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The brain is the central organ involved in perceiving and adapting to social and physical stressors via multiple interacting mediators, from the cell surface to the cytoskeleton to epigenetic regulation and nongenomic mechanisms. A key result of stress is structural remodeling of neural architecture, which may be a sign of successful adaptation, whereas persistence of these changes when stress ends indicates failed resilience. Excitatory amino acids and glucocorticoids have key roles in these processes, along with a growing list of extra- and intracellular mediators that includes endocannabinoids and brain-derived neurotrophic factor (BDNF). The result is a continually changing pattern of gene expression mediated by epigenetic mechanisms involving histone modifications and CpG methylation and hydroxymethylation as well as by the activity of retrotransposons that may alter genomic stability. Elucidation of the underlying mechanisms of plasticity and vulnerability of the brain provides a basis for understanding the efficacy of interventions for anxiety and depressive disorders as well as age-related cognitive decline.
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nature neuroscienceVOLUME 18 | NUMBER 10 | OCTOBER 2015 1353
The brain is the central organ of stress and adaptation to social and
physical stressors because it determines what is threatening, stores
memories, and regulates the physiological as well as behavioral
responses to stressors that may be damaging or protective1. The physi-
ological responses that produce adaptation through ‘allostasis’ include
not only the hypothalamic-pituitary-adrenal (HPA) axis and the auto-
nomic nervous system, but also their nonlinear interactions with the
metabolic system and the pro- and anti-inflammatory components of
the immune defense system1,2. Exposure to multiple stressors and the
dysregulation of the nonlinear interactions (such as failure to turning
on or off responses efficiently) lead to wear and tear on the body and
brain that is termed allostatic load and overload1,3.
Allostasis is the active process of adapting to stressors via mediators
such as cortisol and the autonomic, metabolic and immune system
that act together in a nonlinear fashion to maintain homeostasis2.
Allostatic load refers to the cumulative effect of multiple stressors
as well as the dysregulation of the nonlinear network of allostasis
(for example, production of cortisol, adrenalin or inflammation in
response to a challenge). Allostatic overload refers to the cumulative
pathophysiology that can result from this dysregulation and excess
stress. Allostasis, and allostatic load and overload, are more precise
biological concepts than ‘stress’ to describe adaptation and mal-
adaptation to ‘stressors’, and they include the physiological effects of
health-promoting and health-damaging behaviors as well as stressful
experiences1,2. Health behaviors (such as smoking, alcohol, poor diet,
or lack of sleep), resulting from the experience of stress, also have a
role and contribute to allostatic load and overload1,3.
‘Stress’ can be divided into ‘good stress’, ‘tolerable stress’ and ‘toxic
stress’4. Early life stress can alter neural architecture to increase
adverse reactions to stressors, leading to toxic stress4. ‘Biological
embedding’4,5 of these effects during critical or sensitive periods of
early development has lasting effects through the life course6,7. Among
the most important early life experiences are those that involve abuse
and neglect, on the one hand, versus the establishment of strong,
positive attachment of child to caregiver; these alter the ability of
the individual to engage in cooperative social experiences or to feel
excluded and hostile to the social environment later in life8.
The brain is a target of stressful experiences, and glucocorticoids,
along with excitatory amino acid neurotransmitters, alter neuro-
nal architecture by causing dendritic retraction or expansion and
decreased or increased synapse density, depending on the brain
region, along with inhibition of dentate gyrus neurogenesis 9–11 .
Many intra- and intercellular mediators and processes are involved
in changing the brain during stress and recovery from stressful
experiences12,13 (Box 1).
This Review provides an overview of the mechanisms and media-
tors through which stressors alter brain structure and function. It does
so by focusing primarily on three brain regions, the hippocampus,
amygdala and prefrontal cortex (PFC), although in full recognition
of the fact that stress has widespread effects throughout the brain.
This Review also emphasizes the complex nonlinear interactions
between different stress mediators that are central to the concept of
allostasis and allostatic load and overload3, in which nonlinearity
applies not only to systemic hormones but also to intra- and extra-
cellular mediators in the brain. Because of this, the many changes
caused by stress often result in an inverted-U-shaped dose-response
relationship, as represented in Figure 1.
Mechanisms underlying stress effects on the brain
Stressors alter gene expression through multiple mechanisms, includ-
ing direct effects of glucocorticoids on gene transcription as well as
the activation of epigenetic mechanisms in which histone modifica-
tions and methylation and hydroxymethylation of CpG residues in
1Laboratory of Neuroendocrinology, The Rockefeller University, New York,
New York, USA. 2Hotchkiss Brain Institute, University of Calgary, Calgary,
Alberta, Canada. 3Department of Psychology, University of Massachusetts
Boston, Boston, Massachusetts, USA. 4Department of Integrative Physiology
and Neuroscience, Washington State University, Pullman, Washington, USA.
Correspondence should be addressed to B.S.M. (
Received 19 April; accepted 8 July; published online 25 September 2015;
Mechanisms of stress in the brain
Bruce S McEwen1, Nicole P Bowles1, Jason D Gray1, Matthew N Hill2, Richard G Hunter3, Ilia N Karatsoreos4 &
Carla Nasca1
The brain is the central organ involved in perceiving and adapting to social and physical stressors via multiple interacting
mediators, from the cell surface to the cytoskeleton to epigenetic regulation and nongenomic mechanisms. A key result of
stress is structural remodeling of neural architecture, which may be a sign of successful adaptation, whereas persistence of
these changes when stress ends indicates failed resilience. Excitatory amino acids and glucocorticoids have key roles in these
processes, along with a growing list of extra- and intracellular mediators that includes endocannabinoids and brain-derived
neurotrophic factor (BDNF). The result is a continually changing pattern of gene expression mediated by epigenetic mechanisms
involving histone modifications and CpG methylation and hydroxymethylation as well as by the activity of retrotransposons that
may alter genomic stability. Elucidation of the underlying mechanisms of plasticity and vulnerability of the brain provides a basis
for understanding the efficacy of interventions for anxiety and depressive disorders as well as age-related cognitive decline.
focus on stress review
npg © 2015 Nature America, Inc. All rights reserved.
1354  VOLUME 18 | NUMBER 10 | OCTOBER 2015 nature neuroscience
DNA have roles leading to repression and activation of genetic fac-
tors, including retrotransposons14,15. Glucocorticoids are not the sole
mediators of these effects, in which excitatory amino acids and many
other cellular mediators also play important parts (Box 1). These
mediators span influences from extracellular adhesion molecules to
cytoskeletal elements and at least one nuclear pore complex protein.
In addition to their critical role in complex behavior and
cognition, the hippocampus, amygdala and PFC are important in
regulating the autonomic and HPA stress response, and they are
the main focus of this review (Box 2).
Stress effects on gene expression in an ever-changing brain. As the
first extra-hypothalamic brain structure recognized to have receptors
for adrenal steroids16, the hippocampus has been an important gate-
way to understanding the effects of glucocorticoids and stress on gene
expression in the brain. Recent technological advances have allowed
high-throughput analysis of gene expression changes in response to
stress17. For example, microarray analysis of whole hippocampus after
acute stress, chronic stress and stress recovery in mice revealed that
acute and chronic stress modulate a core set of genes, but that numer-
ous changes are exclusive to each condition, highlighting how duration
and intensity of stress alters reactivity18. Furthermore, corticosterone
injections do not produce the same expression profile as acute stress,
suggesting that in vivo stressors activate a diverse set of pathways
independent of glucocorticoid receptor (GR) activation18 (Fig. 2).
Finally, characterization of expression profiles after extended recov-
ery from 21 d of chronic stress showed that,
despite a normalization of anxiety-related
behaviors, recovery does not represent a
return to the stress-naive baseline but rather a
new state in which reactivity to a novel stres-
sor produces a unique expression profile18.
Studies in rats confirm that gene expres-
sion profiles can change significantly from
the immediate end of stress to 24 h later19
and that chronic stress can alter the tran-
scriptional response to an acute corticos-
terone injection in dentate gyrus20 (Fig. 2).
Together, these studies demonstrate that a
history of stress exposure can have a last-
ing impact on future stress reactivity and
hippocampal function.
Box 1 Examples of molecules that are necessary or permissive for remodeling
Brain-derived neurotrophic factor (BDNF)93,94
Facilitator of plasticity or growth
Overexpression occludes effects of chronic stress
Haploinsufficiency prevents stress-induced plasticity
Tissue plasminogen activator (tPA)73,74
Secreted signaling molecule and protease
Required for stress-induced spine loss in hippocampus and medial amygdala
Required for acute stress-induced increase in anxiety; secretion activated by CRF
In amygdala, regulates tPA release
Corticotropin-releasing factor (CRF)74,135
Secreted in hippocampus by interneurons
Downregulates thin spines via RhoA signaling
Secreted protein of previously unknown function77,78
Induced by acute stress
Downregulates mushroom spines
Knockout increases neuronal excitability and anxiety
Induced via glucocorticoids
Regulate emotionality and HPA habituation and shutoff
CB1 receptor knockout increases anxiety and basolateral amygdala dendrite length and causes stress-like retraction of prefrontal cortical dendrites,
likely through the regulation of glutamatergic transmission
Fatty acid aminohydrolase (FAAH) is a key regulator of endocannabinoid action
Synaptic functions: enhancement of
• Synaptic transmission
• Long-term potentiation
• Learning for self-preservation
Synaptic functions: suppression of
• Synaptic transmission
• Long-term potentiation
• Learning for less important things
Adaptive plasticity:
• Suppression of neurogenesis
• Mediates dendritic remodeling
Loss of resilience:
• Neurochemical distortion
• Impaired remodeling and
lack of recovery from stress
Damage potentiation:
• Mediates excitotoxicity in seizures,
stroke and head trauma
Brain aging:
• Extrasynaptic
• Free radicals and
Adrenal steroids and excitatory
amino acids modulate both
limbs of inverted U
Increasing amounts and frequency
Acute – moderate – enhancement
Acute – intense – suppression
Traumatic – damage, neuron loss
Chronic – adaptive plasticity
Loss of resilience – external
intervention required
Decline of resilience with age
Increased vulnerability for
permanent damage
External intervention needed
Minutes to hours Days to months Months to years
Figure 1 Effects of acute and chronic stress,
mediated in part by glutamate and glucocorticoids
as well as other molecules described in the
text and in Box 1. These effects follow an
inverted U-shaped curve in dose and time.
The timeline shows how acute and chronic
stress and aging interact with the intensity
and duration of stressor.
npg © 2015 Nature America, Inc. All rights reserved.
nature neuroscienceVOLUME 18 | NUMBER 10 | OCTOBER 2015 1355
Many of the genes altered after glucocorticoid and chronic stress
exposure in the hippocampus are known epigenetic regulators21,
providing one possible mechanism underlying the persistent altera-
tions in the expression response beyond the end of stress exposure.
The continually changing pattern of gene expression is consistent
with the finding that, although stress-induced dendritic retraction
in PFC neurons appears to be reversible in terms of dendritic length
and branching, the recovered neurons are different, in that dendrites
that regrow after recover y from stress are more proximal to the
cell body than those that retracted22.
Epigenetic mediation via post-translational histone modifica-
tions. Stress has a clear impact on many types of molecular epige-
netic mechanisms, from histone modifications to DNA methylation
and hydroxymethylation and expression of noncoding RNA14,23–25
(Fig. 3). For instance, social defeat stress in rodents causes changes in
both histone methylation and acetylation26. Acute and chronic stress
promote histone modifications leading to repression or activation
of genes related to memory and other processes. Studies of memory
acquired in the forced swim test and Morris water maze uncovered a
novel, rapid mechanism: glucocorticoids, via GRs, facilitate signaling
of the ERK-MAPK pathway to the downstream nuclear kinases MSK1
and Elk-1 in dentate gyrus granule neurons; and activation of this path-
way results in phosphorylation of serine 10 (S10) acetylation of lysine
14 (K14) of histone H3 (H3S10p-K14ac), leading to the induction
of the immediate-early gene products c-Fos and Egr-1 (ref. 27).
Unlike that of other immediate-early gene products, FosB and its
splice variant FosB increases and remain elevated in the nucleus
accumbens (NAc) after social defeat stress and is deficient in those
animals that show depressive-like behavior, as well as in human patients
with depression postmortem. Moreover, increased FosB/FosB expres-
sion in NAc protects animals from the deleterious effects of chronic
stress28. Epigenetically, the FosB promoter is enriched for dimethylation
of H3 lysine 9 (H3K9me2) in the NAc of humans with depression rela-
tive to that of controls without depression, implicating this repressive
epigenetic modification in the repression of FosB. Moreover, in mice
zinc finger protein (ZFP)-induced enrichment of H3K9me2 at FosB in
NAc not only was sufficient to reduce FosB/FosB expression, but also
induced depression- and anxiety-like behaviors after social stress28.
A current practical application of this approach is the investiga-
tion of rapidly acting antidepressants28,29 that act, at least in part, via
epigenetic mechanisms, as does electroconvulsive therapy26,30. An
epigenetic mechanism connects excitatory amino acid function with
neural remodeling and stress-related behavior in one genetic and one
stress-induced rodent model of anxiety- and depressive-like behavior
in which downregulation of the presynaptic inhibitor of neuronal gluta-
mate release, the mGlu2 receptors, in hippocampus is a key biomar-
ker29. In that connection, drugs that modify glutamate overflow, such as
ketamine, acetyl--carnitine and riluzole, have been show to exert rapid
antidepressant-like effects in animal models29,31 and in humans32.
The novel antidepressant candidate acetyl--carnitine (LAC)
appears to act inside and outside the nucleus to exert fast antidepres-
sant responses: LAC corrects mGlu2 deficits by increasing acetylation
of histone H3 lysine 27 (H3K27) bound to Grm2 promoter gene as
well as acetylation of the NF-κB p65 subunit29. Using the same animal
models, 14 d of treatment with the tricyclic antidepressant clomi-
pramine were needed to promote antidepressant responses, which
disappeared when the treatment was stopped, whereas antidepressant
effects of LAC were still evident after 2 weeks of drug withdrawal.
The persistent effects of LAC highlight the involvement of stable
molecular adaptations that are reflected at the level of histone modi-
fications in controlling mGlu2 transcription in hippocampus.
Transposons and retrotransposons. Acute restraint stress also has
repressive epigenetic effects in the hippocampus and most promi-
nently in the dentate gyrus via trimethylation of H3K27 and H3K9.
The latter is associated with repression of a number of retrotrans-
posable elements (RTE) and reduction of the coding and noncod-
ing RNA normally produced by the repressed DNA, so far only
in hippocampus30,33. This repression is lost with repeated stress,
suggesting that those RTEs may impair genomic stability under
conditions of chronic stress15.
Box 2 Overview of stress effects on the hippocampus, amygdala and prefrontal cortex
Three regions of the brain shown in the illustration have important roles in
behavior and cognitive function as well as in regulating the autonomic and HPA
stress response and are the main focus of this review.
Glucocorticoid and mineralocorticoid receptors were first recognized in the
hippocampal formation16, showing that adrenal steroids affect the brain in more
ways than through the hypothalamus, which is now known to include effects on
spatial and episodic memory and mood regulation. In the hippocampus, stress and
glucocorticoids were first shown to cause dendritic shrinkage and loss of spines.
The rediscovery of neurogenesis in the dentate gyrus11 galvanized widespread
interest in the functional role of neuronal replacement in the adult brain. It was
in the hippocampus that the role of excitatory amino acids in stress effects was
first recognized9.
Effects of acute and chronic stress on the amygdala differ from those in the
hippocampus. Acute traumatic stressors cause increased spine density on basolateral
amygdala neurons, and chronic stress leads to the expansion of basolateral amygdala
dendrites139. Yet the medial amygdala shows a chronic stress–induced loss of
spines75. These alterations are implicated in increased anxiety and in PTSD-like behaviors67,139.
Within the prefrontal cortex, chronic stress causes medial PFC neurons to develop debranching and shrinkage of dendrites that is associated with
cognitive rigidity, while orbitofrontal cortical neurons expand dendrites that may be related to increased vigilance122,140. The PFC under stress has
provided important clues to age-related loss of resilience and impaired memory as well as to the effects of circadian disruption and extinction of fear
These three brain regions have contributed to our knowledge of cellular and molecular mechanisms and cellular processes that are described in this
Review, revealing brain regional specializations as well as common mediators and mechanisms and the complex interactions among the mediators.
Marina Corral Spence/Nature Publishing Group
Prefrontal cortex
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1356  VOLUME 18 | NUMBER 10 | OCTOBER 2015 nature neuroscience
Figure 2 Gene expression changes in hippocampus in response to stress
and glucocorticoid challenge depend on the prior stress history of the
subject. Hippocampal microarray data reveals stress-induced changes
in gene expression. (a) Dark colors represent the number of genes with
significantly increased expression and pastels represent those with
significantly decreased expression as identified by pairwise comparisons
of each stress group with age-matched controls. FST, forced swim test;
Cort, glucocorticoid injection; CRS, chronic restraint stress; Rec, recovery
from CRS. (b) Proportional Venn diagram illustrating the genes with
expression significantly altered by the acute stress, chronic stress and
glucocorticoid (Cort) injection conditions and their overlap. The numbers
of genes unique to each comparison whose expression was increased or
decreased are listed next to arrows indicating the direction of change.
(c) Venn diagram of genes whose expression was altered by each FST
condition reveals a core of 95 genes that were always changed by this
stressor. The large number of unique gene expression changes in each
condition shows that the response to FST is altered by the stress history
of the group, with the vast majority of changes occurring when an animal
is exposed to a novel stressor immediately after a chronic stress exposure,
as also shown in a. (d) Scatter plot of normalized expression values for
each microarray probe comparing CRS (x axis) with recovery from CRS
(y axis). For the majority of genes, expression is increased by CRS, but
decreased after recovery; however, some probes show expression that is
increased by CRS and remains elevated after recovery or that is suppressed
by CRS and remains low in recovery. Highlighted probes are those that
reached significance when compared with age-matched controls (blue,
CRS; red, recovery from CRS; gray, not significant). Several examples of
the highlighted genes are listed below the scatter plot by color designation
and quadrant. For example, blue points in the lower left quadrant represent
genes, such as Nrg3 and Scn1b, whose expression is significantly changed
by CRS as compared with that in unstressed controls and is also decreased
after recovery from CRS. By contrast, red points in the upper right quadrant
represent genes, such as Cdk2 and Gria2, whose expression remains
significantly different from that of controls after recovery from CRS and is
also increased immediately following CRS. (e) Venn diagram illustrating that
the genes whose expression was significantly different from that of controls
after recovery from CRS are mostly distinct from those whose expression
was significantly altered by CRS. Reprinted from ref. 18 with permission
from Macmillan Publishers Ltd. (f) Pie charts of Gene Ontology (GO) terms
that are over-represented among the 576 genes that were differentially
expressed upon GC challenge in naive as compared to chronically stressed rats. The differentially expressed genes were divided into groups that responded
to GCs in both controls and CRS animals (center) or only in controls (left) or in CRS animals (right). The pie charts represent the GO terms that were
overrepresented in the three groups of GC-responsive genes and show that after CRS, GC challenge gives rise to a different gene signature than is seen in
control animals. Reprinted from ref. 20 with permission.
Retrotransposons constitute a tenfold larger fraction of mammalian
genomes than protein coding genes and appear to be unusually active
in brain and steroidogenic tissues15. Consequently, they have recently
attracted increasing attention from neuroscientists, who have shown
that they contribute to neural diversity, cell fate and development as
well as brain disease15,34–36. In addition to transposons’ mobility, they
also seem to contribute the largest fraction of functional elements to
what might be referred to as ‘the RNA genome37–39. This other genome
is composed of genes for noncoding RNAs that are being found to
govern a growing number of cellular processes, including develop-
ment, cell differentiation, chromosome imprinting and the regulation
of the epigenetic machinery40,41; thus RTE-derived RNAs represent a
substantial store of both genetic and epigenetic information.
Barbara McClintock, who discovered transposons over 60 years ago,
noted that they were important contributors to an organism’s ability
to deal with environmental stress42,43, and this insight appears to hold
true with regard to the neurobiology of stress, though as with many
other aspects of stress, transposons are likely to have both adaptive34
and possibly deleterious effects given that their dysregulation has been
observed in both humans with post-traumatic stress disorder (PTSD)
and animal models of stress disorders44–46. Brain transposons there-
fore appear to represent a significant new frontier for stress research.
Role of excitatory amino acids. Excitatory amino acids, particularly
glutamate, play key roles in structural as well as functional changes in
the brain (Fig. 4). Initial studies of restraint stress, in which chronic
stress causes shrinkage of apical dendrites of hippocampal CA3 neu-
rons, showed that acute restraint stress elevates extracellular glutamate
levels through a process that is absent in adrenalectomized animals,
suggesting a role for the adrenal cortex47. Indeed, corticosterone acts
directly via membrane-associated mineralocorticoid receptors (MRs)
and GRs to cause glutamate release29,48,49. Importantly, blocking
NMDA receptors and interfering with excitatory stimulation of ion
channels blocks stress-induced dendritic remodeling within the hip-
pocampus, an effect similar to that of blockade of adrenal steroid
synthesis50,51. Similarly, stress-induced NMDA-dependent dendritic
remodeling has been reported in medial PFC neurons52. Excess gluta-
matergic activity, without adequate reuptake in the aftermath of
trauma from seizures, ischemia and head trauma, leads to permanent
neuronal loss by a process that is exacerbated by glucocorticoids53 .
These relationships can be summarized in an inverted-U-shaped
dose- and time-response curve (Fig. 1).
In that connection, the shrinkage of apical dendrites as a result of
stress in CA3 pyramidal neurons can be thought of as a protective mech-
anism against permanent damage and neuron loss that is caused by the
5,000 Increased
3,618 2,905
–0.2 0 0.2 0.4
367 312
Rec + FST
Control + GCs
unique (267)
Voltage-gated cation activity
Immune response
Signal transduction activity
Nuclear import
G-protein coupled receptor activity
Common (258)
unique (318)
90 36
Rec +
No. of genes
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nature neuroscienceVOLUME 18 | NUMBER 10 | OCTOBER 2015 1357
metastable dentate gyrus–CA3 feedforward and feedback circuitry that is
the basis of its function54 and yet makes it vulnerable to seizure-induced
damage55. This is well illustrated in hibernation, a state of low energy
supply to the brain that is accompanied by rapidly reversible (within
hours) shrinkage of CA3 apical dendrites in the hippocampus56,57. This
hypothesis is further substantiated by studies in which removal of poly-
sialic acid residues from neural cell adhesion molecule (NCAM) leads to
marked increases in dendritic length of CA3 neurons and increased vul-
nerability to excitotoxic damage, supporting the notion that shorter den-
drites reduce the vulnerability of CA3 neurons to overstimulation58.
Role of glucocorticoids via multiple intracellular sites and mecha-
nisms. Glucocorticoids produce both genomic and nongenomic
effects in the brain through multiple sites and pathways. In addition,
glucocorticoids have biphasic effects in which the timing and the level
of GR expression are critical29,59. Glucocorticoid actions via genomic
mechanisms involve both direct interactions with glucocorticoid
response elements (GRE) and indirect actions via tethering to other
transcription factors60. Glucocorticoids can directly stimulate release
of excitatory amino acids via membrane-associated receptors, and
they can indirectly regulate both glutamate and GABA release through
induction of local synthesis of endocannabinoids61 (see below).
In addition, glucocorticoids can also translocate GRs, along with
the anti-apoptotic protein B-cell lymphoma 2 (Bcl-2), to mitochondria
where they together promote Ca2+ sequestration and regulate
mitochondrial oxidation, free radical formation and membrane
potential, three independent measures of mitochondrial function.
Bcl-2 is able to inhibit the formation of Bax-containing pores on the
mitochondrial outer membrane and reduce the release of calcium
and cytochrome c from the mitochondria. Importantly, these three
glucocorticoid effects show an inverted U–shaped dose-response
curve and are biphasic, and high glucocorticoid levels cause a failure
of this mechanism over 72 h, leading to increased free-radical
formation62 (Fig. 5).
Just as location of GR action is an essential consideration, the level
of expression of GRs is also very important. Genetically induced
overexpression of GR in forebrain leads to increased lability of
mood-related behaviors, yet also confers greater responsiveness
to antidepressant drugs63, whereas genetic knockdown of GR has
the opposite effect64. Epigenetic regulation of GR activity also has
significant functional implications, as increased CpG methylation
within the GR promoter is associated with a suboptimal HPA stress
response and with poor maternal care in rodents and early life
abuse in human suicide victims65,66.
Histone acetylation,
methylation DNA methylation
mRNA stability
and translation
Figure 3 Molecular epigenetic modifications. Among the molecular
mechanisms that fall under the epigenetic rubric are covalent modifications
of the histone proteins that package and control access to the DNA, which
include acetylation, methylation and phosphorylation as well as a growing
number of more exotic modifications. The DNA itself may be methylated or
hydroxymethylated at cytosine residues. A suite of noncoding RNA species
such as microRNA (miRNA), piwi-interacting RNA (piRNA) and long
noncoding RNA (lncRNA) also act to convey epigenetic information and to
coordinate interactions between DNA and the transcriptional and chromatin
modification machinery. Many of these mechanisms seem to have evolved in
part from, or as a consequence of the presence of, transposable elements in
eukaryotic genomes. Adapted from ref. 24 with permission of Elsevier.
Figure 4 Glucocorticoids are released from the
adrenal glands. Basal release varies in a diurnal
pattern, and release increases severalfold after
exposure to a stressor. Glucocorticoids can bind,
with different affinities, to glucocorticoid and
mineralocorticoid receptors, which are expressed
throughout the brain and seem to exist in both
membrane-bound form and nuclear form.
Adrenal steroids can have both rapid and delayed
effects. The effects can result from nongenomic
mechanisms (mediated by membrane receptors,
see the figure), indirect genomic mechanisms
(mediated by membrane receptors and second
messengers, see the figure) and genomic
mechanisms (mediated by cytoplasmic
receptors that move to the nucleus and act as
transcription factors; see figure), as seems now
to be the case for all steroid hormones. Although
mineralocorticoid and glucocorticoid receptors
seem to mediate many of these effects, other
membrane-associated receptors, including
G protein–coupled receptors, may also be
involved in some of these actions. In addition, activated glucocorticoid receptors can translocate to mitochondria and enhance their calcium buffering
capacity. Glucocorticoids rapidly induce glutamate release in the hippocampus through a mechanism that is absent when the mineralocorticoid receptor
is deleted and that may involve a membrane-associated form of the mineralocorticoid receptor. An indirect way by which glucocorticoids can influence
neurotransmission (glutamatergic, as well as GABAergic, cholinergic, noradrenergic and serotonergic) is through cross-talk with the endocannabinoid system.
They rapidly stimulate endocannabinoid production in the brain, whereupon endocannabinoids bind to cannabinoid receptor 1 (CB1) and transient receptor
potential cation channel subfamily V member 1 (TRPV1) and inhibit neurotransmitter release (see the figure). Although a G protein–coupled receptor is
implicated in endocannabinoid production, there is also evidence for a mechanism blocked by Ru486—a selective antagonist of the classical cytoplasmic
glucocorticoid receptor—in the rapid actions of glucocorticoids in prefrontal cortex. Modified from ref. 32 with permission from Macmillan Publishers Ltd.
Direct genomic
Marina Corral Spence/Nature Publishing Group
genomic effect
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1358  VOLUME 18 | NUMBER 10 | OCTOBER 2015 nature neuroscience
Figure 5 Biphasic effect of glucocorticoids (Cort)
in regulating mitochondrial function. (a) Cort
readily penetrate the cell membrane and interact
with cytoplasmic glucocorticoid receptors (GRs),
causing a dose-dependent increase in GR
translocation into cell nuclei. Con, vehicle control.
(b) Translocation of GRs into mitochondria as a
complex with the anti-apoptotic protein Bcl-2,
where they upregulate mitochondrial calcium
levels, membrane potential and oxidation; this
is stabilized at a 100 nM dose of Cort (b) and
decreases with time at the high, 1 µM Cort dose (c),
where, after a 3-d treatment, high Cort leads
to decreased abundance of GR and Bcl-2 in
mitochondria. (d,e) Cort modulates membrane
potential, measured by Janus-1 (JC-1) staining,
in a dose- and time-dependent manner. Time
course of JC-1 staining after Cort treatment shows
sustained potential at 100 nM dose and loss
of potential at 1 µM dose (d); dose-dependent
curve for JC-1 staining after Cort treatment
shows that both low and high Cort maintain
potential at 24 h, but high Cort causes failure of
membrane potential at 72 h (e). This regulation of
mitochondrial function by Cort parallels
neuroprotection: that is, treatment with low doses of Cort has a neuroprotective effect, whereas high Cort enhances kainic acid–induced toxicity of cortical
neurons62,133, consistent with the “glucocorticoid endangerment” hypothesis134. Error bars, s.e.m.; *P ≤ 0.05, **P ≤ 0.01, ***P0.001. Modified from
ref. 62 with permission from Macmillan Publishers Ltd.
The actions of glucocorticoids are biphasic, as illustrated above for
mitochondria62, and their timing is important. For example, in several
animal models of traumatic stress–induced PTSD-like delayed anxiety
and traumatic stress–induced spine synapse formation in basolateral
amygdala (BLA), a timed elevation of glucocorticoids, before the
induction of stress, prevents development of the anxiety and synapse
formation67. Data on human PTSD supports a protective role for ade-
quate glucocorticoid levels at time of traumatic stress68,69. Yet repeated
high-dose glucocorticoid treatment mimics chronic stress and induces
dendritic lengthening in BLA70, a result that emphasizes the differ-
ences between acute and chronic elevations of glucocorticoids.
Regarding MRs, which exert both genomic actions and nongenomic
actions to stimulate glutamate release48, mice that spontaneously
show increased anxiety have elevated expression of hippocampal MR,
which mediate a stress-induced suppression of mGlu2 expression
and increased levels of anxiety- and depression-like behavior71.
Importantly, blocking MR receptors and interfering with glucocor-
ticoid stimulation of glutamate activity blocks stress-induced mood
abnormalities. The nature of the experiences of the animals that
develop higher MR is not known, but it may involve epigenetic influ-
ences early in life, such as maternal care and stressors in the neo-
natal nesting environment72. The epigenetic allostasis model points
to developmental origins of individual differences in the responses
to stress and implies that unknown early life epigenetic influences
program each individual to different trajectories of behavioral and
physiological responses to later stressful life events (Fig. 6).
Involvement of secreted signaling molecules. In addition to glu-
cocorticoids, secreted signaling molecules have important roles in
the remodeling of neural tissue during stress (Box 1). Corticotropin-
releasing factor (CRF), which is better known for its role in governing
the secretion of adrenocorticotropic hormone (ACTH) and glucocor-
ticoids, plays a key part in stress-induced dendritic remodeling in the
CA1 region of the hippocampus73,74. Findings over the past decade
have also implicated new players in the regulation of dendritic remod-
eling. For instance, tissue plasminogen activator (tPA), a secreted
signaling molecule as well as protease, is implicated in stress-induced
dendritic remodeling and spine loss in medial amygdala as well as in
the CA1 hippocampus. Specifically, tPA-knockout mice fail to show
chronic stress impairment of memory and spine reduction in CA1
(refs. 73,75). Linking these two factors together, there is evidence that in
the amygdala tPA release is stimulated by CRF76. Similarly, lipocalin-2
is a novel modulator of spine plasticity with different effects in
amygdala and hippocampus77,78. Acute stress increases lipocalin-2
levels, and lipocalin-2 downregulates mushroom spines and
generally inhibits actin motility in hippocampus. Remarkably, dele-
tion of lipocalin-2 increases neuronal excitability and anxiety, and,
in amygdala, the absence of lipocalin-2 increases the basal number of
spines and prevents a stress-induced increase in spine density.
Endocannabinoids are another class of signaling molecules
that importantly regulate multiple aspects of the stress response.
In addition to contributing to the termination79 of the acute response
to stress, as well as habituation to repeated stress80, endocannabinoids
also seem to be important for the regulation of structural plasticity
under conditions of repeated stress (Box 1). For example, cannabi-
noid 1 (CB1) receptor–deficient mice exhibit reductions in prefron-
tal cortical dendritic length and complexity, while having enhanced
and more complex dendritic arbors within the BLA, both of which
effects parallel the effects of chronic stress81,82. More importantly,
chronic stress and corticosterone treatment are both known to impair
endocannabinoid signaling at multiple levels, through both a down-
regulation of the CB1 receptor83 and a reduction in the levels of the
endocannabinoid anandamide that is mediated by an increase in its
hydrolysis by the enzyme fatty acid amide hydrolase (FAAH)84,85.
Given the parallels between genetic deletion of the CB1 receptor
and the ability of chronic stress to impair endocannabinoid signaling,
it is interesting to note that elevation of anandamide via CB1 receptor
signaling, through genetic or pharmacological impairment of FAAH,
retards the ability of chronic stress to produce dendritic hypertrophy in
the BLA as well as concomitant changes in emotional behavior85–88,89.
Collectively, these data indicate that endocannabinoid signaling buff-
ers against many of the effects of stress and seems to be important for
Nuclear GR (% of control)
JC-1, red/green (% of control)
JC-1, red/green (% of control)
0 0 0.2 0.4 0.6
24 h
72 h
0.8 1.0 1.2
Dose (µM)
1 24 72
Time (h)
GR levels in mitochondria
(% of control)
GR levels in mitochondria
(% of control)
Con 1.5 24 72
Time (h)
1.5 24 72
Time (h)
(100 nM)
(1 µM)
1 µM
100 nm
Cort (100 nM)
Cort (1 µM)
a b c
d e
npg © 2015 Nature America, Inc. All rights reserved.
nature neuroscienceVOLUME 18 | NUMBER 10 | OCTOBER 2015 1359
Figure 6 Individual differences in naive C57Bl6
mice in anxiety-related behavior reveal animals
more sensitive to stress-induced downregulation
of hippocampal mGlu2 expression, a biomarker
of depressive-like behavior and antidepressant
response. (ac) The use of the light-dark test
as a screening method (a) allows identification
of clusters of animals with a different baseline
anxiety profile (b) along with differences in
mineralocorticoid receptor gene (MR; Nr3c2)
transcript levels in hippocampus (c). Error bars,
s.e.m.; **P0.01, ***P0.001. (d) The
susceptible (HS) mice, which are characterized
by higher baseline MR transcript levels, show
reduced hippocampal mGlu2 (Grm2) transcript
expression associated with exacerbation of
anxious and of depressive-like behaviors
after acute and chronic stress, respectively.
Conversely, individuals with lower baseline
MR transcript levels (low susceptible, LS)
cope better with stress and show adaptation
in mGlu2 receptor expression in hippocampus.
Ctrl, unstressed sex and age-matched control
animals; ARS, acute restraint stress. (e) The
epigenetic allostasis model points to the
developmental origins of these individual
differences, suggesting that as-yet-unknown
epigenetic influences early in life may lead to alterations in hippocampal MR transcript levels71. (f) Representative mechanisms of action of
acetyl-l-carnitine (LAC): work in our and other laboratories has shown that a decrease in mGlu2 receptors either following stress exposure or occurring
in a genetic animal model of depression is rapidly corrected by 3 d of intraperitoneal administration of the novel antidepressant candidate LAC via
acetylation of either the H3K27 bound to the Grm2 promoter, which encodes mGlu2 receptors, or the NF-κB p65 subunit30. A, acetyl; M, methyl;
P, phosphate; MR (Nr3c2), MGI 99459; mGlu2 (Grm2), MGI 1351339.
limiting the effects of chronic stress on structural plasticity within
these identified limbic circuits. At a mechanistic level, this is likely to
be due to the ability of CB1 receptor signaling to gate glutamatergic
release, as it has been demonstrated that CB1 receptor–deficient mice
show greater changes in glutamatergic signaling and excitotoxicity
within the PFC following chronic stress90. Moreover, in a pattern
similar to the protective effects of CB1 receptor activation identified
within the amygdala, administration of a CB1 receptor agonist during
repeated stress can reduce the increase in glutamatergic signaling,
the induction of pro-inflammatory cytokines and lipid peroxidation
within the PFC90. Thus, the release of endocannabinoids during stress
may temper changes in structural plasticity by limiting the magnitude
of glutamate release in response to stress; and under conditions of
chronic stress, when this system becomes compromised, the loss of
this endogenous buffer facilitates excess glutamate release and the
ensuing changes in dendritic morphology. Linking this model with
the factors previously described, it is interesting to note that in addi-
tion to promoting tPA release, CRF has also been found to induce
anandamide hydrolysis by FAAH91, suggesting that CRF could act as
an orchestrator of multiple signaling molecules, all of which converge
in structural changes within the brain following chronic stress.
Recent studies have suggested that blood-based biomarkers may be
able to predict aspects of brain signaling associated with trauma-related
effects in both males and females, specifically with respect to conver-
gence onto GR signaling pathways. After a predator-scent-stress (PSS)
exposure, male and female rats were classified into vulnerable (“PTSD-
like”) and resilient (minimally affected) phenotypes on the basis of
their performance on a variety of behavioral measures92. Genome-wide
expression profiling in blood, amygdala and hippocampus indicated
that glucocorticoid signaling was the only convergent pathway asso-
ciated with individual differences in susceptibility. Moreover, corti-
costerone treatment 1 h after PSS exposure prevented anxiety and
hyperarousal 7 d later in both sexes, consistent with prior findings in
the same as well as in another PTSD animal model67,68, confirming the
involvement of the GR in sequelae of traumatic stress.
Roles of brain-derived neurotrophic factor (BDNF). BDNF plays an
important role in dendritic remodeling in both hippocampus and BLA
(Box 1). BDNF-overexpressing mice show increases dendritic length
in both CA3 and BLA, which occludes the effects of chronic stress in
decreasing dendritic branching in CA3 and increasing it in BLA93. On
the other hand, in WT animals, chronic stress causes a downregulation
of BDNF in CA3 hippocampus and an upregulation of BDNF in the
BLA. Although the increase in BLA persists beyond 21 d after the stress,
the effect in CA3 normalizes94. These intriguing timing issues become
even more interesting when one considers that after a single acute stress,
BDNF expression in the BLA rises and stays elevated for 10 d, while that
in CA3 shows only a transient increase94. This increase in the BLA is
associated with both increased anxiety and increased density of spines
in BLA neurons85. The mechanism of these effects on BDNF remain
enigmatic, but they are not entirely mediated by glucocorticoid actions
as corticosterone levels increase after both acute and chronic stress and
remained elevated after chronic, but not acute, stress. Thus, it is clear
that BDNF-mediated signaling is involved in the structural effects of
stress, but that the direction and nature of signaling is region specific
and stress specific and is influenced by epigenetic modifications89 along
with post-translational modifications94,95. The epigenetic mechanisms
controlling BDNF expression are influenced by maternal separation
early in life, which, in turn, leads to changes in BDNF expression and
epigenetic regulation via histone acetylation and methylation over the
life course, with consequences for anxiety-like behaviors96.
Cellular processes in remodeling of neural architecture. The neu-
ronal surface, cytoskeleton and nuclear envelope are each implicated
Light-dark test
as screening
method for
6 min
Naive mice
15 min
Time spent in the
light chamber (s)
mRNA/Gapdh mRNA
mGlu2 mRNA/Gapdh
MR mGlu2
Acute stress down
regulates mGlu2; blocked
by spironolactone
Epigenetic allostasis
driven adaptation
Lack of
Microtubules LAC
npg © 2015 Nature America, Inc. All rights reserved.
1360  VOLUME 18 | NUMBER 10 | OCTOBER 2015 nature neuroscience
in the mechanisms of stress-induced retraction and expansion of den-
drites and synapse turnover. The polysialylated form of neural cell
adhesion molecule (PSA-NCAM) is expressed in the CA3 and DG
regions of the hippocampus and is believed to denote the capacity for
adaptive structural plasticity in many parts of the CNS97–99. Repeated
stress causes retraction of CA3 hippocampal dendrites accompanied
by a modest increase in PSA-NCAM expression, possibly as the
result of glucocorticoid mediation100. Using endoneuraminidase
N (EndoN) to remove PSA from NCAM, Sandi reported impairment
of consolidation of contextual fear conditioning101. Using the same
treatment, we observed considerable expansion of the dendritic tree
in both CA3 and CA1 and a marked increase in excitotoxicity and
damage to CA3 neurons; repeated stress still caused some dendrite
retraction after PSA removal58. Thus, although PSA-NCAM is a
facilitator of plasticity, the PSA moiety appears to also limit the
extent of dendritic growth and yet is not necessary for dendritic
retraction under stress.
Two other classes of cell adhesion molecules are reported to change
with chronic stress, with behavioral consequences. Neuroligins
(NLGNs) are important for proper synaptic formation and function-
ing and are critical regulators of the balance between neural excitation
and inhibition (E/I), and chronic restraint stress reduces hippocampal
NLGN-2 levels, in association with reduced sociability and increased
aggression102,103. This occurred along with a reduction of NLGN-2
expression throughout the hippocampus, detectable in different layers
of the CA1, CA3 and DG subfields. Intrahippocampal administration
of neurolide-2, which interferes with the interaction between NLGN-2
and neurexin, led to reduced sociability and increased aggression,
thus mimicking effects of chronic stress102.
Chronic restraint stress also increases activity of matrix metallopro-
teinase-9 (MMP-9) in the CA1. MMP-9 carries out proteolytic process-
ing of another cell adhesion molecule, nectin-3. Chronic stress reduced
nectin-3 in the perisynaptic CA1, but not in the CA3, with conse-
quences for social exploration and social recognition and for a CA1-
dependent cognitive task. Implicated in this is a stress-related increase
in extracellular glutamate and NMDA receptor mediation of MMP-9
(ref. 104). These findings are reminiscent of the CA1-specific effects of
tPA in mediating stress effects on spine density in CA1 (ref. 73).
Actin polymerization plays a key role in filopodial extension and
spine synapse formation as well as in plasticity within the synapse
itself1 05, and cytoskeletal remodeling is an important factor in the
effects of stress and other environmental manipulations. Hibernation
in European hamsters and ground squirrels results in rapid retraction
of dendrites of CA3 pyramidal neurons, and an equally rapid expan-
sion occurs when hibernation torpor is reversed56,57. The retraction
of dendrites is accompanied by increases in a soluble phosphor-
ylated form of tau that may indicate disruption of the cytoskeleton,
which permits the dendrite shortening and possible protection
from excitotoxicity; at the same time, PSA-NCAM expression is lost
during hibernation torpor, reducing the capacity for plasticity106.
This model highlights the important role that tau plays in normal
cytoskeletal function, a fact that should be emphasized when attempt-
ing to understand its role in pathology107.
Even though dendrite retraction and regrowth would appear to
involve a reversible depolymerization and repolymerization of the
cytoskeleton, there are other processes that point to the importance
of nuclear factors. A recent example is the unexpected role of a cell
nuclear pore complex protein, NUP-62, in stress-induced dendritic
remodeling in the CA3 region of the hippocampus108. First identified
as the product of a gene whose expression was downregulated in the
prefrontal cortex of depressed patients109, NUP-62 was also found to
be reduced in response to chronic stress in CA3 neurons of rodents108.
Importantly, the levels of other nuclear pore complex genes were
unchanged with chronic stress, supporting the specificity of its role
in stress remodeling. Subsequent in v itro studies confirmed that the
downregulation of NUP-62 is associated with dendritic retraction and
that this effect is regulated at the molecular level by NUP-62 phosphor-
ylation at a PYK2 site which results in its retention in the cytoplasm108.
A role of NUP-62 in maintaining chromatin structure for transcription
is suggested as well as in nucleocytoplasmic transport108.
Stress: not always what one thinks it is
Just as stress is not a unitary phenomenon at the cell and circuit level,
neither is it one at the level of the whole organism. As noted in the
introduction, a key aspect of stress effects on the brain and body is
the nonlinear interaction of multiple mediators of stress and adapta-
tion that is part of the concept of allostasis1, which refers to the active
process of maintaining homeostasis through the output of hormones
and ANS activity along with immune and metabolic system media-
tors and the mediators in the brain that are the main focus of this
review. When one mediator system changes, the others adjust, and
the resulting output can be distorted, as in chronic inflammation or
a flat cortisol diurnal rhythm caused by sleep deprivation or depres-
sion2. Moreover, the actions of any one mediator may depend on
the actions of other mediators. For example, glucocorticoids and
excitatory amino acids are both involved in stress-induced suppression
of neurogenesis, which has been found not only in rodents but also in
tree shrews and rhesus monkeys110–112. Yet, glucocorticoid levels alone
do not predict the direction of neurogenesis, as shown by studies of
male sexual behavior, which results in increased neurogenesis but also
high glucocorticoid levels; in this scenario oxytocin appears to play
an important role, emphasizing the importance of understanding the
interaction of these distinct signaling molecules113,114.
In seeking to understand where and how stress affects neural cir-
cuits, it has become evident that when these mediators act is also an
important consideration. In most vertebrate species, plasma glucocor-
ticoids rise just before the active phase. This rhythm is largely driven
by changes in the amplitude and frequency of the ultradian secretion of
glucocorticoids115. Indeed, the natural ultradian fluctuations of gluco-
corticoids mediate turnover of a subset of synapses in cerebral cortex;
and inhibiting the fluctuations with a minimal dose of dexamethasone
impairs spine turnover116. Moreover, these diurnal changes in spine
formation and removal are important for motor learning117.
In addition to ultradian pulses, circadian (or diurnal) rhythms
are a crucial factor that impact the stress response. Rhythmic
HPA function seems to be necessary for the normal initiation and
Control Disrupted
Length (µm)
Overall apical
dendrite length
b c
Distance from soma (µm)
Control Disrupted
Apical intersections
Number of intersections
Figure 7 Mice cannot adjust to a 10 h light/10 h dark cycle, as indicated
by body temperature and locomotor activity rhythms. This circadian
disruption, as in humans performing shift work, leads to increase body
fat and leptin and insulin resistance, along with remodeling of apical
dendrites of prefrontal cortical neurons and indications of cognitive rigidity.
(ac) Shown are a representive neuron (a), overall dendritic length (b)
and a Sholl analysis (c). Error bars, s.e.m. Data from ref. 123.
npg © 2015 Nature America, Inc. All rights reserved.
nature neuroscienceVOLUME 18 | NUMBER 10 | OCTOBER 2015 1361
termination of the stress response of ACTH, cortisol and other medi-
ators118. Epidemiologically, disrupted sleep and circadian rhythms
lead to increased risk for development of psychiatric, cardiovascular
or other physiological syndromes in shift workers or populations
undergoing chronic circadian disruption119. Housing mice in a light-
dark cycle of 20 h (10 h light/10 h dark), rather than standard 24-h
cycles, to drive circadian disruption results in metabolic signs of
allostatic load120, with increased weight, adiposity and leptin levels,
as well as an imbalance between insulin and plasma glucose suggest-
ing a pre-diabetic state121 . The metabolic changes are accompanied
by changes in PFC cellular morphology, mirroring those observed in
chronic stress122, with circadian-disrupted animals having shrunken
and less complex apical dendritic trees of cells in layer II/III of the
medial PFC123 (Fig. 7). In addition, circadian-disrupted mice show
altered responses to endotoxin challenge with lipopolysaccharide124,
highlighting the similarities between chronic circadian disrup-
tion and chronic stress. The mechanisms by which these systems
interact is not yet fully understood, but they do not appear to be
driven simply by elevation of glucocorticoids.
Intriguingly, glucocorticoids are able to regulate the expression of
circadian clock genes in several brain regions125 as well as in liver126.
As such, disruption of normal oscillatory profiles of glucocorticoids
could lead to desynchronized activity between different brain regions
as well as peripheral organ systems. This dissonance is thought to
contribute to several pathologies that are similar to the effects of
chronic stress, including obesity and metabolic syndrome119. Thus
circadian disruption is both a ‘stressor’, in that it increases allostatic
load or overload, and a risk factor for other stressful experiences,
emphasizing the importance of timing in glucocorticoid actions
through the brain and body.
Conclusions and future directions
The response of the brain to stressors is a complex process involv-
ing multiple interacting mediators that utilizes both genomic and
nongenomic mechanisms, from the cell surface to the cytoskeleton
to epigenetic regulation via the cell nucleus. Resilience in the face of
stress is a key aspect of a healthy brain, even though gene expression
shows a brain that continually changes with experience127. Therefore,
recovery from stress-induced changes in neural architecture after
stress is not a ‘reversal’ but a form of neuroplastic adaptation that also
may be impaired in mood disorders and reduced with aging (Fig. 1).
Resilience may be thought of as an active process that implies ongoing
adaptive plasticity without external intervention128.
On the other hand, resilience is decreased and vulnerability is
increased by adverse childhood experiences that lead to ‘biological
embedding’ of trajectories of response to stressful life events4 through-
out the life course6, which contribute disproportionately to allostatic
overload in the form of physical and mental health disorders over the
life course7. Evidence from CpG methylation of DNA indicates the
embedded influence of early adversity66. From the original definition
of epigenetics129 as the emergence of characteristics of each individual
of each species, not evident from prior stages of development, inter-
ventions to counteract adverse childhood experiences cannot ‘roll
back the clock’ but rather may be able change the trajectory of brain
and body development in a more positive direction.
Can the effects of stress on the brain be treated even though
there are no ‘magic bullets’ like penicillin for stress-related disorders6?
For psychiatric illnesses such as depression and anxiety disorders,
including PTSD, it is necessary to complement and even replace exist-
ing drugs and adopt strategies that center around the use of targeted
behavioral therapies along with treatments, including pharmaceutical
agents, that open up ‘windows of plasticity’ in the brain and facilitate
the efficacy of the behavioral interventions5,130,131. To that extent,
meeting the demands imposed by stressful experiences through vari-
ous coping resources can lead to growth, adaptation and learning to
promote resilience and improved mental health128,132.
The McEwen laboratory acknowledges research support from US National
Institutes of Health (R01 MH41256), and the Hope for Depression Research
Network and the American Foundation for Suicide Prevention to C.N. and
National Research Service Award F32 MH102065 to J.D.G.
The authors declare no competing financial interests.
Reprints and permissions information is available online at
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... Stress is considered a primary risk factor for neuropsychiatric disorders [1,2]. Accordingly, many animal models of psychopathology are largely based on exposure to validated chronic stress protocols. ...
... Here, we set up a novel paradigm based on differences in sucrose intake in acutely stressed rats, revealing the development of an anhedonic phenotype in about half of the stressed rats. We found no significant changes at the level of HPA axis activation 24 h after stress exposure, in line with previous evidence [1]. ...
... Observing dendritic retraction and simplification in FS-R rats is not surprising. Indeed, neuroarchitecture changes in response to stress are a physiological mechanism in the adult brain required for adaptation and learning [1,20]. Accordingly, we could hypothesize that dendritic retraction early after stress represents an adaptive mechanism to protect neurons from glutamate release induced by stress, while in the long-term, resilience implies the recovery from stress-induced changes in neuronal architecture [1,2]. ...
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Stress represents a main risk factor for psychiatric disorders. Whereas it is known that even a single trauma may induce psychiatric disorders in humans, the mechanisms of vulnerability to acute stressors have been little investigated. In this study, we generated a new animal model of resilience/vulnerability to acute footshock (FS) stress in rats and analyzed early functional, molecular, and morphological determinants of stress vulnerability at tripartite glutamate synapses in the prefrontal cortex (PFC). We found that adult male rats subjected to FS can be deemed resilient (FS-R) or vulnerable (FS-V), based on their anhedonic phenotype 24 h after stress exposure, and that these two populations are phenotypically distinguishable up to two weeks afterwards. Basal presynaptic glutamate release was increased in the PFC of FS-V rats, while depolarization-evoked glutamate release and synapsin I phosphorylation at Ser⁹ were increased in both FS-R and FS-V. In FS-R and FS-V rats the synaptic expression of GluN2A and apical dendritic length of prelimbic PFC layers II–III pyramidal neurons were decreased, while BDNF expression was selectively reduced in FS-V. Depolarization-evoked (carrier-mediated) glutamate release from astroglia perisynaptic processes (gliosomes) was selectively increased in the PFC of FS-V rats, while GLT1 and xCt levels were higher and GS expression reduced in purified PFC gliosomes from FS-R. Overall, we show for the first time that the application of the sucrose intake test to rats exposed to acute FS led to the generation of a novel animal model of resilience/vulnerability to acute stress, which we used to identify early determinants of maladaptive response related to behavioral vulnerability to stress.
... Stress is positively related to chronic illness and negatively associated with the functioning of the immune system. The high levels of stress presented by athletes in this study reveal a risk factor, because this stress could cause organic damage and lead to psychological and physical disorders [41]. The consistency between findings using different methodological approaches strongly support the hypothesis that stress is related to headaches, cardiovascular disease, depression, anxiety, and other psychopathologies [42,43]. ...
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The outbreak and pandemic of COVID-19 forced people into extreme isolation and social distancing, with significant limitations on various activity sectors, including sports. This study aimed to assess the psychological health status of athletes during sports lockdown. Additionally, we intend to verify the mediating role of sleep disorders in stress perception and subjective happiness. Our sample was composed of 1492 Portuguese athletes from eight different team sports. During sports lockdown, athletes were found to have high stress levels and low subjective happiness levels and experience sleep disorders. Finally, these results conclude that sports lockdowns harm athletes' psychological health and well-being. Pay cuts to athletes are an extra stress factor that exacerbate these adverse effects on psychological health. Finally, sleep is a mediator variable between stress perception and subjective happiness levels. This study's significant contributions, limitations, and future directions are discussed in the conclusion.
... Studies have found that exposure to CRS is capable of inducing behavioral effects associated with: (a) depression, such as loss of pleasure in previously reinforcing situations (anhedonia -Liu et al., 2019;Tan et al., 2017;Wang et al., 2016;Wang et al., 2017;Zhu et al., 2019); (b) anxiety, such as greater risk aversion (Bhagya et al., 2017;Bigdeli et al., 2019;Guedri et al., 2017;Mohammadi et al., 2019); and (c) cognitive impairments, such as worsening spatial learning (Jangra et al., 2017;Kitraki et al., 2004;Luine et al., 1994;Zhang et al., 2017). These behavioral effects can be attributed to structural and functional changes in different brain regions, resulting in dendritic retractions in hippocampal and prefrontal cortex neurons and J o u r n a l P r e -p r o o f dendritic outgrowth of amygdala neurons (McEwen, 2015;McEwen et al., 2017;Qiao et al., 2016). ...
Chronic restraint stress (CRS) can have different behavioral effects depending on variables associated with the stressor and the organism. This study aimed to verify the effect of the interaction between sex and duration of the CRS protocol in rats. Sprague-Dawley rats were divided by sex, intervention (CRS; control), and CRS duration (11 days; 22 days). Rats exposed to CRS showed better spatial learning than controls in the Morris water maze test, regardless of sex and stress duration. Males exposed to CRS for 11 days showed a higher rate of behaviors associated with anxiety than males exposed to 22 days of CRS at the elevated plus maze test, but the same was not observed in females. The weight gain of animals exposed to stress decreased in the first 11 days, showing a recovery from day 11 to day 22 of intervention. No effects of CRS were observed on behaviors associated with depression in the sucrose preference test. The results suggest habituation to the protocol, with a progressive decrease in the harmful effects of stress on and maintenance of the beneficial effects. It is possible that females are more resistant to the harmful effects of CRS on anxiety.
... This review outlines recent findings on some of the molecular and cellular mechanisms underlying GC effects in vitro, which can provide some evidence for mechanisms involved in susceptibility to SRDs (Faye et al., 2018;McEwen et al., 2015). We do acknowledge that the neurobiology of stress does not rely solely on the effects of GCs, and that GC exposure does not translate to stress exposure in vitro (MacDougall-Shackleton et al., 2019). ...
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Hypothalamic-pituitary adrenal (HPA)axis dysregulation has long been implicated in stress-related disorders such as major depression and post-traumatic stress disorder. Glucocorticoids (GCs) are released from the adrenal glands as a result of HPA-axis activation. The release of GCs is implicated with several neurobiological changes that are associated with negative consequences of chronic stress and the onset and course of psychiatric disorders. Investigating the underlying neurobiological effects of GCs may help to better understand the pathophysiology of stress-related psychiatric disorders. GCs impact a plethora of neuronal processes at the genetic, epigenetic, cellular, and molecular levels. Given the scarcity and difficulty in accessing human brain samples, 2D and 3D in vitro neuronal cultures are becoming increasingly useful in studying GC effects. In this review, we provide an overview of in vitro studies investigating the effects of GCs on key neuronal processes such as proliferation and survival of progenitor cells, neurogenesis, synaptic plasticity, neuronal activity, inflammation, genetic vulnerability, and epigenetic alterations. Finally, we discuss the challenges in the field and offer suggestions for improving the use of in vitro models to investigate GC effects.
... Various studies have confirmed these results. For example, stress contributes to an unhealthy lifestyle, fast food consumption, and emotional eating [16,28,35,40]. Depression is associated with stress and a bad mood, as well as with loneliness and social isolation, which are also associated with emotional eating [12]. ...
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Emotion can reflect in the perception of food consumption. An increase in food intake during emotional and psychological conditions may have a negative impact on human health. The aim of this cross-sectional study was to determine the associations between food consumption, emotional eating behavior, and emotional conditions such as stress, depression, loneliness, boredom eating, maintaining vigilance and alertness, and emotional food consolation. We used a Motivations for Food Choices Questionnaire (Eating Motivations, EATMOT) to determine the emotional aspects of food consumption in 9052 respondents living in 12 European countries between October 2017 and March 2018. Ordinal linear regression was used to identify the associations between the emotional eating behavior and emotional conditions such as stress, depression, loneliness, emotional consolation, and reasons to improve physical and psychological conditions. The regression models confirmed the associations between food consumption, emotional conditions, and emotional eating behavior. Associations were found between the emotional eating behavior and stress (odds ratio (OR) = 1.30, 95% confidence interval (CI) = 1.07–1.60, p = 0.010), depressive mood (OR = 1.41, 95% CI = 1.40–1.43, p < 0.001), loneliness (OR = 1.60, 95% CI = 1.58–1.62, p < 0.001), boredom (OR = 1.37, 95% CI = 1.36–1.39, p < 0.001), and emotional consolation (OR = 1.55, 95% CI = 1.54–1.57, p < 0.001). Emotional eating was associated with an effort to improve physical and psychological conditions, such as controlling body weight (OR = 1.11, 95% CI = 1.10–1.12, p < 0.001), keeping awake and alert (OR = 1.19, 95% CI = 1.19–1.20, p < 0.001) and consumption to feel good (OR = 1.22, 95% CI = 1.21–1.22, p < 0.001). In conclusion, emotions might provoke emotional eating behavior. The appropriate way to handle stress, depression, or other emotional states is important in conditions of being emotionally overwhelmed. The public should be educated on how to handle different emotional states. The focus should be moved somehow from emotional eating and the consumption of unhealthy food to healthy lifestyle practices, including regular exercise and healthy eating habits. Thus, it is necessary to halt these negative health effects on human health through public health programs.
The menstrual cycle should be considered a “vital sign” of overall health and, therefore, many gynecological conditions have an impact on sexual health, including functional hypothalamic amenorrhea (FHA). The involvement of biomedical variables is strongly modulated by psychosocial factors, and only a unified view allows an individualized approach to female sexual dysfunction (FSD). In FHA, neuroendocrine aberrations associated with several stressors may affect any phase of the sexual response cycle preventing the individual or the couple from experiencing satisfactory sexual behavior. Further studies are needed to fully understand the impact of menstrual failure on the manifestation of FSD, including sexual pain, desire, arousal and orgasmic disorders.
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Background: Cognitive and brain reserve refer to individual differences that allow some people to better withstand brain pathology than others. Although early life stress has been recognized as a risk factor for low reserve in late life, no research yet has studied this across midlife. Objective: To examine the associations of life stress with brain and cognitive reserve in midlife. Methods: We included 1,232 middle-aged women who participated in the ORACLE Study between 2002-2006). Life stress was calculated as the shared variance of four cumulative stress domains, created from items measured between pregnancy and 10 years after childbirth. Brain reserve was defined as healthy-appearing brain volume measured with MRI; cognitive reserve as better cognitive functioning than expected based on age, education, and brain MRI measures, using structural equation modelling. Results: More life stress was associated with lower brain (standardized adjusted difference: -0.18 [95% CI 0.25,-0.12]) and cognitive reserve (-0.19 [-0.28,-0.10]). Although, effect sizes were typically smaller, cumulative stress domains were also associated with brain reserve (life events: -0.10 [-0.16,-0.04]; contextual stress: -0.13 [-0.19,-0.07]; parenting-related stress: -0.13[-0.19,-0.07]; interpersonal stress: -0.10 [-0.16,-0.04]) and cognitive reserve (life events: -0.18 [-0.25,-0.11]; contextual stress: -0.15 [-0.10,-0.02]; parenting-related stress: -0.10 [-0.18,-0.03]; interpersonal stress not significant). Conclusion: Women who experience more life stress in midlife were found to have lower reserve. Effects were primarily driven by shared variance across cumulative stress domains, suggesting that focusing on single domains may underestimate effects. The effect of life stress on lower reserve may make women with stress more prone to neurodegenerative disease later in life than women without stress.
Promising evidence points to gestational physical exercise as the key to preventing various disorders that affect the offspring neurodevelopment, but there are no studies showing the impact of resistance exercise on offspring health. Thus, the aim of this study was to investigate whether resistance exercise during pregnancy is able to prevent or to alleviate the possible deleterious effects on offspring, caused by early life-stress (ELS). Pregnant rats performed resistance exercise throughout the gestational period:they climbed a sloping ladder with a weight attached to their tail, 3 times a week. Male and female pups, on the day of birth (P0), were divided into 4 experimental groups: 1) rats of sedentary mothers (SED group); 2) rats of exercised mothers (EXE group); 3) rats of sedentary mothers and submitted to maternal separation (ELS group) and 4) rats of exercised mothers and submitted to MS (EXE + ELS group). From P1 to P10, pups from groups 3 and 4 were separated from their mothers for 3 hours/day. Maternal behavior was assessed. From P30, behavioral tests were performed and on P38 the animals were euthanized and prefrontal cortex samples were collected. Oxidative stress and tissue damage analysis by Nissl staining were performed. Our results demonstrate that male rats are more susceptible to ELS than females, showing impulsive and hyperactive behavior similar to that seen in children with ADHD. This behavior was attenuated by the gestational resistance exercise. Our results demonstrate, for the first time, that resistance exercise performed during pregnancy seems to be safe for the pregnancy and offspring's neurodevelopment and are effective in preventing ELS-induced damage only in male rats. Interestingly, resistance exercise during pregnancy improved maternal care and it is reasonable to propose that this finding may be related to the protective role on the animals neurodevelopment, observed in our study. DATA AVAILABILITY STATEMENT: Data available on request from the authors.
General anaesthetics have been widely applied to induce reversible loss and recovery of consciousness in clinical practice and have been shown to have reliably safe profiles. Since brief exposure to general anaesthetics can result in long-lasting and global changes in neuronal structures and function, these drugs also exhibit strong therapeutic potential for mood disorders. Preliminary and clinical studies have suggested that the inhalational anaesthetic drug sevoflurane might relieve symptoms of depression. However, the antidepressant effects of sevoflurane and the underlying mechanisms remain elusive. In the present study, we confirmed that the antidepressant and anxiolytic effects of inhaling 2.5% sevoflurane for 30 min were comparable to those of ketamine and could be sustained for 48 h. Activation of GABAergic (γ-aminobutyric acidergic) neurons in the nucleus accumbens core by chemogenetics was shown to mimic the antidepressant effects of inhaled sevoflurane, whereas inhibition of these neurons significantly prevented these effects. Considered together, these results suggested that sevoflurane might exert rapid and long-lasting antidepressant effects via modulation of neuronal activities in the nucleus accumbens core nucleus.
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We recently showed that the mammalian genome encodes >1,000 large intergenic noncoding (linc)RNAs that are clearly conserved across mammals and, thus, functional. Gene expression patterns have implicated these lincRNAs in diverse biological processes, including cell-cycle regulation, immune surveillance, and embryonic stem cell pluripotency. However, the mechanism by which these lincRNAs function is unknown. Here, we expand the catalog of human lincRNAs to ≈3,300 by analyzing chromatin-state maps of various human cell types. Inspired by the observation that the well-characterized lincRNA HOTAIR binds the polycomb repressive complex (PRC)2, we tested whether many lincRNAs are physically associated with PRC2. Remarkably, we observe that ≈20% of lincRNAs expressed in various cell types are bound by PRC2, and that additional lincRNAs are bound by other chromatin-modifying complexes. Also, we show that siRNA-mediated depletion of certain lincRNAs associated with PRC2 leads to changes in gene expression, and that the up-regulated genes are enriched for those normally silenced by PRC2. We propose a model in which some lincRNAs guide chromatin-modifying complexes to specific genomic loci to regulate gene expression.
Dendritic spines form the postsynaptic element at most excitatory synapses in the brain. The spine cytoskeleton consists of actin filaments which, in time-lapse recordings of living neurons expressing actin labeled with green fluorescent protein, can be seen to undergo rapid, dynamic changes. Because actin dynamics are associated with changes in cell shape, these cytoskeletal rearrangements may form a molecular basis for the morphological plasticity at brain synapses. The rapidity of these dynamic events in dendritic spines raises new questions. First, do the changes in actin cytoskeleton that are visible by light microscopy really correspond to changes in spine morphology, or do they represent changes in the relationship between actin and its many binding partners at postsynaptic sites? Second, how are these changes regulated by synaptic transmission? Third, to what extent do these changes occur in organized brain tissue? Answers to these questions are now beginning to emerge. Hippocampus 2000;10:555–560. © 2000 Wiley-Liss, Inc.
Stress has profound effects on brain structure and function, but the underlying mechanisms are still poorly understood. Recent studies imply that neuronal cell adhesion molecules of the immunoglobulin superfamily--NCAM and L1--are important mediators of the effects of stress on the brain. Chronic stress regimes that lead to hippocampal atrophy and spatial-learning impairment in rodents simultaneously induce a pattern of changes in cell adhesion molecule expression that fits with a role for these molecules in stress-induced neuronal damage and neuroprotective mechanisms. These findings highlight cell adhesion molecules as potential therapeutic targets to treat stress-related cognitive disturbances.
Most neurons in the mammalian brain are produced during the embryonic period. In contrast, the granule cell population of the dentate gyrus of the hippocampal formation is produced during an extended period that begins during gestation and continues well into adulthood. The production of new granule neurons is suppressed by stress. These observations suggest that stressful experiences during postnatal development and adulthood have the potential to alter significantly both the structure and function of the hippocampal formation. Because the hippocampus plays a key role in learning and memory, a decrease in the production of granule neurons during development may have a negative impact on learning and memory in adulthood.
Over the past 5 yr, we have examined some of the sharpest edges of the pathology of aging. We have studied the capacity of aged organisms to respond appropriately to stress and the capacity of stress to cumulatively damage aging tissue. The idea of a relationship between stress and aging has permeated the gerontology literature in two forms. First, senescence has been thought of as a time of decreased adaptiveness to stress. This idea has been supported frequently, as many aged physiological systems function normally under basal conditions, yet do not adequately respond to a challenge. For example, aged and young humans have similar basal body temperatures, but the former are relatively impaired in thermoregulatory capacities when heat- or cold-challenged. A second theme in gerontology concerning stress is that chronic stress can accelerate the aging process. Selye and Tuchweber for example, postulated a finite "adaptational energy" in an organism, with prolonged stress prematurely depleting such reserves, thus accelerating the onset of senescence. This idea was derivative of earlier idea that the "rate of living" could be a pacemaker of aging. Experimentally, varied approaches have supported the notion that at least some biomarkers of age can be accelerated by stress. The above hypotheses led us to examine the adrenocortical axis, the endocrine axis which is among the most central to the stress response. Our findings support both of these concepts. We find that the aged male rat is impaired in terminating the secretion of adrenocortical stress hormones, glucocorticoids, at the end of stress. This hormonal excess may be due to degenerative changes in a region of the brain which normally inhibits glucocorticoid release; the degeneration, in turn, is caused by cumulative exposure to glucocorticoids. Together, these effects form a feed-forward cascade with potentially serious pathophysiological consequences in the aged subject. Reproduced by permission. Robert M. Sapolsky, Lewis C. Krey, Bruce S. McEwen, The Neuroendocrinology of Stress and Aging: The Glucocorticoid Cascade Hypothesis. Endocr. Rev. 7 , 284-301 (1986).
The developing human brain is shaped by environmental exposures - for better or worse. Many exposures relevant to mental health are genuinely social in nature or believed to have social subcomponents, even those related to more complex societal or area-level influences. The nature of how these social experiences are embedded into the environment may be crucial. Here we review select neuroscience evidence on the neural correlates of adverse and protective social exposures in their environmental context, focusing on human neuroimaging data and supporting cellular and molecular studies in laboratory animals. We also propose the inclusion of innovative methods in social neuroscience research that may provide new and ecologically more valid insight into the social-environmental risk architecture of the human brain.