrain systems.35,36 The Central control of the ANS involves the hypothalamic
hypothalamus triggers the release of glucocorticoids PVN together with various brainstem and limbic nuclei
and the catecholamines, the primary stress hormones, (caudal raphe, ventromedial and rostral ventrolateral
by way of the paraventricular nuclei (PVN) in the case medulla, the ventrolateral pontine tegmentum). The
of the HPA and the PVN, lateral hypothalamus, arcuate, ANS plays the pivotal role in the early (immediate)
and brainstem nuclei in the case of the SAM sys- response to stress. ANS action is mediated mainly by
tem.3,31,37–40 The amygdala, a prominent component of way of the release of noradenaline from nerve terminals
the limbic system that plays a key role in the evaluation and adrenaline from the chromaffin cells of the adrenal
of emotional events and formation of fearful memories, medulla.40,55 Adrenaline and noradrenaline facilitate
is a prime target of the neurochemical and hormonal the stress response by triggering the synthesis and release
mediators of stress. Clinical and experimental data of glucose from the liver into the blood stream, increasing
have correlated changes in the structure/function the rate and force of cardiac contraction and shunting
of the amygdala with emotional disorders such as blood from the skin and the gastrointestinal system to
anxiety.3,8,31,33,38 the skeletal muscles.
The PVN is subject to differential activation by distinct
neuronal pathways, depending on the quality and/or
Central Neural Stress-Response Mechanisms
immediacy of the demand for an appropriate
response.41,42 Stressors such as hemorrhage, respiratory In addition to the two canonical neural outflow sys-
distress, or systemic inflammation, which represent an tems (ANS and HPA), the stress response involves cen-
immediate threat to homeostasis, directly activate the tral nuclei, such as the locus coeruleus (LC), the principle
PVN, bypassing cortical and limbic areas, by activation brain nucleus for the production of noradrenaline.
of somatic, visceral, or circumventricular sensory path- Located in the pons, the LC and its noradrenergic projec-
ways.43,44 Excitatory ascending pathways originating in tions to the forebrain play a key role in the central con-
the brainstem nuclei that convey noradrenergic inputs trol of arousal, attention, and the response to stress. The
from the nucleus of tractus solitarius,45–48 serotonergic LC receives afferents from the medial prefrontal cortex,
inputs from the raphe nuclei,49,50 or inputs from adjacent cingulate gyrus, amygdala, hypothalamus, and raphe
hypothalamic nuclei42 are well positioned to receive vis- nuclei. In turn LC noradrenergic projections innervate
ceral and autonomic inputs so as to evoke rapid neuroen- the spinal cord, the brain stem, cerebellum, hypothala-
docrine responses. mus, the thalamic relay nuclei, the amygdala, hippo-
The hypothalamic control of the release of pituitary campus, and the neocortex. Noradrenaline released
ACTH is mediated by the 41-amino acid residue neuro- from the LC neuronal projections has an excitatory effect
peptide CRF transported from PVN nerve terminals to on most of the brain, inducing arousal and priming
the anterior pituitary gland by way of the hypophysial central neurons to stimulus-activation. Stress shifts LC
portal vessels.51,52 The action of CRF is potentiated by noradrenergic cell firing, normally moderated by gluta-
the synergistic action of the nonapeptide, arginine vaso- matergic input, to a high tonic firing. This shift is medi-
pressin (AVP), which, like CRF, is synthesized in the ated by CRF projections from the central amygdala and
PVN.53 ACTH stimulates the secretion of adrenal gluco- mediated by CRF-R1 receptors in the LC.39 In turn, LC
corticoids which have powerful metabolic effects that noradrenergic cells project to the basolateral amygdala
promote the stress response. Homeostasis within the (BLA), hippocampal CA1, and the dentate gyrus (DG)
HPA is maintained by a negative feedback system by where noradrenaline released shortly after stress expo-
which the adrenal glucocorticoids (the afferent limb) sure, enhances excitability, promoting the encoding of
moderate ACTH synthesis and release (the efferent limb). stress-related information. Glutamatergic output from
Allostasis, that is, maintenance of constancy through the BLA to the hippocampal DG is thought to provide
change in HPA activity to cope with increased stress load a means to “emotionally tag” information processed in
is brought about by change in feedback set point. It must the hippocampus.39 After cessation of the stress, the
be stressed that in biology, “set point” is a conceptual stress-induced enhancement in activity of the LC, the
construct rather than a precise structural entity.31 BLA, the DG, and CA1 is gradually reversed, resulting
The major sites of glucocorticoid negative feedback are in a return to the pre-stress activity level. In the LC,
the PVN, where glucocorticoids inhibit CRF and AVP the frequency of tonic firing is reduced by opiates that
synthesis and release, and the pituitary gland, where they bind to κ- and μ-opioid receptors. In the BLA, the DG,

1. GENERAL CONCEPTS
8 1. STRESS, DEFINITIONS, MECHANISMS, AND EFFECTS OUTLINED

and CA1, these gradual normalizing effects are pro- imaging that showed amygdala activation to fearful (ver-
duced by glucocorticoids, presumably through GR- sus neutral) faces does not depend on subjects’ awareness
mediated gene-dependent cascades.39 of the presentation of the faces,72 or whether or not the
faces are the focus of attention.73–75 These studies indicate
that the amygdala responds to a fear stimulus automati-
Amygdala: Pivotal Role in Fear, Memory, cally and prior to awareness.
Attention, and Anxiety The bed nucleus of the stria terminalis (BNST), consid-
Animal studies have shown that the amygdala receives ered to be an extension of the amygdala,76 receives dense
sensory information rapidly through the sensory thalamus projections from the BLA, and projects in turn to hypo-
and more slowly and precisely (in terms of topography) thalamic and brainstem target areas that mediate
through the sensory cortex.56–58 The thalamic or cortical autonomic and behavioral responses to aversive or
pathway can be used for simple sensory stimuli such as threatening stimuli. The BNST participates in certain
those typically used in animal conditioning. Brain imaging types of anxiety and stress responses and seems to medi-
findings on the role of the human amygdala in fear learn- ate slower-onset, longer-lasting responses that frequently
ing are consistent with those in animal models. As accompany sustained threats, and that may persist even
assessed by functional magnetic resonance imaging, fear after threat termination.76,77
conditioning in humans results in an increased blood-oxy- In summary, a combination of lesion and imaging
gen-level-dependent (BOLD) signal in the amygdala.59,60 studies have shown that transitory feedback from the
The magnitude of this BOLD response is predictive of human amygdala to sensory cortical regions can facilitate
the strength of the conditioned response.60,61 In addition, attention and perception. The amygdala’s influence on
a subliminally presented conditioned stimulus (CS)— cortical sensory plasticity may also result in enhanced
one presented so quickly that subjects are unaware of its perception for stimuli that have acquired emotional
presentation—leads to coactivation of the amygdala and properties through learning. By influencing attention
the superior colliculus and pulvinar.62 and perception, the amygdala modulates the gateway of
The pivotal role of the amygdala in the response to fear is information processing. The amygdala enables preferen-
underscored by the effects of brain lesions, in that patients tial processing of stimuli that are emotional and potentially
in which the amygdala has been lesioned show no threatening, thus assuring that information of importance
conditioned fear. However, providing the hippocampus to the organism is more likely to influence behavior.
is intact, these patients are able explicitly to recollect and
report the events of fear conditioning procedures.63–65 In
contrast, bilateral lesions of the hippocampus that spare CONCLUSIONS AND RELEVANCE FOR
the amygdala, impair the ability consciously to report the STRESS AND ANXIETY MANAGEMENT
events of fear conditioning, although there is normal
expression of conditioned fear as assessed physiologically The neurobiology of stress and anxiety has highlighted
by skin conduction responses.63 This dissociation following new potential therapeutic targets for the management of
amygdala or hippocampal damage between indirect phys- anxiety. There has been considerable investment, for exam-
iological assessments of the conditioned fear response ple, into new strategies such as the design and development
(amygdala dependent) and awareness of the aversive prop- of central CRF receptors antagonists. Furthermore, much
erties of the CS (hippocampal dependent) supports the ongoing research is focused on cognitive-behavioral (e.g.,
proposition that there are multiple systems for the encoding exposure) therapy, as well as possible pharmacological fear
and expression of emotional learning in the human. extinction. Care obviously needs to be taken to avoid “con-
The amygdala, in addition to modulating memory ditional reinstatement.” Reinstatement of extinguished fear
systems, also alters processing in cortical systems can be triggered by exposure to conditional as well as uncon-
involved in attention and perception and thereby poten- ditional aversive stimuli, and this may help to explain why
tially influences downstream cognitive functions both by relapse is common following clinical extinction therapy in
direct projections and possibly also by way of the nucleus humans.78 Neuropharmacologically we know that norad-
basalis of Meynert (NBM) that receives afferents from the renergic augmentation in the amygdala following retrieval
central nucleus of the amygdala.66 The NMB projects of a traumatic memory enhances memory reconsolidation
widely to the cortical sensory-processing regions. The and makes the memory less susceptible to fear extinction.
NBM projections release acetylcholine, which has been Elevated noradrenergic activity is associated with persis-
shown to facilitate neuronal responsivity.67,68 Transitory tence and severity of PTSD symptoms. That is,
modulation of cortical regions by the amygdala might noradrenergic-modulated reconsolidation processes con-
increase cortical attention and vigilance in situations of tribute to the maintenance and exacerbation of trauma-
danger.69–71 This view receives support from brain related memories in PTSD.79 These and other factors that

1. GENERAL CONCEPTS
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1. GENERAL CONCEPTS
 C H A P T E R

2
The Alarm Phase and the
General Adaptation Syndrome: Two
Aspects of Selye’s Inconsistent Legacy
R. McCarty
Vanderbilt University, Nashville, TN, USA

O U T L I N E

Introduction 13 Dishabituation 17
Related Studies 17
Criticisms of the GAS 15
Evidence for Stressor-Specific Neuroendocrine
Bridging the Chasm Between Cannon and Selye 15
Signatures 17
Learning About Stress 16
Conclusions 19
Habituation 16
Sensitization 16 References 19

Abstract a series of experiments on laboratory rats exposed to a

The general adaptation syndrome (GAS) was first proposed by variety of “nocuous agents.”1 The nocuous agents
Hans Selye in his classic 1936 letter to the editor of Nature. The included cold, surgical injury, spinal shock, muscular
GAS consisted of three phases: (i) the alarm phase, (ii) the phase exercise, or sublethal doses of a variety of drugs or tissue
of adaptation, and (iii) the phase of exhaustion. Selye held that
extracts. He concluded that the rats developed a consis-
the stress syndrome was always a nonspecific response of the
body to any demand and included a triad of responses: enlarge- tent constellation of symptoms in three stages that were
ment of the adrenal cortex, decrease in size of the thymus and independent of the nocuous agent employed. The three
lymphatic tissue, and ulceration of the stomach and duodenum. phases and an abbreviated selection of the symptoms that
Selye also promoted the concept of diseases of adaptation that were observed included:
were connected to stressful stimulation. Much of Selye’s work
has been discounted as knowledge of neural and endocrine sys-
tems expanded and new analytical techniques were introduced.
• General alarm reaction: occurred 6-48 h following
In particular, the doctrine of nonspecificity has been rejected and exposure to a nocuous stimulus and was attended by
replaced with the indication that a given stressor stimulates a decreases in the weights of the thymus, spleen, lymph
unique neuroendocrine signature in test subjects. In addition, glands, and liver; reduced fatty tissue, loss of muscle
many studies have demonstrated that prior stress history affects tone, decrease in body temperature, gastrointestinal
future stress responses across several neural and endocrine sys-
tems. Stress remains a key component of the etiology of many erosions.
diseases and that is an enduring part of Selye’s legacy. • Adaptation: from 48 h until 1-3 months after the
beginning of repetitive exposure to a nocuous
stimulus, the adrenals were greatly enlarged, body
INTRODUCTION growth ceased, there was atrophy of the gonads,
cessation of lactation, and enhanced production of
On July 4, 1936, Hans Selye published a brief letter to thyrotropic and adrenotropic factors from the
the editor of the journal, Nature, in which he summarized pituitary. Animals adapted to the deleterious effects of

Stress: Concepts, Cognition, Emotion, and Behavior 13 Copyright © 2016 Elsevier Inc. All rights reserved.
[Link]
14 2. THE ALARM PHASE AND THE GENERAL ADAPTATION SYNDROME: TWO ASPECTS OF SELYE’S INCONSISTENT LEGACY

the nocuous stimulus but were more susceptible than journals, exchange of correspondence through the mail,
controls to the deleterious effects of another stressor. and discussions at scientific meetings. Over the course
• Exhaustion: depending on the severity of the nocuous of his career, Selye published approximately 1700 articles
agent, animals died at some unspecified point (usually and 40 books, including some for the general public.4,5 In
within 3 months) with symptoms similar to those particular, he contributed a host of articles for specialty
observed during the general alarm reaction. Selye medical and nursing journals and scientific journals to
hypothesized that animals died because they had ensure that a broad spectrum of physicians, nurses, and
exhausted their stores of “adaptation energy,” though scientists would be aware of his work on the GAS and
he was never able to measure it. stress. In many cases, the titles of the journal articles were
the same or very similar. He also lectured throughout the
As recounted by Selye in The Stress of Life (1978), his initial world and was fluent in five languages.6 Imagine what he
experiments with laboratory rats involved injections of could have accomplished in promoting his theory of
ovarian extracts and he hoped to identify a new hormone stress if the Internet was available!
based upon the stimulation by the extract of a triad of
responses, including: (i) adrenocortical hypertrophy, (ii)
atrophy of the thymus and spleen, and (iii) gastric ulcera- KEY POINTS
tion. Much to his dismay, Selye also observed this same
triad of responses following injections of other tissue • Hans Selye first proposed in a brief article in Nature
extracts, and also formalin, a painful irritant to tissue. Expo- a triad of biological responses to stress in
sure of rats to cold also resulted in the same triad of laboratory rats that included enlargement of the
responses, and that finding prompted Selye to dismiss his adrenal cortex, reduction in the weight of the
disappointment in not discovering a new hormone and thymus, and gastric ulcerations.
embrace the new opportunity to explore the “stress syn- • Selye’s general adaptation syndrome (GAS)
drome” and its potential relevance to diseases in humans. delineated the time-course of an organism’s
Remarkably, Selye’s 74-line letter to the editor con- response to stress. The three phases of the GAS
tained no experimental details, no quantitative data, no were (i) the alarm phase, (ii) the phase of
photomicrographs, and no references.2 Yet, it has been adaptation, and (iii) the phase of exhaustion.
cited more than 3000 times according to Google Scholar • Selye defined stress as the nonspecific response of
(as of February 2015) and has stimulated an explosion of the body to any demand placed upon it. This
research on stress and disease since its appearance. How definition was so broad as to be of little use in
has the field of stress research been affected by this initial designing experiments and making predictions
report and the subsequent voluminous publication record about experimental outcomes.
of Selye over the next 46 years until his death in 1982?
• Selye’s enduring contribution was to establish a
Being the first to propose a new theory doesn’t guar-
link between stress and diseases of adaptation.
antee that one’s views will hold up over time. Such may He was vigorous in conveying his theory of
the case with Selye’s initial report in 1936 and many of
diseases of adaptation to scientific and popular
his publications that followed. He very quickly became
audiences through hundreds of articles,
convinced that the general adaptation syndrome (GAS),
many books, and frequent lectures throughout
or stress syndrome, represented a major new approach
the world.
to human disease for clinical medicine and he was
tireless in promoting his views. A first major step in • One approach to investigating the effects of
the promotion of his theory of stress came in 1946 when prior experiences with stressful stimuli on
he gave a series of lectures in Paris at the Collège de subsequent responses of an organism to stressful
France. The significance was not lost on Selye that he stimulation is to employ experimental designs
would lecture at the same institution where, 100 years that include habituation, sensitization, and
earlier, Claude Bernard had lectured on his theory of dishabituation of neural and endocrine systems
the milieu intérieur. Because there was no readily avail- to stressors.
able translation for “stress” in the French language, • A formal and quite exhaustive series of tests of
those present for his first lecture agreed that le stress Selye’s doctrine of nonspecificity revealed that
should be the French equivalent. Stress has now been animals respond with stressor-specific
added as a new word in many other languages, due neuroendocrine signatures. Such a finding
in large part to the tireless efforts and extensive travel supports the notion that neural and endocrine
schedule of Hans Selye.3 systems are exquisitely tuned to respond to the
In the prime years of Selye’s research career (1940- different patterns of homeostatic challenges across
1980), the exchange of ideas between scientists was a variety of stressors.
limited in a large part to books and articles in print

1. GENERAL CONCEPTS
 BRIDGING THE CHASM BETWEEN CANNON AND SELYE 15
organism given the plethora of stressors experienced over
CRITICISMS OF THE GAS the lifespan. Ader8 and Elliott and Eisdorfer9 pointed out
the lack of crisply defined concepts related to stress, such
From the time he was a medical student in Prague, that no definition has yet been advanced that is embraced
Selye was subjected to criticisms of his theory of a by a majority of researchers. Munck et al.10 criticized
syndrome of being sick, initially from his professors, Selye’s concept of diseases of adaptation, noting that this
and later from his colleagues and senior scientists whom concept was largely dismissed after the 1960s. The circu-
he admired. At the beginning of his clinical training in lar reasoning undergirding the GAS has also been a
medical school, Selye was impressed with the constella- source of concern. For example, the only way one could
tion of symptoms that was common to many diseases distinguish between distress and eustress was to assess
(e.g., coated tongues, swollen glands, generalized tissue damage and morbidity. If tissue damage occurred,
body aches, reduced appetite) while his medical school it was a distress response, but if no damage occurred,
professors were more interested in symptoms that then it was a eustress response.11 Mason12,13,33 argued
distinguished one disease from another, permitting a that all of the stressors originally employed by Selye
differential diagnosis.3 caused fear and anxiety in the laboratory rats and it
When Selye began his studies on endocrine responses was not surprising that the pattern of GAS responses
to injections of tissue extracts or formalin, he made the was similar across treatment groups. Indeed, Selye did
connection between those early observations of sick not incorporate central nervous system responses to emo-
patients as a medical student and a possible physiological tional stimuli in his studies and yet emotions are espe-
basis for the symptoms that were common across several cially salient in studies of human stress and disease.
diseases. These nonspecific responses of the GAS could Finally, Selye’s singular focus for the GAS was the
provide a new approach for medical science in the pre- hypothalamic-pituitary-adrenocortical system, to the
vention of disease and he was single-minded in pushing general exclusion of all other stress-responsive neural
for that new approach for his entire career. and endocrine systems.14–17,33
Let’s begin with Selye’s definition of stress—“the non-
specific response of the body to any demand.” Given this
broad definition, virtually anything could be viewed as a
stressor, from getting out of bed in the morning to con- BRIDGING THE CHASM BETWEEN
fronting a robber in a dark alley, to surviving the horrors CANNON AND SELYE
of an extended tour of duty in a combat zone. Further
refinements made by Selye in his theory of stress included Two powerful figures who exerted profound influ-
the following: ences on the development of stress research in the twen-
tieth century were Walter B. Cannon and Hans Selye.
• With exposure to stress, the demand could be
Most discussions relating to the emergence of the field
pleasant or unpleasant and could result in happiness or
of stress research emphasize the pronounced differences
sadness. The pleasant demands were defined as
in approach between these two distinguished scientists
eustress and the unpleasant demands were defined
(refer to Table 1). In spite of their differences in the study
as distress. The biological changes were similar
of stress, there is also much to unite them. They could be
between eustress and distress but the damage to
represented by different points on the same continuum
bodily systems was much greater with distress.
• Stress always expresses itself in a nonspecific
TABLE 1 A Comparison of the Research Profiles of
syndrome and the whole body must be involved. Walter B. Cannon and Hans Selye
• Conditioning factors were introduced to explain why
individuals differed in their responses to the same Variable Cannon Selye
stressor. These included genetic differences, Underlying Basic science— Clinical medicine—
differences in prior experiences, and dietary motivation mechanisms of mechanisms of human
differences. However, if one stripped away these homeostasis disease
conditioning factors, the constellation of nonspecific Key concepts Homeostasis General adaptation
responses remained.7 developed Fight-or-flight syndrome
Cannon-Bard theory of Disease of adaptation
Walter B. Cannon was one of the first senior scientists emotions Stress concept
to criticize Selye’s formulation of stress during a visit to Focus of Adrenal medulla Adrenal cortex (cortisol)
McGill University. According to Selye’s account of their research (epinephrine)
meeting (1978), Cannon expressed reservations about
Time scale of Acute responses to Chronic responses to stress
the nonspecific nature of stress and how a nonspecific experiments stress
response pattern could be adaptive to survival of the

1. GENERAL CONCEPTS
16 2. THE ALARM PHASE AND THE GENERAL ADAPTATION SYNDROME: TWO ASPECTS OF SELYE’S INCONSISTENT LEGACY

and their studies appear to me to be more complementary Habituation

than antagonistic. When their findings are combined
across systems, time scales, and stimuli, their combined Chronic intermittent exposure of laboratory rats to a
impact informs basic and clinical approaches to the study stressful stimulus that is of low to moderate intensity
of stress and enhances the relevance of both investigators results in a significant reduction in plasma levels of nor-
to contemporary stress researchers. epinephrine (NE) and epinephrine (EPI) compared to
controls stressed for the first time (Figure 1). Several
stressors have been tested, including forced swimming,
restraint, immobilization, footshock, and exercise. These
LEARNING ABOUT STRESS chronic intermittent stress paradigms provide animals
with a high degree of predictability regarding such
Over the past 30 years, research from many laborato-
parameters as the type of stressor, intensity of stressor,
ries has demonstrated that prior stress history affects
duration of each daily stress session, and the time of onset
future stress responses. To place these studies into a
of the stressor session each day. When provided with this
well-accepted theoretical context, I have drawn upon
information after several daily stress sessions, animals are
three types of nonassociative learning in interpreting
able to activate stress-responsive neural and hormonal
the results of such studies.18 The three types of learning
systems to the minimum extent necessary to maintain
are (1) habituation, a decrease in the amplitude of the var-
cardiovascular and metabolic homeostasis during each
iable being measured after repeated exposure of an indi-
subsequent exposure to the same stressor. This progres-
vidual to the same low- or moderate-intensity stressor;
sive dampening of plasma catecholamine responses to
(2) sensitization, the enhancement of a nonhabituated
a familiar and highly predictable stressor affords signi-
stress response by repeated exposure to a high-intensity
ficant conservation of energy expenditure.
stressor; and (3) dishabituation, the facilitation of an habit-
uated stress response following exposure to a novel
stressor.
Sensitization
In the following sections, I will summarize studies
from my laboratory on plasma catecholamine responses When laboratory rats are exposed to a high-intensity
of laboratory rats to various chronic intermittent stress stressor, there are recurring alterations in cardiovascular
paradigms as an illustration of the utility of the nonasso- and metabolic homeostasis. One such stressor that has
ciative learning framework.19 An overview of these been studied is immersion of laboratory rats in water
experiments is presented in Figure 1.20,21 maintained at 18 or 24 °C for 15 min per day for 27

200

150
AUC (% Control)

100

50

0
C R C R CA RA NB CB
(a) (b) (c)
FIGURE 1 Typical experimental results addressing nonassociative properties of plasma catecholamine responses (expressed as a percentage of
controls) of rats exposed to chronic intermittent stress. (a) Habituation of plasma catecholamine responses of repeatedly stressed rats to a mild
stressor (R) compared to first-time stressed controls; (b) sensitization of plasma catecholamine responses of repeatedly stressed rats to an intense
stressor (R) compared to first-time stressed controls (C); and (c) dishabituation of plasma catecholamine responses of rats repeatedly exposed to
stressor A and then presented with a novel stressor B. The plasma catecholamine responses of the A and B controls are presented for comparison.
Note that in the same group of chronically stressed animals, the response to a familiar stressor (RA) is diminished compared to the appropriate control
(CA), whereas the response to a novel stressor (NB) is enhanced compared to the appropriate control (CB). AUC, integrated area under the curve for
plasma catecholamine responses.

1. GENERAL CONCEPTS
 EVIDENCE FOR STRESSOR-SPECIFIC NEUROENDOCRINE SIGNATURES 17
consecutive days. When compared to controls exposed to responses to chronic intermittent audiogenic stress or
swim stress for the first time, animals exposed to chronic restraint stress for 10 days. Other groups have reported
intermittent swim stress had significantly greater eleva- evidence of sensitization of neuroendocrine responses
tions in plasma levels of NE and EPI. This sensitized to novel stressors in chronically stressed laboratory
response of the sympathetic-adrenal medullary system rats.24,25 Limitations of space prevent me from a more
to chronic intermittent swim stress is dependent on exhaustive review of the literature. However, nonassocia-
stressor intensity (i.e., water temperature). In contrast, tive experimental designs in stress research may have
chronic intermittent swim stress in water at 30 °C results particular relevance for the development of animal
in habituated plasma catecholamine responses. models of posttraumatic stress disorder or chronic
drug use.

Dishabituation
Dishabituation involves an enhancement of plasma
catecholamine responses to a novel stressor in animals EVIDENCE FOR STRESSOR-SPECIFIC
previously exposed each day to an unrelated stressor. NEUROENDOCRINE SIGNATURES
For example, if laboratory rats are exposed to a brief
period of footshock stress each day for several weeks, A consistent hallmark of Selye’s theories of stress was
the plasma catecholamine response to footshock gradu- the nonspecific nature of the stress response. He empha-
ally decreases over time compared to first-time stressed sized the triad of enlargement of the adrenal cortex, invo-
controls (e.g., habituation). However, if these same rats lution of the thymus, and ulcerations of the stomach and
are then exposed to a novel stressor such as restraint duodenum to the exclusion of other neuroendocrine sys-
stress, their plasma catecholamine responses are tems and target organs.26–30 Selye conceded that other
amplified compared to the response to restraint stress neural and endocrine changes could occur during expo-
of first-time stressed controls (Figure 1). Data from our sure to various stressors; however, there would remain
laboratory and the work of others suggest that exposing a nonspecific component of stress after deletion of the
chronically stressed animals to a novel stressor presents a stressor-specific elements from the total response.
much greater challenge to behavioral and physiological In an elegant series of experiments, Pacak et al.31 and
homeostasis than presentation of that same stressor to a Pacak and Palkovits32 subjected the “doctrine of nonspe-
naïve control. In this case, the abrupt departure from cificity” to an exhaustive test by comparing neuroendo-
the expected appears to be a critical factor in eliciting crine response profiles of laboratory rats across a range
an enhanced plasma catecholamine response to the novel of different stressors and stressor intensities. In their ini-
stressor. These chronically stressed animals live in a mod- tial paper, the authors31 argued that Selye’s theory of
erately challenging, but highly predictable, environment. nonspecific responses is impossible to disprove without
The experimenter arrives at approximately the same time two simplifying assumptions. The first is that, regardless
each day, the stress session begins soon thereafter, the of the stressor, the ratio of the intensity-related increment
intensity of the stressor and its duration are constant, in response for neurohormone X to the intensity-related
and most of the remainder of the day is free from disrup- increment in response for neurohormone Y is a constant.
tion. Against this background of consistency, a novel The second assumption is that the magnitudes of both the
stressor may be viewed as an abrupt, and at times, dra- specific and nonspecific components of the various neu-
matic departure from what is expected. rohormones vary directly across the whole range of
stressor intensities.31
The stressors employed in these experiments included
Related Studies the following:

Other researchers have employed the experimental • Handling and subcutaneous (s.c.) or intravenous (i.v.)
paradigms described above and some have expanded injection of 0.9% saline
the generalizability of these findings by focusing on other • Insulin-induced hypoglycemia: i.v. injection of insulin
neural and endocrine systems. For example, Fernandes in doses of 0.3, 1.0, or 3.0 IU/kg body weight
et al.22 reported decreases in plasma corticosterone and • Formalin-induced pain: 1.0% or 4.0% formaldehyde
decreased expression of CRH mRNA in the paraventricu- solution injected s.c. in right hind leg
lar nucleus of laboratory rats exposed to chronic intermit- • Hypotensive hemorrhage: removal of arterial blood
tent restraint stress (30 min per day) for 15 consecutive from an indwelling catheter equal to 10% or 25%
days. More recently, Babb et al.23 reported that male of estimated blood volume
and female laboratory rats had reduced plasma • Cold exposure for 3 h at 4 or !3 °C
adrenocorticotropin hormone (ACTH) and corticosterone • Immobilization for 2 h

1. GENERAL CONCEPTS
18 2. THE ALARM PHASE AND THE GENERAL ADAPTATION SYNDROME: TWO ASPECTS OF SELYE’S INCONSISTENT LEGACY

Blood samples were collected before and at timed not support Selye’s doctrine of nonspecificity, and
intervals during and after exposure of rats to one of the instead were consistent with each stressor evoking a dis-
stressors. Plasma levels of NE, EPI, and ACTH were tinct neuroendocrine signature based upon the three
quantified and expressed as an integrated area under hormonal measures employed in this study (NE, EPI,
the curve (AUC) measure for each animal to reflect the and ACTH).
amplitude of the response to a given stressor. Pacak and Palkovits32 expanded upon these initial
The data for ACTH and EPI responses to hemorrhage findings by collecting data on additional neural and
and to formalin injection appeared to fulfill the two endocrine responses to the five stressors described above.
assumptions required to test the doctrine of nonspecifi- The other measures included: plasma corticosterone, NE
city. The findings indicated that the ratio of the EPI release in the paraventricular nucleus of the hypothala-
responses to the more severe versus the less severe hem- mus measured by microdialysis, and activation of the
orrhage was smaller than the ratio of the EPI responses to immediate early gene, c-fos, by quantifying Fos immuno-
the more severe versus the less severe formalin injection. reactivity in 34 brain areas. In combining the results of
In contrast, the ratio of the plasma ACTH response for these two exhaustive studies (refer to Table 2), there is
the more severe versus the less severe hemorrhage was strong support for the existence of distinct stressor-
much greater than the ratio of the plasma ACTH response specific neural and endocrine signatures and, based upon
to the more severe versus the less severe formalin their findings, Selye’s doctrine of nonspecificity was
injection (Figure 2). The results of this study clearly did clearly rejected.

6
TABLE 2 Overview of the Effects of Various Stressors on Fos
H Immunoreactivity in Selected Brain Areas, NE
Hemorrhage Release in the Paraventricular Nucleus, and Plasma
25% / 10% Levels of Various Hormones in Laboratory Rats
F
Formalin Variable IMMO COLD HYPO HEMO PAIN
Ratio of responses

4 4% / 1%
Fos in hypothalamus
Paraventricular nucleus +++ + + ++ +++
H Supraoptic nucleus ++ – " ++ ++
F Medial preoptic nucleus + +++ !! + ++
2
F
Fos in limbic system
H Central amygdala ++ !! + !! ++
Hippocampus " !! !! !! "

0 Fos in midbrain
NE EPI ACTH Substantia nigra !! !! !! !! !!
(a) Dorsal raphe + !! !! !! +
Fos in pons
Raphe nuclei ++ + !! !! +
60
Fos in medulla oblongata
50 NE NTS + ++ + + ++
∆ AUC (ng/min/ml)

EPI/2 Fos in CA cell groups

40 A1 +++ + !! + ++
ACTH
A2 ++ " + + +
30 A6 +++ " !! + +++
A12 !! !! !! !! !!
20
NE in paraventricular +++ + + " ++
nucleus
10
Plasma hormone levels
0 NE +++ +++ ++ " +++
(b) Formalin Hemorrhage EPI ++ " +++ " +
ACTH +++ " ++ + ++
FIGURE 2 Tests of doctrine of nonspecificity. (a) Ratios (greater
Corticosterone +++ ++ ++ +++ +++
stress/less stress) of responses of plasma levels of NE, EPI, and ACTH
for hemorrhage (H) and formalin (F). (b) Increments in area under curve +++, high response; ++, moderate response; +, low response; ", barely detectable response;
(ΔAUC) for plasma NE, EPI, and ACTH for formalin and hemorrhage. !!, no response detected.
Doctrine of nonspecificity would predict that arrows should be parallel Abbreviations: IMMO, immobilization; HYPO, hypoglycemia; HEMO, hemorrhage;
to each other and the same length. Taken from Pacak et al.31 with minor CA, catecholamine.
modifications. Data are summarized from Pacak and Palkovits32 and Pacak et al.31

1. GENERAL CONCEPTS
 REFERENCES 19

CONCLUSIONS 12. Mason JW. A historical view of the stress field: part I. J Hum Stress.
1975;1:6–12.
13. Mason JW. A historical view of the stress field: part II. J Hum Stress.
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his classic paper on the GAS in the journal, Nature. With 14. Chrousos GP. Stress and disorders of the stress system. Nat Rev
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of stress research attracted many dedicated researchers 15. McEwen BS. The End of Stress as We Know It. Washington, DC: Joseph
Henry Press; 2002.
and the number of published articles is staggering.
16. McEwen BS. The neurobiology and neuroendocrinology of stress:
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has been added to many languages and it is a frequent perspective. Psychiatr Clin N Am. 2002;25:469–494.
topic of discussion in the popular press. The strong link 17. McEwen BS. Physiology and neurobiology of stress and adaptation:
between stress and many diseases is all but taken for central role of the brain. Physiol Rev. 2007;87:873–904.
18. McCarty R. Stress research: principles, problems and prospects.
granted. These are important aspects of Selye’s rich
In: Van Loon GR, Kvetnansky R, McCarty R, Axelrod J, eds. Stress:
legacy as a thought leader in medical science in the Neurochemical and Humoral Mechanisms. New York: Gordon and
middle part of the twentieth century. Breach; 1989:3–13.
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pituitary-adrenocortical axis and his insistence on the chol Rev. 1970;77:419–450.
20. McCarty R, Gold PE. Catecholamines, stress, and disease: a psycho-
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sensitization of stress-induced hypothalamic-pituitary-adrenal activ-
throughs in understanding stress-related diseases in
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humans through the study of animal models will depend bed nuclei of the stria terminalis. J Neuroendocrinol. 2002;14:593–602.
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pituitary-adrenocortical axis hormones to repeated homotypic
stress and subsequent heterotypic stressor exposure in male and
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1. Neylan TC. Hans Selye and the field of stress research. J Neuropsy-
of the pituitary-adrenal response to heterotypic stressors: indepen-
chiatry. 1998;10:230–231.
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2. Selye H. A syndrome produced by diverse nocuous agents. Nature.
Horm Behav. 2012;62:515–524.
1936;138:32.
25. Uschold-Schmidt N, Nyuyki KD, Fuchsl AM, et al. Chronic psycho-
3. Selye H. The Stress of Life. revised ed. New York: McGraw-Hill; 1978.
social stress results in sensitization of the HPA axis to acute hetero-
4. Szabo S. The creative and productive life of Hans Selye: a review of
typic stressors despite a reduction of adrenal in vitro ACTH
his major scientific discoveries. Experientia. 1985;41:564–567.
responsiveness. Psychoneuroendocrinology. 2012;37:1676–1687.
5. Taché Y, Brunnhuber S. From Hans Selye’s discovery of biological
26. Selye H. Stress and disease. Science. 1955;122:625–631.
stress to the identification of corticotropin-releasing factor signaling
27. Selye H. What is stress? Metabolism. 1956;5:525–530.
pathways: implications in stress-related functional bowel diseases.
28. Selye H. The evolution of the stress concept. Am Sci. 1973;61:
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6. Guillemin R. A personal reminiscence of Hans Selye. Experientia.
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8. Ader R. Psychosomatic and psychoimmunologic research. Psycho-
31. Pacak K, Palkovits M, Yadid G, et al. Heterogeneous neurochemical
som Med. 1980;42:307–321.
responses to different stressors: a test of Selye’s doctrine of nonspe-
9. Elliott GR, Eisdorfer C. Stress and Human Health. New York:
cificity. Am J Physiol. 1998;275:R1247–R1255.
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32. Pacak K, Palkovits M. Stressor specificity of central neuroendocrine
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Endocr Rev. 1984;5:25–44.
33. Mason JW. A re-evaluation of the concept of nonspecificity in stress
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Johns Hopkins University Press; 2006.

1. GENERAL CONCEPTS
 C H A P T E R

3
Corticosteroid Receptor Balance Hypothesis:
Implications for Stress-Adaptation
E.R. de Kloet
Leiden University Medical Center, Leiden, The Netherlands

O U T L I N E

Introduction 21 Testing the Balance Hypothesis 27

Changing Bioavailability of CORT 27
MR, GR, and Cellular Homeostasis 22
Genetic and Epigenetic Changes in MR:GR Balance 27
Processing of Stressful Information 24 Effect of Chronic Stress 28
Anticipation 24
Concluding Remarks 28
Appraisal and Selection of Behavioral
Response 25 Acknowledgments 29
Behavioral Adaptation 26
References 29
Setpoint in CORT Oscillations 26

Abstract
The corticosteroid receptor balance hypothesis refers to the central INTRODUCTION
action of cortisol and corticosterone (CORT) on stress adaptation,
which is mediated by mineralocorticoid receptors (MR) and gluco-
The stress concept has been a source of inspiration for
corticoid receptors (GR). Upon imbalance of MR:GR-regulated
limbic-cortical signaling pathways, the initiation and/or manage- almost a century for numerous investigators to explain
ment of the neuroendocrine stress response is compromised. At a diseases of adaptation.1 Central to this concept of stress
certain threshold this may lead to a condition of hypothalamus- and adaptation are the sympathetic nervous system and
pituitary-adrenal axis dysregulation and impaired behavioral the hypothalamus-pituitary-adrenal (HPA)-axis, the lat-
adaptation, which can enhance susceptibility to stress-related neu-
ter with its end products cortisol and corticosterone
rodegeneration and mental disorders. Here the progress is pre-
sented to test this hypothesis from the perspective of CORT (collectively abbreviated as CORT). In recent years,
coordinating three complementary phases of stressful information extensive overviews of the role of HPA-axis hormones
processing. First is the onset of the stress reaction when MR in the pathophysiology of stress-related mental disor-
mediates CORT action on appraisal of novel information and ders have appeared.2–5 This chapter is about CORT
emotional reactivity. Second is the termination characterized by
and its receptors in the brain that act in concert with
CORT promoting behavioral adaptation and memory storage.
Third is the basal phase when ultradian and circadian oscillations neurotransmitters, neuropeptides, and other factors in
of CORT permit recovery and growth, while maintaining respon- the onset, termination, and recovery of the stress
sivity to stress. response.

Stress: Concepts, Cognition, Emotion, and Behavior 21 Copyright © 2016 Elsevier Inc. All rights reserved.
[Link]
22 3. CORTICOSTEROID RECEPTOR BALANCE HYPOTHESIS: IMPLICATIONS FOR STRESS-ADAPTATION

individual to inflammation and hypertension, while

KEY PO INTS excess glucocorticoids increased the risk for infection.1
• The failure to cope with a stressful experience Importantly in the current CoRe Balance hypothesis,
enhances vulnerability to disease for which the Selye's opposing hormone actions are now represented
individual is predisposed. by MR and GR that can mediate in a complementary fash-
• The nature and context of this experience ion the action of one single adaptive hormone: CORT. MR
determines circuit connectivity involved in overactivity relative to GR seems linked to anxiety and
processing of stressful information. aggression-related disorders, while MR underactivity
appears linked to depression (Figure 1).
• Circuit connectivity is biased by stress hormones
Here the evolution of the stress concept (Box 2) is
such as corticosteroids.
highlighted from the perspective of CORT action aimed
• Corticosteroids act as a double-edged sword by to promote stress adaptation. The MR and GR that medi-
affecting in a complementary manner first ate CORT action differ in localization and properties that
appraisal of and then adaptation to stressful enable activation of signaling pathways in three distinct
information via brain MR and GR, respectively. domains of stressful information processing: onset,
termination, and recovery. The importance of the MR:
GR balance is tested by either manipulation of the
The CORT receptor balance hypothesis, or corticoste-
MR- and GR-multimeric complexes or the bioavailability
roid receptor (CoRe) Balance hypothesis, is fundamental
of their ligands. The chapter concludes with a transla-
for understanding the role of CORT in stress coping,
tional perspective of the current knowledge of diagnosis
adaptation, and recovery. The hypothesis is based on
and treatment of stress-adaptation diseases.
the action of CORT, which is mediated by two receptor
systems: the mineralocorticoid receptors (NR3C2, MR)
and the glucocorticoid receptors (NR3C1, GR). MR and
GR act as nuclear receptors in gene transcription and
MR, GR, AND CELLULAR HOMEOSTASIS
are as membrane variants engaged in rapid nongenomic
GR is expressed in all neurons and glial cells, but
membrane actions. These actions exerted by CORT via
expression is particularly high in cells engaged in the
MR and GR coordinate and integrate—as hormones
stress response, (e.g., ascending serotonergic, (nor)adren-
do—the function of systems, tissues, organs, circuits,
ergic and dopaminergic neurons, paraventricular (PVN),
and cells in body and brain. The focus here is on brain
hippocampus, amygdala, and prefrontal cortex). MR
because of its crucial role in anticipation and processing
expression is more restricted and occurs in abundance
of stressful information, which upon dysregulation may
in all hippocampus and dentate gyrus neurons, lateral
result in pathogenesis of stress-related diseases. Hence
septum, and other areas of the limbic network involved
the CoRe Balance hypothesis formulated almost 30 years
in processing salient information. While thus MR and
ago,6–10 reads as follows (Box 1).
GR are coexpressed abundantly in limbic neurons, the
The CoRe Balance hypothesis has its roots in Selye's
most profound difference is, however, the 10-fold higher
original pendulum hypothesis where mineralocorticoids
affinity of MR for CORT than displayed by GR (Box 3).11
and glucocorticoids were considered antagonistic adap-
Genomic effects mediated by MR and GR have a slow
tive hormones. In Selye's hypothesis, a relative excess
onset and are long-lasting. The effects occur with a delay
of mineralocorticoid was thought to predispose the
of at least 30 min and may last for several hours. Marian
Joëls demonstrated with intracellular recording of CA1
BOX 1 neurons in in vitro hippocampal slices that cellular excit-
ability displayed an U-shaped curve with rising concen-
CORTICOSTEROID trations of CORT.14 Thus ion conductances and
RECEPTOR BALANCE transmitter responses were large in the tissue of adrenal-
HYPOTHESIS ectomized animals lacking steroid as well as during very
high CORT concentrations occupying both MR + GR. The
Upon imbalance in MR:GR-regulated limbic-cortical
cellular responses were small in the presence of low
signaling pathways, the initiation and/or management
CORT concentrations occupying mainly MR.
of the stress response is compromised. At a certain
Three MR-mediated responses seem to be most impor-
threshold, this may lead to a condition of HPA-axis
tant in hippocampal CA1 neurons: the reduction of 5HT1A
dysregulation and impaired behavioral adaptation,
hyperpolarization, the stability of amino acid transmis-
which can enhance susceptibility to stress-related
sion, and the decrease of Ca and Ca-dependent conduc-
neurodegeneration and mental disorders.
tances. The small magnitude of these responses during
MR activation results in stabilization of ongoing activity,

1. GENERAL CONCEPTS
 MR, GR, AND CELLULAR HOMEOSTASIS 23
FIGURE 1 Hypotheses. (a) Pendulum hypothesis as formulated
by Selye1 more than 60 years ago showing the balance in action
between mineralocorticoid (MC) and glucocorticoid hormones
(GC) maintaining. Excess MC was thought to enhance the danger
of inflammation; excess GC the danger of infection. This hypoth-
esis was focused on maintaining a stable equilibrium or homeosta-
sis. (b) Corticosteroid receptor balance hypothesis (CoRe Balance)
showing the balance of MR:GR-mediated actions maintaining a
labile equilibrium.6–9 The extent of MR and GR activity can slide
over the two arms as a function of hormone concentration and
receptor properties. MR is concerned with emotional reactivity
and excess MR over GR seems linked with anxiety and
aggression-driven disorders. Inadequate MR vs. GR is a character-
istic feature of major depressive disorder. Dashed line represents a
different hormone concentration.

BOX 2

THE STRESS CONCEPT

Stress: Hans Selye coined the term “stress”7 as “a state of Coping: Since all physical stressors have a psychological
nonspecific tension in living matter, which manifests itself by component, some researchers rather restrict the definition
tangible morphologic changes in various organs and particularly of stress to “conditions where an environmental demand exceeds
in the endocrine glands which are under anterior pituitary con- the regulatory and adaptive capacity of an organism, in parti-
trol.” This “state of stress” is evoked by a stressor, which is cular in case of unpredictability and uncontrollability.”12 The
defined as any stimulus that disrupts cellular “homeosta- most stressful condition is: no information, no control,
sis” or, on the organismic level, as “a real or interpreted and no prediction of upcoming events with an uncertain
threat to the physiological and psychological integrity.”2,61 feeling of threat. A safe place, social context, and self-
The stressor activates the organism's defense reactions, esteem help to cope.63 It is not so much what happens
which are coordinated by the sympathetic nervous system but rather how the individuals takes it and copes. It implies
and neuroendocrine HPA-axis. that anticipation and appraisal of a stressful condition is
CORT and stress: Alan Munck4,62 reasoned that the action extremely important, and this is governed by MR.
of the stress mediators are integrated over time. Hence exci- Allostasis: To capture this “state of readiness” in the face of a
tatory transmitters, adrenaline and the neuropeptides of presumed threat, the concept of “allostasis” was introduced,
the HPA-axis are secreted rapidly in response to a stressor; when structure and function of brain networks already adjust
part of their action is also fast, lasting over seconds to in order to be prepared. Allostasis describes a labile equilib-
minutes. Because adrenal CORT secretion rises only rium characterized by variable setpoints (cf a juggler who
minutes after the stressor, the hormone has actually a special keeps dinner plates in delicate balance on a pointer) as opposed
role in the timing of this cascade of rapid initial stress to homeostasis where the stability of pH, electrolyte concentra-
reaction. As stated by Munck: “CORT prevents initial stress tion or body temperature is a conditio sine qua non. The cost of
reactions (e.g., autonomic, immune, inflammatory, metabolic, allostasis through energy consuming anticipatory adaptations
brain) from overshooting and becoming damaging to themselves.” is called allostatic load.3,64 (See Chapter 5 by McEwen.)

which is favorable for neuronal integrity and survival. This increase in excitability. However, the CA1 is unique for
condition can be achieved after substitution of adrenalec- such U-shaped responses, since different patterns are
tomized animals with small amounts of CORT or aldoste- observed elsewhere in the brain.15
rone in sufficient amounts to occupy MR, suggesting that Karst and Joëls demonstrated that MR promotes via a
the changes are due to steroids and not due to disturbances rapid membrane effect the release of glutamate and
in catecholamines released by the adrenal medulla.14,15 simultaneous decreases postsynaptically K+ to increase
Brief GR activation is required to reverse the MR-mediated excitability.16 The enhanced glutamate release

1. GENERAL CONCEPTS
24 3. CORTICOSTEROID RECEPTOR BALANCE HYPOTHESIS: IMPLICATIONS FOR STRESS-ADAPTATION

CORT via nongenomic and genomic MR and GR.

BOX 3 Regarding the neuroendocrine feature the focus is on the
well-known cascade of HPA-axis hormones starting with
CORT RECEPTORS AND hypothalamic CRH and vasopressin that stimulate after
BLOOD-BRAIN-BARRIER transport via the pituitary portal vessels the synthesis of
Bruce McEwen65 discovered that 3H-corticosterone pro-opiomelanocortin in the anterior pituitary corti-
administered to adrenalectomized rats was retained in cotrophs and the release in the circulation of corticotropin
cell nuclei of the hippocampus and other limbic brain (ACTH) which stimulates melanocortin-2 receptors on
regions through binding to nuclear receptors. Yet, if the the adrenocortical zona reticularis to secrete CORT.
potent synthetic glucocorticoid dexamethasone was In the next sections, the action of CORT is discussed on
administered, it did not compete for CORT binding the three phases of stressful information processing
and neither was it retained very well in brain cell nuclei.66 (Box 4). These include the initial phase of the stress reaction
First it was found that the receptors with very high followed by stress adaptation which terminates the stress
affinity for CORT actually are MR.11,67,68 Then, 30 years response while reinstating the basal function of CORT.
later we discovered that dexamethasone is recognized The latter phase is characterized by oscillating CORT levels
by the mdr-Pgp in the blood-brain-barrier, which which act permissively to promote growth and the storage
severely hampers its central penetration. The access of of energy resources important for the state of readiness
cortisol, but not of corticosterone, to the brain, is also and stress responsivity. Anticipation and accompanying
hampered.44,45 arousal are important determinants for readiness.

Anticipation
Anticipation of upcoming stressful events is affected
downregulates the presynaptic mGLU2 receptor.17 This by CORT as is demonstrated by schedule-induced behav-
rapid MR-mediated CORT action was not inhibited by ior. This occurs when rats are presented restricted feeding
protein synthesis inhibitors and occurred only in the pres- at a fixed point of the day. For instance, if rats receive at
ence of hormone, also when CORT was conjugated to 16.00 h only 80% of their daily need of food, the animals
BSA to prevent it from acting intracellularly. Trafficking
of AMPA receptors at the postsynaptic membrane was
enhanced by CORT with a short onset and long-last- BOX 4
ing.18,19 Rapid actions were also observed for GR involv-
ing endocannabinoid release causing presynaptically an THREE PHASES IN CORT
immediate suppression of the release of excitatory trans- ACTION
mitters.20 Interestingly, membrane MR has a 10-fold Onset stress reaction: MR localized in limbic regions
lower affinity than its nuclear variant, allowing this mem- mediates rapid CORT action in anticipation and
brane MR version to respond to rising CORT levels.16 appraisal of novel information, retrieval of previous
experience, response selection, and emotional reactiv-
ity expressed as fear and aggression. MR is a determi-
nant in the initiation of the integrated autonomic,
PROCESSING OF STRESSFUL
neuroendocrine, and behavioral stress reaction.
INFORMATION
Stress adaptation: When the experience is perceived
as a stressor, CORT levels rise, GR activation reallo-
After having attended numerous panel discussions
cates energy resources to limbic-frontocortical circuits
centered around the seminal question: “what is stress?”
engaged in executive function and memory storage,
one of the pioneers, Seymour Levine, used an operational
and behavioral adaptation occurs, terminating the
definition: “Stress is defined as a composite multidimensional
stress reaction and reinstating a basal state.
construct in which three components interact: (i) the input,
Recovery: During this basal phase CORT secretion
when a stimulus, the stressor, is perceived and appraised,
shows ultradian and circadian oscillations and acts
(ii) the processing of stressful information, and (iii) the output,
permissively to support neuronal plasticity, growth,
or stress response. The three components interact via complex
and storage of energy resources to maintain stress
self-regulating feedback loops with the goal to restore homeosta-
responsivity for upcoming challenges. This state of
sis through behavioral and physiological adaptations.”21
readiness can vary depending on arousal triggered by
With this operational definition in mind, in this section
anticipation of all kinds.
the autonomous, neuroendocrine, and behavioral features
of stress adaptation will be integrated with the action of

1. GENERAL CONCEPTS
 PROCESSING OF STRESSFUL INFORMATION 25
show increased arousal and strongly enhanced HPA-axis
activation in anticipation of food. Arousal and HPA-axis BOX 5
activity drop precipitously when the food is presented.
The animals also show displacement behavior by exces- THE DIFFERENT MODES OF
sive wheel running or polydipsia in anticipation of the NEUROENDOCRINE CORT
food. Adrenalectomy prevents normal acquisition of this FEEDBACK9,69
schedule-induced behavior, while it can be reinstated by Fast feedback: Operating within minutes via a
CORT but not dexamethasone replacement. Since dexa- GABA-ergic network at the PVN level that attenuates
methasone alone is not active, CORT activation of MR stress-induced HPA-axis activation and involves a
seems a prerequisite.22 rapid action of CORT via membrane MR and GR,
the latter mediated by endocannabinoid.
Intermediate feedback: From 30 min to 2 h, that is reg-
ulated by the action of CORT in higher brain regions
Appraisal and Selection of Behavioral Response
with the goal to promote stress adaptation and as a
The perception (or anticipation) of a salient situation consequence the drive toward the PVN subsides.
instantaneously triggers an alarm reaction expressed as Emergency brake: Exerted by extreme levels of
generalized arousal caused by enhanced activity of CORT that exceed CBG capacity in blood and pituitary
ascending excitatory pathways stemming from the n. corticotrophs. Dexamethasone bypasses the CBG
gigantocellularis.23 At the same time the novel informa- barrier and targets the pituitary, but the synthetic
tion is processed in the limbic-cortical circuitry to make glucocorticoid poorly penetrates the brain.
decisions, such as: is this individual a friend or a foe? Variable setpoint regulation69: Epigenetic factors are
Was a similar situation encountered before and how recruited by GR to clamp CRH gene transcription
was it dealt with? How did I cope? These are questions reciprocally with the concentration of bioavailable
that require retrieval of previous experiences to support CORT and the drive from higher brain centers. The
appraisal and decision-making. If the outcome of this variable setpoint regulation requires further proof.
appraisal process is interpreted as a threat to integrity,
defensive reactions are activated. Central norepinephrine
and epinephrine pathways from the n. tractus solitarii
(NTS)/A2 as well as the locus coeruleus/A6 are activated
resulting in increased attention, alertness and vigilance. via an inhibitory transmitter network around the PVN
The CRH neurons in the PVN and amygdala orchestrate (Box 5). One candidate for fast feedback is the GABA-
the sympathetic, neuroendocrine and behavioral stress ergic network that receives projections from limbic struc-
response.24 tures, another candidate the endocannabinoids.26
The amygdala generates emotionally loaded informa- MR functioning is tightly linked to this initial phase of
tion, which is labeled in time, place, and context when the stress response and mediates the effect of CORT on
processed in the hippocampus. In mutual feedback and the appraisal process, risk assessment, response selec-
feedforward loops, the amygdala and hippocampus com- tion, and emotional expressions of fear and aggression.
municate with frontal brain regions. Over time, energy Thus, blockade of MR by administering MR-antagonists
resources are allocated, notably to the mesolimbic- interferes with acquisition and retrieval of fear-
cortical DA pathways of reward and adversity, and the motivated behavior.5 Blockade of MR also interferes
prefrontal cortex in which subregions are involved in spe- with the propensity to aggressive behavior, provided
cific higher cognitive functions. The appraisal process this blockade is present prior to the first violent encoun-
drives coping behavior to fulfill an expectancy. If coping ter.27 Blockade of MR attenuates sympathetic outflow as
behavior is adequate the stress response is extinguished. measured from the attenuated stress-induced blood
If inadequate, then feelings of uncertainty and anxiety, pressure response.28 MR antagonism also rapidly blocks
as well as the stress response are reinforced. excitatory outflow from the hippocampus toward the
inhibitory GABA-ergic PVN network governed by excit-
atory transmission, and thus can activate the HPA-axis
Anxiolytic and Antiaggressive Activity resulting in higher basal and stress-induced ACTH and
of MR Blockade CORT levels.29 Interestingly, the opposite effect is
Mary Dallman25 identified a fast rate-sensitive feed- observed after administration of antiglucocorticoids in
back mechanism of CORT which operates within minutes the hippocampus, causing enhanced inhibition of
to attenuate the initial activation of the neuroendocrine stress-induced ACTH.7 The blockade of hippocampal
stress response. Subsequent research demonstrated that GR apparently enhances MR-mediated hippocampal
this fast rate-sensitive feedback action probably proceeds inhibition of the HPA-axis.

1. GENERAL CONCEPTS
26 3. CORTICOSTEROID RECEPTOR BALANCE HYPOTHESIS: IMPLICATIONS FOR STRESS-ADAPTATION

Habit Versus Spatial Learning in learning, but synergism with noradrenaline in the
If individuals are exposed daily to homotypic amygdala is required for adequate learning of the task.5
stressors, they habituate and stress-induced ACTH and Distinctly different effects were observed with antago-
CORT responses gradually diminish. If prior to the daily nists for MR and GR. intracerebroventricular (ICV) infu-
stressor exposure, the animals are given MR-antagonists, sion of the MR antagonist—but not of the GR
this habituation is prevented and thus CORT responses antagonist—impaired retrieval of learned information if
remain the same.30 In the behavioral realm, hippocampal given 24 h later at 15 min before the retrieval test. The rats
MR appeared to have a crucial role in the stress-induced used a different strategy to search for an escape route,
switch from spatial declarative performance toward than the intact animals. The GR antagonist mifepristone
caudate stimulus-response (habit). For instance, in the cir- impaired learning of the maze when administered imme-
cular hole board test, naive male mice locate with a diately after the learning trial, and thus interferes with con-
hippocampal-associated spatial strategy an exit hole at solidation of the learned information. This observation
a fixed location flagged by a proximal stimulus. How- supports the evidence that CORT released after stressful
ever, if exposed to a stressful context, close to 50% of learning tasks facilitates memory storage via GR. In addi-
the mice perseverated in the previously learned tion, GR activation promotes extinction of fear-motivated
response.31 This habit response was associated with behavior when given after retest in the absence of the
hypertrophy of the caudate and atrophy of the hippocam- unconditioned stimulus.
pus under chronic stress conditions.3,32 CORT acts on higher brain circuits to facilitate behav-
The switch toward the caudate stimulus-response or ioral adaptation causing dissipation of the drive toward
habit strategy was accompanied by a rescue of perfor- the PVN to release CRH. This so-called intermediate feed-
mance. However, the performance declined of the back mechanism takes 30 min to a few hours depending on
stressed mice that kept using the hippocampal spatial the ability to cope and adapt. If a GR antagonist is given
strategy as could be predicted from their atrophied hip- behavioral adaptation is impaired delaying the intermedi-
pocampal circuitry. Pretreatment with an MR antagonist ate feedback.29 A recent study using ChIP failed to show
did prevent the switch toward the stimulus-response binding of GR near the Crf-promotor, while p-CREB stim-
strategy, but did not improve the deterioration of ulated by afferent projections did bind indicating that
hippocampus-dependent performance in these stressed CRH cannot be a primary feedback site for CORT.35 The
mice. These findings show that MR-mediated CORT pituitary also was ruled out as a primary feedback site
action is linked to flexibility in the transition from spatial because selective GR knockout in pituitary corticotrophs
to stimulus-response memory systems. Also in humans, did not alter HPA-axis activity in the mutants.36 This lack
stress prior to learning facilitated simple stimulus- of effect of CORT in adult animals probably is due to the
response behavior at the expense of a more cognitive presence of tissue-like corticosteroid binding globulin
learning strategy.31 (CBG) in pituitary corticotrophs that prevents CORT from
The sexes differ strikingly in their MR-dependent cog- binding to the GR.9 Hence only very high CORT levels
nitive flexibility. In spatial tasks, male mice performed exceeding CBG capacity during extreme stress would
superior to females. As mentioned, under stress spatial serve as some kind of emergency brake (Box 5).
memory of males was impaired, while females actually
improved their spatial abilities, depending on the task Setpoint in CORT Oscillations
and type of stressor. Moreover, we found in the females
that the performance of a spatial strategy depends on the Termination of stress-induced HPA-axis activation as
phase in the estrous cycle, with females in estrus being a result of behavioral adaptation raises the question of
most resistant to cognitive deterioration during stressor what the CORT feedback on CRH transcription in the
exposure.33 These findings further support the relevance PVN means? One attractive viewpoint comes from the
of MR for behavioral flexibility. studies of Elliott and Chen37 showing that elevated CORT
activates GR to promote an epigenetic mechanism meant
to keep a sustained level of CRH expression for a pro-
longed period of time. This epigenetic action implies a
Behavioral Adaptation mechanism that seems more concerned with regulation
For study of the complementary role of MR and GR in of the HPA-axis setpoint involving recruitment of
behavioral performance, we selected the Morris water methyltransferases and histone (de)acetylases by CORT
maze, because this is a test of the function of the hippo- in the PVN37,38 and possibly also elsewhere in the brain.
campus. Melly Oitzl observed that removal of the adrenal This would explain why GR knockout from the mouse
medulla did not affect maze performance, while complete PVN parvocellular neuron increased circulating ACTH
adrenalectomy did.34 This finding shows that physiolog- and CORT levels39; it would represent a rise of basal
ical levels of peripheral catecholamines are not implicated ACTH levels as is the case after adrenalectomy.

1. GENERAL CONCEPTS
 TESTING THE BALANCE HYPOTHESIS 27
Also MR is involved in setpoint regulation, since glycerrhetinic acid or its analogs limits regeneration of
MR-antagonists infused systemically, ICV or in the hip- CORT and therefore may prevent unwanted effects.
pocampus elevate basal circulating CORT in animals Alternatively, also gene delivery of additional 11βHSD-
and man for a prolonged period of time, both at the peak 2 inactivating excess CORT in the hippocampal dentate
and the trough. This suggests that the nuclear MR which gyrus can reverse its damaging effects.43
is largely occupied by circulating hormone seems to par- Mdr-Pgp recognizes in the rodent exogenous cortisol
ticipate in regulation of the tone of the HPA-axis.6 and synthetic glucocorticoids as substrate, but not endog-
Chronic GR blockade with moderate doses antagonist enous corticosterone. Dexamethasone and cortisol there-
also causes a pronounced adrenal hypertrophy with fore poorly penetrate the blood-brain-barrier.44,45 If
deeper troughs and higher peaks in circadian CORT dexamethasone is given in low doses the HPA-axis is sup-
patterns.40 pressed and CORT levels are decreased, but the synthetic
The circadian pattern entrained by the day-night steroid hardly substitutes in brain. Moreover, since dexa-
rhythm is based on the ultradian rhythm in CORT secre- methasone does not have an affinity for MR, in particular,
tion of about 1 pulse per hour. The ultradian rhythm is— the MR becomes depleted of endogenous hormone and as
as a computational analysis suggests—intrinsic to the a consequence the MR:GR balance is severely disturbed
HPA-axis and entirely caused by the delay between cen- even though MR levels increase in compensation to lack
tral drive toward the HPA-axis and the negative feedback of ligand.46 One way to ameliorate this deficit is by giving
action of CORT.41 The amplitude of the pulse is largest at CORT as add-on to dexamethasone treatment. Indeed in
the circadian peak in anticipation of the energy expendi- animal experiments, the need for additional intermittent
ture for the upcoming activity period. It appears that the administration of CORT to promote learning-dependent
affinity of MR is high enough to stay occupied over the synaptic plasticity was demonstrated.47 This finding pro-
interpulse interval42; in contrast, GR occupation follows vides proof-of-principle for a combination therapy with
the ultradian changes of cortisol levels. CORT to restore the MR:GR balance as an approach to
The ultradian rhythm was shown to support respon- limit the severe adverse effects of prolonged therapy with
siveness to stressors.42 The pattern can change in fre- synthetic glucocorticoids.
quency and amplitude, and becomes disorganized at
old age, implying that the organism is less well prepared
to deal with stressors. CORT oscillations under basal con-
Genetic and Epigenetic Changes in MR:GR
ditions are very important for recovery. First, under these
conditions CORT is permissive for growth, recovery, and
Balance
storage of energy resources in cooperation with the para- The Lewis rat shows in comparison with Wistars
sympathetic nervous system and trophic factors.4 Sec- enhanced inflammatory and immune responses in the
ond, because of the storage of resources, the individual face of a reduced HPA-axis response. The Lewis rat
is brought into a state of readiness to deal with upcoming shows increased expression of hippocampal MR. Hence,
challenges as appears from the CORT awakening an augmented hippocampal MR-mediated effect of
response which occurs the first hour after awakening CORT underlies likely its hyporeactive HPA-axis. The
and prepares the individual and its energy resources in lower hypothalamic CRH mRNA and circulating ACTH
anticipation of the day to come. and CORT in response to various stimuli are apparently
the consequences of a life-long suppressive action of
CORT via central MR.48
Using mice with forebrain MR over-expression (MR-
TESTING THE BALANCE HYPOTHESIS
high) and/or simultaneous global GR under-expression
(GR-low), a significant interaction was found between
In this section, two categories of factors are briefly dis-
MR and GR in control of the HPA-axis. With reduced
cussed that potentially can affect the outcome of the coor-
overall GR levels, HPA-axis activity in response to
dinate MR:GR-mediated actions: the bioavailability of
restraint stress was enhanced. However, in combination
CORT and changes in its receptors.
with high limbic MR, this excessive stress-induced
HPA-axis activation was very much reduced.49 MR:GR
balance also played a role in determining the behavioral
Changing Bioavailability of CORT strategy during Morris watermaze performance. In com-
Bioavailability depends on binding to CBG, multidrug bination with GR-low, MR-high showed enhanced per-
resistance P-glycoprotein (mdr-Pgp) in the blood- severation in the probe trial in the retrieval phase 24 h
brain-barrier and intracellular enzymes such as after maze learning, suggesting enhanced spatial mem-
11βHSD-1 (11β-hydroxysteroid-dehydrogenease type 1) ory recall or reduced exploratory flexibility. Other alter-
and -2. For instance, blockade of 11βHSD-1 by ations in cognitive functions were specific to a single

1. GENERAL CONCEPTS
28 3. CORTICOSTEROID RECEPTOR BALANCE HYPOTHESIS: IMPLICATIONS FOR STRESS-ADAPTATION

receptor without interaction, with both MR-high and GR- Chronically stressed animals show profound changes in
low manipulations independently impairing reversal neuroendocrine regulations due to an altered phenotype
learning in spatial and fear memory tasks.49 of the CRH neurons expressing much more vasopressin
Genetic variants of MR, GR, and their regulatory pro- as co-secretagog54 and profound changes in brain
teins such as FKBP5 have been identified that appeared plasticity.3
to be associated with risk for depression and efficacy of In animal experiments using dentate gyrus (where
antidepressant therapy. In vitro the MR gene has three neurogenesis occurs) of controls 26 different GO terms
levels of control (promoter, translation, primary structure) could be assigned in pathway analysis, but the diversity
that can be modified by genetic variability. In vivo these in the CORT responsive pathways was in the stressed
different levels of genetic control merge into three haplo- group reduced to only 7. After chronic stress, CORT or
types in the MR promotor region with frequencies of 50%, acute stress induced particularly genes involved in
35%, and 12%, respectively.50 In a series of human studies, chromatin modification, epigenetics, and the cytokine/
MR haplotype 1 and 3 associate with basal and stress NFκB pathway.55 One highly responsive gene network
levels of cortisol, psychological measures, signs of depres- revealed by this procedure is the mammalian target of
sion, suicidal ideation, and life history. MR-haplotype 2 rapamycin (mTOR) signaling pathway which is critical
associates in women with dispositional optimism and for different forms of synaptic plasticity and appears to
protection against depression.50 be associated with depression.
The GR variant N363S was found hypersensitive to Since CORT challenge was used to identify dysregu-
cortisol and associated with an unhealthy metabolic pro- lated pathways in limbic regions of the chronically
file while ER22/23EK is linked to steroid resistance and stressed animals, it may also represent a target for treat-
enhanced risk of depression. The Bcl-1 polymorphism ment. Indeed, enhanced expression of MR locally in the
predicts cardiovascular risk and contributes to individ- hippocampus or amygdala was protective to the effect
ual differences in emotional and traumatic memories as of stress. Reduced MR expression is observed during
well as PTSD symptoms after intensive care treatment. the aging process56 and depression.57 Furthermore, in
Currently, trials are underway to exploit this knowledge such stressed animals blocking GR with an antagonist
on MR and GR variants for its potential as a biomarker improved cognitive performance,7,58 reversed suppres-
to support diagnosis of anxiety disorders and sion of neurogenesis, Ca current and long term potentia-
depression.51 tion (LTP),5 and rescued the CREB-signaling pathway.59
MR and GR expression shows life-long changes in Antiglucocorticoid treatment or genetic deletion of GR
parallel with the amount of maternal care the rodents after chronic stress restored the hyperactive dopaminer-
experience,52 probably because of stable changes in his- gic mesolimbic/cortical-amygdala loop and social
tone acetylation and DNA methylation. This epigenetic behavior.60
signature imposed by early life experience is a determi-
nant of plasticity in neuronal networks underlying later
emotional expression and cognitive performance, and CONCLUDING REMARKS
seems a significant factor in the precipitation of
stress-related mental disorders. In particular, the epige- According to the CoRe Balance hypothesis, imbal-
netic change in GR was found to be associated with a ance in MR:GR-regulated limbic-cortical signaling
programmed HPA-axis and behavioral response pat- pathways causes HPA-axis dysregulation which would
terns. This is not restricted to rodents. Also in man, after passing a certain threshold impair behavioral
decreased expression of GR due to DNA methylation adaptation resulting in enhanced susceptibility to
in the hippocampus induced by emotional neglect in stress-related mental disorders. Studies over the past
early life was found to be associated with adult 25 years revealed that the strength of this hypothesis
neuro-behavioral endpoints.53 is in the integration and coordination of MR- and
GR-mediated actions over time in neuroendocrine reg-
ulation associated with behavioral performance. Thus,
reduced MR expression in limbic regions associates
Effect of Chronic Stress
with an increased initial HPA-axis response to stress,
According to Selye, “the imperfections of the adaptation while a reduced GR causes at a later time point in a
syndrome”7 coincide with an altered balance in adaptive more prolonged stress response.
hormones and are important in the pathogenesis of most These altered neuroendocrine responses over time
stress-related diseases. Selye referred in this context to the actually reflect temporal changes in processing of
pendulum hypothesis, where excess mineralocorticoid stressful information (Figure 2). Thus, an impaired MR
over glucocorticoid enhanced vulnerability to inflamma- function frustrates proper appraisal and decision-
tion whereas the reverse enhanced risk of infection.1 making which impairs subsequent coping, leading to

1. GENERAL CONCEPTS
 REFERENCES 29
stress-related pathophysiology.64 Another approach is
Hellhammer's Neuropattern™ tool that adopts 13 distinct
constructs based on regulations in the HPA-axis, sympa-
thetic and parasympathetic systems each characterized
by an endophenotype of biological, psychological, and
symptomatic measures.71 This functional phenotype, if
combined with genotyping of stress markers linked to clin-
ical symptoms, is a possible answer to the ambition
expressed in the NIMH Research Domain Criteria
(RDoC [Link]
FIGURE 2 Time-dependent CORT action on processing of stressful
rdoc/[Link]).and the Roadmap for Mental Health
information. CORT action on stress onset, termination, and recovery. Research in Europe72.
Increasing CORT concentration initially affects emotional reactivity
via nuclear MR and then progressively activates also nuclear GR to real- Acknowledgments
locate energy to circuits underlying behavioral adaptation and memory
storage of the experience. CORT returns to baseline oscillations allowing The support by the Royal Netherlands Academy of Arts and Sciences,
recovery. In red: membrane MR and GR have a lower affinity and rap- COST Action ADMIRE BM1301 and STW Take-off 14095 is gratefully
idly respond to rising CORT concentrations, while the nuclear receptors acknowledged.
mediate CORT action on gene transcription with a slow onset producing ERdk is scientific advisor to Pharmaseed Ltd, Dynacorts Therapeutics
primary, secondary, etc. waves of gene transcripts. Adapted from BV and Corcept Therapeutics Inc and owns stock of Corcept.
de Kloet.8

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31. Schwabe L, Schächinger H, de Kloet ER, Oitzl MS. Corticosteroids 52. Champagne DL, Bagot RC, van Hasselt F, et al. Maternal care and
operate as switch between memory systems. J Cogn Neurosci. hippocampal plasticity: evidence for experience-dependent struc-
2009;22:1362–1372. tural plasticity, altered synaptic functioning, and differential respon-
32. Dias-Ferreira E1, Sousa JC, Melo I, et al. Chronic stress causes fron- siveness to glucocorticoids and stress. J Neurosci. 2008;28:6037–6045.
tostriatal reorganization and affects decision-making. Science. 53. Turecki G, Meaney MJ. Effects of the social environment and stress
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Behav Brain Res. 2013;241:92–95. 54. Herman JP. Neural control of chronic stress adaptation. Front Behav
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1992;106:62–71. Kloet ER, McEwen BS. Previous history of chronic stress changes
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36. Schmidt MV, Sterlemann V, Wagner K, et al. Postnatal glucocorti- 56. Van Eekelen JA, Oitzl MS, De Kloet ER. Adrenocortical hyporespon-
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2009;150:2709–2716. 57. Klok MD, Alt SR, Irurzun Lafitte AJ, et al. Decreased expression of
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ience to social stress coincides with functional DNA methylation of mortem brain regions of patients with major depressive disorder.
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58. Dumas TC, Gillette T, Ferguson D, Hamilton K, Sapolsky RM. 66. De Kloet R, Wallach G, McEwen BS. Differences in corticosterone
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elevated corticosterone on spatial memory, hippocampal ogy. 1975;96:598–609.
neuronal excitability, and synaptic plasticity. J Neurosci. 2010;30: 67. Moguilewsky M, Raynaud JP. Evidence for a specific
1712–1720. mineralocorticoid receptor in rat pituitary and brain. J Steroid
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911–912.

1. GENERAL CONCEPTS
 C H A P T E R

4
The Fight-or-Flight Response: A Cornerstone
of Stress Research
R. McCarty
Vanderbilt University, Nashville, TN, USA

O U T L I N E

Introduction 33 Theories of Emotions 35

The Concept of Homeostasis 33 The Legacy of Walter B. Cannon 36
The Fight-or-Flight Response 34 References 37
Fight-or-Flight Taken to an Extreme 35

Abstract sympathetic nervous system in laboratory animals. In

The fight-or-flight response was a concept developed by addition to studying the physiology of the adrenal
Walter B. Cannon in the course of his studies on the secretion medulla, he broadened his focus to include psychological
of epinephrine from the adrenal medulla of laboratory animals. stimuli and emotional responses that were often associ-
This concept was an outgrowth of his studies of homeostatic
mechanisms, particularly as they related to the sympathetic-
ated with sympathetic nervous system discharge and
adrenal medulla system. Cannon’s research on homeostasis adrenal medullary secretion.3,4
and the fight-or-flight response led him to delve into mechanisms
of “voodoo death” and to propose a new theory of emotions,
known as the Cannon-Bard theory. Cannon thought that the
sympathetic nervous system and the adrenal medulla operated THE CONCEPT OF HOMEOSTASIS
as a functional unit, with epinephrine as the chemical messenger.
He did not understand that the postganglionic sympathetic To place Cannon’s research on the fight-or-flight
nerves utilized norepinephrine as a chemical transmitter.
response in context, it is important to first consider his
Cannon’s research legacy is a rich one and his work is still cited
frequently by contemporary researchers in the field of stress. path-breaking work on homeostasis, which was an out-
growth of earlier studies in France. Beginning in the
mid-nineteenth century and continuing until his death
INTRODUCTION in 1878, the renowned French physiologist, Claude
Bernard, advanced the theory that bodily systems oper-
Walter B. Cannon was one of the most influential ate in concert to maintain a relatively constant internal
physiologists of the first half of the twentieth century.1 environment, or milieu intérieur.5 These bodily systems
Following the lead of his advisor and mentor at Harvard would also join together to effect a return to a constancy
Medical School, Professor Henry P. Bowditch, Cannon of the milieu intérieur even after major disruptions to an
devoted much of his early research career to studies of organism. Thus, Bernard’s view at the end of his career
the digestive system, including the use of newly discov- was that higher animals are in a close and informed
ered X-rays to visualize digestive processes.2 Beginning relationship with the external world, and the relative
in 1910, Cannon moved into a new area of investigation constancy of the milieu intérieur results from moment-to-
that included studies of the adrenal medulla and the moment adjustments in various physiological systems.6

Stress: Concepts, Cognition, Emotion, and Behavior 33 Copyright © 2016 Elsevier Inc. All rights reserved.
[Link]
34 4. THE FIGHT-OR-FLIGHT RESPONSE: A CORNERSTONE OF STRESS RESEARCH

Cannon was mistaken on several critical details relating

KEY PO INTS to the sympathetic nervous system and the adrenal
• Walter B. Cannon expanded upon Claude Bernard’s medulla but was largely correct on the bigger picture.
concept of the milieu intérieur and introduced the For example, Cannon8 argued that the sympathetic ner-
concept of homeostasis. He recognized that stressful vous system and the adrenal medulla were a single
stimuli could disrupt the constancy of the internal functional unit that employed the same chemical messen-
environment and he demonstrated that central ger, epinephrine. The chemical arsenal of the sympathetic
control of epinephrine secretion from the adrenal nerves was expanded, Cannon thought, through the
medulla was important in reestablishing conversion of epinephrine into two other substances,
homeostatic balance. sympathin E (excitation) and sympathin I (inhibition).9,10
• The fight-or-flight response was a term coined by It was not until immediately after World War II that von
Cannon to describe the activation of an organism Euler11 provided definitive evidence that norepinephrine
when exposed to a conspecific or a predator. was the neurotransmitter released from sympathetic
The physiological changes in these situations, nerve endings, not epinephrine. It was later still that a
including epinephrine release into the circulation, host of investigators revealed the two broad classes of
enhance survival by increasing the delivery of adrenergic receptors, alpha- and beta- and their
oxygen and glucose to skeletal muscles and brain subclasses.12
at the expense of the viscera and skin.
• Cannon’s investigations into “voodoo death” in
primitive societies revealed his broad interests in
behavioral sciences and the scientific rigor of his
THE FIGHT-OR-FLIGHT RESPONSE
approach. He hypothesized that voodoo death
resulted in hyperactivity of the adrenal medulla,
The fight-or-flight response presents a special chal-
which resulted in life-threatening changes in
lenge to the maintenance of homeostasis in animals and
cardiac function. Later studies by Curt P.
humans. Cannon recognized that the sympathetic-
Richter using an animal model of sudden death
adrenal medullary system would at critical times, such
suggested that the mechanism was more likely
as aggressive encounters with conspecifics or exposure
associated with increases in vagal drive to
to a predator, drive the individual out of homeostatic bal-
the heart.
ance. On such occasions, increased blood flow to the skel-
• Cannon challenged the prevailing theory of etal muscles, release of glucose from the liver, dilation of
emotions, the James-Lange theory, in a paper in the bronchi to increase availability of oxygen, reduced blood
American Journal of Psychology in 1927. The Cannon- flow to the skin and digestive system, and a host of other
Bard theory of emotions, which drew on research changes were all directed toward enhancing the immedi-
by Cannon and his student, Philip Bard, focused ate survival of the organism (see Table 1). Homeostasis
attention on the hypothalamus and thalamus as could be reestablished at a later time, or even at different
critical brain areas for generating emotions and set points, when the threat was eliminated and the sur-
their associated peripheral physiological changes. vival of the organism was certain.13–15
• Cannon’s publications continue to serve as a strong The linkage between epinephrine secretion from the
foundation for contemporary studies of stress. adrenal medulla and increases in glucose in the circula-
In particular, his work on homeostasis, the tion prompted Cannon to write the following entry in
fight-or-flight response, and the emergency his journal on January 20, 1911—“Got idea that adrenals
functions of the adrenal medulla are still widely in excitement serve to affect muscular power and mobi-
referenced by researchers. lize sugar for muscular use—thus in wild state readiness
for fight or run!” In due course, fight or run was modified
into the more familiar fight or flight.
As Cannon came into the picture, these major disrup- It is important to note that Cannon, a classically
tions to an organism were expanded to include stressful trained physiologist, did not hesitate to weave psycho-
stimuli. Cannon built directly upon Bernard’s theory by logical concepts into his work on the adrenal medulla
introducing the concept of homeostasis, with the central and the control of epinephrine release. In addition, he
nervous system playing a critical role in maintaining also published important papers in behavioral
the constancy of the internal environment. A key compo- science journals (e.g., Cannon16,17). His surprisingly
nent of this homeostatic balance was the central control of broad embrace of scientific domains was captured in a
the adrenal medulla and the sympathetic nerves and the letter from Cannon to his friend and colleague, Dr. Carl
secretion of epinephrine. As Goldstein7 has noted, Binger, a Harvard psychiatrist, in October 193427:

1. GENERAL CONCEPTS
 THEORIES OF EMOTIONS 35
TABLE 1 Sympathetic-Adrenal Medullary Components person on the receiving end of the curse moved very
of the Flight-or-Flight Response quickly into a persistent and catastrophic state of fear,
Physiological and death often ensued within 48 h of the placement of
System Physiological effect consequences the curse. Cannon focused on those cases where there
were no apparent injuries to the individual and poisoning
Heart • Increased rate • Increase in blood flow
• Dilation of coronary • Increased availability of could be eliminated as a cause of death. He then proposed
vessels O2 and energy to cardiac a possible explanation for “voodoo death” that encom-
myocytes passed the sympathetic-adrenal medullary system and
Circulation • Dilation of vessels • Increased availability of its deleterious impact on the cardiovascular system.
serving skeletal muscle O2 to skeletal muscle As Sternberg and Walter18 has pointed out, Cannon’s
cells cells hypotheses obviously could not include a role for neuro-
• Vasoconstriction of • Facilitates shunting of endocrine systems that had not yet been discovered;
vessels serving blood to skeletal muscles
prominent among these is the hypothalamic-pituitary-
digestive organs and and brain
skin • Increased delivery of O2 adrenocortical system. However, within the limits of
• Contraction of spleen to metabolically active his knowledge and his own specialized research interests,
cells Cannon did succeed in tackling a phenomenon from the
Lungs • Dilation of bronchi • Increased availability anthropological literature that on the surface defied logic.
• Increased respiratory of O2 in blood His success was tied to his care in sorting through case
rate • Increased availability studies, his attempts to eliminate alternative explanations
of O2 in blood (e.g., poisoning, the supernatural), and his vast knowl-
Liver • Increased conversion • Increased availability edge of cardiovascular physiology. He is given high
of glycogen to glucose of glucose in skeletal marks for linking “voodoo death” with the physiology
muscle and brain cells of emotions and his work has, at least in part, stood the
test of time (Sternberg and Walter18).
I personally conceive of the well-grounded work of It was left to Curt P. Richter of The Johns Hopkins Uni-
the psychologist and the psychiatrist as being related versity to suggest a possible mechanism of “voodoo
to one aspect, while the work of the physiologist is death” through development of an animal model. Richter
related to another aspect of the same unit. Therefore, employed wild-trapped and domesticated laboratory rats
I do not hesitate to use psychological terms along with in his studies. Wild rats were initially restrained in a black
physiological terms in descriptions. If the physiologist bag to facilitate handling and experimental manipulations
has observations which support or yield interpretation and they were then placed individually into cylinders of
of the views of the psychologist or psychiatrist, why water. Many had their vibrissae shaved off prior to immer-
should they not be accepted and incorporated into sion in the water. Heart rates were recorded from
the general scheme of things? implanted electrodes and revealed an initial significant
increase in heart rate followed by a pronounced bradycar-
Cannon’s openness to combining psychology and evo- dia, especially in those animals that died.
lutionary biology with physiology through his experi- Richter marshaled evidence that this animal model of
ments in homeostasis, the fight-or-flight response, “voodoo” or sudden death was explained by hyperactiva-
stress, and emotions has ensured his continuing influence tion of the vagus nerve and not over-activity of the sympa-
on contemporary researchers. This is in spite of the fact thetic nerves and the adrenal medulla. Behaviorally, those
that many of his fundamental findings related to the sym- wild rats that died quickly in the swim cylinders showed
pathetic nervous system and the adrenal medulla have signs of hopelessness given that their avenues of fight-or-
not stood the test of time. flight had been eliminated. Under normal conditions,
these same rats were extremely aggressive and reactive
and to manage them in the laboratory required great care.
FIGHT-OR-FLIGHT TAKEN TO AN In contrast, domesticated laboratory rats that were more
EXTREME familiar with restraint and handling and the general labo-
ratory environment survived much longer in the swim cyl-
Toward the end of his career, Cannon17 became inter- inders and usually died of exhaustion.19
ested in case studies, mostly anecdotal, of “voodoo
death” from the anthropological and medical literature.
These reports described instances from primitive peoples THEORIES OF EMOTIONS
in Brazil, Africa, Australia, New Zealand, Haiti, and
Hawaii that included curses placed on individuals As Cannon extended his research into central control
through bone pointing or other forms of magic. The of sympathetic-adrenal medullary outflow, he also

1. GENERAL CONCEPTS
36 4. THE FIGHT-OR-FLIGHT RESPONSE: A CORNERSTONE OF STRESS RESEARCH

proposed a new theory of emotions.16 The prevailing include the central nervous system (hypothalamus and
view of emotions was one developed more than 40 years thalamus) as the primary site for receiving sensory infor-
earlier by the noted American psychologist William mation; directing peripheral nervous system, visceral and
James and the Danish physiologist G.C. Lange. The vascular changes; and generating the psychological man-
James-Lange theory of emotions included the following ifestations of the emotional experience.16,23
important elements: What has become known as the Cannon-Bard theory
of emotions was incomplete in that it did not encompass
• An emotionally charged event occurs and stimulates
limbic areas of the brain, especially the amygdala, in the
sensory receptors.
expression of emotions. Later work by Papez24 and
• Afferent nerve signals reach the cerebral cortex and the
MacLean25 expanded the brain areas involved in the con-
event is perceived.
trol of emotions to include limbic areas through the
• Efferent nerve impulses are sent to the skeletal
Papez-MacLean theory of emotions.26
muscles and visceral tissues and alter their levels of
activity in preparation for the event.
• Afferent nerve signals once again go to the cerebral
cortex and the emotionally relevant details of the event
are perceived. THE LEGACY OF WALTER B. CANNON
James20 emphasized the importance of visceral affer- Articles, chapters, and books written by Walter B.
ent signals and the stimulation of emotions, whereas Cannon are frequently referenced today by researchers
Lange21 focused in a more limited way upon the relation- in physiology, neuroscience, psychology, the medical
ships between vascular afferent activity and emotions. sciences, and related fields more than 100 years after
The James-Lange theory dominated the field until the start of his scientific career in 1900. Several aspects
Cannon’s seminal paper was published in the American of his work and the approaches he took have clearly stood
Journal of Psychology in 1927. the test of time:
Cannon argued that a critical test of the James-Lange
theory would involve an experiment on emotional • He introduced the concept of homeostasis and
expression in animals lacking visceral afferent feed- emphasized the importance of the sympathetic
back. In such an approach, the critical link between vis- nervous system and the adrenal medulla in
ceral afferent changes and cerebral expression of maintaining a stable internal environment.
emotions would be decoupled. Cannon advanced five • He first described the fight-or-flight response and
prevailing lines of evidence to discount the James- the importance of epinephrine secretion from the
Lange theory: adrenal medulla in directing the body’s response to
potentially life-threatening stimuli.
• Sherrington22 reported that dogs exhibited intense
• He provided a foundation for the continuing study
emotional expressions following complete destruction
of central mechanisms in controlling emotional
of the sympathetic and spinal sensory roots.
expression through his contributions to the
• Cannon observed that cats remained emotionally
Cannon-Bard theory.
responsive following surgical destruction of the
• He exhibited an unusually broad view of physiological
sympathetic nervous system.
experimentation that extended over to the
• The timeframe for afferent impulses to signal an
behavioral sciences and psychiatry. His paper on
emotional expression in the brain was simply too slow
“voodoo death” is but one example of his
to account for experimental observations.
interdisciplinary approach to research.
• Artificial production of visceral changes (e.g., injection
• Not discussed in this article, but in 1917-1918, Cannon
of epinephrine) did not in and of itself produce
worked during World War I on traumatic shock in
emotions.
severely injured soldiers as a member of the Harvard
• Clinical case studies demonstrated that patients with
University Hospital Unit in England and France. His
transections of the spinal cord remained emotionally
studies emphasized the importance of restoring blood
responsive despite being completely paralyzed below
volume in severely injured soldiers to enhance their
the cervical area.
survival.
Cannon was joined in this line of research by one of his • Also not discussed in this article was Cannon’s strong
most notable students, Philip Bard, who spent most of his public support for the use of animals in medical
illustrious career as a professor at The Johns Hopkins experimentation. This was but one aspect of his
University. Their combined efforts, beginning in the distinguished service in the public arena as one of the
1920s, changed the focus of research on emotions to nation’s most distinguished researchers.

1. GENERAL CONCEPTS
 REFERENCES 37

References 13. Cannon WB. The emergency function of the adrenal medulla in pain
and the major emotions. Am J Physiol. 1914;33:356–372.
1. Benison S, Barger AC. Walter B. Cannon: The Life and Times of a Young 14. Cannon WB. Bodily Changes in Pain, Hunger, Fear and Rage. New
Scientist. Cambridge, MA: Belknap Press; 1987. York: Appleton-Century; 1915.
2. Cannon WB. Movements of the intestines studied by means of the 15. Cannon WB. The Wisdom of the Body. New York: W.W. Norton; 1932.
R€oentgen rays. J Med Res. 1902;7:72–75. 16. Cannon WB. The James-Lange theory of emotions: a critical exami-
3. Cannon WB. Studies on the conditions of activity of adrenal glands. V. nation and an alternative theory. Am J Psychol. 1927;39: 106–124.
The isolated heart as an indicator of adrenal secretion induced by pain, 17. Cannon WB. Voodoo death. Am Anthropol. 1942;44:169–181.
asphyxia and excitement. Am J Physiol. 1919;50: 399–432. 18. Sternberg EM, Walter B. Cannon and “Voodoo Death”: a perspec-
4. Cannon WB, de la Paz D. Emotional stimulation of adrenal secre- tive from 60 years on. Am J Public Health. 2002;92:1564–1566.
tion. Am J Physiol. 1911;28:64–70. 19. Richter CP. On the phenomenon of sudden death in animals and
5. Bernard C; Hoff HE, Guillemin R, Guillemin L (Translators). Lec- man. Psychosom Med. 1957;19:191–198.
tures on the Phenomena of Life Common to Animals and Plants. 20. James W. What is an emotion? Mind. 1884;os-IX:188–205.
Springfield, IL: Charles C. Thomas; 1974. 21. Lange CG. The mechanism of the emotions. In: Dunlap D, ed. The
6. Holmes FL. Claude Bernard, the milieu intérieur and regulatory Emotions. Baltimore, MD: Williams and Wilkins; 1885:33–92.
physiology. Hist Philos Life Sci. 1986;8:3–25. 22. Sherrington CS. The Integrative Action of the Nervous System. New
7. Goldstein DS. Adrenaline and the Inner World. Baltimore, MD: The Haven, CT: Yale University Press; 1906.
Johns Hopkins University Press; 2006. 23. Bard P. A diencephalic mechanism for the expression of rage with
8. Cannon WB. The adrenal medulla. Bull N Y Acad Med. 1940;16: 3–13. special reference to the sympathetic nervous system. Am J Physiol.
9. Cannon WB, Rosenblueth A. Studies on conditions of activity in 1928;84:490–515.
endocrine organs. XXIX. Sympathin E and sympathin I. Am J Physiol. 24. Papez J. A proposed mechanism of emotion. Arch Neur Psychiat.
1933;104:557–574. 1937;38:725–743.
10. Rosenblueth A, Cannon WB. Studies on conditions of activity in 25. MacLean P. Psychosomatic disease and the 'visceral brain', recent
endocrine organs. XXVIII. Some effects of sympathin on the nictitat- developments bearing on the Papez theory of emotion. Psychosom
ing membrane. Am J Physiol. 1932;99:398–407. Med. 1950;11:338–353.
11. von Euler US. Identification of the sympathomimetic ergone in 26. Weisfeld GE, Goetz SMM. Applying evolutionary thinking to the
adrenergic nerves of cattle (Sympathin N) with laevo-noradrenaline. study of emotion. Behav Sci. 2013;3:388–407.
Acta Physiol Scand. 1948;16:63–74. 27. Psychosom. Med. 1957;19:180.
12. Ahles A, Engelhardt S. Polymorphic variants of adrenoceptors:
pharmacology, physiology and role in disease. Pharmacol Rev.
2014;66:598–637.

1. GENERAL CONCEPTS
 C H A P T E R

5
Central Role of the Brain in Stress and
Adaptation: Allostasis, Biological
Embedding, and Cumulative Change
B.S. McEwen
The Rockefeller University, New York, NY, USA

O U T L I N E

Introduction 40 Translation to the Human Brain 47

Homeostasis, Allostasis and Allostatic Load and Sex Differences in Stress Responsiveness and
Overload 41 What This Means for the Rest of the Brain 48
Characteristics of Homeostatic Systems 41
Lessons from Gene Expression 48
Need for Refocusing 41
What is Stress? 42 Lessons from Epigenetic Influences 49
Stressors and Stress Responses 42
The Life Course and the Epigenetics of
Individual Differences 43
Individual Differences 50
Allostasis 43
Allostatic States 43 Interventions 51
Allostatic Load and Overload 43
Acknowledgments 52
Role of Behavior in Allostatic Overload 45
References 52
Plasticity and Vulnerability of the Brain 45
Glucocorticoids, Stress, and the Hippocampus 45
Extension of Stress Effects to Amygdala and
Prefrontal Cortex 47

Abstract unhealthy behaviors (“allostatic load”) that can lead to disease,

The brain is the central organ of stress and adaptation because it e.g., diabetes, cardiovascular disease (“allostatic overload”).
perceives what is threatening and determines behavioral and Besides the embedding of early life experiences, the most potent
physiological responses. Brain circuits are remodeled by stress– of stressors are those arising from the social and physical environ-
which changes the ability to self-regulate anxiety and mood–to ment that affects both brain and body. Gradients of socioeco-
perform working and episodic memory, as well as executive nomic status reflect the cumulative burden of coping with
function and decision making. The brain regulates the body limited resources, toxic environments, and negative life events,
via the neuroendocrine, autonomic, immune, and metabolic sys- as well as health-damaging behaviors that result in chronic acti-
tems, and the mediators of these systems and those within the vation of physiological systems that lead to allostatic load and
brain and other organs activate epigenetic programs that alter overload. Can we intervene to change this progression? After
expression of genetic information so as to alter cellular and organ describing the new view of epigenetics that negates the old
function. While the initial active response to stressors promotes notion that “biology is destiny,” this chapter summarizes some
adaptation (“allostasis”), there can be cumulative change (e.g., of the underlying cellular, molecular, and neuroendocrine mech-
body fat, hypertension) from chronic stress and resulting anisms of stress effects upon brain and body. It then discusses

Stress: Concepts, Cognition, Emotion, and Behavior 39 Copyright © 2016 Elsevier Inc. All rights reserved.
[Link]
40 5. CENTRAL ROLE OF THE BRAIN IN STRESS AND ADAPTATION

integrative or “top down” approaches involving behavioral expression of genetic information so as to change cellular
interventions that take advantage of the increasing ability to reac- and organ function.
tivate plasticity in the brain. At the societal level, policies of gov-
ernment and the private sector affect health directly or indirectly
Besides developmental influences associated with
and must be redirected, to allow people to make choices that parent-infant interactions and the quality of early life
improve their chances for a healthy life. experiences that result in long-term effects (“biological
embedding”), the most potent of influences as one
proceeds through adult life are those arising from the
INTRODUCTION family, neighborhood, workplace, and exposure to local,
national, and international events in the media that can
“Stress” is a word that is with us in almost everything affect both brain and body health and progression
we do. Yet the word “stress” is ambiguous and we forget toward a variety of diseases.
that the major “stress hormone,” cortisol, so often associ- Social ordering in human society is associated with
ated with bad outcomes, is actually an important mediator gradients of disease, with an increasing frequency of mor-
of the ability of the body and brain to adapt to the diurnal tality and morbidity along a gradient of decreasing
cycle, as well as to experiences that we call stressors. This income and education (socioeconomic status, SES;
review presents a conceptual framework for understand- [Link] Although the causes of
ing the protective, as well as damaging, aspects of media- these gradients of health are very complex, they likely
tors of adaptation like cortisol within a life course reflect, with increasing frequency going down the SES
perspective that emphasizes biological embedding of ladder, the cumulative burden of coping with limited
early-life experiences along with cumulative change. resources, toxic and otherwise stressful living environ-
This perspective also encourages the possibility of ments and negative life events, as well as differences in
interventions to prevent or ameliorate negative effects health-related behaviors (aka “lifestyle”), and resulting
of stressors. Under this view, the brain is the central organ chronic activation of physiological systems involved in
of stress and adaptation because it perceives what is adaptation ([Link] leading to
threatening and determines behavioral and physiological allostatic overload,2 as will be discussed below.
responses (Figure 1). Brain circuits are remodeled by The brain mediates adaptation to changes in the phys-
stress so as to change the ability to self-regulate anxiety ical and social environment through the autonomic, neu-
and mood, to perform working and episodic memory, roendocrine, and immune systems, as well as through
as well as executive function and decision making. The behavioral responses that include fighting or fleeing, as
brain regulates the body via the neuroendocrine, auto- well as health-promoting or health-damaging responses.
nomic, immune, and metabolic systems, and the media- Adaptation to stressful events or environmental changes
tors of these systems and those within the brain and is an active process that involves the output of mediators
other organs activate epigenetic programs that alter such as neurotransmitters and modulators, as well as

FIGURE 1 The stress response and development of allostatic load. The perception of stress is influenced by one's experiences, genetics, and
behavior, and the social and physical environment provides the stressors that require adaptation via epigenetic processes. When the brain perceives
an experience as stressful, physiologic and behavioral responses are initiated, leading to allostasis and adaptation. Over time, allostatic load can
accumulate, and the overexposure to mediators of neural, endocrine, and immune stress can have adverse effects on various organ systems, includ-
ing the brain, leading to disease. From Ref. 1 by permission.

1. GENERAL CONCEPTS
 HOMEOSTASIS, ALLOSTASIS AND ALLOSTATIC LOAD AND OVERLOAD 41
many hormones and cytokines and chemokines of the
• Policies of government and the private sector,
immune system. The goal of this adaptation is to main-
including targeted community programs, can
tain homeostasis and promote survival of the organism.
create the conditions to promote resilience and to
However, the process of adaptation also produces an
prevent or reduce effects of early life adversity.
almost inevitable wear and tear on the body and brain,
and this wear and tear is exacerbated if there are many
stressful events and/or if the mediators that normally
promote adaptation are dysregulated, that is, not turned
on when needed or not turned off efficiently when no lon-
HOMEOSTASIS, ALLOSTASIS AND
ger needed. The description and analysis of this scenario
ALLOSTATIC LOAD AND OVERLOAD
has entailed the addition of some new terminology, such
as allostasis, and the refinement of some classical termi-
nology, such as homeostasis and stress, which we shall
Characteristics of Homeostatic Systems
now discuss before describing the central role of the brain Homeostasis refers to the ability of an organism to
and its plasticity and ability to change. We begin this dis- maintain the internal environment of the body within
cussion by summarizing concepts related to homeostasis. limits that allow it to survive. Homeostasis also refers
to self-regulating processes that return critical systems
KEY POINT S of the body to a set point within a narrow range of oper-
• Allostasis and allostatic load/overload are more ation, consistent with survival of the organism. Homeo-
precise biological concepts than “stress” to describe stasis is highly developed in warm-blooded animals
adaptation and maladaptation to “stressors” and living on land, which must maintain body temperature,
they include the physiological effects of health- fluid balance, blood pH, and oxygen tension within
promoting and health-damaging behaviors as well rather narrow limits, while at the same time obtaining
as stressful experiences. nutrition to provide the energy to maintain homeostasis.
This is because maintaining homeostasis requires the
• “Good stress,” “tolerable stress,” and “toxic stress”
expenditure of energy. Energy is used for locomotion,
are terms that better characterize use of the word
as the animal seeks and consumes food and water, for
“stress.” Allostatic overload is the consequences of
maintaining body temperature via the controlled release
toxic stress.
of calories from metabolism of food or fat stores, and for
• There are multiple interacting mediators of sustaining cell membrane function as it resorbs electro-
allostasis that operate nonlinearly. lytes in the kidney and intestine and maintains neutral
• The brain is a target of mediators of stress and blood pH. Homeostasis also refers to the body's defensive
allostasis and it responds epigenetically, affecting mechanisms. These include protective reflexes against
brain architecture and neurochemical functions by such things as inhaling matter into the lungs, the vomit-
both genomic and nongenomic mechanisms. ing reflex as a protection to expel toxic materials from the
• Epigenetically regulated gene expression changes esophagus or stomach, the eye blink reflex, and the with-
continuously with experience. drawal response to hot or otherwise painful skin sensa-
tions. There is also the defense against pathogens
• Adverse early life events lead to long-lasting
through innate and acquired immunity, the latter of
changes in the brain and body and increase
which is stimulated by acute stress via cortisol and adren-
vulnerability to later experiences that increase
alin and inhibited by chronic stress and high levels of
allostatic overload and contribute
cortisol.3,4
disproportionately to the health care burden.
• The healthy brain is resilient after stress; lack of
resilience characterizes anxiety and depressive
disorders and the aging brain, but these are Need for Refocusing
treatable. Yet, there are paradoxes and problems with the notion
• Besides the urgent need for prevention, of a set point that is always maintained, in the case of
interventions to ameliorate allostatic load/ obesity, for example. Another problem with “homeosta-
overload include pharmaceutical agents or sis” is that, taken literally, it is a rather static concept, akin
behaviors (e.g., physical activity) which open to the notion of equilibrium in classical thermodynamics,
“windows of plasticity” that allow targeted whereas in real life, an organism experiences changing set
behavioral interventions to change brain points around which it maintains stability over a finite
architecture and function. period of time. Moreover, unlike the closed systems of
classical thermodynamics, a living organism is an open

1. GENERAL CONCEPTS
42 5. CENTRAL ROLE OF THE BRAIN IN STRESS AND ADAPTATION

system in which energy and matter flow in and out, with major life events, but also the conflicts and pressures of
equilibrium being replaced by steady state. daily life that elevate physiological systems so as to cause
Cannon recognized this ([Link] a cumulative chronic stress burden on brain and body
wiki/Walter_Bradford_Cannon) and used the term that can be referred to as “allostatic load and overload”
steady state and even suggested that “homeodynamics” (see below). This view is in agreement with a recent com-
might be a better term than “homeostasis.” The same mentary on use of the word ‘stress’ and what it should
problem was also recognized by a number of other mean: “We propose that the term ‘stress’ should be
authors. Nicolaides introduced the term “homeorheusis,” restricted to conditions where an environmental demand
in which “stasis” is replaced by “rheusis,” meaning exceeds the natural regulatory capacity of an organism, in
“something flowing.” Mrosovsky5 introduced “rheosta- particular situations that include unpredictability and
sis” in which, at any one instant, homeostatic defenses uncontrollability.”9
are still present but over a span of time there is a change This burden, which is greater in “toxic” than in
in the regulated level, or set point of a system. “tolerable” stress, reflects not only the impact of life expe-
Mrosovsky considers this concept advantageous in riences but also of genetic variations; individual
explaining how organisms adjust to changing environ- health-related behaviors such as diet, exercise, sleep
ments such as seasons of the year by storing body fat and substance abuse, and epigenetic modifications in
or changing reproductive physiology, and he believes development and throughout life that set lifelong pat-
that “rheostasis” allows for the kinds of physiological terns of behavior and physiological reactivity through
plasticity that is involved in evolution. both biological embedding and cumulative change.1
Epigenetics is the now popular way to describe
gene ! environment interactions via molecular mecha-
nisms that do not change the genetic code but rather acti-
What is Stress? vate, repress, and modulate expression of the code.10
The word and concept of “stress” was introduced by Indeed, epigenetics denies the notion that “biology is des-
Hans Selye6,7 with emphasis on physical stressors such tiny” and opens new opportunities for collaboration
as physical injury, heat, and cold and later modified to between the biological, behavioral, and social sciences
include psychological stressors by the work of John and preventative and palliative care.
Mason.8 “Stress” is a word often used in daily life and Acting epigenetically, hormones associated with stress
has a number of meanings. In biomedicine, stress often protect the body in the short run and promote adaptation
refers to situations in which the adrenal glucocorticoids (allostasis), but, in the long run, the burden of chronic
and catecholamines are elevated because of an experi- stress causes changes in the brain and body that lead to
ence—hence, the frequent negative associates of these cumulative change such as accumulation of body fat
mediators with “bad stress.” Stress is also a subjective (allostatic load) or disease such as diabetes or cardiovas-
experience that may or may not correspond to physiolog- cular disease (allostatic overload) (Figure 1). As will be
ical responses, and the word stress is widely used in discussed below, brain circuits are plastic and appear
many languages as part of daily discourse. There is “good to be continuously remodeled by stress, as well as by
stress” and “bad stress,” and people talk about bad stress other experiences, so as to change the balance between
as “being stressed out.” anxiety, self-regulatory behaviors including mood con-
Stress may be defined as a real or interpreted threat trol and impulsivity, memory, and decision making.
to the physiological or psychological integrity of an Such changes may have adaptive value in danger but
individual that results in physiological and/or behav- their persistence and lack of reversibility in brains that
ioral responses. Yet this results in three different mean- are not resilient can be maladaptive.
ings ([Link]
activities/council/): “Good stress” refers to rising to a
Stressors and Stress Responses
challenge, like having to give a speech or taking an exam,
and feeling rewarded by a successful outcome and “bad Stress involves a stressor and a stress response. A
stress” takes two forms. “Tolerable stress” refers to a life stressor may be a physical insult, such as trauma or
experience that one can cope with and adapt to because injury, or physical exertion, particularly when the body
one has sufficient internal and external support. “Toxic is being forced to operate beyond its capacity. Other
stress” means life experiences for which one does not physical stressors include noise, overcrowding, excessive
have adequate internal and external resources and sup- heat or cold. Stressors also include primarily psycholog-
port and, as a result, the individual experiences adverse ical experiences such as time-pressured tasks, interper-
physical and mental consequences. Indeed, stress is a sonal conflict, unexpected events, frustration, isolation
condition of the mind and a factor in the expression of dis- and loneliness, and traumatic life events, and all of these
ease that differs among individuals and reflects not only types of stressors may produce behavioral responses and

1. GENERAL CONCEPTS
 HOMEOSTASIS, ALLOSTASIS AND ALLOSTATIC LOAD AND OVERLOAD 43
evoke physiological consequences such as increased Allostasis
blood pressure, elevated heart rate, increased cortisol
levels, impaired cognitive function, and altered metabo- Allostasis means “achieving stability through change”;
lism, as well as anxiety and depression. it was introduced by P. Sterling and J. Eyer in 1988.11 Allos-
Behavioral responses to stressors may decrease risk tasis refers to the process that maintains homeostasis, as
and get the individual out of trouble or involve health- defined above, and it recognizes that “set points” and
promoting activities such as a good diet and regular exer- other boundaries of control may change with environmen-
cise, but they may also include responses that exacerbate tal conditions. There are primary mediators of allostasis
the physiological consequences of stress, for example, such as, but not confined to, hormones of the HPA axis,
self-damaging behaviors like smoking, drinking, overeat- catecholamines, the parasympathetic nervous system
ing, or consuming a rich diet, or risk-taking behaviors like and pro- and anti-inflammatory cytokines. These operate
driving an automobile recklessly. The physiological as a nonlinear network in which changes in the output of
stress responses include primarily the activation of the each mediator influences the output of other mediators
autonomic nervous system and the hypothalamo-pitui- (Figure 3). Allostasis also clarifies the inherent ambiguity
tary-adrenal (HPA) axis, leading to increased blood and in the term homeostasis and distinguishes between the
tissue levels of catecholamines and glucocorticoids. It is systems that are essential for life (homeostasis) and those
these physiological responses that have both protective that maintain these systems in balance (allostasis). Allo-
and damaging effects (see sections on Allostasis and static systems enable an organism to respond to its phys-
Allostatic Load and Overload). ical state (e.g., awake, asleep, supine, standing, exercising)
There are two important features of the physiological and to cope with noise, crowding, isolation, hunger,
stress response1: the first involves turning it on in extremes of temperature, physical danger, psychosocial
amounts that are adequate to the challenge. The second stress, and to microbial or parasitic infections.
is turning off the response when it is no longer needed
(Figure 2). The physiological mediators of the stress
response, namely, the catecholamines of the sympathetic Allostatic States
nervous system and the glucocorticoids from the adrenal An allostatic state13 refers to the altered and sustained
cortex, initiate cellular events that promote adaptive activity levels of the primary mediators, for example, glu-
changes in cells and tissues throughout the body, cocorticoids, that integrate energetic and associated
which in turn protect the organism and promote survival. behaviors in response to changing environments, chal-
However, too much stress, or inefficient operation of the lenges such as social interactions, weather, disease, pred-
acute responses to stress, can cause wear and tear and ators, pollution, etc. An allostatic state results in an
exacerbate disease processes. imbalance of the primary mediators reflecting excessive
production of some and inadequate production of others.
Examples are hypertension, a perturbed cortisol rhythm
Individual Differences in major depression or after chronic sleep deprivation,
chronic elevation of inflammatory cytokines and low cor-
There are enormous individual differences in interpret- tisol in chronic fatigue syndrome, imbalance of cortisol,
ing and responding to what is stressful, as well as individ- corticosteroid-releasing factor (CRF), and cytokines in
ual differences in the susceptibility to diseases, in which the Lewis rat that increases risk for autoimmune and
stress may play a role.1 Genetic predispositions exist which inflammatory disorders.14 Allostatic states can be sus-
increase the risk of certain disorders. In addition, dev- tained for limited periods if food intake and/or stored
elopmental processes, such as prenatal stress or nurturing energy, such as fat, can fuel homeostatic mechanisms
postnatal experiences, contribute to the lifelong respon- (e.g., bears and other hibernating animals preparing for
siveness of the behavioral and physiological responses to the winter). If imbalance continues for longer periods
stressors. Furthermore, experiences throughout the life and becomes independent of maintaining adequate
course resulting in memories of particularly unpleasant energy reserves, then symptoms of allostatic overload
or pleasant situations combine with the genetic and devel- appear. Abdominal obesity is an example of this
opmental influences to produce large differences among condition.2
individuals in how they react to stress and what the
long-term consequences may be. We now consider two
terms, allostasis and allostatic load/overload, that are
Allostatic Load and Overload
intended to eliminate ambiguity in using the word stress
in so many ways and at the same time, highlight the Allostatic load and allostatic overload refers to the
biphasic role of the physiological mediators of adaptation cumulative result of an allostatic state. For example, as
that can also contribute to pathophysiology. noted, fat deposition in a bear preparing for the winter,

1. GENERAL CONCEPTS
44 5. CENTRAL ROLE OF THE BRAIN IN STRESS AND ADAPTATION

FIGURE 2 Three types of allostatic load. The top panel illustrates the normal allostatic response, in which a response is initiated by a stressor,
sustained for an appropriate interval, and then turned off. The remaining panels illustrate four conditions that lead to allostatic load: repeated “hits”
from multiple stressors; lack of adaptation; prolonged response due to delayed shutdown; and inadequate response that leads to compensatory
hyperactivity of other mediators (e.g., inadequate secretion of glucocorticoids, resulting in increased concentrations of cytokines that are normally
counterregulated by glucocorticoids). From Ref. 1 by permission.

a bird preparing to migrate or a fish preparing to spawn in the wild), and social interactions, then allostatic load
are examples of animals experiencing an allostatic load.2 can increase dramatically and become allostatic overload,
This is a largely beneficial and adaptive condition and can which can become a pathophysiological condition.
be considered the result of the daily and seasonal routines There are two distinctly different outcomes of an allo-
which organisms use to obtain food and survive, and static state in terms of allostatic load or overload.2 First, if
obtain the extra energy needed to migrate, molt, and energy demands exceed energy intake, and also exceeds
breed. Within limits, they are adaptive responses to sea- what can be mobilized from stores, then type 1 allostatic
sonal and other demands. However, if one superimposes overload occurs. For example, breeding birds use increas-
on this additional load of unpredictable events in the ing food abundance in spring to reproduce and raise their
environment, disease, human disturbance (for animals young. If inclement weather then increases costs of

1. GENERAL CONCEPTS
 PLASTICITY AND VULNERABILITY OF THE BRAIN 45

CNS function Metabolism

e.g., cognition e.g., diabetes
depression obesity
aging
diabetes Cortisol
Alzheimer’s
DHEA Inflammatory cytokines

Sympathetic Anti-inflammatory cytokines

Parasympathetic Oxidative stress

Cardiovascular function Immune function

e.g., endothelial cell damage e.g., immune enhancement
atherosclerosis immune suppression

FIGURE 3 Nonlinear network of mediators of allostasis involved in the stress response. Arrows indicate that each system regulates the others in a
reciprocal manner, creating a nonlinear network. Moreover, there are multiple pathways for regulation—e.g., inflammatory cytokine production is
negatively regulated via anti-inflammatory cytokines as well as via parasympathetic and glucocorticoid pathways, whereas sympathetic activity
increases inflammatory cytokine production. Parasympathetic activity, in turn, restrains sympathetic activity. From Ref. 12 by permission.

maintaining homeostasis and the allostatic load of breed- For example, salivary cortisol levels increase within
ing, and at the same time reduces food available to fuel 30 min after waking in individuals who are under consid-
that allostatic load, then negative energy balance results erable psychological stress due to work or family matters.
in loss of body mass and suppression of reproduction, Moreover, intrusive memories from a traumatic event
in part via cortisol secretion. Second, if energy demands (e.g., in post-traumatic stress disorder (PTSD)) can pro-
are not exceeded and the organism continues to take in or duce a form of chronic, internal stress and can drive phys-
store as much or even more energy than it needs, perhaps iological responses.
as a result of diet, or metabolic imbalances (prediabetic Allostasis, allostatic states, and allostatic overload
state) that favor fat deposition, then type 2 allostatic over- are also affected by health-damaging behaviors, such as
load occurs. Besides fat deposition, there are other cumu- smoking, drinking, excess calorie intake, and poor or lim-
lative changes in other systems that can result from ited sleep, or, on the opposite side, health-promoting
repeated stressors, for example, neuronal remodeling or behaviors, such as a healthy diet and regular, moderate
loss in hippocampus, atherosclerotic plaques, left ventric- exercise.1 These behaviors are integral to the overall notion
ular hypertrophy of the heart, glycosylated hemoglobin of allostasis—how individuals cope with a challenge—and
and other proteins by advanced glycosylation end prod- also contribute to increasing or decreasing allostatic over-
ucts as a measure of sustained hyperglycemia, high cho- load by known pathways. For example, a rich diet acceler-
lesterol with low high-density lipoprotein (HDL), ates atherosclerosis and progression to noninsulin-
increased oxidative stress, elevated proinflammatory dependent diabetes by increasing cortisol, leading to fat
mediators, and chronic pain and fatigue, for example, deposition and insulin resistance; smoking elevates blood
in arthritis or psoriasis, associated with imbalance of pressure and atherogenesis. Yet, regular, moderate exercise
immune mediators. protects one against cardiovascular disease, prevents dia-
betes, counteracts depression and increases decision mak-
ing and memory.1
Role of Behavior in Allostatic Overload
Anticipation and worry can also contribute to allo-
static overload.15 Anticipation is involved in the reflex
PLASTICITY AND VULNERABILITY
that prevents us from blacking out when we get out of
OF THE BRAIN
bed in the morning and is also a component of worry,
anxiety, and cognitive preparation for a threat. Anticipa-
Glucocorticoids, Stress, and the Hippocampus
tory anxiety can drive the output of mediators like
ACTH, cortisol, and adrenalin; thus, prolonged anxiety The hippocampus was the first higher brain center that
and anticipation is likely to result in allostatic overload. was recognized as a target of adrenal steroids16 and it has

1. GENERAL CONCEPTS
46 5. CENTRAL ROLE OF THE BRAIN IN STRESS AND ADAPTATION

FIGURE 4 Three brain regions that undergo

remodeling of dendrites and synapses. The hippo-
campus, amygdala, and prefrontal cortex commu-
nicate with each other and mediate cognitive
function, fear, aggression and self-regulation, as
well as turning on and off the autonomic and
HPA response to stressors.

figured prominently as a gateway to our understanding active synaptic zones between thorny excrescences and
of how stress impacts neural architecture and behavior mossy fiber terminals is rapidly modulated during hiber-
(Figure 4). The hippocampus expresses both Type I min- nation and recovery from the hibernating state.33 The
eralocorticoid receptor (MR) and Type II glucocorticoid thorny excrescences are not the only spines affected by
receptor (GR),17 and these receptors mediate a biphasic CRS. Dendritic spines also show remodeling, with
response to adrenal steroids in the CA1 region, although increased spine density reported after CRS on apical den-
only facilitation in the dentate gyrus,18 nevertheless, drites of CA3 neurons34 and decreased spine density
shows a diminished excitability in the absence of adrenal reported for CA1 pyramidal neurons.35
steroids.19 Other brain regions, such as the paraventricu- Exploration of the underlying mechanism for this
lar nucleus, lacking in MR but having GR, show a mono- remodeling of dendrites and synapses reveals that it is
phasic negative response to increasing glucocorticoid not adrenal size or presumed amount of physiological
levels.18 Adrenal steroids exert biphasic effects on excit- stress per se that determine dendritic remodeling, but
ability of hippocampal neurons in terms of long-term rather a complex set of other factors that modulate neu-
potentiation and primed burst potentiation20–23 and ronal structure.27 Indeed, after repeated stress, dendritic
show parallel biphasic effects on memory.24,25 remodeling is reversible,36 and in species of mammals
A form of structural plasticity is the remodeling of den- that hibernate, dendritic remodeling is a reversible pro-
drites in the hippocampus, as well as in the amygdala and cess and occurs within hours of the onset of hibernation
prefrontal cortex.26 In hippocampus, chronic restraint in European hamsters and ground squirrels, and it is also
stress (CRS), daily for 21 days, causes retraction and sim- reversible within hours of wakening of the animals from
plification of dendrites in the CA3 region of the hippo- torpor.33,37–39 Along with data on post-translational mod-
campus.27,28 Such dendritic reorganization is found in ification of cytoskeletal proteins, this implies that reorga-
both dominant and subordinate rats undergoing adapta- nization of the cytoskeleton is taking place rapidly and
tion to psychosocial stress in the visible burrow system reversibly39 and that changes in dendrite length and
and it is independent of adrenal size.29 It also occurs in branching are not damage, but a form of adaptive struc-
psychosocial stress in intruder tree shrews in a tural plasticity.
resident-intruder paradigm, with a time course of Cellular and molecular mechanisms involving steroids
28 days,30 a procedure that does not cause a loss of pyra- contribute to structural remodeling. Specifically, adrenal
midal neurons in the hippocampus.31 steroids are important mediators of remodeling of hippo-
The mossy fiber input to the CA3 region in the stratum campal neurons during repeated stress, and exogenous
lucidum appears to drive the dendritic remodeling lead- adrenal steroids can also cause remodeling in the absence
ing to the retraction of the apical dendrites above this of an external stressor.40,41 The role of adrenal steroids in
input.27 Moreover, the thorny excrescences, giant spines the hippocampus involves many interactions with neuro-
on which the mossy fiber terminals form their synapses, chemical systems including serotonin, endogenous opi-
show stress-induced modifications.32 And the number of oids, calcium currents, gamma amino butyric acid

1. GENERAL CONCEPTS
 TRANSLATION TO THE HUMAN BRAIN 47
(GABA)-benzodiazepine receptors, and excitatory amino after acute stress, but did so only transiently.50 CORT
acids.42 Central to all of these interactions is the role of levels increased after both acute and chronic stress and
excitatory amino acids, such as glutamate. Excitatory remained elevated after chronic, but not after acute
amino acids released by the mossy fiber pathway play stress.
a key role in the remodeling of the CA3 region of the hip- Although some of the immediate consequences of
pocampus, and regulation of glutamate release by adre- stress—elevated glucocorticoids and glutamate—are
nal steroids may play an important role.27 similar in amygdala and hippocampus, they lead to con-
Among the consequences of restraint stress is the ele- trasting patterns of BDNF expression and structural plas-
vation of extracellular glutamate levels, leading to induc- ticity. This implies that signaling mechanisms more
tion of glial glutamate transporters, as well as increased downstream of the initial changes in glucocorticoids
activation of the nuclear transcription factor, phospho- and glutamate, but upstream of BDNF, may hold the
CREB.43 Moreover, 21 days of CRS leads to depletion key to the differential impact of stress in these brain areas.
of clear vesicles from mossy fiber terminals and increased Importantly, BDNF infusion into the hippocampus
expression of presynaptic proteins involved in vesicle of stressed rodents helped to protect against the deleteri-
release.44,45 Taken together with the fact that vesicles ous effects of stress despite high levels of circulating
which remain in the mossy fiber terminal are near active CORT. This suggests that BDNF could be a final point
synaptic zones and that there are more mitochondria in of convergence for the stress induced effects in the hippo-
the terminals of stressed rats, this suggests that CRS campus. BDNF-mediated signaling is involved in stress
increases the release of glutamate.44 response but the direction and nature of signaling is
region specific, stress specific, and is influenced by
epigenetic modifications along with post-translational
modifications.50,55
Extension of Stress Effects to Amygdala
Concurrently, with changes in the amygdala, neurons
and Prefrontal Cortex in the medial prefrontal cortex show reversible dendritic
Besides the hippocampus, the amygdala and prefrontal shrinkage after chronic stress,56,57 with spine loss,58 that
cortex are targets of stress and display structural plasticity can be inhibited by blocking N-methy-D-aspartate
after both acute and chronic stress (Figure 4). Neurons in (NMDA) receptors,59 similar to stress-induced atrophy
the basolateral amygdala (BlA) expand dendrites after of neurons in the CA3 hippocampus (see above). This
chronic immobilization stress and increase spine density,46 chronic stress-induced atrophy is associated with deficits
whereas neurons in medial amygdala show reduced spine in executive function and cognitive flexibility,60,61 and the
density after chronic stress.47 The latter changes are depen- stressors that cause this to happen also include circadian
dent on tissue plasminogen activator released by CRF,48 disruption.62 While medial prefrontal cortical neurons
based on a tPA-ko mouse, whereas stress effects in BlA atrophy with chronic stress, neurons in the orbitofrontal
are not so dependent.47 These stress-induced changes are cortex show hypertrophy60 similar to what happens in
accompanied by increases in anxiety-like behavior46,49 the BlA.46
and suggest that stress causes a reorganization and dys-
function of circuits within the amygdala.
Glucocorticoids and excitatory amino acids are TRANSLATION TO THE HUMAN BRAIN
involved in the mechanism for dendritic expansion in
the BlA with chronic stress, along with brain derived Studies of the human hippocampus have demon-
neurotrophic factor (BDNF)50,51 and, indeed, a single strated in many, but not all studies,63 shrinkage of the
bolus of corticosterone (CORT) mimics the effects of hippocampus not only in mild cognitive impairment
10 days of chronic immobilization to cause BlA dendrite and Alzheimer's,64 but also in Type 2 diabetes,65 pro-
expansion.52 Overexpression of BDNF in mice increases longed major depression,66 Cushing's disease,67 and
dendritic length in both CA3 and BlA and occludes the PTSD.68 Moreover, in nondisease conditions, such as
effects of chronic stress to decrease dendritic bran- chronic stress,69 chronic inflammation,70 lack of physical
ching in CA3 and increase it in BlA.53 Without such activity,71 and jet lag,72 smaller hippocampal or temporal
overexpression, chronic stress causes a down-regulation lobe volumes have been reported. In the human brain,
of BDNF in CA3 hippocampus and an up-regulation of MRI has shown amygdala enlargement and overactivity,
BDNF in the BlA, and the effect in BlA persists after as well as hippocampal and prefrontal cortical shrinkage
21-day post-stress while that in CA3 has normalized50; in a number of mood disorders.66,73 Moreover, amygdala
moreover, acute stress with a 10-day delay, which causes reactivity to sad and angry faces is enhanced by sleep
BlA to develop increased anxiety and increased density deprivation and living in an urban environment, and
of spines in BlA neurons,54 caused BDNF expression to excessive amygdala reactivity is associated with early
rise and stay elevated for 10 days while that in CA3 fell signs of cardiovascular disease.26

1. GENERAL CONCEPTS
48 5. CENTRAL ROLE OF THE BRAIN IN STRESS AND ADAPTATION

These changes may not be due to neuron loss but impairment of hippocampal dependent memory,
rather to volume reduction in dentate gyrus due to inhib- whereas females do not.82–84
ited neuronal replacement, as well as dendritic shrinkage In contrast, acute tail shock stress during classical eye-
and glial cell loss. Autopsy studies on depression-suicide blink conditioning improves performance in males, but
have indicated loss of glial cells and smaller neuron soma suppresses it in females85 by mechanisms influenced by
size,74 which is indicative of a smaller dendritic tree. With gonadal hormones in development and in adult life.86,87
regard to Type 2 diabetes, it should be emphasized that However, giving male and female rats control over the
the hippocampus has receptors for, and the ability to take shock abolishes both the stress effects and the sex differ-
up and respond to, insulin, ghrelin, insulin-like growth ences.88 These findings suggest that sex differences
factor-1 (IGF1), and leptin; importantly, IGF-1 mediates involve brain systems that mediate how males and
exercise-induced neurogenesis.14 Thus, besides its females interpret stressful stimuli and that a sense of con-
response to glucocorticoids, the hippocampus is an trol is paramount to coping with those stimuli.
important target of metabolic hormones that have a vari- Female rats fail to show the mPFC dendritic remodel-
ety of adaptive actions in the healthy brain which is per- ing seen in males after CRS in those neurons that do not
turbed in metabolic disorders, such as diabetes.14 It project to amygdala. Instead, they show an expansion of
should also be noted that amygdala volume is reported the dendritic tree in the subset of neurons that project to
to decrease in anxiety-disorder subjects in relation to suc- the basolateral amygala.89 Moreover, ovariectomy pre-
cessful anxiety reduction using cognitive-behavioral ther- vented these CRS effects on dendritic length and branch-
apy (CBT).75 Conversely, longitudinal increases in medial ing. Furthermore, estradiol treatment of ovariectomized
prefrontal cortex volume have been reported after CBT in (OVX) females increased spine density in mPFC neurons,
chronic fatigue patients.76 irrespective of where they were projecting.89
One surprising finding from animal models and Taken together with the fact that estrogen, as well as
human studies concerning PTSD is that a timed elevation androgen, effects are widespread in the central nervous
of glucocorticoids can prevent PTSD symptoms. This system, these findings indicate that there are likely to
comes from epidemiologic studies showing that low cor- be many more examples of sex ! stress interactions
tisol is a risk factor for PTSD77 and is also supported by related to many brain regions and multiple functions,
interventions for possible PTSD with cortisol supplemen- as well as developmentally programmed sex differences
tation for low normal cortisol levels during surgery.78 that affect how the brain responds to stress (e.g., in the
Another finding is that glucocorticoid administration locus ceruleus).90,91 Clearly, the impact of sex and sex dif-
within an hour or so after a traffic accident reduces inci- ferences has undergone a revolution and much more is to
dence of PTSD symptoms.79 Two animal models support come,92–96 including insights into X and Y chromosome
this,79,80 the latter of which showed that elevation of contributions to brain sex differences.97 In men and
CORT at the time of trauma prevented the increased anx- women, neural activation patterns to the same tasks are
iety and spine density of BlA neurons in a rat model quite different between the sexes even when performance
10 days later.80 is similar.98 This leads to the concept that men and
women often use different strategies to approach and
deal with issues in their daily lives, in part because of
the subtle differences in brain architecture. Nevertheless,
SEX DIFFERENCES IN STRESS from the standpoint of gene expression and epigenetic
RESPONSIVENESS AND WHAT THIS effects, the principles of what we have learned in animal
MEANS FOR THE REST OF THE BRAIN models regarding plasticity, damage, and resilience, are
likely to apply to both males and females.
All of the animal model studies of stress effects sum-
marized above and below were carried out on male
rodents. Thus, it is very important to note before proceed- LESSONS FROM GENE EXPRESSION
ing further by discussing sex differences in how the brain
responds to stressors. Indeed, female rodents do not Even when the healthy brain and associated behavior
show the same pattern of neural remodeling after chronic appears to have recovered from a stressful challenge,
stress as do males. The first realization of this was for studies of gene expression have revealed that the brain
the hippocampus, in which the remodeling of CA3 den- is not the same, just as the morphology after recovery
drites did not occur in females after CRS, even though all appears to be somewhat different from what it was before
the measures of stress hormones indicated that the stress.99 Transcriptional profiling of the mouse hippo-
females were experiencing the stress as much as males.81 campus has revealed that after a recovery period from
Females and males also differ in the cognitive conse- chronic stress, which is equivalent to the duration of
quences of repeated stress, with males showing the stressor (21 days) and is sufficient to restore

1. GENERAL CONCEPTS
 LESSONS FROM EPIGENETIC INFLUENCES 49
anxiety-like behaviors to pre-stress baselines, the expres- predicted sum of either pathway activated alone.102
sion levels of numerous genes remained distinct from the These findings illustrate that gene expression changes
stress naïve controls.100 Further, exposure to a novel in response to stress are not solely the product of gluco-
swim stress 24 h after chronic stress or after a 21-day corticoid activity. Increasingly, research into stress resil-
recovery period from the chronic stress, produced dis- ience is looking beyond GR-dependent transcription in
tinct gene expression profiles from mice that experienced order to capture the complexity of the cellular response
a swim stress but had no history of chronic stress. to stress.
Together, these findings suggest that gene expression
patterns after recovery from stress do not reflect a return
to the stress naïve baseline (even when the behaviors LESSONS FROM EPIGENETIC
have recovered) and chronic stress alters reactivity to INFLUENCES
future stressors. Studies examining longer recovery
periods, as well as how intermittent stress during recov- Functional insights into the ever-changing brain come
ery might alter gene expression will be necessary to from studies of epigenetic regulation. The term “epige-
answer whether these seemingly lasting changes might netics” now extends beyond its original definition103 to
eventually reverse, or if an additional stressor can com- include the continuous, seamless interaction between
pound certain changes. These changes in transcriptome genes and the factors which regulate gene expression
reactivity represent one molecular signature for resilience over the life course. The core of the genomic response
that are themselves likely to be driven by epigenetic to those environmental factors such as hormones, cyto-
changes discussed in the next section. kines, and chemokines and other neuromodulators
Importantly, recent evidence has suggested that the involves modification of histones,104 methylation of cyto-
in vivo transcriptional changes in response to stress rep- sine residues on DNA, noncoding RNAs that modify
resent a synthesis of multiple cellular pathways, not sim- expression of mRNA molecules, and retrotransposon
ply CORT activation of GR-dependent transcription. DNA elements10 (Figure 5).
Chronic stress increases inflammatory tone and this In our studies of stress neurobiology, acute restraint
release of cytokines can activate other signaling path- stress was shown to increase expression in the dentate
ways, such as NF-κB-dependent transcription.100 Micro- gyrus of a repressive histone mark, H3K9me3, and this
array studies have found that glucocorticoid injections was accompanied by the repression of certain retrotran-
produce distinct gene expression profiles from naïve sposon elements of as yet unidentified function; this
acute stress and that the gene expression response to a repressive response habituates with repeated stress
glucocorticoid injection changes after exposure to chronic raising the possibility of increased genomic instability.
stress.100,101 In support of these findings, in vitro studies Such instability may manifest itself in terms of genomic
have demonstrated that simultaneous activation of GR activity that is no longer responsive to environmental
and NF-κB-dependent transcription results in a unique influences or lead to genomic activity that is increased
pattern of gene expression that is distinct from the as a result of chronic stress, as in accelerated aging.106,107

FIGURE 5 “Epigenetics” in its present definition refers to

mechanisms for regulation of gene expression that do not
change the genetic code.10 Transposons and retrotransposons
are somewhat of an exception in that pieces of DNA are
removed and inserted into other locations “jumping
genes.”105

1. GENERAL CONCEPTS
50 5. CENTRAL ROLE OF THE BRAIN IN STRESS AND ADAPTATION

Loss of reversal of stress induced structural plasticity, as of mice was associated with higher baseline levels of MR
seen in aging rats108 is one example, and increased genes than the LS subset, showing an MR-dependent
expression of inflammatory mediators together with loss down-regulation of mGlu2 receptors in hippocampus.
of cholinergic and dopaminergic function109 is another. These findings led to the introduction of the “epigenetic
In contrast, there are examples of epigenetic activation allostasis model,” which incorporates an epigenetic core
of neural activity. Indeed, acute swim stress as well as into the allostasis-allostatic load model of stress and adap-
novelty exposure induce an activational histone mark tation to emphasize the gene-environment interactions. In
in dentate gyrus, namely, acetylation of lysine residue particular, the epigenetic allostasis model helps to eluci-
14 and phosphorylation of the serine residue on histone date how nonshared experience early in life can epigenet-
H3, which is dependent on both GR and NMDA activa- ically set each individual, via MR genes or other genes, to a
tion and is associated with c-fos induction among other somewhat different trajectory of development as far as
genes.110 Acetylation of another lysine residue, K27 on responses to subsequent stressful life experiences.113 In
histone H3, is associated with increased expression of agreement, juvenile stress was associated with increased
metabotropic glutamate receptor, mGlu2, in hippocam- hippocampal MR mRNA levels and anxiety-like behavior
pus of Flinders Sensitive Line (FSL) rats as shown by in adulthood.114
chromatin immunoprecipitation.111 mGlu2 is known to
exert an inhibitory tone on glutamate release from synap-
ses. The acetylating agent L-acetylcarnitine (LAC), a nat- THE LIFE COURSE AND THE
urally occurring substance, behaves as an antidepressant, EPIGENETICS OF INDIVIDUAL
at least in part by the epigenetic up-regulation of mGlu2 DIFFERENCES
receptors via this epigenetic mechanism. LAC caused a
rapid and long-lasting antidepressant effect in both FSL The individual traits that allow these adaptive or mal-
rats and in mice exposed to chronic unpredictable stress, adaptive outcomes depend upon the unique neurological
which, respectively, model genetic and environmentally capacity of each individual, which is built upon experi-
induced depression. Beyond the epigenetic action on ences in the life course, particularly those early in life.115
the acetylated H3K27 bound to the Grm2 promoter, These influences can result in healthy or unhealthy brain
LAC also increased acetylation of NF-κB-p65 subunit, architecture and in epigenetic regulation that either pro-
thereby enhancing the transcription of Grm2 gene motes or fails to promote gene expression responses to
encoding for the mGlu2 receptor in hippocampus and new challenges. Genetically similar or identical individ-
prefrontal cortex. The involvement of NF-κB in LAC uals differ in many ways ranging from length of den-
antidepressant-like effects supports a growing literature drites in the prefrontal cortex116 to differences in MR
that shows depression may be associated with a chronic levels in hippocampus,113 locomotor activity, and neuro-
inflammatory response.112 Importantly, LAC reduced the genesis rates,117 and the influences that lead to those dif-
immobility time in the forced swim test and increased ferences begin early in life. For example, identical twins
sucrose preference as early as 3 days of treatment, diverge over the life course in patterns of CpG methyla-
whereas 14 days of treatment were needed for the antide- tion of their DNA reflecting the influence of “nonshared”
pressant effect of chlorimipramine.111 This suggests LAC experiences.118
is important for stress resilience. Early life events related to maternal care in animals, as
A recent study from our laboratory has shown that hip- well as parental care in humans, play a powerful role in
pocampal expression of mGlu2, is also a marker of individ- later mental and physical health, as demonstrated by the
ual susceptibility to mood disorders. Interestingly, mGlu2 adverse childhood experiences studies,119 and recent
is the same receptor regulating inhibitory glutamate tone work that will be noted below. Animal models have con-
that has been shown to be elevated by treatment with tributed enormously to our understanding of how the
LAC in FSL rats to reverse depressive-like behavior.111 brain and body are affected, starting with the “neonatal
Using a novel and acute approach for rapidly screening handling” studies of Levine and Denenberg120 and the
an inbred population of laboratory animals, it has been more recent, elegant work of Meaney and Syzf121 involv-
shown that both chronic unpredictable stress and acute ing methylation of CpG residues in DNA. Such epige-
restraint stress results in individual behavioral and molec- netic, transgenerational effects transmitted by maternal
ular differences in wild-type mice that are more (high sen- care are central to these findings. Besides the amount of
sitivity, HS) or less (low sensitivity, LS) susceptible to maternal care, the consistency over time of that care
stress-induced mood abnormalities. At the molecular and the exposure to novelty are also very important
level, HS and LS mice differ in the ability of stress to induce not only in rodents,122,123 but also in monkey models.124
a decrease of mGlu2 receptor expression in hippocampus. Prenatal stress impairs hippocampal development in rats,
Mapping the steps of this intricate dance that allow some as does stress in adolescence.125 Insufficient maternal care
individuals to face adverse life experience, the HS subset in rodents126 and the surprising attachment shown by

1. GENERAL CONCEPTS
 INTERVENTIONS 51
infant rats to their less-attentive mothers appears to to slow the decline of physical and mental health and to
involve an immature amygdala,127 activation of which improve prefrontal cortical blood flow in a similar man-
by glucocorticoids causes an aversive conditioning ner to regular physical activity.145,146
response to emerge. Maternal anxiety in the variable for- Depression and anxiety disorders are examples of a
aging demand model in rhesus monkeys leads to chronic loss of resilience, in the sense that changes in brain cir-
anxiety in the offspring, as well as signs of metabolic cuitry and function, caused by the stressors that precipi-
syndrome.128,129 tate the disorder, become “locked” in a particular state
and thus need external intervention. Indeed, prolonged
depression is associated with shrinkage of the hippocam-
INTERVENTIONS pus66,147 and prefrontal cortex.148 While there appears to
be no neuronal loss, there is evidence for glial cell loss and
What can be done to remediate the effects of chronic smaller neuronal cell nuclei,74,149 which is consistent with
stress over the life course at both individual and societal a shrinking of the dendritic tree described above after
levels? For the individual, the complexity of interacting, chronic stress. Indeed, a few studies indicate that phar-
nonlinear and biphasic actions of the mediators of stress macological treatment may reverse the decreased hippo-
and adaptation, as described above, emphasizes behav- campal volume in unipolar150 and bipolar151 depression,
ioral, or “top-down,” interventions (i.e., interventions but the possible influence of concurrent CBT in these
that involve integrated CNS activity) that include CBT, studies is unclear. One useful model is the reversal of
mindfulness-based stress reduction, including medita- amblyopia (lazy eye; monocular visual field created by
tion, physical activity, and programs such as the Experi- closing one eye early in life) via plasticity-inducing inter-
ence Corps that promote social support and integration ventions such as fluoxetine, caloric restrictions, and corti-
and meaning and purpose in life.14,130,131 In contrast, sol combined with binocular visual stimulation in
pharmacological agents, which are useful in many cir- amblyopic adult animals.152,153 These studies support
cumstances to redress chemical and molecular imbal- the concept that a combination of a pharmaceutical inter-
ances, nevertheless run the risk of dysregulating other vention, like fluoxetine, or physical activity, that opens
adaptive pathways (i.e., no pharmaceutical is without up a “window of plasticity” might improve the efficacy
side effects). It should also be noted that many interven- of targeted behavioral therapies.
tions that are intended to promote plasticity and slow In this connection it is important to reiterate that suc-
decline with age, such as physical activity and positive cessful behavioral therapy, which is tailored to individual
social interactions that give meaning and purpose, are needs, can produce volumetric changes in both prefrontal
also useful for promoting “positive health” and “eudai- cortex in the case of chronic fatigue,76 and in amygdala, in
monia”132–134 independently of any notable disorder the case of chronic anxiety,75 as measured in same sub-
and within the range of normal behavior and physiology. jects longitudinally. This reinforces the notion that
A powerful “top down” therapy (i.e., an activity, usu- plasticity-facilitating treatments should be given within
ally voluntary, involving activation of integrated nervous the framework of a positive behavioral or physical ther-
system activity, as opposed to pharmacological therapy apy intervention. On the other hand, negative experi-
which has a more limited target) is regular physical ences during the window of enhanced plasticity may
activity, which has actions that improve prefrontal and have negative consequences, such as a person going back
parietal cortex blood flow and enhance executive func- into a bad family environment that may have precipi-
tion.135 Moreover, regular physical activity, consisting tated anxiety or depression in the first place.154 In that
of walking an hour a day, 5 out of 7 days a week, connection, it should be noted that BDNF, a plasticity-
increases hippocampal volume in previously sedentary enhancing class of molecules, also has the ability to pro-
adults.136 This finding complements work showing that mote pathophysiology, as in seizures.155–157
fit individuals have larger hippocampal volumes than At the societal level, the most important top-down
sedentary adults of the same age-range.71 It is also well interventions are the policies of government and the pri-
known that regular physical activity is an effective anti- vate sector that not only improve education but also
depressant and protects against cardiovascular disease, allow people to make choices that improve their chances
diabetes, and dementia.137–141 Moreover, intensive learn- for a healthy life.130 This point was made by the Acheson
ing has also been shown to increase volume of the human report of the British Government in 1998158 which recog-
hippocampus.142 nized that no public policy of virtually any kind should
Social integration and support and finding meaning be enacted without considering the implications for
and purpose in life are known to be protective against health of all citizens. Thus basic education, housing, tax-
allostatic load and overload143 and dementia,144 and pro- ation, setting of a minimum wage, and addressing occu-
grams such as the Experience Corps that promote these pational health and safety and environmental pollution
along with increased physical activity, have been shown regulations are all likely to affect health via a myriad of

1. GENERAL CONCEPTS
52 5. CENTRAL ROLE OF THE BRAIN IN STRESS AND ADAPTATION

mechanisms. At the same time, providing higher quality 17. Reul JM, DeKloet ER. Two receptor systems for corticosterone in
food and making it affordable and accessible in poor, as rat brain: microdistribution and differential occupation. Endocrinol-
ogy. 1985;117:2505–2511.
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eat.159 Likewise, making neighborhoods safer and more 19. Margineanu D-G, Gower AJ, Gobert J, Wulfert E. Long-term adre-
congenial and supportive160,161 can improve opportuni- nalectomy reduces hippocampal granule cell excitability in vivo.
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20. Diamond DM, Bennett MC, Fleshner M, Rose GM. Inverted-U rela-
tional physical activity. However, governmental tionship between the level of peripheral corticosterone and the
policies are not the only way to reduce allostatic load. magnitude of hippocampal primed burst potentiation. Hippocam-
For example, businesses that encourage healthy lifestyle pus. 1992;2:421–430.
practices among their employees are likely to gain 21. Pavlides C, Kimura A, Magarinos AM, McEwen BS. Type I adrenal
reduced health insurance costs and possibly a more loyal steroid receptors prolong hippocampal long-term potentiation.
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workforce.162–164 22. Pavlides C, Kimura A, Magarinos AM, McEwen BS. Hippocampal
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adrenal steroids. Neuroscience. 1995;68:379–385.
23. Pavlides C, Watanabe Y, Magarinos AM, McEwen BS. Opposing
Acknowledgments role of adrenal steroid Type I and Type II receptors in hippocampal
This review is dedicated to current and former postdoctoral fellows long-term potentiation. Neuroscience. 1995;68:387–394.
and students, as well as collaborators, who, in many cases, catalyzed 24. Pugh CR, Tremblay D, Fleshner M, Rudy JW. A selective role for
the research discussed in this review, many of whose names are noted corticosterone in contextual-fear conditioning. Behav Neurosci.
in the text and references. I am very proud of their accomplishments! 1997;111:503–511.
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