Mechanisms of Stress in The Brain: Review

focus on stress
review
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
2015 Nature America, Inc. All rights reserved.
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.
The brain is the central organ of stress and adaptation to social and Stress can be divided into good stress, tolerable stress and toxic
physical stressors because it determines what is threatening, stores stress4. Early life stress can alter neural architecture to increase
memories, and regulates the physiological as well as behavioral adverse reactions to stressors, leading to toxic stress 4. Biological
responses to stressors that may be damaging or protective1. The physi- embedding4,5 of these effects during critical or sensitive periods of
ological responses that produce adaptation through allostasis include early development has lasting effects through the life course6,7. Among
not only the hypothalamic-pituitary-adrenal (HPA) axis and the auto- the most important early life experiences are those that involve abuse
nomic nervous system, but also their nonlinear interactions with the and neglect, on the one hand, versus the establishment of strong,
metabolic system and the pro- and anti-inflammatory components of positive attachment of child to caregiver; these alter the ability of
the immune defense system1,2. Exposure to multiple stressors and the the individual to engage in cooperative social experiences or to feel
dysregulation of the nonlinear interactions (such as failure to turning excluded and hostile to the social environment later in life8.
on or off responses efficiently) lead to wear and tear on the body and The brain is a target of stressful experiences, and glucocorticoids,
brain that is termed allostatic load and overload1,3. along with excitatory amino acid neurotransmitters, alter neuro-
Allostasis is the active process of adapting to stressors via mediators nal architecture by causing dendritic retraction or expansion and
such as cortisol and the autonomic, metabolic and immune system decreased or increased synapse density, depending on the brain
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that act together in a nonlinear fashion to maintain homeostasis2. region, along with inhibition of dentate gyrus neurogenesis 911.
Allostatic load refers to the cumulative effect of multiple stressors Many intra- and intercellular mediators and processes are involved
as well as the dysregulation of the nonlinear network of allostasis in changing the brain during stress and recovery from stressful
(for example, production of cortisol, adrenalin or inflammation in experiences12,13 (Box 1).
response to a challenge). Allostatic overload refers to the cumulative This Review provides an overview of the mechanisms and media-
pathophysiology that can result from this dysregulation and excess tors through which stressors alter brain structure and function. It does
stress. Allostasis, and allostatic load and overload, are more precise so by focusing primarily on three brain regions, the hippocampus,
biological concepts than stress to describe adaptation and mal amygdala and prefrontal cortex (PFC), although in full recognition
adaptation to stressors, and they include the physiological effects of of the fact that stress has widespread effects throughout the brain.
health-promoting and health-damaging behaviors as well as stressful This Review also emphasizes the complex nonlinear interactions
experiences1,2. Health behaviors (such as smoking, alcohol, poor diet, between different stress mediators that are central to the concept of
or lack of sleep), resulting from the experience of stress, also have a allostasis and allostatic load and overload 3, in which nonlinearity
role and contribute to allostatic load and overload1,3. 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
1Laboratory of Neuroendocrinology, The Rockefeller University, New York, relationship, as represented in Figure 1.
New York, USA. 2Hotchkiss Brain Institute, University of Calgary, Calgary,
Alberta, Canada. 3Department of Psychology, University of Massachusetts
Mechanisms underlying stress effects on the brain
Boston, Boston, Massachusetts, USA. 4Department of Integrative Physiology
and Neuroscience, Washington State University, Pullman, Washington, USA. Stressors alter gene expression through multiple mechanisms, includ-
Correspondence should be addressed to B.S.M. (mcewen@rockefeller.edu). ing direct effects of glucocorticoids on gene transcription as well as
Received 19 April; accepted 8 July; published online 25 September 2015; the activation of epigenetic mechanisms in which histone modifica-
doi:10.1038/nn.4086 tions and methylation and hydroxymethylation of CpG residues in
nature neuroscience VOLUME 18 | NUMBER 10 | OCTOBER 2015 1353

Review
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
Lipocalin-2
Secreted protein of previously unknown function77,78
Induced by acute stress
Downregulates mushroom spines
Knockout increases neuronal excitability and anxiety
Endocannabinoids136138
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
DNA have roles leading to repression and activation of genetic fac- for adrenal steroids16, the hippocampus has been an important gate-
tors, including retrotransposons14,15. Glucocorticoids are not the sole way to understanding the effects of glucocorticoids and stress on gene
mediators of these effects, in which excitatory amino acids and many expression in the brain. Recent technological advances have allowed
other cellular mediators also play important parts (Box 1). These high-throughput analysis of gene expression changes in response to
mediators span influences from extracellular adhesion molecules to stress17. For example, microarray analysis of whole hippocampus after
cytoskeletal elements and at least one nuclear pore complex protein. acute stress, chronic stress and stress recovery in mice revealed that
In addition to their critical role in complex behavior and acute and chronic stress modulate a core set of genes, but that numer-
cognition, the hippocampus, amygdala and PFC are important in ous changes are exclusive to each condition, highlighting how duration
regulating the autonomic and HPA stress response, and they are and intensity of stress alters reactivity18. Furthermore, corticosterone
the main focus of this review (Box 2). injections do not produce the same expression profile as acute stress,
suggesting that in vivo stressors activate a diverse set of pathways
Stress effects on gene expression in an ever-changing brain. As the independent of glucocorticoid receptor (GR) activation18 (Fig. 2).
first extra-hypothalamic brain structure recognized to have receptors Finally, characterization of expression profiles after extended recov-
ery from 21 d of chronic stress showed that,
despite a normalization of anxiety-related
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Synaptic functions: suppression of

Synaptic transmission
Long-term potentiation behaviors, recovery does not represent a
Synaptic functions: enhancement of
Learning for less important things return to the stress-naive baseline but rather a
Synaptic transmission Adaptive plasticity: new state in which reactivity to a novel stres-
Long-term potentiation
Learning for self-preservation
Suppression of neurogenesis
Mediates dendritic remodeling
sor produces a unique expression profile18.
Studies in rats confirm that gene expres-
Loss of resilience: sion profiles can change significantly from
Neurochemical distortion
Impaired remodeling and the immediate end of stress to 24 h later19
lack of recovery from stress and that chronic stress can alter the tran-
Adrenal steroids and excitatory
scriptional response to an acute corticos-
Damage potentiation:
amino acids modulate both Mediates excitotoxicity in seizures, terone injection in dentate gyrus20 (Fig. 2).
limbs of inverted U stroke and head trauma Together, these studies demonstrate that a
Increasing amounts and frequency
Brain aging:
history of stress exposure can have a last-
Extrasynaptic ing impact on future stress reactivity and
glutamate
Free radicals and
hippocampal function.
inflammation
Figure 1 Effects of acute and chronic stress,
Decline of resilience with age mediated in part by glutamate and glucocorticoids
Acute moderate enhancement Chronic adaptive plasticity Increased vulnerability for as well as other molecules described in the
Acute intense suppression Loss of resilience external permanent damage text and in Box 1. These effects follow an
Traumatic damage, neuron loss intervention required External intervention needed inverted U-shaped curve in dose and time.
The timeline shows how acute and chronic
Minutes to hours Days to months Months to years
stress and aging interact with the intensity
Timeline and duration of stressor.
1354 VOLUME 18 | NUMBER 10 | OCTOBER 2015 nature neuroscience

review
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 Prefrontal cortex
stress response and are the main focus of this review.
Glucocorticoid and mineralocorticoid receptors were first recognized in the
Marina Corral Spence/Nature Publishing Group

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 Hippocampus
in the hippocampus that the role of excitatory amino acids in stress effects was
9
first recognized . Amygdala
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 stressinduced 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
memory141.
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.
Many of the genes altered after glucocorticoid and chronic stress zinc finger protein (ZFP)-induced enrichment of H3K9me2 at FosB in
exposure in the hippocampus are known epigenetic regulators21, NAc not only was sufficient to reduce FosB/FosB expression, but also
providing one possible mechanism underlying the persistent altera- induced depression- and anxiety-like behaviors after social stress28.
tions in the expression response beyond the end of stress exposure. A current practical application of this approach is the investiga-
The continually changing pattern of gene expression is consistent tion of rapidly acting antidepressants28,29 that act, at least in part, via
with the finding that, although stress-induced dendritic retraction epigenetic mechanisms, as does electroconvulsive therapy26,30. An
in PFC neurons appears to be reversible in terms of dendritic length epigenetic mechanism connects excitatory amino acid function with
and branching, the recovered neurons are different, in that dendrites neural remodeling and stress-related behavior in one genetic and one
that regrow after recovery from stress are more proximal to the stress-induced rodent model of anxiety- and depressive-like behavior
cell body than those that retracted22. in which downregulation of the presynaptic inhibitor of neuronal gluta-
mate release, the mGlu2 receptors, in hippocampus is a key biomar-
Epigenetic mediation via post-translational histone modifica- ker29. In that connection, drugs that modify glutamate overflow, such as
tions. Stress has a clear impact on many types of molecular epige- ketamine, acetyl-l-carnitine and riluzole, have been show to exert rapid
netic mechanisms, from histone modifications to DNA methylation antidepressant-like effects in animal models29,31 and in humans32.
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and hydroxymethylation and expression of noncoding RNA14,2325 The novel antidepressant candidate acetyl-l-carnitine (LAC)
(Fig. 3). For instance, social defeat stress in rodents causes changes in appears to act inside and outside the nucleus to exert fast antidepres-
both histone methylation and acetylation26. Acute and chronic stress sant responses: LAC corrects mGlu2 deficits by increasing acetylation
promote histone modifications leading to repression or activation of histone H3 lysine 27 (H3K27) bound to Grm2 promoter gene as
of genes related to memory and other processes. Studies of memory well as acetylation of the NF-B p65 subunit29. Using the same animal
acquired in the forced swim test and Morris water maze uncovered a models, 14 d of treatment with the tricyclic antidepressant clomi-
novel, rapid mechanism: glucocorticoids, via GRs, facilitate signaling pramine were needed to promote antidepressant responses, which
of the ERK-MAPK pathway to the downstream nuclear kinases MSK1 disappeared when the treatment was stopped, whereas antidepressant
and Elk-1 in dentate gyrus granule neurons; and activation of this path- effects of LAC were still evident after 2 weeks of drug withdrawal.
way results in phosphorylation of serine 10 (S10) acetylation of lysine The persistent effects of LAC highlight the involvement of stable
14 (K14) of histone H3 (H3S10p-K14ac), leading to the induction molecular adaptations that are reflected at the level of histone modi-
of the immediate-early gene products c-Fos and Egr-1 (ref. 27). fications in controlling mGlu2 transcription in hippocampus.
Unlike that of other immediate-early gene products, FosB and its
splice variant FosB increases and remain elevated in the nucleus Transposons and retrotransposons. Acute restraint stress also has
accumbens (NAc) after social defeat stress and is deficient in those repressive epigenetic effects in the hippocampus and most promi-
animals that show depressive-like behavior, as well as in human patients nently in the dentate gyrus via trimethylation of H3K27 and H3K9.
with depression postmortem. Moreover, increased FosB/FosB expres- The latter is associated with repression of a number of retrotrans-
sion in NAc protects animals from the deleterious effects of chronic posable elements (RTE) and reduction of the coding and noncod-
stress28. Epigenetically, the FosB promoter is enriched for dimethylation ing RNA normally produced by the repressed DNA, so far only
of H3 lysine 9 (H3K9me2) in the NAc of humans with depression rela- in hippocampus30,33. This repression is lost with repeated stress,
tive to that of controls without depression, implicating this repressive suggesting that those RTEs may impair genomic stability under
epigenetic modification in the repression of FosB. Moreover, in mice conditions of chronic stress15.

Review
Figure 2 Gene expression changes in hippocampus in response to stress

and glucocorticoid challenge depend on the prior stress history of the
5,000 a Increased
d 3,618 2,905
0.4
No. of genes
subject. Hippocampal microarray data reveals stress-induced changes Decreased
3,000
in gene expression. (a) Dark colors represent the number of genes with 0.2
significantly increased expression and pastels represent those with
1,000
Rec
significantly decreased expression as identified by pairwise comparisons 0
0
of each stress group with age-matched controls. FST, forced swim test;
FS +
FS c +
Re c
rt
C S
T
Re
0.2
Co
S
FS
R
Cort, glucocorticoid injection; CRS, chronic restraint stress; Rec, recovery
T
R
C
from CRS. (b) Proportional Venn diagram illustrating the genes with
expression significantly altered by the acute stress, chronic stress and b71 0.4
3,608 10,682
FST CRS
glucocorticoid (Cort) injection conditions and their overlap. The numbers 271
432 0.4 0.2 0 0.2 0.4
of genes unique to each comparison whose expression was increased or 713 392 CRS
decreased are listed next to arrows indicating the direction of change. 6
(c) Venn diagram of genes whose expression was altered by each FST 90 Cort 36 e Ctnnb1 Eif5a Ank3 Hdac8
condition reveals a core of 95 genes that were always changed by this 369
Neurod2 Cdc34 Cdk2 Kcna1
stressor. The large number of unique gene expression changes in each 433 Traf6 Traf4 Gria2 Per2
condition shows that the response to FST is altered by the stress history Dusp4 Ephb2 Cart Cort
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,
c Egfr Nrg3
Slc1a2 Scn1b Grin2a
Camk2d Dcx
II1a
CRS + FST
299 Fgfr1 Wnt7b
as also shown in a. (d) Scatter plot of normalized expression values for FST 890
each microarray probe comparing CRS (x axis) with recovery from CRS 300 2502 36
(y axis). For the majority of genes, expression is increased by CRS, but 555 Rec CRS
decreased after recovery; however, some probes show expression that is 95
increased by CRS and remains elevated after recovery or that is suppressed 77
438 367 312

by CRS and remains low in recovery. Highlighted probes are those that 314 324 428
327
reached significance when compared with age-matched controls (blue,
Rec + FST
CRS; red, recovery from CRS; gray, not significant). Several examples of
the highlighted genes are listed below the scatter plot by color designation f
Control + GCs
unique (267) Common (258)
CRS + GCs
unique (318)
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
Voltage-gated cation activity Transcription
after recovery from CRS are mostly distinct from those whose expression
Immune response G-protein coupled receptor activity
was significantly altered by CRS. Reprinted from ref. 18 with permission
Signal transduction activity Development
from Macmillan Publishers Ltd. (f) Pie charts of Gene Ontology (GO) terms
Nuclear import
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.
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Retrotransposons constitute a tenfold larger fraction of mammalian Role of excitatory amino acids. Excitatory amino acids, particularly
genomes than protein coding genes and appear to be unusually active glutamate, play key roles in structural as well as functional changes in
in brain and steroidogenic tissues15. Consequently, they have recently the brain (Fig. 4). Initial studies of restraint stress, in which chronic
attracted increasing attention from neuroscientists, who have shown stress causes shrinkage of apical dendrites of hippocampal CA3 neu-
that they contribute to neural diversity, cell fate and development as rons, showed that acute restraint stress elevates extracellular glutamate
well as brain disease15,3436. In addition to transposons mobility, they levels through a process that is absent in adrenalectomized animals,
also seem to contribute the largest fraction of functional elements to suggesting a role for the adrenal cortex47. Indeed, corticosterone acts
what might be referred to as the RNA genome3739. This other genome directly via membrane-associated mineralocorticoid receptors (MRs)
is composed of genes for noncoding RNAs that are being found to and GRs to cause glutamate release29,48,49. Importantly, blocking
govern a growing number of cellular processes, including develop- NMDA receptors and interfering with excitatory stimulation of ion
ment, cell differentiation, chromosome imprinting and the regulation channels blocks stress-induced dendritic remodeling within the hip-
of the epigenetic machinery40,41; thus RTE-derived RNAs represent a pocampus, an effect similar to that of blockade of adrenal steroid
substantial store of both genetic and epigenetic information. synthesis50,51. Similarly, stress-induced NMDA-dependent dendritic
Barbara McClintock, who discovered transposons over 60 years ago, remodeling has been reported in medial PFC neurons52. Excess gluta-
noted that they were important contributors to an organisms ability matergic activity, without adequate reuptake in the aftermath of
to deal with environmental stress42,43, and this insight appears to hold trauma from seizures, ischemia and head trauma, leads to permanent
true with regard to the neurobiology of stress, though as with many neuronal loss by a process that is exacerbated by glucocorticoids 53.
other aspects of stress, transposons are likely to have both adaptive34 These relationships can be summarized in an inverted-U-shaped
and possibly deleterious effects given that their dysregulation has been dose- and time-response curve (Fig. 1).
observed in both humans with post-traumatic stress disorder (PTSD) In that connection, the shrinkage of apical dendrites as a result of
and animal models of stress disorders4446. Brain transposons there- stress in CA3 pyramidal neurons can be thought of as a protective mech-
fore appear to represent a significant new frontier for stress research. anism against permanent damage and neuron loss that is caused by the

review
Figure 3 Molecular epigenetic modifications. Among the molecular

H
H
C H Histone acetylation,
C O
O O phosphorylation, mechanisms that fall under the epigenetic rubric are covalent modifications
P O
O methylation DNA methylation
C
H
H
H
of the histone proteins that package and control access to the DNA, which
miRNA 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
piRNA
such as microRNA (miRNA), piwi-interacting RNA (piRNA) and long
noncoding RNA (lncRNA) also act to convey epigenetic information and to
IncRNA
coordinate interactions between DNA and the transcriptional and chromatin
mRNA stability modification machinery. Many of these mechanisms seem to have evolved in
and translation
part from, or as a consequence of the presence of, transposable elements in
eukaryotic genomes. Adapted from ref. 24 with permission of Elsevier.
metastable dentate gyrusCA3 feedforward and feedback circuitry that is In addition, glucocorticoids can also translocate GRs, along with
the basis of its function54 and yet makes it vulnerable to seizure-induced the anti-apoptotic protein B-cell lymphoma 2 (Bcl-2), to mitochondria
damage55. This is well illustrated in hibernation, a state of low energy where they together promote Ca2+ sequestration and regulate
supply to the brain that is accompanied by rapidly reversible (within mitochondrial oxidation, free radical formation and membrane
hours) shrinkage of CA3 apical dendrites in the hippocampus56,57. This potential, three independent measures of mitochondrial function.
hypothesis is further substantiated by studies in which removal of poly- Bcl-2 is able to inhibit the formation of Bax-containing pores on the
sialic acid residues from neural cell adhesion molecule (NCAM) leads to mitochondrial outer membrane and reduce the release of calcium
marked increases in dendritic length of CA3 neurons and increased vul- and cytochrome c from the mitochondria. Importantly, these three
nerability to excitotoxic damage, supporting the notion that shorter den- glucocorticoid effects show an inverted Ushaped dose-response
drites reduce the vulnerability of CA3 neurons to overstimulation58. curve and are biphasic, and high glucocorticoid levels cause a failure
of this mechanism over 72 h, leading to increased free-radical
Role of glucocorticoids via multiple intracellular sites and mecha- formation62 (Fig. 5).
nisms. Glucocorticoids produce both genomic and nongenomic Just as location of GR action is an essential consideration, the level
effects in the brain through multiple sites and pathways. In addition, of expression of GRs is also very important. Genetically induced
glucocorticoids have biphasic effects in which the timing and the level overexpression of GR in forebrain leads to increased lability of
of GR expression are critical29,59. Glucocorticoid actions via genomic mood-related behaviors, yet also confers greater responsiveness
mechanisms involve both direct interactions with glucocorticoid to antidepressant drugs63, whereas genetic knockdown of GR has
response elements (GRE) and indirect actions via tethering to other the opposite effect64. Epigenetic regulation of GR activity also has
transcription factors60. Glucocorticoids can directly stimulate release significant functional implications, as increased CpG methylation
of excitatory amino acids via membrane-associated receptors, and within the GR promoter is associated with a suboptimal HPA stress
they can indirectly regulate both glutamate and GABA release through response and with poor maternal care in rodents and early life
induction of local synthesis of endocannabinoids61 (see below). abuse in human suicide victims65,66.
Figure 4 Glucocorticoids are released from the

Direct genomic
adrenal glands. Basal release varies in a diurnal effect
Glucocorticoids
pattern, and release increases severalfold after Nongenomic
exposure to a stressor. Glucocorticoids can bind, effect
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with different affinities, to glucocorticoid and Glucocorticoid Postsynaptic

Indirect
mineralocorticoid receptors, which are expressed Mineralocorticoid
genomic effect
receptor neuron
throughout the brain and seem to exist in both receptor
membrane-bound form and nuclear form.

Adrenal steroids can have both rapid and delayed +
NMDA
receptor
effects. The effects can result from nongenomic Nucleus
mechanisms (mediated by membrane receptors,
Marina Corral Spence/Nature Publishing Group
Vesicle
see the figure), indirect genomic mechanisms Second
(mediated by membrane receptors and second messengers
AMPA
messengers, see the figure) and genomic
receptor
mechanisms (mediated by cytoplasmic Presynaptic
neuron Glutamate
receptors that move to the nucleus and act as CB1 Mitochondrion
transcription factors; see figure), as seems now
to be the case for all steroid hormones. Although Membrane
glucocorticoid
mineralocorticoid and glucocorticoid receptors +
receptor
seem to mediate many of these effects, other Endocannabinoid
membrane-associated receptors, including production
G proteincoupled 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 proteincoupled receptor is
implicated in endocannabinoid production, there is also evidence for a mechanism blocked by Ru486a selective antagonist of the classical cytoplasmic
glucocorticoid receptorin the rapid actions of glucocorticoids in prefrontal cortex. Modified from ref. 32 with permission from Macmillan Publishers Ltd.

Review
Figure 5 Biphasic effect of glucocorticoids (Cort) a 160 Con b 180 Con c

in regulating mitochondrial function. (a) Cort 200 140 * Cort (100 nM) 160 *
Cort (1 M)
GR levels in mitochondria
*
GR levels in mitochondria
readily penetrate the cell membrane and interact 180
Nuclear GR (% of control)
120 140
with cytoplasmic glucocorticoid receptors (GRs), 160
(% of control)
(% of control)
140 120
100
causing a dose-dependent increase in GR 100
120
translocation into cell nuclei. Con, vehicle control. 80
100 80
(b) Translocation of GRs into mitochondria as a 80 60
60 *
complex with the anti-apoptotic protein Bcl-2, 60 40 40
where they upregulate mitochondrial calcium 40
20 20 20
levels, membrane potential and oxidation; this 0 0 0
is stabilized at a 100 nM dose of Cort (b) and Con Cort Cort 1.5 24 72 1.5 24 72
decreases with time at the high, 1 M Cort dose (c), (100 nM) (1 M)
Time (h) Time (h)
where, after a 3-d treatment, high Cort leads
to decreased abundance of GR and Bcl-2 in Con d e
mitochondria. (d,e) Cort modulates membrane 220 1 M 24 h
JC-1, red/green (% of control)

240
JC-1, red/green (% of control)

potential, measured by Janus-1 (JC-1) staining, 200 100 nm 220 72 h #
in a dose- and time-dependent manner. Time * #
200 **
180 **
course of JC-1 staining after Cort treatment shows *** 180 ***
160
sustained potential at 100 nM dose and loss ** * 160
140 140
of potential at 1 M dose (d); dose-dependent 120
120
curve for JC-1 staining after Cort treatment 100
100
shows that both low and high Cort maintain 80
potential at 24 h, but high Cort causes failure of 80 60
0 1 24 72 0 0.2 0.4 0.6 0.8 1.0 1.2
membrane potential at 72 h (e). This regulation of
Time (h) Dose (M)

mitochondrial function by Cort parallels
neuroprotection: that is, treatment with low doses of Cort has a neuroprotective effect, whereas high Cort enhances kainic acidinduced toxicity of cortical
neurons62,133, consistent with the glucocorticoid endangerment hypothesis134. Error bars, s.e.m.; *P 0.05, **P 0.01, ***P 0.001. Modified from
ref. 62 with permission from Macmillan Publishers Ltd.
The actions of glucocorticoids are biphasic, as illustrated above for signaling molecule as well as protease, is implicated in stress-induced
mitochondria62, and their timing is important. For example, in several dendritic remodeling and spine loss in medial amygdala as well as in
animal models of traumatic stressinduced PTSD-like delayed anxiety the CA1 hippocampus. Specifically, tPA-knockout mice fail to show
and traumatic stressinduced spine synapse formation in basolateral chronic stress impairment of memory and spine reduction in CA1
amygdala (BLA), a timed elevation of glucocorticoids, before the (refs. 73,75). Linking these two factors together, there is evidence that in
induction of stress, prevents development of the anxiety and synapse the amygdala tPA release is stimulated by CRF76. Similarly, lipocalin-2
formation67. Data on human PTSD supports a protective role for ade- is a novel modulator of spine plasticity with different effects in
quate glucocorticoid levels at time of traumatic stress68,69. Yet repeated amygdala and hippocampus77,78. Acute stress increases lipocalin-2
high-dose glucocorticoid treatment mimics chronic stress and induces levels, and lipocalin-2 downregulates mushroom spines and
dendritic lengthening in BLA70, a result that emphasizes the differ- generally inhibits actin motility in hippocampus. Remarkably, dele-
ences between acute and chronic elevations of glucocorticoids. tion of lipocalin-2 increases neuronal excitability and anxiety, and,
Regarding MRs, which exert both genomic actions and nongenomic in amygdala, the absence of lipocalin-2 increases the basal number of
actions to stimulate glutamate release48, mice that spontaneously spines and prevents a stress-induced increase in spine density.
show increased anxiety have elevated expression of hippocampal MR, Endocannabinoids are another class of signaling molecules
npg
which mediate a stress-induced suppression of mGlu2 expression that importantly regulate multiple aspects of the stress response.
and increased levels of anxiety- and depression-like behavior71. In addition to contributing to the termination79 of the acute response
Importantly, blocking MR receptors and interfering with glucocor- to stress, as well as habituation to repeated stress80, endocannabinoids
ticoid stimulation of glutamate activity blocks stress-induced mood also seem to be important for the regulation of structural plasticity
abnormalities. The nature of the experiences of the animals that under conditions of repeated stress (Box 1). For example, cannabi-
develop higher MR is not known, but it may involve epigenetic influ- noid 1 (CB1) receptordeficient mice exhibit reductions in prefron-
ences early in life, such as maternal care and stressors in the neo- tal cortical dendritic length and complexity, while having enhanced
natal nesting environment72. The epigenetic allostasis model points and more complex dendritic arbors within the BLA, both of which
to developmental origins of individual differences in the responses effects parallel the effects of chronic stress81,82. More importantly,
to stress and implies that unknown early life epigenetic influences chronic stress and corticosterone treatment are both known to impair
program each individual to different trajectories of behavioral and endocannabinoid signaling at multiple levels, through both a down-
physiological responses to later stressful life events (Fig. 6). regulation of the CB1 receptor83 and a reduction in the levels of the
endocannabinoid anandamide that is mediated by an increase in its
Involvement of secreted signaling molecules. In addition to glu- hydrolysis by the enzyme fatty acid amide hydrolase (FAAH)84,85.
cocorticoids, secreted signaling molecules have important roles in Given the parallels between genetic deletion of the CB1 receptor
the remodeling of neural tissue during stress (Box 1). Corticotropin- and the ability of chronic stress to impair endocannabinoid signaling,
releasing factor (CRF), which is better known for its role in governing it is interesting to note that elevation of anandamide via CB1 receptor
the secretion of adrenocorticotropic hormone (ACTH) and glucocor- signaling, through genetic or pharmacological impairment of FAAH,
ticoids, plays a key part in stress-induced dendritic remodeling in the retards the ability of chronic stress to produce dendritic hypertrophy in
CA1 region of the hippocampus73,74. Findings over the past decade the BLA as well as concomitant changes in emotional behavior8588,89.
have also implicated new players in the regulation of dendritic remod- Collectively, these data indicate that endocannabinoid signaling buff-
eling. For instance, tissue plasminogen activator (tPA), a secreted ers against many of the effects of stress and seems to be important for

review
Figure 6 Individual differences in naive C57Bl6 a c e

Epigenetic allostasis
mice in anxiety-related behavior reveal animals 2.5 Naive-LS Environmental-
more sensitive to stress-induced downregulation 6 min ** Naive-HS driven adaptation
mRNA/Gapdh mRNA
Light-dark test 2.0 LS HS
of hippocampal mGlu2 expression, a biomarker as screening Naive mice
of depressive-like behavior and antidepressant method for 1.5
mGlu2
response. (ac) The use of the light-dark test individual
differences 1.0
as a screening method (a) allows identification Sacrifice
15 min 0.5 Lack of
of clusters of animals with a different baseline
recovery resilience
anxiety profile (b) along with differences in 0
MR mGlu2
mineralocorticoid receptor gene (MR; Nr3c2) MR
Hippocampus
transcript levels in hippocampus (c). Error bars,
s.e.m.; **P 0.01, ***P 0.001. (d) The
susceptible (HS) mice, which are characterized
b d f
Naive-LS Ctrl
by higher baseline MR transcript levels, show 200 1.5
Naive-HS ARS-LS
reduced hippocampal mGlu2 (Grm2) transcript
mGlu2 mRNA/Gapdh
ARS-HS A
Time spent in the

LAC
light chamber (s)

150
expression associated with exacerbation of ** 1.0
Microtubules A
A
anxious and of depressive-like behaviors *
mRNA
100
after acute and chronic stress, respectively.
Conversely, individuals with lower baseline 0.5 **
50
MR transcript levels (low susceptible, LS) Nucleus
cope better with stress and show adaptation 0 0
in mGlu2 receptor expression in hippocampus. Hippocampus A A A
Ctrl, unstressed sex and age-matched control Acute stress down P300
animals; ARS, acute restraint stress. (e) The regulates mGlu2; blocked NF-B
by spironolactone Grm2
epigenetic allostasis model points to the A M A P M
H3K27ac
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-B 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 hyperarousal 7 d later in both sexes, consistent with prior findings in
these identified limbic circuits. At a mechanistic level, this is likely to the same as well as in another PTSD animal model67,68, confirming the
be due to the ability of CB1 receptor signaling to gate glutamatergic involvement of the GR in sequelae of traumatic stress.
release, as it has been demonstrated that CB1 receptordeficient mice
show greater changes in glutamatergic signaling and excitotoxicity Roles of brain-derived neurotrophic factor (BDNF). BDNF plays an
within the PFC following chronic stress90. Moreover, in a pattern important role in dendritic remodeling in both hippocampus and BLA
similar to the protective effects of CB1 receptor activation identified (Box 1). BDNF-overexpressing mice show increases dendritic length
within the amygdala, administration of a CB1 receptor agonist during in both CA3 and BLA, which occludes the effects of chronic stress in
repeated stress can reduce the increase in glutamatergic signaling, decreasing dendritic branching in CA3 and increasing it in BLA93. On
the induction of pro-inflammatory cytokines and lipid peroxidation the other hand, in WT animals, chronic stress causes a downregulation
npg
within the PFC90. Thus, the release of endocannabinoids during stress of BDNF in CA3 hippocampus and an upregulation of BDNF in the
may temper changes in structural plasticity by limiting the magnitude BLA. Although the increase in BLA persists beyond 21 d after the stress,
of glutamate release in response to stress; and under conditions of the effect in CA3 normalizes94. These intriguing timing issues become
chronic stress, when this system becomes compromised, the loss of even more interesting when one considers that after a single acute stress,
this endogenous buffer facilitates excess glutamate release and the BDNF expression in the BLA rises and stays elevated for 10 d, while that
ensuing changes in dendritic morphology. Linking this model with in CA3 shows only a transient increase94. This increase in the BLA is
the factors previously described, it is interesting to note that in addi- associated with both increased anxiety and increased density of spines
tion to promoting tPA release, CRF has also been found to induce in BLA neurons85. The mechanism of these effects on BDNF remain
anandamide hydrolysis by FAAH91, suggesting that CRF could act as enigmatic, but they are not entirely mediated by glucocorticoid actions
an orchestrator of multiple signaling molecules, all of which converge as corticosterone levels increase after both acute and chronic stress and
in structural changes within the brain following chronic stress. remained elevated after chronic, but not acute, stress. Thus, it is clear
Recent studies have suggested that blood-based biomarkers may be that BDNF-mediated signaling is involved in the structural effects of
able to predict aspects of brain signaling associated with trauma-related stress, but that the direction and nature of signaling is region specific
effects in both males and females, specifically with respect to conver- and stress specific and is influenced by epigenetic modifications89 along
gence onto GR signaling pathways. After a predator-scent-stress (PSS) with post-translational modifications94,95. The epigenetic mechanisms
exposure, male and female rats were classified into vulnerable (PTSD- controlling BDNF expression are influenced by maternal separation
like) and resilient (minimally affected) phenotypes on the basis of early in life, which, in turn, leads to changes in BDNF expression and
their performance on a variety of behavioral measures92. Genome-wide epigenetic regulation via histone acetylation and methylation over the
expression profiling in blood, amygdala and hippocampus indicated life course, with consequences for anxiety-like behaviors96.
that glucocorticoid signaling was the only convergent pathway asso-
ciated with individual differences in susceptibility. Moreover, corti- Cellular processes in remodeling of neural architecture. The neu-
costerone treatment 1 h after PSS exposure prevented anxiety and ronal surface, cytoskeleton and nuclear envelope are each implicated

Review
a b c of dendrites is accompanied by increases in a soluble phosphor-

Overall apical Apical intersections ylated form of tau that may indicate disruption of the cytoskeleton,
Number of intersections
dendrite length 8 Control Disrupted
1,400
which permits the dendrite shortening and possible protection
1,200 6 * *
Length (m)
1,000 from excitotoxicity; at the same time, PSA-NCAM expression is lost
* 4
800 during hibernation torpor, reducing the capacity for plasticity106.
2
600
0
This model highlights the important role that tau plays in normal
400
Control Disrupted cytoskeletal function, a fact that should be emphasized when attempt-
0
30
60
120
150
180
210
240
270
0
9
Distance from soma (m) ing to understand its role in pathology107.
Figure 7 Mice cannot adjust to a 10 h light/10 h dark cycle, as indicated
Even though dendrite retraction and regrowth would appear to
by body temperature and locomotor activity rhythms. This circadian involve a reversible depolymerization and repolymerization of the
disruption, as in humans performing shift work, leads to increase body cytoskeleton, there are other processes that point to the importance
fat and leptin and insulin resistance, along with remodeling of apical of nuclear factors. A recent example is the unexpected role of a cell
dendrites of prefrontal cortical neurons and indications of cognitive rigidity. nuclear pore complex protein, NUP-62, in stress-induced dendritic
(ac) Shown are a representive neuron (a), overall dendritic length (b) remodeling in the CA3 region of the hippocampus108. First identified
and a Sholl analysis (c). Error bars, s.e.m. Data from ref. 123.
as the product of a gene whose expression was downregulated in the
prefrontal cortex of depressed patients109, NUP-62 was also found to
in the mechanisms of stress-induced retraction and expansion of den- be reduced in response to chronic stress in CA3 neurons of rodents108.
drites and synapse turnover. The polysialylated form of neural cell Importantly, the levels of other nuclear pore complex genes were
adhesion molecule (PSA-NCAM) is expressed in the CA3 and DG unchanged with chronic stress, supporting the specificity of its role
regions of the hippocampus and is believed to denote the capacity for in stress remodeling. Subsequent in vitro studies confirmed that the
adaptive structural plasticity in many parts of the CNS9799. Repeated downregulation of NUP-62 is associated with dendritic retraction and
stress causes retraction of CA3 hippocampal dendrites accompanied that this effect is regulated at the molecular level by NUP-62 phosphor-
by a modest increase in PSA-NCAM expression, possibly as the ylation at a PYK2 site which results in its retention in the cytoplasm108.
result of glucocorticoid mediation 100. Using endoneuraminidase A role of NUP-62 in maintaining chromatin structure for transcription
N (EndoN) to remove PSA from NCAM, Sandi reported impairment is suggested as well as in nucleocytoplasmic transport108.
of consolidation of contextual fear conditioning101. Using the same
treatment, we observed considerable expansion of the dendritic tree Stress: not always what one thinks it is
in both CA3 and CA1 and a marked increase in excitotoxicity and Just as stress is not a unitary phenomenon at the cell and circuit level,
damage to CA3 neurons; repeated stress still caused some dendrite neither is it one at the level of the whole organism. As noted in the
retraction after PSA removal58. Thus, although PSA-NCAM is a introduction, a key aspect of stress effects on the brain and body is
facilitator of plasticity, the PSA moiety appears to also limit the the nonlinear interaction of multiple mediators of stress and adapta-
extent of dendritic growth and yet is not necessary for dendritic tion that is part of the concept of allostasis1, which refers to the active
retraction under stress. process of maintaining homeostasis through the output of hormones
Two other classes of cell adhesion molecules are reported to change and ANS activity along with immune and metabolic system media-
with chronic stress, with behavioral consequences. Neuroligins tors and the mediators in the brain that are the main focus of this
(NLGNs) are important for proper synaptic formation and function- review. When one mediator system changes, the others adjust, and
ing and are critical regulators of the balance between neural excitation the resulting output can be distorted, as in chronic inflammation or
and inhibition (E/I), and chronic restraint stress reduces hippocampal a flat cortisol diurnal rhythm caused by sleep deprivation or depres-
NLGN-2 levels, in association with reduced sociability and increased sion2. Moreover, the actions of any one mediator may depend on
npg
aggression102,103. This occurred along with a reduction of NLGN-2 the actions of other mediators. For example, glucocorticoids and
expression throughout the hippocampus, detectable in different layers excitatory amino acids are both involved in stress-induced suppression
of the CA1, CA3 and DG subfields. Intrahippocampal administration of neurogenesis, which has been found not only in rodents but also in
of neurolide-2, which interferes with the interaction between NLGN-2 tree shrews and rhesus monkeys110112. Yet, glucocorticoid levels alone
and neurexin, led to reduced sociability and increased aggression, do not predict the direction of neurogenesis, as shown by studies of
thus mimicking effects of chronic stress102. male sexual behavior, which results in increased neurogenesis but also
Chronic restraint stress also increases activity of matrix metallopro- high glucocorticoid levels; in this scenario oxytocin appears to play
teinase-9 (MMP-9) in the CA1. MMP-9 carries out proteolytic process- an important role, emphasizing the importance of understanding the
ing of another cell adhesion molecule, nectin-3. Chronic stress reduced interaction of these distinct signaling molecules113,114.
nectin-3 in the perisynaptic CA1, but not in the CA3, with conse- In seeking to understand where and how stress affects neural cir-
quences for social exploration and social recognition and for a CA1- cuits, it has become evident that when these mediators act is also an
dependent cognitive task. Implicated in this is a stress-related increase important consideration. In most vertebrate species, plasma glucocor-
in extracellular glutamate and NMDA receptor mediation of MMP-9 ticoids rise just before the active phase. This rhythm is largely driven
(ref. 104). These findings are reminiscent of the CA1-specific effects of by changes in the amplitude and frequency of the ultradian secretion of
tPA in mediating stress effects on spine density in CA1 (ref. 73). glucocorticoids115. Indeed, the natural ultradian fluctuations of gluco-
Actin polymerization plays a key role in filopodial extension and corticoids mediate turnover of a subset of synapses in cerebral cortex;
spine synapse formation as well as in plasticity within the synapse and inhibiting the fluctuations with a minimal dose of dexamethasone
itself105, and cytoskeletal remodeling is an important factor in the impairs spine turnover116. Moreover, these diurnal changes in spine
effects of stress and other environmental manipulations. Hibernation formation and removal are important for motor learning117.
in European hamsters and ground squirrels results in rapid retraction In addition to ultradian pulses, circadian (or diurnal) rhythms
of dendrites of CA3 pyramidal neurons, and an equally rapid expan- are a crucial factor that impact the stress response. Rhythmic
sion occurs when hibernation torpor is reversed56,57. The retraction HPA function seems to be necessary for the normal initiation and

review
termination of the stress response of ACTH, cortisol and other medi- agents, that open up windows of plasticity in the brain and facilitate
ators118. Epidemiologically, disrupted sleep and circadian rhythms the efficacy of the behavioral interventions5,130,131. To that extent,
lead to increased risk for development of psychiatric, cardiovascular meeting the demands imposed by stressful experiences through vari-
or other physiological syndromes in shift workers or populations ous coping resources can lead to growth, adaptation and learning to
undergoing chronic circadian disruption119. Housing mice in a light- promote resilience and improved mental health128,132.
dark cycle of 20 h (10 h light/10 h dark), rather than standard 24-h
Acknowledgments
cycles, to drive circadian disruption results in metabolic signs of
The McEwen laboratory acknowledges research support from US National
allostatic load120, with increased weight, adiposity and leptin levels, Institutes of Health (R01 MH41256), and the Hope for Depression Research
as well as an imbalance between insulin and plasma glucose suggest- Network and the American Foundation for Suicide Prevention to C.N. and
ing a pre-diabetic state 121. The metabolic changes are accompanied National Research Service Award F32 MH102065 to J.D.G.
by changes in PFC cellular morphology, mirroring those observed in
COMPETING FINANCIAL INTERESTS
chronic stress122, with circadian-disrupted animals having shrunken The authors declare no competing financial interests.
and less complex apical dendritic trees of cells in layer II/III of the
medial PFC123 (Fig. 7). In addition, circadian-disrupted mice show Reprints and permissions information is available online at http://www.nature.com/
altered responses to endotoxin challenge with lipopolysaccharide124, reprints/index.html.
highlighting the similarities between chronic circadian disrup-
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focus on stress

Mechanisms of stress in the brain

nature neuroscience VOLUME 18 | NUMBER 10 | OCTOBER 2015 1353

Box 1 Examples of molecules that are necessary or permissive for remodeling

likely through the regulation of glutamatergic transmission

Synaptic functions: suppression of

1354 VOLUME 18 | NUMBER 10 | OCTOBER 2015 nature neuroscience

Marina Corral Spence/Nature Publishing Group

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Figure 2 Gene expression changes in hippocampus in response to stress

438 367 312

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Figure 3 Molecular epigenetic modifications. Among the molecular

Figure 4 Glucocorticoids are released from the

with different affinities, to glucocorticoid and Glucocorticoid Postsynaptic

membrane-bound form and nuclear form.

nature neuroscience VOLUME 18 | NUMBER 10 | OCTOBER 2015 1357

Figure 5 Biphasic effect of glucocorticoids (Cort) a 160 Con b 180 Con c

JC-1, red/green (% of control)

JC-1, red/green (% of control)

Time (h) Dose (M)

1358 VOLUME 18 | NUMBER 10 | OCTOBER 2015 nature neuroscience

Figure 6 Individual differences in naive C57Bl6 a c e

Time spent in the

light chamber (s)

nature neuroscience VOLUME 18 | NUMBER 10 | OCTOBER 2015 1359

a b c of dendrites is accompanied by increases in a soluble phosphor-

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DNA methylation: life at the interface between a dynamic environment and a

nature neuroscience VOLUME 18 | NUMBER 10 | OCTOBER 2015 1361

1362 VOLUME 18 | NUMBER 10 | OCTOBER 2015 nature neuroscience

form of regulated plasticity at excitatory synapses. Hippocampus 10, 555560 (1998).

nature neuroscience VOLUME 18 | NUMBER 10 | OCTOBER 2015 1363

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