Opinion
VIEWPOINT
Allostasis and the Epigenetics of Brain
and Body Health Over the Life Course
The Brain on Stress
Bruce S. McEwen, PhD Overview
Laboratory of The brain is the central organ of responding to stress and
Neuroendocrinology, is vulnerable but resilient; it communicates reciprocally
The Rockefeller
with the rest of the body. This Viewpoint explains the
University, New York,
New York. concepts of allostasis and allostatic loads as they epi-
genetically affect neural and systemic processes over the
lifecourse. These concepts reveal how the brain and body
influence each other during the course of psychiatric dis-
orders with frequent multimorbidity,1-3 a point that needs
more acknowledgement in the Research Domain Crite-
ria matrix.
Stressful experiences can precipitate major psychi-
atric disorders such as schizophrenia, bipolar illness, anxi-
ety disorders, and major depression. The brain per-
ceives and determines what is threatening as well as the
behavioral and physiological responses to the stressor,
which not only promote adaptation (“allostasis”) but also
contribute to pathophysiology (“allostatic load/
overload”) when those responses are overused and
dysregulated.4 Health-promoting behaviors are an es-
sential component of successful allostasis, along with ad-
equate sleep, normal circadian function, and an effi-
cient energy metabolism.1 Health-damaging behaviors
contribute to allostatic loads/overloads (Figure).
The Existing Evidence
Allostasis refers to the multiple adaptive and survival-
promoting systemic and neural processes that are acti-
vated by novel and potentially threatening experi-
ences. By mediators, we mean not only cortisol and
adrenalin but also the parasympathetic nervous sys-
tem, pro- and anti-inflammatory cytokines, and meta-
bolic hormones.1 Moreover, the brain uses interacting
mediators to alter neural circuitry and functions.3,5 Al-
lostatic loads and overloads, representing degrees of se-
verity of a cumulative effect on body and brain, are terms
that acknowledge that the same mediators, when over-
used and dysregulated among themselves (eg, too much
or too little cortisol or inflammation, not enough para-
sympathetic tone, or insulin resistance), cause patho-
physiology, particularly if sustained.1 These represent “al-
lostatic states,”6 states of dysregulated activity in the
brain and body that can occur during the development
Corresponding of a psychiatric illness and lead to allostatic overload.
Author: Bruce S. Allostatic brain plasticity mechanisms and allo-
McEwen, PhD,
Laboratory of
static hormonal influences provide adults, as well as the
Neuroendocrinology, developing brain, with a remarkable ability to adapt via
The Rockefeller structural and functional plasticity in response to stress-
University, 1230 York
ful and other experiences, including neuronal replace-
Ave, New York, NY
10021 (mcewen@mail ment, dendritic remodeling, and synapse turnover.
.rockefeller.edu). Changes in neural architecture influence not only be-
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havior but also systemic physiology, which feeds back
on the brain epigenetically.5
Epigenetics refers to the ongoing regulation of gene
expression via molecular processes involving posttrans-
lational histone modifications, the methylation of cyto-
sine bases on deoxyribonucleic acid, the actions of tran-
scription regulators, the translational regulation of
messenger ribonucleic acid (RNA) by microRNA, RNA
splicing, and RNA editing. Transposable elements that
make up around 40% of the human genome also play
an emerging regulatory role in stress and aging in the
brain.3,5
Epigenetic cellular and molecular mechanisms pro-
duce continuous changes in gene expression.3,5 Thus,
one cannot “roll back the clock” after a stressful experi-
ence is over, and we must speak of “resilience” and “re-
covery” rather than “reversal.” Although alterations in
neuronal structure and function may appear to be “re-
versed,” they are not the same as before.
Acute and chronic stress can cause an imbalance of
neural circuitry subserving cognition, decision making,
anxiety, and mood with increased or decreased expres-
sion of behaviors. This imbalance affects the systemic
physiology via neuroendocrine, autonomic, immune, and
metabolic mediators.1-3 In the short term, such as for in-
creased fearful vigilance and anxiety in a threatening en-
vironment, these changes may be adaptive; however, if
the danger passes and the behavioral state and changes
in neural circuitry become “stuck,” such maladaptation
may need intervention with a combination of pharma-
cological and behavioral therapies to get it “unstuck,” as
is the case for chronic anxiety or depressive disorders.1,3,5
Structural and functional allostatic plasticity is par-
ticularly evident in the hippocampus, a key structure for
episodic and spatial memory and mood regulation in
which all 3 types of structural plasticity have been rec-
ognized and investigated using morphological, molecu-
lar, pharmacological, electrophysiological, and behav-
ioral approaches . The hippocampus was the first brain
structure outside of the hypothalamus that was found
to possess stress and sex hormone receptors, and it pro-
vided a gateway into the hormone sensitivity of the rest
of the brain.3
The amygdala, mediating fear, anxiety, and aggres-
sion, and the prefrontal cortex, important for working
memory, executive function, and cell regulation, show
structural plasticity. In amygdala, basolateral neurons ex-
pand dendrites from chronic stress,5 while medial pre-
frontal cortex neurons, as well as the hippocampal neu-
rons, show dendritic shrinkage from the same stressful
experience.7
(Reprinted) JAMA Psychiatry June 2017 Volume 74, Number 6 551
 Opinion Viewpoint

other cellular mediators and processes.3,5 These mediators provide

Figure. Central Role of the Brain in Allostasis and the Behavioral and
Physiological Response to Stressors a foundation for developing more effective treatments to more rap-
idly alleviate depression and slow down the progress of dementia.2,3,5
Stress Circadian disruptions affect the brain, as well as systemic physi-
Environmental stressors ology, leading to the prefrontal cortex dendrites shrinking and cog-
Major life events nitive rigidity as well as insulin and leptin resistance.1 Likewise, poor
Trauma, abuse
sleep impairs the parasympathetic/sympathetic balance, increases
systemic inflammation, and impairs glucose regulation.1,3,7 Diabe-
BRAIN
tes and insulin resistance are risk factors for depression, which in-
Development of individual Epigenetic changes
susceptibility to stress in brain circuitry creases the risk for dementia.2
Genes and function Mitochondria, which have their own deoxyribonucleic acid and
Early life experiences are inherited via the mother, are glucocorticoid- and estrogen-
sensitive for regulating calcium sequestration and a free radical bal-
Perceived stress ance, and make their own contributions to allostasis and allostatic
Vigilance loads and overloads.5
Helplessness
There are important differences among sexes in how the brain
responds to stressors as far as structural and functional plasticity7
that contribute to the important concept that men and women dif-
fer in the “strategies” that they use to do the same things.3 The en-
Behavioral responses Physiologic responses tire brain has subtle sex differences along with receptors for sex
Fight or flight Neural
Personal behavior: Hormonal hormones among both sexes.3
diet, smoking, drinking, Immune Finally, poverty and adverse early life experiences and interact-
exercise, social avoidance Metabolic
ing with alleles of certain genes produce lasting effects on the brain
and body via epigenetic mechanisms,3 leading to the multimorbid-
Allostasis
ity of mental and physical health disorders.1 Preconception epige-
netic factors2 and stressful experiences before conception2 and
during gestation1,2 also have important influences.
Adaptation Allostatic load Pathophysiology
Repeated stress Conclusions
Dysregulated stress response
While prevention is most important,1 brain plasticity gives hope for
Adapted from McEwen. 4 therapies that consider brain-body interactions, open “windows of
plasticity” via pharmacological or behavioral means, and facilitate
more effective behavioral interventions that include regular physi-
Excitatory amino acids and the brain-derived neurotrophic fac- cal activity and cognitive behavioral therapies such as mindfulness
tor are mediators of this allostatic plasticity along with endocannabi- and meditation and activities that produce positive social interac-
noids, the corticotropin-releasing factor, noradrenalin, serotonin, and tions and meaning and purpose in life.1

ARTICLE INFORMATION
Published Online: April 26, 2017.
doi:10.1001/jamapsychiatry.2017.0270
Conflict of Interest Disclosures: None reported.
REFERENCES
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stress and adaptation: central role of the brain.
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2. Rasgon NL, McEwen BS. Insulin resistance-a
missing link no more. Mol Psychiatry. 2016;21(12):
1648-1652.
3. McEwen BS, Gray JD, Nasca C. 60 Years of
neuroendocrinology: redefining
neuroendocrinology: stress, sex and cognitive and
emotional regulation. J Endocrinol. 2015;226(2):
T67-T83.
4. McEwen BS. Protective and damaging effects of
stress mediators. N Engl J Med. 1998;338(3):171-179.
5. McEwen BS, Nasca C, Gray JD. Stress effects on
neuronal structure: hippocampus, amygdala, and
prefrontal cortex. Neuropsychopharmacology.
2016;41(1):3-23.
6. Koob GF, Le Moal M. Drug addiction,
dysregulation of reward, and allostasis.
Neuropsychopharmacology. 2001;24(2):97-129.
7. McEwen BS, Morrison JH. The brain on stress:
vulnerability and plasticity of the prefrontal cortex
over the life course. Neuron. 2013;79(1):16-29.

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