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Mechanisms of stress in the brain

October 2015
Nature Neuroscience 18(10):1354

DOI:10.1038/nn.4086

Authors:

Bruce S Mcewen

The Rockefeller University

Nicole Bowles

The Rockefeller University

Jason Gray

The Rockefeller University

Matthew N Hill

The University of Calgary

Show all 7 authorsHide

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.

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. (a–c) Shown are a representive neuron (a), overall dendritic length (b) and a Sholl analysis (c). Error bars, s.e.m. Data from ref. 123.

…

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nature neuroscience VOLUME 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. (mcewen@rockefeller.edu).

Received 19 April; accepted 8 July; published online 25 September 2015;

doi:10.1038/nn.4086

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

1354 VOLUME 18 | NUMBER 10 | OCTOBER 2015 nature neuroscience

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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

Lipocalin-2

• Secreted protein of previously unknown function77,78

• Induced by acute stress

• Downregulates mushroom spines

• Knockout increases neuronal excitability and anxiety

Endocannabinoids136–138

• 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

glutamate

• Free radicals and

inflammation

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

Timeline

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.

nature neuroscience VOLUME 18 | NUMBER 10 | OCTOBER 2015 1355

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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

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.

Marina Corral Spence/Nature Publishing Group

Amygdala

Prefrontal cortex

Hippocampus

1356 VOLUME 18 | NUMBER 10 | OCTOBER 2015 nature neuroscience

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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.

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 genome’37–39. 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

Ctnnb1

Neurod2

Traf6

Dusp4

Egfr

Slc1a2

Eif5a

Scn1b

Nrg3

Ephb2

Traf4

Cdc34

Hdac8

Kcna1

Per2

Cort

Dcx

II1a

Wnt7b

Ank3

Cdk2

Gria2

Cart

Camk2d

Grin2a

Fgfr1

5,000 Increased

Decreased

3,618 2,905

10,6823,608

Rec

CRS

3,000

1,000

0.4

0.2

–0.2

–0.2 0 0.2 0.4

–0.4

FST

432

713

271

392

433

369

300

555

890

2502

367 312

428

324

438

314

CRS

CRS + FST

Rec CRS

Rec + FST

Control + GCs

unique (267)

Voltage-gated cation activity

Immune response

Signal transduction activity

Nuclear import

Development

G-protein coupled receptor activity

Transcription

Common (258)

CRS + GCs

unique (318)

Cort

90 36

299

327

FST

Cort

CRS

CRS +

FSTRec

Rec +

FST

No. of genes

nature neuroscience VOLUME 18 | NUMBER 10 | OCTOBER 2015 1357

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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,

phosphorylation,

methylation DNA methylation

miRNA

piRNA

IncRNA

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

effect

Endocannabinoid

production

Marina Corral Spence/Nature Publishing Group

–

Mineralocorticoid

receptor

NMDA

receptor

AMPA

receptor

Glucocorticoid

receptor

Postsynaptic

neuron

Presynaptic

neuron

CB1

Vesicle

Membrane

glucocorticoid

receptor

Nucleus

Second

messengers

Mitochondrion

Glucocorticoids

Glutamate

Nongenomic

effect

Indirect

genomic effect

1358 VOLUME 18 | NUMBER 10 | OCTOBER 2015 nature neuroscience

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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, ***P ≤ 0.001. 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)

200

220

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

***

180

160

140

120

100

200

220

240

180

160

140

120

100

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)

160

180

140

120

100

Con 1.5 24 72

Time (h)

1.5 24 72

Time (h)

Cort

(100 nM)

Cort

(1 µM)

1 µM

Con

100 nm

200

180

160

140

120

100

160

140

120

100

Con

Cort (100 nM)

Con

Cort (1 µM)

***

a b c

d e

nature neuroscience VOLUME 18 | NUMBER 10 | OCTOBER 2015 1359

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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. (a–c) 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.; **P ≤ 0.01, ***P ≤ 0.001. (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

APM

Light-dark test

as screening

method for

individual

differences

6 min

Naive mice

15 min

recovery

Sacrifice

Time spent in the

light chamber (s)

mRNA/Gapdh mRNA

mGlu2 mRNA/Gapdh

mRNA

Naive-LS

Naive-HS

200

150

100

ARS-LS

Ctrl

ARS-HS

1.5

1.0

0.5

Naive-LS

Naive-HS

2.5

2.0

1.5

1.0

0.5

MR mGlu2

Hippocampus

Acute stress down

regulates mGlu2; blocked

by spironolactone

Epigenetic allostasis

mGlu2

Environmental-

driven adaptation

Lack of

resilience

LS HS

Microtubules LAC

Nucleus

NF-κB

P300

Grm2

H3K27ac

1360 VOLUME 18 | NUMBER 10 | OCTOBER 2015 nature neuroscience

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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

1,400

1,200

1,000

800

600

400

Control Disrupted

Length (µm)

Overall apical

dendrite length

b c

120

150

180

210

240

270

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.

(a–c) Shown are a representive neuron (a), overall dendritic length (b)

and a Sholl analysis (c). Error bars, s.e.m. Data from ref. 123.

nature neuroscience VOLUME 18 | NUMBER 10 | OCTOBER 2015 1361

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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.

ACKNOWLEDGMENTS

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.

COMPETING FINANCIAL INTERESTS

The authors declare no competing financial interests.

Reprints and permissions information is available online at http://www.nature.com/

reprints/index.html.

1. McEwen, B.S. Protective and damaging effects of stress mediators. N. Engl. J.

Med. 338, 171–179 (1998).

2. McEwen, B.S. Protective and damaging effects of stress mediators: central role

of the brain. Dialogues Clin. Neurosci. 8, 367–381 (2006).

3. McEwen, B.S. & Wingﬁeld, J.C. The concept of allostasis in biology and

biomedicine. Horm. Behav. 43, 2–15 (2003).

4. Shonkoff, J.P., Boyce, W.T. & McEwen, B.S. Neuroscience, molecular biology, and

the childhood roots of health disparities. J. Am. Med. Assoc. 301, 2252–2259

(2009).

5. McEwen, B.S. Brain on stress: how the social environment gets under the skin.

Proc. Natl. Acad. Sci. USA 109 (suppl. 2): 17180–17185 (2012).

6. Halfon, N., Larson, K., Lu, M., Tullis, E. & Russ, S. Lifecourse health development:

past, present and future. Matern. Child Health J. 18, 344–365 (2014).

7. Felitti, V.J. et al. Relationship of childhood abuse and household dysfunction to

many of the leading causes of death in adults. The Adverse Childhood Experiences

(ACE) Study. Am. J. Prev. Med. 14, 245–258 (1998).

8. Tost, H., Champagne, F.A & Meyer-Lindenberg, A. Environmental inﬂuence in the

brain, human welfare and mental health. Nat. Neurosci. 18, 1421–1431 (2015).

9. McEwen, B.S. Stress and hippocampal plasticity. Annu. Rev. Neurosci. 22,

105–122 (1999).

10. McEwen, B.S. & Chattarji, S. in Handbook of Neurochemistry and Molecular

Neurobiology (A. Lajtha & G. Baker, eds.) 572–593 (Springer-Verlag, 2007).

11. Cameron, H.A. & Gould, E. in Receptor Dynamics in Neural Development

Pharmacology and Toxicology: Basic and Clinical Aspects (ed. C.A. Shaw)

141–157 (CRC Press, 1996).

12. McEwen, B.S. Physiology and neurobiology of stress and adaptation: central role

of the brain. Physiol. Rev. 87, 873–904 (2007).

13. McEwen, B.S. Stress, sex, and neural adaptation to a changing environment:

mechanisms of neuronal remodeling. Ann. NY Acad. Sci. 1204 (suppl.): E38–E59

(2010).

14. Meaney, M.J. & Szyf, M. Environmental programming of stress responses through

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

ﬁxed genome. Dialogues Clin. Neurosci. 7, 103–123 (2005).

15. Hunter, R.G., Gagnidze, K., McEwen, B.S. & Pfaff, D.W. Stress and the dynamic

genome: steroids, epigenetics, and the transposome. Proc. Natl. Acad. Sci. USA

112, 6828–6833 (2015).

16. McEwen, B.S., Weiss, J. & Schwartz, L. Selective retention of corticosterone by

limbic structures in rat brain. Nature 220, 911–912 (1968).

17. Rubin, T.G., Gray, J.D. & McEwen, B.S. Experience and the ever-changing brain:

what the transcriptome can reveal. BioEssays 36, 1072–1081 (2014).

18. Gray, J.D., Rubin, T.G., Hunter, R.G. & McEwen, B.S. Hippocampal gene

expression changes underlying stress sensitization and recovery. Mol. Psychiatry

19, 1171–1178 (2014).

19. Wang, K. et al. Transcriptome proﬁling analysis reveals region-distinctive changes

of gene expression in the CNS in response to different moderate restraint stress.

J. Neurochem. 113, 1436–1446 (2010).

20. Datson, N.A. et al. Previous history of chronic stress changes the transcriptional

response to glucocorticoid challenge in the dentate gyrus region of the male rat

hippocampus. Endocrinology 154, 3261–3272 (2013).

21. de Kloet, E.R., Fitzsimons, C.P., Datson, N.A., Meijer, O.C. & Vreugdenhil, E.

Glucocorticoid signaling and stress-related limbic susceptibility pathway: about

receptors, transcription machinery and microRNA. Brain Res. 1293, 129–141

(2009).

22. Goldwater, D.S. et al. Structural and functional alterations to rat medial prefrontal

cortex following chronic restraint stress and recovery. Neuroscience 164, 798–808

(2009).

23. Hunter, R.G. & McEwen, B.S. Stress and anxiety across the lifespan: structural

plasticity and epigenetic regulation. Epigenomics 5, 177–194 (2013).

24. Grifﬁths, B.B. & Hunter, R.G. Neuroepigenetics of stress. Neuroscience 275,

420–435 (2014).

25. Reul, J.M. Making memories of stressful events: a journey along epigenetic, gene

transcription, and signaling pathways. Frontiers Psychiatry 5, 5 (2014).

1362 VOLUME 18 | NUMBER 10 | OCTOBER 2015 nature neuroscience

review

26. Tsankova, N.M. et al. Sustained hippocampal chromatin regulation in a mouse model

of depression and antidepressant action. Nat. Neurosci. 9, 519–525 (2006).

27. Reul, J.M.H.M. & Chandramohan, Y. Epigenetic mechanisms in stress-related

memory formation. Psychoneuroendocrinology 32, S21–S25 (2007).

28. Heller, E.A. et al. Locus-speciﬁc epigenetic remodeling controls addiction- and

depression-related behaviors. Nat. Neurosci. 17, 1720–1727 (2014).

29. Nasca, C. et al. l-Acetylcarnitine causes rapid antidepressant effects through the

epigenetic induction of mGlu2 receptors. Proc. Natl. Acad. Sci. USA 110,

4804–4809 (2013).

30. Dyrvig, M., Gotzsche, C.R., Woldbye, D.P. & Lichota, J. Epigenetic regulation of

Dnmt3a and Arc gene expression after electroconvulsive stimulation in the rat.

Mol. Cell Neurosci. 67, 137–143 (2015).

31. Hunter, R.G., McCarthy, K.J., Milne, T.A., Pfaff, D.W. & McEwen, B.S. Regulation

of hippocampal H3 histone methylation by acute and chronic stress. Proc. Natl.

Acad. Sci. USA 106, 20912–20917 (2009).

32. Popoli, M., Yan, Z., McEwen, B.S. & Sanacora, G. The stressed synapse: the

impact of stress and glucocorticoids on glutamate transmission. Nat. Rev.

Neurosci. 13, 22–37 (2012).

33. Monteggia, L.M. & Zarate, C. Jr. Antidepressant actions of ketamine: from

molecular mechanisms to clinical practice. Curr. Opin. Neurobiol. 30, 139–143

(2015).

34. Erwin, J.A., Marchetto, M.C. & Gage, F.H. Mobile DNA elements in the generation

of diversity and complexity in the brain. Nat. Rev. Neurosci. 15, 497–506

(2014).

35. Reilly, M.T., Faulkner, G.J., Dubnau, J., Ponomarev, I. & Gage, F.H. The role of

transposable elements in health and diseases of the central nervous system.

J. Neurosci. 33, 17577–17586 (2013).

36. Hunter, R.G., McEwen, B.S. & Pfaff, D.W. Environmental stress and transposon

transcription in the mammalian brain. Mob. Genet. Elements 3, e24555 (2013).

37. Khalil, A.M. et al. Many human large intergenic noncoding RNAs associate with

chromatin-modifying complexes and affect gene expression. Proc. Natl. Acad. Sci.

USA 106, 11667–11672 (2009).

38. Johnson, R. & Guigo, R. The RIDL hypothesis: transposable elements as functional

domains of long noncoding RNAs. RNA 20, 959–976 (2014).

39. Kelley, D. & Rinn, J. Transposable elements reveal a stem cell-speciﬁc class of

long noncoding RNAs. Genome Biol. 13, R107 (2012).

40. Khalil, A.M. & Rinn, J.L. RNA-protein interactions in human health and disease.

Semin. Cell Dev. Biol. 22, 359–365 (2011).

41. Pauli, A., Rinn, J.L. & Schier, A.F. Non-coding RNAs as regulators of embryogenesis.

Nat. Rev. Genet. 12, 136–149 (2011).

42. McClintock, B. Chromosome organization and genic expression. Cold Spring Harb.

Symp. Quant. Biol. 16, 13–47 (1951).

43. McClintock, B. The signiﬁcance of responses of the genome to challenge. Science

226, 792–801 (1984).

44. Rusiecki, J.A. et al. DNA methylation in repetitive elements and post-traumatic

stress disorder: a case-control study of US military service members. Epigenomics

4, 29–40 (2012).

45. Ponomarev, I., Rau, V., Eger, E.I., Harris, R.A. & Fanselow, M.S. Amygdala

transcriptome and cellular mechanisms underlying stress-enhanced fear learning

in a rat model of posttraumatic stress disorder. Neuropsychopharmacology 35,

1402–1411 (2010).

46. Ponomarev, I., Wang, S., Zhang, L., Harris, R.A. & Mayﬁeld, R.D. Gene

coexpression networks in human brain identify epigenetic modiﬁcations in alcohol

dependence. J. Neurosci. 32, 1884–1897 (2012).

47. Lowy, M.T., Gault, L. & Yamamoto, B.K. Adrenalectomy attenuates stress-induced

elevations in extracellular glutamate concentrations in the hippocampus.

J. Neurochem. 61, 1957–1960 (1993).

48. Karst, H. et al. Mineralocorticoid receptors are indispensable for nongenomic

modulation of hippocampal glutamate transmission by corticosterone. Proc. Natl.

Acad. Sci. USA 102, 19204–19207 (2005).

49. Treccani, G. et al. Stress and corticosterone increase the readily releasable pool

of glutamate vesicles in synaptic terminals of prefrontal and frontal cortex.

Mol. Psychiatry 19, 433–443 (2014).

50. Magariños, A.M. & McEwen, B.S. Stress-induced atrophy of apical dendrites of

hippocampal CA3c neurons: involvement of glucocorticoid secretion and excitatory

amino acid receptors. Neuroscience 69, 89–98 (1995).

51. Watanabe, Y., Gould, E. & McEwen, B.S. Stress induces atrophy of apical dendrites

of hippocampus CA3 pyramidal neurons. Brain Res. 588, 341–345 (1992).

52. Martin, K.P. & Wellman, C.L. NMDA receptor blockade alters stress-induced

dendritic remodeling in medial prefrontal cortex. Cereb. Cortex 21, 2366–2373

(2011).

53. Sapolsky, R.M., Krey, L.C. & McEwen, B.S. The neuroendocrinology of stress and

aging: the glucocorticoid cascade hypothesis. Endocr. Rev. 7, 284–301

(1986).

54. Lisman, J.E. Relating hippocampal circuitry to function: recall of memory

sequences by reciprocal dentate-CA3 interactions. Neuron 22, 233–242

(1999).

55. McEwen, B.S. Stress and hippocampal plasticity. Annu. Rev. Neurosci. 22,

105–122 (1999).

56. Magariños, A.M., McEwen, B.S., Saboureau, M. & Pevet, P. Rapid and reversible

changes in intrahippocampal connectivity during the course of hibernation in

European hamsters. Proc. Natl. Acad. Sci. USA 103, 18775–18780 (2006).

57. Popov, V.I., Bocharova, L.S. & Bragin, A.G. Repeated changes of dendritic

morphology in the hippocampus of ground squirrels in the course of hibernation.

Neuroscience 48, 45–51 (1992).

58. McCall, T. et al. Depletion of polysialic acid from neural cell adhesion molecule

(PSA-NCAM) increases CA3 dendritic arborization and increases vulnerability to

excitotoxicity. Exp. Neurol. 241, 5–12 (2013).

59. Joëls, M. Corticosteroid effects in the brain: U-shape it. Trends Pharmacol. Sci.

27, 244–250 (2006).

60. Revollo, J.R. & Cidlowski, J.A. Mechanisms generating diversity in glucocorticoid

receptor signaling. Ann. NY Acad. Sci. 1179, 167–178 (2009).

61. Hill, M.N. & McEwen, B.S. Involvement of the endocannabinoid system in the

neurobehavioural effects of stress and glucocorticoids. Prog. Neuropsychopharmacol.

Biol. Psychiatry 34, 791–797 (2010).

62. Du, J. et al. Dynamic regulation of mitochondrial function by glucocorticoids.

Proc. Natl. Acad. Sci. USA 106, 3543–3548 (2009).

63. Wei, Q. et al. Glucocorticoid receptor overexpression in forebrain: a mouse model

of increased emotional lability. Proc. Natl. Acad. Sci. USA 101, 11851–11856

(2004).

64. Jacobson, L. Forebrain glucocorticoid receptor gene deletion attenuates behavioral

changes and antidepressant responsiveness during chronic stress. Brain Res.

1583, 109–121 (2014).

65. Szyf, M., Weaver, I.C.G., Champagne, F.A., Diorio, J. & Meaney, M.J. Maternal

programming of steroid receptor expression and phenotype through DNA

methylation in the rat. Front. Neuroendocrinol. 26, 139–162 (2005).

66. McGowan, P.O. et al. Epigenetic regulation of the glucocorticoid receptor in human

brain associates with childhood abuse. Nat. Neurosci. 12, 342–348 (2009).

67. Rao, R.P., Anilkumar, S., McEwen, B.S. & Chattarji, S. Glucocorticoids protect

against the delayed behavioral and cellular effects of acute stress on the amygdala.

Biol. Psychiatry 72, 466–475 (2012).

68. Zohar, J. et al. High dose hydrocortisone immediately after trauma may alter the

trajectory of PTSD: interplay between clinical and animal studies. Eur.

Neuropsychopharmacol. 21, 796–809 (2011).

69. Schelling, G., Roozendaal, B. & De Quervain, D.J.-F. Can posttraumatic stress

disorder be prevented with glucocorticoids? Ann. NY Acad. Sci. 1032, 158–166

(2004).

70. Mitra, R. & Sapolsky, R.M. Acute corticosterone treatment is sufﬁcient to induce

anxiety and amygdaloid dendritic hypertrophy. Proc. Natl. Acad. Sci. USA 105,

5573–5578 (2008).

71. Nasca, C., Bigio, B., Zelli, D., Nicoletti, F. & McEwen, B.S. Mind the gap:

glucocorticoids modulate hippocampal glutamate tone underlying individual

differences in stress susceptibility. Mol. Psychiatry 20, 755–763 (2015).

72. Francis, D., Diorio, J., Liu, D. & Meaney, M.J. Nongenomic transmission across

generations of maternal behavior and stress responses in the rat. Science 286,

1155–1158 (1999).

73. Pawlak, R. et al. Tissue plasminogen activator and plasminogen mediate stress-

induced decline of neuronal and cognitive functions in the mouse hippocampus.

Proc. Natl. Acad. Sci. USA 102, 18201–18206 (2005).

74. Chen, Y., Fenoglio, K.A., Dube, C.M., Grigoriadis, D.E. & Baram, T.Z. Cellular

and molecular mechanisms of hippocampal activation by acute stress are age-

dependent. Mol. Psychiatry 11, 992–1002 (2006).

75. Bennur, S. et al. Stress-induced spine loss in the medial amygdala is mediated

by tissue-plasminogen activator. Neuroscience 144, 8–16 (2007).

76. Matys, T. et al. Tissue plasminogen activator promotes the effects of corticotropin

releasing factor on the amygdala and anxiety-like behavior. Proc. Natl. Acad. Sci.

USA 101, 16345–16350 (2004).

77. Mucha, M. et al. Lipocalin-2 controls neuronal excitability and anxiety by

regulating dendritic spine formation and maturation. Proc. Natl. Acad. Sci. USA

108, 18436–18441 (2011).

78. Skrzypiec, A.E. et al. Stress-induced lipocalin-2 controls dendritic spine formation

and neuronal activity in the amygdala. PLoS ONE 8, e61046 (2013).

79. Hill, M.N. et al. Recruitment of prefrontal cortical endocannabinoid signaling by

glucocorticoids contributes to termination of the stress response. J. Neurosci. 31,

10506–10515 (2011).

80. Hill, M.N. et al. Endogenous cannabinoid signaling is essential for stress

adaptation. Proc. Natl. Acad. Sci. USA 107, 9406–9411 (2010).

81. Hill, M.N., Hillard, C.J. & McEwen, B.S. Alterations in corticolimbic dendritic

morphology and emotional behavior in cannabinoid CB1 receptor-deﬁcient mice

parallel the effects of chronic stress. Cereb. Cortex 21, 2056–2064 (2011).

82. Lee, T.T., Filipski, S.B., Hill, M.N. & McEwen, B.S. Morphological and behavioral

evidence for impaired prefrontal cortical function in female CB1 receptor deﬁcient

mice. Behav. Brain Res. 271, 106–110 (2014).

83. Hill, M.N. et al. Downregulation of endocannabinoid signaling in the hippocampus

following chronic unpredictable stress. Neuropsychopharmacology 30, 508–515

(2005).

84. Bowles, N.P. et al. Chronic, noninvasive glucocorticoid administration suppresses

limbic endocannabinoid signaling in mice. Neuroscience 204, 83–89 (2012).

85. Mitra, R., Jadhav, S., McEwen, B.S., Vyas, A. & Chattarji, S. Stress duration

modulates the spatiotemporal patterns of spine formation in the basolateral

amygdala. Proc. Natl. Acad. Sci. USA 102, 9371–9376 (2005).

86. Lomazzo, E. et al. Therapeutic potential of inhibitors of endocannabinoid

degradation for the treatment of stress-related hyperalgesia in an animal model

of chronic pain. Neuropsychopharmacology 40, 488–501 (2015).

nature neuroscience VOLUME 18 | NUMBER 10 | OCTOBER 2015 1363

review

87. Bortolato, M. et al. Antidepressant-like activity of the fatty acid amide hydrolase

inhibitor URB597 in a rat model of chronic mild stress. Biol. Psychiatry 62,

1103–1110 (2007).

88. Rossi, S. et al. Preservation of striatal cannabinoid CB1 receptor function

correlates with the antianxiety effects of fatty acid amide hydrolase inhibition.

Mol. Pharmacol. 78, 260–268 (2010).

89. Tsankova, N., Renthal, W., Kumar, A. & Nestler, E.J. Epigenetic regulation in

psychiatric disorders. Nat. Rev. Neurosci. 8, 355–367 (2007).

90. Zoppi, S. et al. Regulatory role of cannabinoid receptor 1 in stress-induced

excitotoxicity and neuroinﬂammation. Neuropsychopharmacology 36, 805–818

(2011).

91. Gray, J.M. et al. Corticotropin-releasing hormone drives anandamide hydrolysis in

the amygdala to promote anxiety. J. Neurosci. 35, 3879–3892 (2015).

92. Daskalakis, N.P., Cohen, H., Cai, G., Buxbaum, J.D. & Yehuda, R. Expression

proﬁling associates blood and brain glucocorticoid receptor signaling with trauma-

related individual differences in both sexes. Proc. Natl. Acad. Sci. USA 111,

13529–13534 (2014).

93. Govindarajan, A. et al. Transgenic brain-derived neurotrophic factor expression

causes both anxiogenic and antidepressant effects. Proc. Natl. Acad. Sci. USA

103, 13208–13213 (2006).

94. Lakshminarasimhan, H. & Chattarji, S. Stress leads to contrasting effects on the

levels of brain derived neurotrophic factor in the hippocampus and amygdala.

PLoS ONE 7, e30481 (2012).

95. Gray, J.D., Milner, T.A. & McEwen, B.S. Dynamic plasticity: the role of

glucocorticoids, brain-derived neurotrophic factor and other trophic factors.

Neuroscience 239, 214–227 (2013).

96. Suri, D. et al. Early stress evokes age-dependent biphasic changes in hippocampal

neurogenesis, BDNF expression, and cognition. Biol. Psychiatry 73, 658–666

(2013).

97. Seki, T. & Arai, Y. Different polysialic acid-neural cell adhesion molecule expression

patterns in distinct types of mossy ﬁber boutons in the adult hippocampus.

J. Comp. Neurol. 410, 115–125 (1999).

98. Rutishauser, U. Polysialic acid in the plasticity of the developing and adult

vertebrate nervous system. Nat. Rev. Neurosci. 9, 26–35 (2008).

99. Theodosis, D.T., Bonhomme, R., Vitiello, S., Rougon, G. & Poulain, D.A.

Cell surface expression of polysialic acid on NCAM is a prerequisite for

activity-dependent morphological neuronal and glial plasticity. J. Neurosci. 19,

10228–10236 (1999).

100. Pham, K., Nacher, J., Hof, P.R. & McEwen, B.S. Repeated restraint stress

suppresses neurogenesis and induces biphasic PSA-NCAM expression in the adult

rat dentate gyrus. Eur. J. Neurosci. 17, 879–886 (2003).

101. Sandi, C. Stress, cognitive impairment and cell adhesion molecules. Nat. Rev.

Neurosci. 5, 917–930 (2004).

102. van der Kooij, M.A. et al. Impaired hippocampal neuroligin-2 function by chronic

stress or synthetic peptide treatment is linked to social deﬁcits and increased

aggression. Neuropsychopharmacology 39, 1148–1158 (2014).

103. Wood, G.E., Young, L.T., Reagan, L.P. & McEwen, B.S. Acute and chronic restraint

stress alter the incidence of social conﬂict in male rats. Horm. Behav. 43,

205–213 (2003).

104. van der Kooij, M.A. et al. Role for MMP-9 in stress-induced downregulation

of nectin-3 in hippocampal CA1 and associated behavioural alterations.

Nat. Commun. 5, 4995 (2014).

105. Matus, A., Brinkhaus, H. & Wagner, U. Actin dynamics in dendritic spines: a

form of regulated plasticity at excitatory synapses. Hippocampus 10, 555–560

(2000).

106. Arendt, T. et al. Reversible paired helical ﬁlament-like phosphorylation of tau is

an adaptive process associated with neuronal plasticity in hibernating animals.

J. Neurosci. 23, 6972–6981 (2003).

107. Morris, M., Maeda, S., Vossel, K. & Mucke, L. The many faces of tau. Neuron

70, 410–426 (2011).

108. Kinoshita, Y. et al. Role for NUP62 depletion and PYK2 redistribution in dendritic

retraction resulting from chronic stress. Proc. Natl. Acad. Sci. USA 111,

16130–16135 (2014).

109. Tochigi, M. et al. Gene expression proﬁling of major depression and suicide in

the prefrontal cortex of postmortem brains. Neurosci. Res. 60, 184–191

(2008).

110. Gould, E., McEwen, B.S., Tanapat, P., Galea, L.A.M. & Fuchs, E. Neurogenesis

in the dentate gyrus of the adult tree shrew is regulated by psychosocial stress

and NMDA receptor activation. J. Neurosci. 17, 2492–2498 (1997).

111. Gould, E., Tanapat, P., McEwen, B.S., Flugge, G. & Fuchs, E. Proliferation of

granule cell precursors in the dentate gyrus of adult monkeys is diminished by

stress. Proc. Natl. Acad. Sci. USA 95, 3168–3171 (1998).

112. Cameron, H.A. & Gould, E. Adult neurogenesis is regulated by adrenal steroids

in the dentate gyrus. Neuroscience 61, 203–209 (1994).

113. Leuner, B., Glasper, E.R. & Gould, E. Sexual experience promotes adult

neurogenesis in the hippocampus despite an initial elevation in stress hormones.

PLoS ONE 5, e11597 (2010).

114. Leuner, B., Caponiti, J.M. & Gould, E. Oxytocin stimulates adult neurogenesis

even under conditions of stress and elevated glucocorticoids. Hippocampus 22,

861–868 (2012).

115. Lightman, S.L. et al. The signiﬁcance of glucocorticoid pulsatility. Eur. J.

Pharmacol. 583, 255–262 (2008).

116. Liston, C. & Gan, W.B. Glucocorticoids are critical regulators of dendritic

spine development and plasticity in vivo. Proc. Natl. Acad. Sci. USA 108,

16074–16079 (2011).

117. Liston, C. et al. Circadian glucocorticoid oscillations promote learning-dependent

synapse formation and maintenance. Nat. Neurosci. 16, 698–705 (2013).

118. Akana, S.F., Jacobson, L., Cascio, C.S., Shinsako, J. & Dallman, M.F. Constant

corticosterone replacement normalizes basal adrenocorticotropin (ACTH) but

permits sustained ACTH hypersecretion after stress in adrenalectomized rats.

Endocrinology 122, 1337–1342 (1988).

119. Karatsoreos, I.N. & McEwen, B.S. Timing is everything: a collection on how clocks

affect resilience in biological systems. F1000 Res. 3, 273 (2014).

120. Seeman, T., Epel, E., Gruenewald, T., Karlamangla, A. & McEwen, B.S. Socio-

economic differentials in peripheral biology: cumulative allostatic load. Ann. NY

Acad. Sci. 1186, 223–239 (2010).

121. Karatsoreos, I.N. & McEwen, B.S. Psychobiological allostasis: resistance, resilience

and vulnerability. Trends Cogn. Sci. 15, 576–584 (2011).

122. Radley, J.J. et al. Chronic behavioral stress induces apical dendritic reorganization

in pyramidal neurons of the medial prefrontal cortex. Neuroscience 125, 1–6

(2004).

123. Karatsoreos, I.N., Bhagat, S., Bloss, E.B., Morrison, J.H. & McEwen, B.S.

Disruption of circadian clocks has ramiﬁcations for metabolism, brain, and

behavior. Proc. Natl. Acad. Sci. USA 108, 1657–1662 (2011).

124. Phillips, D.J., Savenkova, M.I. & Karatsoreos, I.N. Environmental disruption of

the circadian clock leads to altered sleep and immune responses in mouse. Brain

Behav. Immun. 47, 14–23 (2015).

125. Lamont, E.W., Robinson, B., Stewart, J. & Amir, S. The central and

basolateral nuclei of the amygdala exhibit opposite diurnal rhythms of expression

of the clock protein Period2. Proc. Natl. Acad. Sci. USA 102, 4180–4184

(2005).

126. Reddy, A.B. et al. Glucocorticoid signaling synchronizes the liver circadian

transcriptome. Hepatology 45, 1478–1488 (2007).

127. McEwen, B.S., Gray, J. & Nasca, C. Recognizing resilience: learning from the

effects of stress on the brain. Neurobiol. Stress 1, 1–11 (2015).

128. Russo, S.J., Murrough, J.W., Han, M.H., Charney, D.S. & Nestler, E.J. Neurobiology

of resilience. Nat. Neurosci. 15, 1475–1484 (2012).

129. Waddington, C.H. The epigenotype. Endeavour 1, 18–20 (1942).

130. Bavelier, D., Levi, D.M., Li, R.W., Dan, Y. & Hensch, T.K. Removing brakes on

adult brain plasticity: from molecular to behavioral interventions. J. Neurosci. 30,

14964–14971 (2010).

131. Castrén, E. & Rantamaki, T. The role of BDNF and its receptors in depression

and antidepressant drug action: Reactivation of developmental plasticity. Dev.

Neurobiol. 70, 289–297 (2010).

132. McEwen, B.S. & Gianaros, P.J. Stress- and allostasis-induced brain plasticity.

Annu. Rev. Med. 62, 431–445 (2011).

133. Yan, X.-X., Toth, Z., Schultz, L., Ribak, C.E. & Baram, T.Z. Corticotropin-

releasing hormone (CRH)-containing neurons in the immature rat hippocampal

formation: light and electron microscopic features and colocalization

with glutamate decarboxylase and parvalbumin. Hippocampus 8, 231–243

(1998).

134. Hill, M.N. & McEwen, B.S. Involvement of the endocannabinoid system in the

neurobehavioural effects of stress and glucocorticoids. Prog. Neuropsychopharmacol.

Biol. Psychiatry 34, 791–797 (2010).

135. Gunduz-Cinar, O., Hill, M.N., McEwen, B.S. & Holmes, A. Amygdala FAAH and

anandamide: mediating protection and recovery from stress. Trends Pharmacol.

Sci. 34, 637–644 (2013).

136. Hill, M.N. et al. Disruption of fatty acid amide hydrolase activity prevents the

effects of chronic stress on anxiety and amygdalar microstructure. Mol. Psychiatry

18, 1125–1135 (2013).

137. Vyas, A., Mitra, R., Rao, B.S.S. & Chattarji, S. Chronic stress induces contrasting

patterns of dendritic remodeling in hippocampal and amygdaloid neurons.

J. Neurosci. 22, 6810–6818 (2002).

138. Liston, C. et al. Stress-induced alterations in prefrontal cortical dendritic

morphology predict selective impairments in perceptual attentional set-shifting.

J. Neurosci. 26, 7870–7874 (2006).

139. McEwen, B.S. & Morrison, J.H. The brain on stress: vulnerability and plasticity

of the prefrontal cortex over the life course. Neuron 79, 16–29 (2013).

140. Du, J., McEwen, B.S. & Manji, H.K. Glucocorticoid receptors modulate

mitochondrial function. Commun. Integr. Biol. 2, 350–352 (2009).

141. Armanini, M.P., Hutchings, C., Stein, B. & Sapolsky, R. Glucocorticoid

endangerment of hippocampal neurons is NMDA-receptor dependent. Brain Res.

532, 7–12 (1990).

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Feb 2023

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.

Sexual Dysfunction in Functional Hypothalamic Amenorrhea

Chapter

Mar 2023

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.

The Association of Life Stress with Subsequent Brain and Cognitive Reserve in Middle-Aged Women

Article

Full-text available

Mar 2023
J ALZHEIMERS DIS

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.

Resistance exercise was safe for the pregnancy and offspring’s development and partially protected rats against early life stress-induced effects

Article

Mar 2023
BEHAV BRAIN RES

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.

GABAergic neurons in the nucleus accumbens core mediate the antidepressant effects of sevoflurane

Article

Mar 2023
EUR J PHARMACOL

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.

Investigation of the Role of L-Arginine and L-NAME in Dorsal Hippocampus on Anxiety, Depression and Brain Level of BDNF after Stress in Male Mice

Article

Full-text available

Dec 2022

Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression

Article

Full-text available

Jul 2009

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.

Chronic Stress Induces Contrasting Patterns of Dendritic Remodeling in Hippocampal and Amygdaloid Neurons

Article

Aug 2002

Actin dynamics in dendritic spines: A form of regulated plasticity at excitatory synapses

Article

Jan 2000
HIPPOCAMPUS

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, cognitive impairment and cell adhesion molecules

Article

Jan 2004

Carmen Sandi

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.

Role of neuronal cell adhesion molecules in stress-induced cognitive impairment

Conference Paper

Aug 2005

Carmen Sandi

Neurogenesis

Article

Jan 2010

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.

REPEATED CHANGES OF DENDRITIC MORPHOLOGY IN THE HIPPOCAMPUS OF GROUND SQUIRRELS IN THE COURSEOFHIBERNA TION

Article

Jan 1992

The Neuroendocrinology of Stress and Aging: The Glucocorticoid Cascade Hypothesis

Article

Sep 2002
Sci Aging Knowl Environ

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).

Environmental influence in the brain, human welfare and mental health

Article

Sep 2015

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.

Protective and Damaging Effects of Stress Mediators

Article

Jan 1998
NEW ENGL J MED

Bruce S Mcewen

Mechanisms of stress in the brain

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