Frontiers in Neuroendocrinology 49 (2018) 8–30

Contents lists available at ScienceDirect

Frontiers in Neuroendocrinology
journal homepage: www.elsevier.com/locate/yfrne

Review article

Redefining neuroendocrinology: Epigenetics of brain-body communication T

over the life course
⁎
Bruce S. McEwen
Laboratory of Neuroendocrinology, The Rockefeller University, 1230 York Ave, New York, NY 10065, USA

A R T I C L E I N F O A B S T R A C T

Keywords: The brain is the central organ of stress and adaptation to stress that perceives and determines what is threa-
Stress tening, as well as the behavioral and physiological responses to the stressor, and it does so somewhat differently
Hippocampus in males and females. The expression of steroid hormone receptors throughout the brain has broadened the
Amygdala definition of ‘neuroendocrinology’ to include the reciprocal communication between the entire brain and body
Prefrontal cortex
via hormonal and neural pathways. Mediated in part via systemic hormonal influences, the adult and developing
Immune
brain possess remarkable structural and functional plasticity in response to stress, including neuronal replace-
Metabolic
Autonomic ment, dendritic remodeling, and synapse turnover. This article is both an account of an emerging field eluci-
Neuroplasticity dating brain-body interactions at multiple levels, from molecules to social organization, as well as a personal
Sex differences account of my laboratory’s role and, most importantly, the roles of trainees and colleagues, along with my
Social environment involvement in interdisciplinary groups working on this topic.
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1. Prologue brother, Dr. Craig McEwen, a Sociologist at Bowdoin College, is ful-

This article provides an overview of a rapidly emerging field as well
as a personal account of my laboratory’s contributions to it. I highlight
the roles of trainees and colleagues in elucidating brain-body interac-
tions at multiple levels, from molecules to social organization. This
ongoing process was and is immeasurably enhanced by my scientific
colleague and wife, Dr. Karen Bulloch, a neuroimmumunologist, who,
in addition to her novel and pioneering research on brain dendritic
cells, microglia and RNA editing summarized in Section 13, below,
helped me to see and enjoy life beyond science and academics.
Furthermore, my recent and now ongoing collaboration with my
filling for both of us and would have made our parents, George and
Esther, very proud!
2. Introduction
The discovery of steroid hormone receptors in brain regions that
mediate virtually every aspect of brain function has broadened the
definition of “neuroendocrinology” to include the reciprocal commu-
nication between the brain and the body via hormonal and neural
pathways. Discovery of adrenal steroid receptors in hippocampus led
the way and became the “gateway” for other discoveries and a better

⁎
Address: Alfred E. Mirsky Professor, Head, Harold and Margaret Milliken Hatch, Laboratory of Neuroendocrinology, The Rockefeller University, 1230 York Avenue, New York, NY
10065, USA.
E-mail address: mcewen@mail.rockefeller.edu.
URL: http://www.rockefeller.edu/labheads/mcewen/mcewen-lab.php.

https://doi.org/10.1016/j.yfrne.2017.11.001
Received 29 July 2017; Received in revised form 1 November 2017; Accepted 4 November 2017
Available online 10 November 2017
0091-3022/ © 2017 Elsevier Inc. All rights reserved.
B.S. McEwen
understanding of the meaning of “stress” in terms of the concepts of
allostasis and allostatic load and overload where life style and health
behaviors are key factors along with stressful experiences themselves.
Discovery of hormone receptors in brain has led to the discovery of
structural and functional plasticity in the brain, mediated in part by
hormones, and this has helped to facilitate the emergence of the science
of “epigenetics” by revealing effects of the social and physical en-
vironment on adult as well as developing brain structure and function.
At the same time, cellular and molecular mechanisms for this plasticity
have emerged and have revealed other mechanisms of steroid hormone
action than direct genomic stimulation, including actions on mi-
tochondria as well as regulation of cellular signaling pathways. Besides
steroid hormones, metabolic hormones enter and affect the brain and
their relationship to brain metabolism; and mitochondrial function has
become important for understanding disorders like diabetes, depression
and dementia. Another important hormone discovery is the widespread
effects of sex hormones throughout the brain along with diverse me-
chanisms for sex hormone action at both genomic and non-genomic
levels, including actions in mitochondria. This has helped highlight the
need to understand sex differences in normal brain function and dis-
ease. Finally, hormone actions via epigenetic mechanisms operating
over the life course are changing the way we look at the development of
disorders and the possibilities for intervention.
The story begins appropriately with “stress” since it was the dis-
covery of glucocorticoid receptors in hippocampus in 1968 (McEwen
et al., 1968) that started this line of research for us.
3. “Stress” is all around us!
“Stress” is everywhere in our daily experiences and conversations
and yet, except for describing the “fight or flight” response most people
do not understand what is going on in the brain and body. We become
anxious hearing about violence, chaos and discord. And, in our rela-
tively secure world, the pace of our daily lives and the demands upon us
and our children often leads us to feel that there is too much to do in so
little time! This disrupts our natural biological rhythms and encourages
unhealthy behaviors, like eating too much of the wrong things, ne-
glecting exercise and good sleep, and it results in an unhealthy life style.
Poverty and racial and ethnic discrimination, and lack of educa-
tional opportunities and economic advancement, take their toll on a
large segment of our population where incarceration is the rule rather
than the exception for some of the most vulnerable. Adverse experi-
ences in infancy and childhood, including poverty, leave a life-long
imprint on the brain and body and undermine long-term health, in-
creasing the incidence of cardiovascular disease, diabetes, depression,
substance abuse, anti-social behavior and dementia. How does all of
this stress “get under our skin”, what does it do to our brains and our
body’s, how does it do it, and what can we do about it?
4. What is “stress”?
Jerome Kagan has noted that the word “stress” is used so much in
different ways so as to be ambiguous and almost meaningless; and he
suggested that the word “stress” be used only in the cases where an
event poses a serious threat to someone’s well-being (Kagan, 2016). He
also noted the “reluctance” of researchers to give up the term “stress”.
While I agree that the word “stress” is ambiguous and overused, the
word is too embedded in human language and culture to be abandoned
- and that includes researchers! Rather, my brother, Craig and I, re-
cently proposed in print (McEwen and McEwen, 2016) a more biolo-
gical way of looking at stress by, first, using additional words along
with “stress” and, second, putting that added wording into a biological
and behavioral context. Fortunately, my participation in an inter-
disciplinary network, The National Scientific Council for the Devel-
oping Child, of which I am now a member (http://developingchild.
harvard.edu/science/national-scientific-council-on-the-developing-
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Frontiers in Neuroendocrinology 49 (2018) 8–30
child/) provided a solution.
For starters, “good stress” involves our taking a chance on some-
thing one wants, like interviewing for a job or school, or giving a talk
before strangers, and feeling rewarded when we are successful.
“Tolerable stress” means that something bad happens, like losing a job
or death of a loved one, but we have the personal resources and support
systems to weather the storm. “Toxic stress” means what Kagan refers
to, that is, something bad happens but we don’t have the personal re-
sources or support systems, and, as a result, we lack a sense that we
have some control. As a result, we are “knocked for a loop” and may
suffer mental and physical health problems of over time as a result,
particularly if the situation is not resolved.
5. Allostasis and allostatic load and overload
Now let us put these three forms of “stress” into a biological and
behavioral context. We know that “homeostasis” means the physiolo-
gical state which the body maintains to keep us alive - that is, body
temperature and pH within a narrow range and adequate oxygen
supply. In order to maintain homeostasis, our body activates hormone
secretion and turns on our autonomic and central nervous system (we
call these “mediators” like cortisol, adrenalin, the immune system and
metabolism) to help us adapt, for example, when we get out of bed in
the morning, walk up a flight of stairs, have a conversation. These
systems are also turned on when we are surprised by something un-
expected, or get into an argument, or run to catch a train. Some of these
experiences we may refer to as “stressful” but other we do not. So using
the word stress does not really recognize all of the underlying biology.
The “mediators” help us adapt as long as they are turned on in a
balanced way when we need them and then turned off again when the
challenge is over. When that does not happen, they can cause unhealthy
changes in brain and body. This is also the case when the “mediators”
are not produced in an orchestrated and balanced manner – for ex-
ample, too much or too little cortisol or an elevated or too low blood
pressure. When this happens and continues over weeks and months, we
call it “allostatic load” (see Box 1) to refer to the wear and tear on the
body that results from the chronic overuse and imbalance of the
“mediators”. Accumulation of belly fat is an example as is the devel-
opment of chronic hypertension.
When the wear and tear is strongest, we call it allostatic overload
and this is what is occurring in toxic stress. An example is when hy-
pertension leads to coronary artery blockade, and the belly fat con-
tributes chemicals that accelerate the coronary artery blockade. Note,
however, that we are talking, not about one mediator, like cortisol, but
a host of mediators that are all released in allostasis in a coordinated
manner to help us adapt but which can also cause damage when
overused and dysregulated as described aboe. Because cortisol is well
known in relation to stress, its role is often misunderstood (see Box 2).
6. Health promoting and health damaging behaviors contribute to
allostatic load
We must go one step further and recognize that bad health beha-
viors, often the result of a “stressful” life style, like eating too much of
the wrong things, smoking, drinking, loneliness, poor sleep and lack of
exercise all contribute to that hypertension, belly fat and blockade of
coronary arteries. And they do so through the same “mediators” that
are activated to help us adapt but which also, when overused and
dysregulated, cause allostatic load and overload (McEwen, 2006,
2017).
So the “mediators” that help us adapt and enable us to maintain our
homeostasis and survive can also contribute to well-know diseases of
modern life. These ideas are the basis of the concepts of “allostasis” and
“allostatic load/overload”, whereas they are not so obvious from the
word “stress” which is usually explained as the “fight or flight response”
when we are, for example, threatened by a mugger and run away. What
B.S. McEwen Frontiers in Neuroendocrinology 49 (2018) 8–30

Box 1
How An Interdisciplinary Research Network Created the Allostatic Load Concept.

In 1988, Peter Sterling and Joseph Eyer published a paper on the concept of allostasis as applied to the cardiovascular system (Sterling and
Eyer, 1988). Around that time, Eliot Stellar, then Provost at Penn and a collaborator on the topic of hormonal control of salt appetite in
brain, knew of our work on stress and invited me to become a member of a MacArthur Network on Health and Behavior where I heard
Sterling speak. A MacArthur Network is an interdisciplary group of social, behavioral and medical scientists interested in a common
problem. As my role in the network developed, Stellar and I wrote a paper that broadened the allostasis concept and introduced the notion
of cumulative change as a result of excessive or dysregulated allostasis (McEwen and Stellar, 1993) that was ultimately named “allostatic
load” (McEwen, 1998). The MacArthur Network “morphed” into the MacArthur Research Network on Socioeconomic Status and Health
that continued the development and validation of allostatic load with the important role of Teresa Seeman from UCLA (McEwen and
Seeman, 1999; Seeman et al., 2010b, 2010c; Wiley et al., 2016). The basic concept behind allostatic load is an outgrowth of Robert
Sapolsky’s “glucocorticoid cascade hypothesis” of stress and aging (Sapolsky et al., 1986) that was broadened, like that of Sterling and Eyer,
to encompass not only glucocorticoids but also other interacting mediators of adaptation. One more development of the allostatic load
concept was contributed by a field biologist, John Wingfield, who pointed out that animals in the wild are continually searching for calories
to stay alive while we humans, at least in affluent societies, are oversupplied with calories (McEwen and Wingfield, 2003). Moreover,
Wingfield pointed out that forms of what we might call “allostatic load” are important adaptive features in bears putting on body fat for the
winter, during which they burn it off. Yet, bears in a zoo can develop obesity associated with cardiovascular disease out of over-feeding and
boredom. This led to Wingfield’s suggestion that “allostatic overload” might apply to those health damaging aspects of dysregulated
allostasis (McEwen and Wingfield, 2003, 2010). Yet, migrating salmon and marsupial mice experience “allostatic overload” as a natural
part of the elimination of part of the population to provide resources to the next generation (Carruth et al., 2002; Poskitt et al., 1984).

really affects our health and well-being are the more subtle, gradual and these contribute to allostatic load and overload through the same bio-
long-term influences from our social and physical environment like logical “mediators” that help us adapt and keep us alive - and they
family and neighborhood chaos and conflict, demands of a job, shift shape our brains as well!
work and jet lag, sleeping badly, living in an ugly, noisy and polluted
environment, being lonely, not getting enough physical activity, eating
too much of the wrong foods, smoking, drinking too much alcohol. All

Box 2
What cortisol does and does not tell us!.

Even though we now know that there are multiple “mediators” for allostasis and allostatic load/overload, we often hear that measuring our
cortisol levels will tell us if we are stressed. This reflects a misunderstanding at two levels. First, a single measure of cortisol will tell us
nothing since cortisol levels go up and down within minutes. Moreover, we have noted the a day-night (diurnal) rhythm of this pulsating
cortisol that goes up in the early morning and wakes us up, then declines, except for a rise at lunch time, and which is normally low in the
evening before we go to bed. This is true unless, of course, “stressful” experiences occur or unless we are depressed or sleep deprived, or
both, when the diurnal rhythm is flat. There are several ways around the measurement problem – we can collect urine overnight or over the
day or we can measure cortisol in hair from the forehead, which gives as an even longer, over multiple days, index of our cortisol
production. Or we can measure cortisol in our saliva at multiple times during the day or before, during and after a stressful challenge, such
as talking about something personal before a group of strangers. The stressful challenge gives us a picture of the efficiency of our allostasis,
namely, turning on our cortisol when we are challenged and need it and then turning off our cortisol response when the stressor is over.
Failure to turn it on when needed is bad – other systems that balance it, like inflammation, may over-react; failure to turn it off when stress
is over produces negative effects on metabolism and other processes, like obesity, diabetes, depression and eventual heart disease, that
contribute to allostatic load/overload (McEwen, 1998).
The second misunderstanding is that the cortisol response is not the “bad guy”, as it is often implied by its elevation in the context of a
bad experience; rather, cortisol has a normal physiological role not only helping us adapt to stressors but also coordinating our metabolism
with our daily activity and sleep patterns (McEwen et al., 1993). We would not live very long or well without our cortisol! So let’s not blame
it for our problems! For example, we’ll see later that diurnal fluctuations of cortisol promote the formation and elimination of synapses in
our brains and this helps us learn and adapt (Liston et al., 2013; Liston and Gan, 2011). Moreover, the diurnal early morning rise of cortisol,
as well as a stress response activates adaptive immune function so that we can fight an infection or repair a wound. This grew out of the PhD
research of a former student, Firdaus Dhabhar, now Professor at the University of Miami. So an acute stress-induced rise of cortisol and
adrenalin actually helps the immune system to respond to a pathogen or repair a wound (Dhabhar and McEwen, 1997). Likewise, the
morning awakening rise of cortisol enhances the body’s response to an immunization (Dhabhar et al., 1994). Beside cortisol and adrenalin
involvement in this important adaptive function, key biochemicals of the immune system are also necessary and, together, they help
immune cells “go to their battle stations” where they are needed! (Dhabhar et al., 2012) The body’s response is like an orchestra involving
many players that need to work in harmony! But, indeed, too much cortisol also causes problems as it does with a flat diurnal rhythm and in
Cushing’s Disease when excess cortisol is produced by a pituitary gland tumor!
A third misunderstanding is that glucocorticoids do not play the same role across the life course but rather serve different functions,
starting with their role in “wakening” of the amygdala in neonatal life, from work of Regina Sullivan (Moriceau and Sullivan, 2004) to their
role in promoting ponderal growth in adolescence, based on work of Russell Romeo (Romeo et al., 2006) and their influence on the
vulnerability of the adolescent brain to stressful experiences (Pattwell et al., 2011, 2016; Romeo, 2017) as well as the age-accelerating role
of excess cortisol in aging (Lupien et al., 1998; Sapolsky et al., 1986).

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B.S. McEwen Frontiers in Neuroendocrinology 49 (2018) 8–30

Box 3
Epigenetics.

“Epigenetics” originally meant the emergence of developmentally-programmed characteristics as a fertilized egg develops into a living
organism characteristic of that species (Waddington, 1942). This is programmed into each species, but the individual characteristics are
influenced by experiences, and that is where the modern use of “epigenetics” comes from. An example of this is a pair of identical twins
with genes that predispose them to schizophrenia or bipolar illness. Even with the same DNA, the probability that one twin will develop the
disease when the other twin gets it is only in the range of 40–60%, which leave plenty of room for experiences and other environmental
factors to either prevent of precipitate the disorder. As an indicator of this, the methylation patterns of DNA diverge as identical twins grow
older (Fraga et al., 2005). Thus, “epigenetics”, now meaning “above the genome”, that is, not changing the genetic code, replaces and
makes unnecessary the old question: “which is more important, genes or environment?”. The CpG methylation of DNA is now a well-known
form of epigenetic modification (Szyf et al., 2008). But there are other mechanisms that include histone modifications that repress or
activate chromatin unfolding (Allfrey, 1970) and the actions of non-coding RNA’s (Mehler, 2008), as well as transposons and retro-
transposons (Griffiths and Hunter, 2014) and RNA editing (Mehler and Mattick, 2007).

7. Central role of the brain
Up to this point I have left out the brain. The brain, “keeps the
score” by storing memories from bad as well as good experiences, and
yet the brain, working with the body, also “knows what to do” to keep
us alive if we give it a chance by minimizing those subtle and long-term
influences that cause allostatic load and overload (McEwen and Getz,
2013). We call that the “wisdom of the body” and it refers back to
“allostasis”, the active process of biological adaptation, and its role in
maintaining homeostasis. Indeed the brain is a plastic and vulnerable
organ of the body, and is continually sculpted by experiences. The brain
is also a vulnerable organ, along with our heart, liver and kidneys and
other organs. The brain changes its architecture and function as part of
“allostasis” and the development of the notion of structural plasticity of
the brain has come about over the last half century with an accelerating
pace as will be described below (see Box 4) ! We also need to consider
where our genes fit in and understand that they do not rigidly de-
termine our destiny but, rather, provide the foundation on which our
experiences shape our brains and bodies over the life course via “epi-
genetic” mechanisms (Box 3).
8. How we started down this path: steroid hormone actions in
hippocampus and beyond
Though I did not think of it that way at the time, “epigenetics” has
been the core of my laboratory’s work on the brain and brain-body
interactions. My mentors for my dissertation, in 1964, Vincent Allfrey
and Alfred Mirsky, taught me the fundamentals of “epigenetics” in the
1960s before there was much interest in it, and when the name,
epigenetics, meant something quite different (see Box 3). What Allfrey
and Mirsky did was to show how proteins called histones, which wrap
around DNA, are modified chemically to cause them to unwrap the
DNA double helix and allow genes to be expressed. Around 1960,
hormones like cortisol and estradiol were shown by others to use this
mechanism to turn on genes in the uterus and liver, and this became a
focus of my work in 1966 after I was recruited back to Rockefeller to
work with a famous psychologist, Neal Miller, as his biochemist, having
spent 2 years in Sweden and a brief period at the University of Min-
nesota.
Learning about how hormones regulate gene expression in the
uterus and liver led me to my interest in how hormones of the adrenals
and gonads alter gene expression in brain and produce their epigenetic
effects. This led to my discovery, in the brain in 1968, that the adrenal
stress hormone, cortisol, acts epigenetically on a brain structure called
the hippocampus, which we now know mediates memory of daily
events in space and time and also regulates mood. In fact, the hippo-
campus was the subject of the Nobel Prize into UK-based researcher
Prof John O'Keefe and Norwegian scientists, May-Britt Moser and
Edvard Moser in 2014 as the “GPS” of the brain.
Getting ahead of the story for the moment, the hippocampus is
important for episodic and spatial memory and is now also recognized
for its role in mood regulation. For spatial memory, the hippocampus
becomes active in London cab drivers during functional MRI imaging
when they remember a route from one place to another (Maguire et al.,
1997) and the hippocampus is also important for food caching behavior
in squirrels and birds (Biegler et al., 2001; Burger et al., 2013; Clayton,
2001). The hippocampus is also “the canary in the coal mine” as far as
conditions such as ischemia and seizures that cause brain damage as

Box 4
The Adult as Well as Developing Brain Shows Structural Plasticity.

Long regarded as a rather static and unchanging organ, except for electrophysiological responsivity, such as long-term potentiation (Bliss
and Lomo, 1973), the brain has gradually been recognized as capable of undergoing rewiring after brain damage (Parnavelas et al., 1974)
and also able to grow and change as seen by dendritic branching, angiogenesis and glial cell proliferation during cumulated experience
(Bennett et al., 1964; Greenough and Volkmar, 1973). More specific physiological changes in synaptic connectivity were also recognized in
relation to hormone action in the spinal cord (Arnold and Breedlove, 1985), and in environmentally directed plasticity of the adult songbird
brain (DeVoogd and Nottebohm, 1981). Seasonally varying neurogenesis in restricted areas of the adult songbird brain is recognized as part
of this plasticity (Nottebohm, 2002). Indeed, adult neurogenesis in the adult mammalian brain was initially described (Altman and Das,
1965; Kaplan and Bell, 1983) and then suppressed (Kaplan, 2001), only to be rediscovered in the dentate gyrus of the hippocampus
(Cameron and Gould, 1994; Gould and McEwen, 1993) in the context of studies of neuron cell death and actions of adrenal steroids and
excitatory amino acids in relation to stress. Neurogenesis in the dentate gyrus has gone on to become a huge topic related to effects of stress
(Gould et al., 1997), exercise (van Praag et al., 1999), enriched environment (Kempermann et al., 1997), antidepressants (Duman et al.,
1997) and learning and memory (Leuner et al., 2006) More than neurogenesis, structural plasticity includes dendrite remodeling, synapse
formation and synaptic pruning. For example, a recent study shows how the brain architecture of a mother is sculpted during pregnancy as
part of the formation of attachment to the child (Hoekzema et al., 2017). Moreover, a musician’s brain develop with enhanced size and
connections of sensory and motor control regions of the cerebral cortex! (Merzenich, 1998)

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B.S. McEwen
well as brain aging (Sapolsky, 1992). And the hippocampus responds to
sex hormones with effects on spatial memory and other functions
(Sandstrom and Williams, 2001), as will also be discussed later.
But we did not begin with the hippocampus. The initial discovery of
steroid hormone receptors in the brain was based on the model of cell
nuclear steroid hormone receptors developed in the 1960s (Jensen and
Jacobson, 1962; Toft and Gorski, 1966). Based upon the fundamental
discovery of the communication between hypothalamus and pituitary
by Geoffrey Harris (Harris, 1970) and isolation of releasing factors in
the hypothalamus for pituitary hormones (eg., (Guillemin, 1978;
Schally et al., 1973; Vale et al., 1981) the hypothalamus was the initial
target. The hypothalamus was also implicated in the control of re-
productive behavior, and my colleague Don Pfaff’s pioneering work
elucidated the brain circuit for lordosis behavior in the female rat
(Pfaff, 1980). Using steroid autoradiography with tritium labeled es-
tradiol, putative cell nuclear receptor sites for estradiol were demon-
strated in hypothalamus (Pfaff and Keiner, 1973; Stumpf, 1971) and
also by cell fractionation and sucrose density gradient centrifugation by
my first graduate student, Richard Zigmond (Zigmond and McEwen,
1970). We continued to collaborate with Don on molecular and neu-
rochemical factor for lordosis for some years before we focused on the
hippocampus and other extra-hypothalamic brain regions. More re-
cently, we collaborated again on epigenetics and the transposon/ret-
rotransposons, as is described elsewhere (Hunter et al., 2013, 2012).
9. Two major Steps forward
Then came the hippocampus which I had learned about as a post-
doctoral fellow in Goteborg Sweden in 1964–66 in the Institute of
Neurobiology headed by Holger Hyden. By administering 3H corticos-
terone into adrenalectomized rats, we discovered receptors for adrenal
steroids in the hippocampal formation of the rat and, later, the rhesus
monkey (Gerlach and McEwen, 1972; Gerlach et al., 1976; McEwen and
Plapinger, 1970; McEwen et al., 1968). Other studies revealed such
receptors in the hippocampal equivalent in other species including
birds (Dickens et al., 2009; McEwen, 1976). While there was very little
interest in 1968 in epigenetics in the brain, the hippocampus has since
become a “gateway” into learning how stress hormones, and also sex,
thyroid and metabolic hormones like insulin, enter the brain, bind to
receptors and act epigenetically to positively regulate structure and
function throughout many part of the brain and affect behavior and our
ability to function in our daily lives (McEwen et al., 2015b). But these
“mediators”, as we have noted, also contribute to allostatic load and
overload under conditions of toxic stress and the brain is very much a
target of this, just as are the heart and other organs.
How my laboratory participated and, in some cases, initiated these
discoveries involves other remarkable students, postdoctoral fellows
and colleagues, some of whom I shall now mention. Ron de Kloet, a
Professor at the University of Leiden, was one of my first postdoctoral
fellows. He found that synthetic glucocorticoids like dexamethasone
(DEX) (cortisol is also a glucocorticoid) are actively excluded from the
brain via the “multi-drug resistance p glycoprotein”, while cortisol gets
in!) Indeed, DEX is a very potent inhibitor of inflammation and immune
function and stimulates of liver glucose metabolism (hence the name
“glucocorticoid”). We now know that synthetic glucocorticoids like
DEX, when given to quell inflammation can shut of the ability to make
cortisol, and when DEX treatment is terminated the body and brain
become deficient in cortisol and this results in terrible mood swings and
metabolic and immune disruption. After that, Ron de Kloet went on in
his own laboratory with his student, Hans Reul, to show that cortisol in
the hippocampus binds to two receptor types, called MR and GR, to
produce its myriad of important actions. Work by Reul and de Kloet
demonstrated that there are two types of adrenal steroid receptors,
mineralocorticoid (Type 1 or MR) and glucocorticoid (Type 2 or GR), in
hippocampus and other brain regions (Reul and DeKloet, 1985). This
was further elaborated by immunocytochemical mapping of the
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Frontiers in Neuroendocrinology 49 (2018) 8–30
receptors (Ahima et al., 1991; Ahima and Harlan, 1990). Studies in our
laboratory as well as by Diamond and Joëls have shown biphasic effects
mediated by MR and GR (Diamond et al., 1992; Joels, 2006; Pavlides
et al., 1995). Ultradian fluctuations of glucocorticoids drive GR acti-
vation and reactivation, while MR occupancy for nuclear activation is
more constant and promotes excitability (Stavreva et al., 2009).
Another important advance was made by Robert Sapolsky who
found that, over the lifespan of a rat, that the cortisol equivalent in the
rat, corticosterone, gradually cause a “wear and tear” on the hippo-
campus which impairs not only memory and mood but also the ability
to shut off the production of its glucocorticoids (Sapolsky, 1992). This
effect is more evident in animals and also people who have experienced
toxic stress. The “glucocorticoid-cascade hypothesis of stress and
aging”, as it is called, was one of the bases for the concept of allostatic
load and overload (Box 1). Sapolsky also did seminal work on dominant
and subordinate baboons in Africa and laid the groundwork for how
income, education and human social hierarchies impact physical and
mental health. His books “Why Zebra’s Don’t Get Ulcers”, “A Primate’s
Memoir” and “Behave”, and writings in the Wall Street Journal have
made him an important figure for public awareness of behavioral sci-
ence, along with his popularity as a teacher at Stanford University.
While Robert Sapolsky’s findings emphasized the role of gluco-
corticoids in neural damage and systemic pathophysiology, there was
another side to the story, namely, the role of glucocorticoids and other
hormones in adaptive plasticity of the adult as well as developing brain.
10. Hormones and structural plasticity in brain
Up to this point in our work and in the field of neuroscience, the
brain was regarded as structurally stable in adult life and the main focus
for understanding normal and abnormal function was upon neu-
rochemistry and neuropharmacology. That was the era when anti-
depressants like Prozac were introduced in 1985, along with an array of
antipsychotic medications. Now there is a totally different view of
plasticity (see Box 4). Here is how our lab came into investigating this
topic. In 1988, Elizabeth Gould came to my laboratory as a postdoctoral
fellow and started us down the path of discovering structural plasticity
in the adult brain which includes spine synapse turnover, dendritc re-
modeling and dentate gyrus neurogenesis.
Neurogenesis: Neurogenesis in the adult brain is now recognized as
an important feature of brain plasticity (Box 4). Gould with, at that
time, students, Catherine Woolley and Heather Cameron, also estab-
lished that neurons of the dentate gyrus part of the hippocampus die
and are replaced via neurogenesis that continues over the entire life
course (Cameron and Gould, 1996; Gould et al., 1992). Kara Pham and
Juan Nacher later found that toxic stress suppresses that neurogenesis
and shrinks the hippocampus (Pham et al., 2003), while other labora-
tories went on to show that physical activity increases neurogenesis not
only in young but also older animals (Kempermann and Gage, 1999;
van Praag et al., 2005). These revelations about adult brain neuro-
genesis have huge implications through the recognition that so-called
stem or progenitor cells might be used to treat brain damage. And they
also have meaning for lifestyle, in that regular physical activity in-
creases this neurogenesis, in old as well as young, and improves
memory and mood and even enlarges the hippocampus, which tends to
shrink in depression, diabetes among other conditions (McEwen, 2007).
Within 6 months to a year, regular aerobic activity such as walking an
hour a day 5 out of 7 days a week not only makes the hippocampus
larger and improves memory (Erickson et al., 2011) but it also improves
decision making by improving blood flow and metabolic function in the
prefrontal cortex (Colcombe et al., 2004b; Kramer et al., 1999), a brain
region essential for self-regulation of emotions and impulses as well as
decision making and working memory. Regarding sex differences, there
is evidence that women’s executive processes may benefit more from
exercise than men (Barha et al., 2017). The benefits of moderate phy-
sical activity on the brain as well as the body cannot be
B.S. McEwen Frontiers in Neuroendocrinology 49 (2018) 8–30

Box 5
The Brain Can Generate Steroid Hormones from Cholesterol.

Besides progesterone generation by Schwann cells and oligodendrocytes (Schumacher et al., 2012), the brain is capable of making estradiol
and also androgens. Estradiol production “on demand” from cholesterol via aromatization in an ischemic brain has been documented (Hojo
et al., 2003), and knocking out aromatase in brain exacerbates the damaging effects of ischemia (McCullough et al., 2003). Furthermore,
after ovariectomy estrogen level are detectable after 3 weeks of gonadectomy in the male or female amygdala and in the female prefrontal
cortex but not in hippocampus, suggesting a local source (Barker and Galea, 2009). For androgens, the ability of exercise to stimulate
neurogenesis in male rat hippocampus is dependent on extra-gonadal production of dihydrotestosterone (Okamoto et al., 2012). The brain
also has the capacity to generate neuroactive steroids such as A-ring reduced metabolites of progesterone that are allosteric modulators of
the GABAa receptor that mediate its anaesthetic and sedative effects (Baulieu and Robel, 1990; Gee et al., 1987).

overemphasized! Indeed, regular physical activity is the most important
behavior that one can do to maintain brain and body health! And, as a
further illustration of brain-body communication, the ability of exercise
to stimulate neurogenesis requires at least two hormones to be taken up
from the body into the brain. One of them, IGF-1, comes from the liver
(Aberg et al., 2000; Trejo et al., 2001) and the other, cathepsin B, comes
from muscle (Moon et al., 2016). There are likely other mediators to be
discovered!
Spine synapse turnover and dendritic remodeling: While neu-
roscience research in the mid-to-late 1980s focused on the effects of
gonadal and adrenal steroids on neurotransmitter and neuromodulator
receptors, and we were involved in this through the work in our la-
boratory of William Rostene, Scott Mendelson, Anabelle Segarra,
Christine Fischette, Lori Flanagan, Anita Danielsson, Anat Biegon, Jesus
Angulo, Alan Johnson, Bruce Nock, Maureen Gannon, Michael
Schumacher, Zoltan Sarnyai and Hector Coirini, we were about to
embark on yet another new direction with the arrival of Elizabeth
Gould (see Box 5).
Elizabeth Gould introduced us to an old method introduced in the
late 1800s by Camelio Golgi, an Italian neuroanatomist who won a
Nobel Prize for it. The Golgi technique, when done right, allows the
investigator to visualize and measure the dendrites (like tree branches)
and even the spines (sites of synapses with other neurons) on those
dendrites. Using the Golgi technique, Gould and her student, Catherine
Woolley, along with Yoshifumi Watanabe, showed that dendrites shrink
and spines synapses are lost on hippocampal neurons after chronic
stress lasting several weeks due, in part to the actions of glucocorticoids
(McEwen, 2016), while, in contrast, spine synapse come and go during
the estrous cycle of the female rat because of the fluctuations of the
ovarian hormone, estradiol and progesterone (Woolley and McEwen,
1992). These findings have lead in two different directions in terms not
only of application but also underlying mechanisms. Thus, circulating
hormones not only enter the brain and bind to receptors but also par-
ticipate with the brain’s own neurotransmitters in what we now call
“adaptive plasticity”, which underlies behavioral and neurological
adaptation. For example, shrinkage of dendrite in hippocampus pro-
tects those neurons from damage by over-stimulation during toxic stress
(McCall et al., 2013), and cyclic fluctuations of spine synapses during
the estrous cycle (and in the human menstrual cycle) underlie differ-
ences in behavior, including mood swings (Hara et al., 2015). Re-
markably, in both cases, the hormones did not work alone and require,
among other “mediators” the main neurotransmitter in the brain, glu-
tamate (see Box 6). I shall first discuss the effects of estradiol.
Estradiol, progestins and the brain outside of the hypothalamus:
Elizabeth Gould together with Catherine Woolley and Maya Frankfurt
discovered estradiol-induced spine synapse formation in hippocampus
along with ventromedial hypothalamus (Frankfurt et al., 1990; Gould
et al., 1990). The seminal work of Catherine Woolley as a graduate
student and in her academic career to date paved the way not only to
recognize synaptic turnover, first in hippocampus and then in cortex
and other brain regions, dependent on estradiol and progestins, but also
to recognize mechanisms of estradiol and other steroid hormone actions
that are non-genomic and involve the co-opting by the hormone of
signallng pathways used in other cell types for other purposes (Woolley,
1999). Our colleague, Teresa Milner, Weill Cornell Medical College,
together with postdoctoral fellow Steve Alves, identified im-
munochemically and later by autoradiography the non-genomic sites
for estradiol receptor alpha in post-synaptic densities and spine appa-
ratus (Milner et al., 2008, 2001). All this was preceded by work of Neil
MacLusky as a postdoctoral fellow, to show estradiol inducible pro-
gestin receptors in hippocampus (MacLusky and McEwen, 1978) that
turn out to be non-nuclear (Mitterling et al., 2010) and to mediate
progesterone-induced down-regulation of spine synapses in hippo-
campus as seen in the estrous cycle (Woolley and McEwen, 1993).
Estradiol treatment increases NMDA receptor binding and expres-
sion (Fischer et al., 2002; Weiland, 1992) and increases NMDA-medi-
ated synaptic input (Woolley et al., 1997). In addition, blocking NMDA
receptors during estradiol treatment of ovariectomized rats prevents
estradiol-induced spine synapse formation in the CA1 region of the
hippocampus (Woolley and McEwen, 1994). An example of tipping the
excitatory/inhibitory balance towards excitation to facilitate plasticity
(Bavelier et al., 2010), the up-regulation of NMDA receptors in the CA1
region of female rat hippocampus by estradiol is indirect, in that it is
blocked by M2 muscarinic receptor antagonists and mimicked, by-
passing estradiol, by elevating cholinergic activity (Daniel and
Dohanich, 2001) and this appears to involve disinhibition of inhibitory
GABAergic input to CA1 pyramidal neurons (Rudick et al., 2003). In
this connection it is important to note, as shown by Victorial Luine, that
estradiol up-regulate choline acetyltransferase activity (Luine et al.,
1975) as well as potassium-stimulated acetylcholine release (Gibbs
et al., 1997) and that they may do the latter via non-genomic ER α
receptors in cholinergic terminals (Towart et al., 2003). The up-reg-
ulation of NMDA receptors led to initiation of a cascade of filopodial
formation (Yuen et al., 2011) and translation of PSD-95 mRNA in
dendrites to form scaffolding for new synapses (Akama and McEwen,
2003; Znamensky et al., 2003). These signaling pathways involving
BDNF, trkB, phosphorylated Akt and LIMkinase were carefully mapped
across the estrous cycle by Joanna Spencer-Segal in BDNF val/66/val
and met/66/met mice (McEwen et al., 2012).
There are 3 types of estradiol receptors in the brain, and, as far as
the respective role of ER α, ER β and the G-protein coupled GPER1, ER
α ko mice fail to show E induced increases in spinophilin, a marker of
spine formation, while ER β ko mice allow some E up-regulation of
spinophilin, while both ERα and ERβ agonists increase spinophilin
immunoreactivity in mouse hippocampus (Spencer et al., 2008).
GPER1, formerly GPR30, also appears to be involved, according to work
spearheaded by Beth Waters and Teri Milner; the GPER1 agonist, “G1,
increased PSD95-IR in strata oriens, lucidum, and radiatum of CA3 in
ovariectomized mice 6 h after administration. In contrast, estradiol but
not G1 increased Akt phosphorylation levels. Thus, GPER1 actions in
the synapse may be due to interactions with synaptic scaffolding pro-
teins, such as SAP97. These results suggest that although estradiol’s
actions via GPER1 may converge on the same synaptic elements, dif-
ferent pathways are used to achieve these actions” (Waters et al., 2015).

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B.S. McEwen Frontiers in Neuroendocrinology 49 (2018) 8–30

Box 6
Translation to human brain.

Recognition that hormones play an important role in modulating brain structure and function has opened the way to show how circulating
hormones contribute to brain disorders when their normal functions to promote adaptation go awry. Here are some additional examples
showing the value of translation and also reverse translation. Regarding glucocorticoids, Cushing’s Disease is a prominent example. In
Cushing’s disease, there are depressive symptoms along with a smaller hippocampus and memory problems that can be relieved by surgical
correction of the hypercortisolemia (Murphy, 1991; Starkman and Schteingart, 1981). However, there are residual effects associated with
the exposure to glucocorticoids in Cushing’s (Bas-Hoogendam et al., 2015; van der Werff et al., 2015) Both major depression and Cushing’s
disease are associated with chronic elevation of cortisol that results in gradual loss of minerals from bone and also can contribute to
abdominal obesity. In major depressive illness, as well as in Cushing’s disease, the duration of the illness and not the age of the subjects
predicts a progressive reduction in volume of the hippocampus, determined by structural magnetic resonance imaging (MacQueen et al.,
2003; Sheline et al., 1999; Starkman et al., 1992).
The hippocampus figures prominently, as there are a variety of other anxiety-related disorders, such as post-traumatic stress disorder
(PTSD) (Pitman, 2001; Vythilingam et al., 2002) and borderline personality disorder (Driessen et al., 2000), in which atrophy of the
hippocampus has been reported, suggesting that this is a common process reflecting chronic imbalance in the activity of adaptive systems,
such as the HPA axis, but also including endogenous neuro-transmitters, such as glutamate. Inflammation is also a factor related to many
disorders of modern life, and elevation of IL6 has been linked to reduced hippocampal volume (Marsland et al., 2008) as well as to poor
sleep (Friedman et al., 2005). Although there is little evidence regarding the effects of ordinary life stressors on brain structure, there are
indications from functional imaging of individuals undergoing ordinary stressors, such as counting backwards that there are lasting changes
in neural activity (Wang et al., 2005). Moreover, a 20 year history of chronic perceived stress has been linked in a cross-sectional study to
smaller hippocampal volume (Gianaros et al., 2007). Moreover, jet-lag and lack of adequate recovery is reported to lead to a smaller
temporal lobe, memory impairment and dysregulated and elevated cortiisol (Cho, 2001).
Brain regions besides the hippocampus, particularly the amygdala and prefrontal cortex, show altered patterns of activity in PET and
fMRI and also demonstrate changes in volume with recurrent depression: decreased volume of hippocampus and prefrontal cortex and
amygdala (Drevets et al., 1997; Sheline, 2003; Sheline et al., 1998, 1999). Interestingly, however, amygdala volume has been reported to
increase in the first episode of depression, whereas hippocampal volume is not decreased (Frodl et al., 2003; MacQueen et al., 2008).
Moreover, amygdala volume is greater in children living with a depressed mother for a decade (Lupien et al., 2011).
It has been known for some time that stress hormones, such as cortisol, are involved in psychopathology, reflecting emotional arousal
and psychic disorganization rather than the specific disorder per se (Sachar et al., 1973). But there is more than cortisol affecting the brain
and, in particular, metabolic hormones have many effects that alter systemic physiology and mental health and there is co-morbidity of
systemic disorders with mental health disorders (Tomasdottir et al., 2015). See Box 1. Toxic stress can increase anxiety by causing neurons
in the amygdala, a brain region controlling anxiety and aggression, to become larger; and, yet, a successful mindfulness stress reduction can
ameliorate that (Holzel et al., 2010), as. And regular physical activity, like walking every day, causes genesis of new neurons in the
hippocampus, a brain region that is essential for memory of daily events and spatial orientation; and it improves memory and also mood
(Erickson et al., 2011).

In contrast to the female hippocampus, where there is the complex
interaction between cholinergic, GABAergic and glutamatergic neu-
ronal activity for the induction of NMDA receptor expression and sub-
sequent estradiol-dependent spine synapse formation, the male hippo-
campus shows androgen-induced NMDA receptor up-regulation that
does not involve any androgen effect on the cholinergic system (Romeo
et al., 2005) and shows an androgen-induced spine formation that is
abolished by fimbria-fornix transection implying the importance of
some form of neuronal activity (Kovacs et al., 2003).
Focusing on estradiol-induced synapse formation, Susan Lee, Russ
Romeo and Wayne Brake showed the effect of estradiol up-regulation of
spine synapses in female hippocampus and a lack of that up-regulation
in males using radioimmunocytochemistry with antibodies to spino-
phillin (Lee et al., 2004). Before that, Wayne Brake had used that
technique to demonstrate spine formation immunocytochemically
(Brake et al., 2001); and Chenjian Li used radioimmunocytochemistry
in mouse brain along with Golgi to look at spine density after estradiol
treatment along with size and shape that showed an estradiol effect to
promote spine maturation (Li et al., 2004) In parallel, Steve Alves with
Brake, Victoria Luine and Russ Romeo showed that pharmacological
depletion of serotonin reduced spine density in the CA1 region of the rat
hippocampus but did not prevent estradiol-induced increases in spine
density (Alves et al., 2002).
The actions of estradiol on cognitive function and their absence
after the menopause have become the focus of hormone therapy to slow
cognitive aging and prevent Alzheimer’s disease, and the work on this
topic by colleague John Morrison, now Director of the Primate Center
at UC Davis, some in collaboration with us, has been very influential
(Dumitriu et al., 2010; Hara et al., 2015, 2016). Likewise, the con-
tributions by former postdoctoral fellow, Roberta Brinton, now at the
University of Arizona, have opened new avenues for use of the hor-
mone, progesterone, as a protective agent for the aging and a damaged
brain (Wang et al., 2010a).
Similarly, former postdoctoral fellow Michael Schumacher, now
head of an INSERM Unit (the French NIH) in Paris has found that the
cells in our brains that make myelin, the insulation of the brain, can
make the hormone, progesterone, and respond to it to make myelin
(Schumacher et al., 2012). He and a senior colleague, Professor Ale-
jandro DeNicola from Buenos Aires, are investigating use of proges-
terone and progesterone-like drugs to repair and regenerate myelin in
diseases like multiple sclerosis where there is loss of myelin
(Labombarda et al., 2015). There seems to be no end to the uses and
potential uses for these sex hormones that go well beyond reproduction
and this is a topic we shall return to later.
Stress-Induced Structural Plasticity: Our demonstration of stress-
induced remodeling of dendrites in hippocampal CA3 neurons provided
a neuroanatomical mechanism that helped to explain behavioral effects
of stress on memory and related processes (Conrad et al., 1996; Luine
et al., 1994; McEwen, 1999, 2007; McEwen, 2016). These discoveries
have led to a cascade of investigations in stress neurobiology that have
increasing relevance to human mental and physical health. What these
findings helped to demonstrate is the remarkable feature of the adult as
well as developing brain, namely, recognition of its capacity for re-
modeling of dendrites, turnover of synapses and neurogenesis that

14
B.S. McEwen
began with the enriched environment studies on brain cortex thickness
(Bennett et al., 1964; Greenough et al., 1973) based on the work of
Donald Hebb (Hebb, 1949). For stress-induced remodeling, which can
be mimicked by chronic glucocorticoid treatment, excitatory amino
acids and other cellular mediators are involved (McEwen, 1999, 2010).
The work of Robert Sapolsky emphasized damaging aspects of gluco-
corticoid action on hippocampus mediated also by excitatory amino
acids (Popoli et al., 2012; Sapolsky, 1992; Sapolsky et al., 1986). Put-
ting this together with stress induced neural remodeling, what emerged
is an inverted U shaped dose-response curve (see Fig. 1) in which
physiological levels of glucocorticoids and excitatory amino acids op-
erate synergistically and beneficially to facilitate LTP and memory. This
was shown by Constantine Pavlides at Rockefeller and also by David
Diamond (Diamond et al., 1992; Pavlides et al., 1995) over a short time
frame of minutes to hours. Over a time frame of days to weeks, the same
mediators promote dendritic remodeling that shows resilience and re-
covery in a healthy brain (McEwen, 1999). In contrast, acute traumatic
events such as stroke, seizures and head trauma cause permanent da-
mage and neuron loss via synergy between glutamate and glucocorti-
coids (Conrad et al., 1999a; Sapolsky, 1992).
Cheryl Conrad, whose work as a postdoctoral fellow showed that the
novel antidepressant, tianeptine, prevented chronic stress induced CA3
dendritic atrophy and spatial memory deficits while not preventing
chronic stress enhancement of fear conditioning (Conrad et al., 1996,
1999b) went on at the Arizona State University to show, among other
achievements, that conditions that cause CA3 dendrites to shrink make
those neurons more vulnerable to excitotoxic damage (Conrad et al.,
2007) while elevated CORT levels at the time of testing are responsible
for the spatial memory impairment and not the CA3 atrophy per se
apparently because of an altered sensitivity to CORT (Wright et al.,
2006).
The prefrontal cortex also responds to what we can call “tolerable
stress”. During his MD-PhD thesis research, the same Conor Liston as-
sessed perceived stress (how much or little they felt in control of their
daily lives) in a group of medical students during their studies and we
found that those with the highest perceived stress were slower in doing
a cognitive-flexibility test and also had slower functional connectivity
in a brain circuit involving the prefrontal cortex when tested in a
functional MRI machine (Liston et al., 2009). The reason we can call
this “tolerable stress” is that, after a vacation, these impairments
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Frontiers in Neuroendocrinology 49 (2018) 8–30
Fig. 1. Inverted U-shaped dose response curve for ef-
fects of adrenal steroids interacting with excitatory
amino acids to affect brain plasticity and vulnerability
to damage.
disappeared, showing the resilience, at least of the young adult brain!
Parallel studies on an animal model of perceived stress allowed Liston
and Jason Radley, now at the University of Iowa, working also with
John Morrison, to see shrinkage of neuronal dendrites and reduction of
synapses in the prefrontal cortex that explained the deficits in cognitive
flexibility (Liston et al., 2006; Radley et al., 2005).
To complete the present story of brain plasticity we need to describe
what happens in the amygdala under the same stressors that cause
dendrites to shrink and synapses to be lost in the prefrontal cortex and
hippocampus, namely, that dendrites in the basolateral amygdala grow
and become more branched and, as a result, there is increased anxiety.
This was discovered by a scientific colleague and now a collaborator,
Sumantra Chattarji, a Professor at the National Centre for Biological
Sciences in Bangalore, India (Vyas et al., 2002). Conor Liston found that
dendrites in the orbitofrontal part of the prefrontal cortex also expand
with chronic stress, and there is increased vigilance (Liston et al.,
2006). In the short term, these changes may be adaptive, as anxiety and
vigilance are adaptive in a dangerous or uncertain environment; but, if
the threat passes and the behavioral state “gets stuck” and persists
along with the changes in neural circuitry, such maladaptation requires
intervention to open “windows of plasticity” with a combination of
pharmacological and behavioral therapies.
Again, regular physical activity, as described earlier, can strengthen
both prefrontal cortex and hippocampus control of the amygdala
(Colcombe et al., 2004a). Another approach to chronic anxiety is
mindfulness based stress reduction (MBSR) that has been shown to
reduce the size of the amygdala in those anxiety sufferers who are able
to reduce their anxiety by MBSR (Holzel et al., 2010). Both MBSR and
meditation are gaining in popularity as a way of reducing anxiety and
thus reducing perceived stress, with increasing evidence of changes in
the brain (McEwen, 2016).
Some of this research on traumatic stress also has implications for
PTSD. In a collaboration with Shona Chattarji’s laboratory, we found
that a single, traumatic stressor causes new synapses to form in baso-
lateral amygdala with a delay of a week or so that is accompanied by a
gradual increase in anxiety (Mitra et al., 2005). This type of delay is a
feature of PTSD in people. What we have further shown with the
Chattarji group is that a timed elevation of cortisol at the time or, or
shortly after, a traumatic stressor actually prevents the delayed increase
in amygdala synapses and anxiety-like behavior (Rao et al., 2012). Now
B.S. McEwen
there is evidence for human PTSD that low cortisol at the time of
trauma, eg during open heart surgery or after a traffic accident, is a risk
factor and that elevating cortisol during or right after trauma can re-
duce later PTSD symptoms (Schelling et al., 2004; Zohar et al., 2011).
See Box 6 for other examples of translation to the human brain.
11. Psychosocial stressors provides a clue to mechanism
Although glucocorticoids like cortisol in humans and corticosterone
in rats and mice play an important role in brain structural remodeling
and neurochemistry, they are not working alone and require other
mediators and modulators that participate. Realization of this in my
laboratory came from an unusual direction, namely, the study of psy-
chosocial stress in the rat visible burrow system, developed by Caroline
and Robert Blanchard, in which Randall Sakai, Christine McKittrick and
Kellie Tamashiro played key roles (McEwen et al., 2015c). Chronic
social stress in this model, producing a dominant male and 4 sub-
ordinates led to changes in serotonin transporter (5HTT) binding, as
well as shrinkage of dendritic arborization in both dominants and
subordinates, compared to rats housed in ordinary group housed cages.
These changes occurred despite apparent differences in stressor severity
experienced by the animals (greater in subordinates which had larger
adrenals), suggesting that these changes may be part of the normal
adaptive response to chronic social stress (McEwen et al., 2015c). Yet,
because of the greater dendritic shrinkage in dominants compared to
subordinates, in spite of the larger adrenals in subordinates, these
findings took us away from simplistic idea that corticosterone (CORT)
caused it all, and it also turned attention to the existence of other
mediators and processes synergisitic with glucocorticoid functions. In-
deed, the mechanism for dendritic shrinkage has subsequently been
shown to involve multiple interacting mediators, with excitatory amino
acid receptors playing a major role, along with other mediators such as
brain derived neurotrophic factor (BDNF), tissue plasminogen activator
(tPA), corticotrophin releasing hormone (CRH) and others (see Table 1,
Box 7 and Fig. 2).
Table 1
Molecules that are necessary/permissive for remodeling.
A. Secreted signaling molecules
* BDNF - brain derived neurotrophic factor (Bath et al., 2013; Chen et al., 2006;
Govindarajan et al., 2006)
- Facilitator of plasticity or growth; FLOOR AND CEILING
* CRF – corticotrophin releasing factor (Chen et al., 2016)
- Down-regulates thin spines via RhoA signaling
* tPA - tissue plasminogen activator (Bennur et al., 2007; Matys et al., 2004; Pawlak
et al., 2003, 2005)
- required for stress-induced spine loss in CA1 hippocampus and medial
amygdala
- CRF regulates tPA release.
* Lipocalin-2 - secreted protein (Mucha et al., 2011; Skrzypiec et al., 2013)
- Acute stress induces Lipocalin-
- Lipocalin-2 ko increases neuronal excitability and anxiety
* Endocannabinoids (Gunduz-Cinar et al., 2013; Hill et al., 2013, 2010; Hill and
McEwen, 2010)
- Induced via glucocorticoids
- Regulate emotionality and HPA habituation and shut off
- Buffer against stress induced remodeling
B. Cell surface and nucleo-cytoplasmic interaction
*PSA-NCAM – cell surface “anti-stickiness” (McCall et al., 2013; Nacher et al., 2013;
Rutishauser, 2008; Sandi, 2004)
- Endonuclease N removes PSA from NCAM; dendrite expansion
- Facilitate plasticity but also limits it.
* Cell adhesion molecules: neuroligin-2; nectin-3 (van der Kooij et al., 2014a, 2014b)
- Chronic stress disrupts neuroligin-neurexin interaction
- Chronic stress reduces nectin-3 via MMP9 protease.
* Nuclear pore complex NUP-62 (Kinoshita et al., 2014)
- Reduction leads to dendrite shrinkage
- Possibly due to nuclear-cytoplasmic communication
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12. Glutamate overflow in depression and dementia
Not only is glutamate an essential excitatory transmitter throughout
the brain, but also dysregulated glutamate contributes to disorders such
as major depression and also aging and dementia, as documented by
ongoing work in the McEwen laboratory (see Box 8).
Depression: An unregulated overflow of glutamate appears to play a
role in depressive-like behavior in animal models in which shrinkage of
dendrites in the hippocampus and suppression of neurogenesis occurs.
Carla Nasca arrived in our laboratory in 2012 and introduced us to
acetyl-L-carnitine (LAC), a natural molecule that she showed rapidly
up-regulates the metabotrophic glutamate receptor, mGlu2, via an
epigenetic mechanism involving acetylation of lysine 27 on histone H3;
this is mimicked by histone deacetylase (HDAC) inhibitors, which act in
a few days, and by SSRI’s which act more slowly (Nasca et al., 2013,
2015). Thus LAC is a putative rapidly-acting antidepressant candidate
as shown in several animal models that have a deficiency of LAC with
normal levels of carnitine (Bigio et al., 2016; Nasca et al., 2013). On-
going studies in human major depression, which now involve a pro-
ductive collaboration with Natalie Rasgon of Stanford University, also
shows that LAC deficiency may be a factor (unpublished). Moreover,
LAC deficiency is also associated with insulin resistance that can be
corrected by LAC supplementation (Bigio et al., 2016), as will be dis-
cussed further below (see Box 9).
Aging and dementia: Unregulated glutamate overflow is also im-
plicated in aging and dementia. During aging in the rat, treatment with
riluzole, which is known to retard glutamate release and promote glu-
tamate reuptake by astrocytes, retards aging in the hippocampus as
measured by preservation of spatial memory and thin spines that are
found in young hippocampal neurons, as shown by Cognitive
Neurologist, Ana Pereira, in collaboration with the John Morrison la-
boratory (Pereira et al., 2014). Moreover, assessing gene expression
changes associated with aging in rodents using RNA-sequencing (RNA-
seq), riluzole prevented many of the hippocampal age-related gene
expression changes. Moreover, a comparison of the effects of riluzole in
rats against human AD data sets revealed that many of the gene changes
in AD are reversed by riluzole (Pereira et al., 2016). Glutamate also
plays a role in plasticity in the prefrontal cortex and amygdala, de-
scribed above. Dr. Pereira, a Clinical Assistant Professor associated with
the McEwen lab is conducting a clinical trial of early Alzheimer’s Dis-
ease with riluzole. Because of her interest in etiologies of dementia, she
has conducted a study of 33 older adults, average age 64 years, and
show that levels of the inhibitory neurotransmitter γ-aminobutyric acid
(GABA) in the left dorsolateral prefrontal cortex (DLPFC), a brain re-
gion that controls executive function, were lower in people with mod-
erate to severe sleep disordered breathing (SDB) than in controls; this
correlated with minimum oxygen saturation and severity of disease,
suggesting that SDB-induced hypoxia could reduce DLPFC GABA levels,
leading to neuronal hyperexcitability, neuronal damage and cognitive
decline (Pereira et al., 2017).
13. Microglia and brain dendritic cells
Astrocytes and their role in glutamate reuptake and oligoden-
drocytes and their role in myelin formation are complemented in the
brain by “microglia” that are related to the circulating monocytes of the
immune system, a subset of which are brain dendritic cells (D'Agostino
et al., 2012a). Karen Bulloch’s Neuroimmune and Neuroinflammation
Program at Rockefeller began with a study of the role of microglia in
the increased inflammation that occurs with aging in the brain (Sierra
et al., 2007). Using a mouse with a transgene expression in peripheral
dendritic cells, she and her colleagues went on to demonstrate the
presence of dendritic-like cells in the developing and adult brain
(Bulloch et al., 2008) that increase with age (Kaunzner et al., 2012) and
after stroke damage (Felger et al., 2010) and show unique properties in
the pituitary gland (Glennon et al., 2015). They also found that virally-
B.S. McEwen Frontiers in Neuroendocrinology 49 (2018) 8–30

Box 7
Central Role of Glutamate and Other Mediators in Plasticity and Damage.

Excitatory amino acids, particularly glutamate, play a key role in structural as well as functional changes in the brain since glutamate is the
major excitatory transmitter, while, at the same time, excess glutamate causes damage and inflammation (McEwen, 1999). Using chronic
corticosterone treatment and, separately, repeated restraint stress, Yoshi Watanabe and Gould, caused shrinkage of apical dendrites of
hippocampal CA3 neurons that could be blocked by phenytoin, implicating glutamate (McEwen, 2016). Indeed, acute restraint stress
elevates extracellular glutamate levels via a process that is blocked in adrenalectomized animals, implicating the adrenal cortex and
possible direct effects of adrenal steroids on glutamate release (Lowy et al., 1993). Indeed, corticosterone was subsequently shown to act
directly via membrane associated MR and GR to cause glutamate release (Karst et al., 2005; Treccani et al., 2014). Blocking NMDA
receptors and interfering with excitatory stimulation of ion channels blocks stress induced dendritic remodeling, as also does blockade of
adrenal steroid synthesis (Magarinos and McEwen, 1995; Watanabe et al., 1992). A stress-induced NMDA-dependent dendritic remodeling
has also been reported in medial prefrontal cortex neurons (Martin and Wellman, 2011).
Besides glutamate, there are other mediators that participate in structural and functional remodeling of brain circuits with experience,
as summarized in Table 1. These included ongoing studies of BDNF with our collaborators Francis Lee (Weill Cornell) and Kevin Bath
(Brown), past investigations of tissue plasminogen activator and lipocalin 2 with Robert Pawlak and Sid Strickland and Shona Chattarji and
extensive investigations of endocannabinoids with Matt Hill and Cecilia Hillard, as well as the important studies by Tallie Baram and
colleagues at UC Irvine.
Moreover, Table 1 shows a number of cellular processes are involved in dendritic remodeling including cytoskeletal depolymerization
caused by a soluble phosphorylated tau (Arendt et al., 2003) and stress-induced reduction in expression of a cell nuclear pore complex
protein (Kinoshita et al., 2014), suggesting that ongoing gene expression may be involved in maintaining the dendritic tree. Excess glu-
tamatergic 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 glucorticoids (Sapolsky et al., 1986).
These relationships can be summarized in an inverted U-shaped dose and time response curve in Fig. 1.

varies over the circadian cycle and it mediated by nuclear receptor

Fig. 2. Gene expression hippocampus after a bolus of corticosterone compared to the
effects of a novel acute forced swim (FST) in naïve, chronically restrained (CRS) and
recovered (Rec after CRS) showing largely unique gene expression responses, indicating
that the brain is continually changing with experience. There is a set of genes always
activated by FST (e.g., immediately early genes). From Gray et al. (2014) with permis-
sion.
induced encephalitis initiates distinct and functional CD103+ CD11b+
brain dendritic cell populations within the olfactory bulb (D'Agostino
et al., 2012b) and that the mortality of virally-induced encephalitis
REV-ERBalpha (Gagnidze et al., 2016).
Karen Bulloch’s group established a collaboration with Nina
Papavasiliou at Rockefeller on the RNA editing enzyme, APOBEC1, and
this has resulted in a remarkable set of findings. Microglia (MG), a
heterogeneous population of phagocytic cells, aid in maintaining
homeostasis by producing anti-inflammatory cytokines and neuro-
trophic factors, supporting myelin production, removing synapses and
cellular debris as well as participating in “cross correction”, a process
that supplies neurons with key factors for executing autophagy-lyso-
somal function. As sentinels for the immune system, MG also detect
“danger” signals (pathogenic or traumatic insult), become activated,
produce pro-inflammatory cytokines, and recruit monocytes and den-
dritic cells to the site of damage through a breached blood brain barrier
or via brain lymphatics. Failure to effectively resolve MG activation can
be problematic and lead to chronic inflammation, a condition proposed
to underlie CNS pathophysiology in heritable brain disorders and age-
related neurodegenerative and cognitive decline. They have shown that
APOBEC1-mediated RNA editing occurs within microglia and is key to
maintaining their resting status (Rayon-Estrada et al., 2017). Like bone
marrow-derived macrophages, RNA editing in MG leads to overall
changes in the abundance of edited proteins which coordinate and
harmonize the function of multiple cellular pathways. Conversely, mice
lacking the APOBEC1 editing function in MG, display evidence of
dysregulation, with progressive, age-related signs of

Box 8
Non-genomic Mechanisms of Steroid Action.

After the initial focus on cell nuclear actions of steroid hormones in brain, it became evident that there are other mechanisms of steroid
hormone action (Kelly and Levin, 2001; Levin and Hammes, 2016; Liposits and Bohn, 1993; Norman et al., 1999; Wehling, 1997). Besides
the non-genomic actions of estradiol on synapse formation via pAkt and pLIMK, there are non-genomic actions of adrenal steroids that
figure prominently in the findings described herein. For MR and GR, membrane associated localizations of GR and MR are linked to the
direct stimulation and regulation of excitatory amino acid release (Karst et al., 2005; Tang et al., 2011; Treccani et al., 2014). One of the
first examples of a rapid non-genomic action of glucocorticoids was the rapid activation of tryptophan hydroylase for serotonin formation
by Efrain Azmitia, as a graduate student in the McEwen laboratory (Azmitia and McEwen, 1968). As a postdoctoral fellow, Anat Biegon
explored non-genomic mechanisms for estradiol to affect serotonin and noradrenalin receptors in the brain (Biegon et al., 1983) There is
also an important feed-forward cycle between glucocorticoids and trkB, the receptor for BDNF (McEwen, 2015) as summarized in Fig. 3.

17
B.S. McEwen Frontiers in Neuroendocrinology 49 (2018) 8–30

Fig. 3. Glucocorticoids produce direct and indirect

genomic actions as well as nongenomic signaling ac-
tions via glucocorticoid (GR) and mineralocorticoid
(MR) receptors. These involve not only direct and in-
direct genomic actions, but also direct stimulation of
glutamate release and stimulation of endocannabinoid
production, which then feed back on glutamate and
GABA release and actions in mitochondria to affect Ca
++ buffering and free radical formation (Popoli et al.,
2012) (Upper Right). As shown in the article by
Arango-Lievano et al. (2015), BDNF, in the presence of
glucocorticoids, phosphorylates the GR at sites that
facilitate its translocation to the cell nucleus for tran-
scriptional actions; this effect is synergistic with the
ability of glucocorticoids to activate, via a genomic
mechanism, the phosphorylation of the Trk B receptor
independently of BDNF, thus creating a positive feed-
back loop. From McEwen (2015) with permission.

neurodegeneration, characterized by clustering of activated microglia,
aberrant myelination, increased inflammation and lysosomal anomalies
that culminate in behavioral and motor deficiencies, as in so-called
lysosomal storage diseases (Cole et al., 2017).
14. Gene expression continually changes with experience
As the first extra-hypothalamic brain structure recognized to have
receptors for adrenal steroids (McEwen et al., 1968), the hippocampus
is an important gateway for understanding the effects of glucocorticoids
and stress on gene expression in the brain. Recent technological ad-
vances have allowed high-throughput analysis of gene expression
changes in response to stress (Rubin et al., 2014). For example, work by
current postdoctoral fellow, Jason Gray, using a microarray analysis of
whole hippocampus after acute stress, chronic stress, and stress re-
covery in mice revealed that acute and chronic stress modulate a core
set of genes, but that numerous changes are exclusive to each condition,
highlighting how duration and intensity of stress alters reactivity (Gray
et al., 2014). Furthermore, corticosterone injections do not yield the
same expression profile as acute stress, suggesting that in vivo stressors

Box 9
Metabolic Hormones Enter the Brain and Affect Many Functions.

See Fig. 4. Metabolic hormones are transported into the brain and have multiple functions in the healthy brain. Besides glucocorticoids and
excitatory amino acids, a number of protein hormones have been shown to affect the hippocampus. The hippocampus has receptors for IGF-
1 and insulin and it responds to circulating insulin to translocate glucose transporters to cell membranes (Dore et al., 1997; Piroli et al.,
2007). Circulating IGF-1 is a key mediator of the ability of physical activity to increase neurogenesis in the dentate gyrus of the hippo-
campal formation (Aberg et al., 2000; Carro et al., 2001). IGF-1 is taken up into brain via a transport system different from that which
transports insulin, although there is some overlap (Banks et al., 2012; Pulford and Ishii, 2001; Yu et al., 2006). IGF-1 is a member of the
growth hormone family, and growth hormone is implicated in cognitive function and mood regulation (Donahue et al., 2006; Nyberg,
2000). Growth hormone is expressed in the hippocampus where it is up-regulated by acute stress and also, in females, by estradiol
(Donahue et al., 2006). Interestingly, although growth hormone mRNA is expressed in hippocampus (Donahue et al., 2002) and growth
hormone also enters the brain in small amounts from the circulation, although not by a specific transport system (Pan et al., 2005).
Furthermore, circulating ghrelin, a pro-appetitive hormone, has been shown to increase synapse formation in hippocampal pyramidal
neurons and to improve hippocampal-dependent memory (Diano et al., 2006). Ghrelin is transported into brain via a saturable system
(Banks et al., 2002) and receptors for ghrelin are expressed in hippocampus, as well as in other regions of the brain (Zigman et al., 2006).
Another metabolic hormone, leptin, has been found to exert antidepressant effects when infused directly into the hippocampus (Lu et al.,
2006). Leptin is transported into the brain, and both glucose and insulin mediate the ability of fasting to increase leptin transport into the
brain (Kastin and Akerstrom, 2001). Leptin receptors are found in hippocampus among other brain regions and leptin has actions in
hippocampus, via excitatory amino acid receptors, that reduce the probability of seizures and enhance aspects of cognitive function
(Harvey et al., 2005).

18
B.S. McEwen
activate a diverse set of pathways independent of glucocorticoid re-
ceptor (GR) activation (Gray et al., 2014). Finally, characterization of
expression profiles after extended recovery from 21 days of chronic
stress showed that, despite a normalization of anxiety-related beha-
viors, recovery did not represent a return to the stress-naïve baseline,
but rather represents a new state in which reactivity to a novel stressor
produces a unique expression profile (Gray et al., 2014).
Studies in rats confirm that gene expression profiles can vary sig-
nificantly from the immediate end of stress to 24 h later (Wang et al.,
2010b), and that chronic stress can alter the transcriptional response to
an acute corticosterone injection in dentate gyrus, as showing in a
collaboration with Dutch scientists, Nicole Datson, and Ron de Kloet
(Datson et al., 2013). Together, these studies demonstrate that a history
of stress exposure can have a lasting impact on future stress reactivity
and hippocampal function. It seems logical to assume that this gen-
eralizes to all experiences that we have, whether or not we call them
“stress”.
Histone modifications are keys to epigenetic regulation of gene
expression, Besides the acetylation of histones involved in the up-reg-
ulation of mGlu2 gene expression described above, repressive epige-
netic modifications of histones are also evident after acute and chronic
stress, as shown by Richard Hunter, now a faculty member at U Mass
Boston. Acute stress dramatically increased the levels of H3K9 tri-me-
thylation (H3K9me3) in the dentate gyrus (DG) and CA1, while chronic
restraint stress (CRS) for 21 days abolished this effect. Treatment with
fluoxetine during CRS reversed the decrease in DG H3K9me3 (Hunter
et al., 2009). To dig deeply into the substantial, regionally specific,
increase in hippocampal levels of the repressive histoneH3 lysine 9
trimethylation (H3K9me3), Hunter used ChIP coupled with next gen-
eration sequencing (ChIP-Seq) to determine the genomic localization of
the H3K9me3 response. We found that acute stress increases in
H3K9me3 trapped and therefore repressed expression enrichment at
transposable element loci and, using RT-PCR, we demonstrate that this
effect represses expression of intracisternal- A particle endogenous
retrovirus elements and B2 short interspersed elements, but it does not
appear to have a repressive effect on long interspersed element RNA. In
addition, the histone H3K9-specific methyltransferases Suv39h2 is up-
regulated by acute stress in the hippocampus, and that this may explain
the hippocampal specificity (Hunter et al., 2012). This response may
represent a genomic stress response aimed at maintaining genomic and
transcriptional stability in vulnerable brain regions such as the hippo-
campus, although the transposome might have adaptive functions at the
level of both evolution and the individual organism (Hunter et al.,
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Frontiers in Neuroendocrinology 49 (2018) 8–30
Fig. 4. Metabolic hormones are transported into the
brain and have multiple functions in the healthy brain.
From McEwen (2007).
2013).
15. Mitochondria have their special place in plasticity and
damage and hormone action
Mitochondria have emerged as major players in steroid hormone
actions and containment of excitotoxicity because of their ability to
generate free radicals and to sequester Ca++ ions to contain that
process, as well as to express genes from its own genome and receive
nuclear coded genes that, together, regulate a host of important cell
functions (Picard et al., 2014). Mitochondria are also known to respond
to glucocorticoid receptors translocated into them (Moutsatsou et al.,
2001). In the McEwen lab this interest began with a collaborative study
with Richard Hunter in my lab and Jing Du and Husseini Manji at NIMH
that showed a biphasic effect of glucocorticoids on mitochondria
function in which physiological levels of glucocorticoids promote Ca+
+ sequestration, moderate oxidation and maintain mitochondrial
membrane potential while supra-physiological glucocorticoid levels
start to do so but fail after 24 h and lead to a failure of all three mea-
sures (Du et al., 2009). Hunter went on to more recently locate the site
on the mitochondrial circular DNA where glucocorticoid receptors exert
their transcriptional effects (Hunter et al., 2016).
Martin Picard, while at the University of Pennsylvania as a post-
doctoral fellow, introduced us to mitochondrial dysfunction on the
premise that the experience of psychological stress triggers neu-
roendocrine, inflammatory, metabolic, and transcriptional perturba-
tions that ultimately predispose to disease via allostatic load/overload.
To examine the role of mitochondria, using the hypothesis that ab-
normal mitochondrial functions would differentially modulate the or-
ganism’s multisystemic response to psychological stress, he uses mice
with mutations or deletions of key mitochondrial genes to selectively
impair mitochondrial respiratory chain function, energy exchange, and
mitochondrial redox balance in mice. In a collaborative study we found
that mitochondrial dysfunctions altered the hypothalamic– pituitar-
y–adrenal axis, sympathetic adrenal–medullary activation and ca-
techolamine levels, the inflammatory cytokine IL-6, circulating meta-
bolites, and hippocampal gene expression responses to stress. Each
mitochondrial defect generated a distinct whole-body stress response
signature. Thus mitochondria are stress-response modulators, with
implications for understanding the mechanisms of stress pathophy-
siology and mitochondrial diseases (Picard et al., 2015). And it is also
important not to ignore estradiol which regulates mitochondrial oxi-
dation, since estradiol receptor beta is also translocated into
B.S. McEwen
mitochondria and has neuroprotective actions (Rettberg et al., 2014). In
particular, after a surgical menopause, as shown in rhesus monkeys,
circular mitochondria are formed in cortical neurons that are known to
generate free radicals and oxidative and inflammatory damage (Hara
et al., 2014; Picard and McEwen, 2014), where estradiol treatment may
be particularly important as a neuroprotective strategy.
16. Diurnal cycles and circadian disruption
Plasticity of the brain extends to the day-night (diurnal) cycle of
waking and sleeping and it goes beyond the hippocampus to other brain
regions. During his postdoctoral work, Conor Liston, now an Assistant
Professor of Psychiatry at Cornell Medical School, found that some, but
not all, synapses in many parts of the cerebral cortex turn over during
the diurnal cycle due to the fluctuation of cortisol and that interfering
with that cycle by elevated cortisol at the wrong time of day interferes
with motor learning, like learning to play golf (Liston et al., 2013).
Considering how many ways we modern humans interfere with our
natural day-night rhythm, for example, by turning on a light in the
middle of the night, this is a lesson to all of us to give the “wisdom of
the body” a better chance to help us.
Another way we interfere with the natural cycle is through shift
work and jet lag. As a post-doctoral fellow, Ilia Karatsoreos, now an
Associate Professor at Washington State University, found that creating
an animal model of shift work caused dendrites in the prefrontal cortex,
the brain region that governs our ability to regulate emotions and im-
pulses as well as working memory, to shrink and the animal to become
cognitively rigid when challenged with a memory task that required
changing the rules; moreover, the shift work animals became fatter and
insulin resistant, signs of pre-diabetes and depressive-like behavior
(Karatsoreos et al., 2011). Shift work in our own species is associated
with greater obesity, diabetes, cardiovascular disease and mental health
problems (Bowles et al., 2017; McEwen and Karatsoreos, 2015). As
shown by Nicole Bowles working with Karatsoreos, Cecilia Hillard and
Matt Hill, one of the mediators for this obesity, acting peripherally, are
endocannabinoids acting via the CB1 receptor (Bowles et al., 2015).
Nicole Bowles, who is now at Oregon Health Sciences University as a
postdoctoral fellow, has gone on to begin to relate this story to the
health effects of shift work in transit workers (Bowles et al., 2017).
17. Sex hormones and sex differences
As noted at the beginning, we and others found that sex hormones
act on the hippocampus and virtually every extra-hypothalamic brain
region to affect a wide range of neurological and behavioral processes
(McEwen et al., 2012; McEwen and Milner, 2007, 2017). Up to this
point in the review, we have not considered how men and women
differ. Women are more prone to depression after toxic stress while men
show more antisocial behavior as their response (Eme, 2007; Kessler
et al., 1994, 1993). Over the years until the present, many McEwen lab
members have gone on to study sex differences in how the brain re-
sponds to stress. Liisa Galea, now at University of British Columbia,
showed that female rats did display the same chronic stress-induced
dendritic retraction that is evident in males and she did so together with
postdoctoral fellows Bob Spencer and student Firdaus Dhabhar (Galea
et al., 1997). (Galea has gone on to make seminal contributions re-
garding estradiol regulation of neurogenesis (Galea et al., 2013) and
neural and behavioral effect of pregnancy, including post-partum de-
pression (Barha et al., 2007; Galea et al., 2001; Pawluski and Galea,
2007; Workman et al., 2016).)
Likewise, in collaboration with us, postdoctoral fellow Rebecca
Shansky and John Morrison showed that males and females differ in
response to stress in the medial prefrontal cortex – males show stress-
induced shrinkage of dendrite that project cortically whereas females
do not show that change but, rather, show stress-induced expansion of
dendrites that project to the amygdala but only when there were
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Frontiers in Neuroendocrinology 49 (2018) 8–30
estradiol on board and not after ovariectomy (Shansky et al., 2010).
Shansky, now at Northeastern University, is investigating the con-
sequences of such sex differences for the behavioral mechanistic sex
differences in how male and female rats learn and extinguish fear
conditioning even though the outcome is similar (Gruene et al., 2015).
In the hippocampus of male rats, 21 days of chronic restraint stress
(CRS) causes apical dendrites of CA3 neurons to retract and a loss of
∼30% of the parvalbumin (PARV)-containing neurons in the dentate
gyrus; these changes do not occur following CRS in female rats (Galea
et al., 1997; Milner et al., 2013). Moreover, female and male rats show
effects in the opposite direction of chronic stress on hippocampal de-
pendent memory, with males showing impairment and females showing
enhancement or no effect (Bowman et al., 2003; Luine et al., 1996,
1994). Moreover, exposure of male and female rats to restraint plus
intermittent tail shock has opposite effects on classical eyeblink con-
ditioning, inhibiting it in females and enhancing it in males; in females,
this effect is abolished by ovariectomy and is therefore estradiol de-
pendent (Shors et al., 2001; Wood and Shors, 1998). A morphological
correlate of this in the hippocampus is the finding that acute stress
inhibits estradiol-depending spine formation in CA1 neurons of the
hippocampus, whereas the same acute stressors enhance spine density
in male CA1 neurons, possibly by increasing testosterone secretion
(Shors et al., 2001) upon which spine formation in the male CA1 is
dependent (Leranth et al., 2003). Neonatal masculinizaton of females
made them respond positively, like genetic males, to the shock stressor
(Shors, 2016) Moreover, in females, depending on reproductive status
and previous experience, the negative stress effect was altered, e.g., it
was absent in mothers and virgin females with experience with infants
(Shors, 2016).
Among possible mechanisms for the sex differences, the cortico-
trophin releasing factor receptor stands out since in hippocampus as
well as in locus coeruleus, there are sex differences in the association of
the CRF receptor (CRF1) with the G protein s and beta-arrestin 2 that
make females more responsive to acute stress and less able to adapt to
chronic stress as a result of compromised CRF1 internalization
(Valentino et al., 2013) Thus the failure of female rats and mice to show
spine loss and dendrite shrinkage (Galea et al., 1997; Pawlak et al.,
2005) may be related to this sex difference.
Sex differences in stress-induced remodeling of hippocampal, pre-
frontal cortex and amygdala neurons develop during the adolescent
maturation, and they are quantitatively, but not qualitatively, evident
in adolescent rats subjected to repeated restraint stress for 21d, ac-
cording to studies carried out by Lisa Eiland and reviewed together with
studies of how stress affects the adolescent brain and body development
by Eiland and Romeo (Eiland et al., 2012; Eiland and Romeo, 2012).
However, restraint stress in adolescents suppresses neurogenesis in fe-
males but not in males (Barha et al., 2011). Then, in adulthood, there
are striking qualitative sex differences in stress-induced remodeling, as
noted above.
Sex differences in hormones are also evident in the hippocampus.
Neil MacLusky and colleagues, when Neil was at Yale, have docu-
mented how male rats do not show estradiol-induced synapse formation
in hippocampus, although androgens induce synapses in male hippo-
campus (Leranth et al., 2003), although males will respond to estradiol
if sexual differentiation is blocked at birth by aromatase inhibitors
(Lewis et al., 1995). Moreover, testosterone, but not estradiol, increases
the survival of dentate gyrus neurons in the male brain (Hamson et al.,
2013; Spritzer and Galea, 2007). Androgen receptors are present in the
nucleus and non-nuclear locations of CA1 pyramidal cells where the
synapse formation occurs and in non-nuclear (Kerr et al., 1995; Tabori
et al., 2005). Other sex differences in hormone acton have been docu-
mented in a special issue of the Journal of Neuroscience Research
edited by Larry Cahill (Cahill, 2017).
The field of sex differences research now recognizes that men and
women typically handle stress in different ways even though we do
many of the same things equally well – hence, the “Men are from Mars
B.S. McEwen
and Women are from Venus” distinction. This is evident in an imaging
study on men and women during tests of emotional sensitivity, where
men and women sored equally well but showed marked differences in
the brain regions activated by the same tasks (Derntl et al., 2010). In-
deed, although we and others find that there are receptors for both
estradiol, androgens and progestins in both the male and female brain
that regulate memory, pain, coordinated movement and other func-
tions, there important developmentally- and genetically-programmed
sex differences in our brains and in how the brain responds to stressors
and other experiences.
These sex differences occur throughout the brain and not just in
brain regions like the hypothalamus that are involved in reproduction
(McEwen and Milner, 2017). In fact, new research indicates that, at the
molecular level, male and female responses to stress in the hippo-
campus, can be strikingly different (Marrocco and McEwen, 2016;
Marrocco et al., 2017). For example, RNA sequencing of ribosome-
bound RNA from a single neuron type, hippocampal CA3 neurons re-
vealed remarkable qualitative sex differences. For example, female
mice displayed greater gene expression activation after acute stress
than males and the direction of stress regulation of genes was often in
the opposite direction in males and females. Moreover, heterozygous
BDNF Val66Met mice, a model that is genetically susceptible to stress,
recapitulated the effects of acute stress on mRNA levels in wild-type
mice without any applied stress (a “pre-stress” state). However, like
wild-type mice, heterozygous BDNF Val66Met mice only displayed
activation of immediate early genes when actually stressed. This phe-
notype included the expression of genes related to glutamatergic and
glucocorticoid pathways. Behaviorally, only heterozygous BDNF
Val66Met females exhibited spatial memory impairment, regardless of
acute stress, and this effect was not observed in ovariectomized het-
erozygous BDNF Val66Met females, suggesting that circulating ovarian
hormones induce cognitive impairment in Met carriers. Cognitive def-
icits were not observed in males of either genotype, which instead
showed impaired memory only after stress. This work sheds further
light on ways that genes, environment and sex interact to affect the
transcriptome, furthering our understanding of sexually dimorphic
molecular mechanisms that underlie the response to stress in men and
women.
18. Metabolic hormones, glucose and the brain
Because of the work of Robert Sapolsky on glucocorticoid en-
dangerment of the hippocampus, I was drawn into a collaboration with
Mony de Leon at NYU that showed in Alzheimer’s patients an increase
in cortisol secretion with a glucose challenge that increased with the
extent of hippocampal atrophy (DeLeon et al., 1988). A follow up study
among normal individuals showed that a pharmacological dose of
cortisol, reduced the glucose utilization of the hippocampus, and serum
glucose levels increased. This did not occur in Alzheimer’s patients,
indicating that glucocorticoid-mediated regulation of glucose transport
is altered in AD, and that this may underlie both the hippocampal in-
sensitivity to cortisol and the failure in these patients to mount a per-
ipheral glucose response (de Leon et al., 1997; DeLeon et al., 1988).
Indeed an important factor for hippocampal structure and function
is glucose regulation; and this realization has led to insights about the
ability of metabolic hormones such as insulin, leptin, ghrelin and IGF-1
to enter and regulate hippocampal health and function. When the
hippocampus is activated by a cognitive task it needs glucose (McNay
et al., 2000) and activation of glucose mobilization occurs by a choli-
nergically-mediated pathway to the liver (Uemura et al., 1989). These
changes decline with aging (Gold, 1987; McNay and Gold, 2001).
Consistent with Robert Sapolsky’s glucocorticoid endangerment hy-
pothesis (Sapolsky, 1992), cortisol inhibits glucose uptake in the
healthy aging brain as a way of preventing damaging glycation of
proteins by excess glucose, as shown by Larry Reagan (Reagan et al.,
2000). And, yet, according to Sapolsky, excess glucocorticoids impairs
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Frontiers in Neuroendocrinology 49 (2018) 8–30
the ability of neurons to obtain an adequate energy supply, particularly
in the hippocampus when it is activated by a cognitive challenge
(Sapolsky, 1992; de Leon et al., 1997).
Insulin receptors in hippocampus and hypothalamus: In order to
understand the nature of the insulin resistance in the brain, work by
former postdoctoral fellows, Claudia Grillo, Gerardo Piroli and Larry
Reagan at the University of South Carolina, has led to important dis-
tinctions between hypothalamus and hippocampus. When hypotha-
lamic insulin receptors were depleted by a locally applied antisense
(Grillo et al., 2014), systemic features of diabetes appeared and there
was also increased depressive- and anxiety-like behavior along with a
depletion of BDNF in the hippocampus and hypothalamus. Indeed, a
short-term corticosterone treatment causes not only systemic insulin
resistance but also insulin resistance in the hippocampus reflected by
decreased GLUT4 levels and reduced insulin-stimulated insulin receptor
phosphorylation (Piroli et al., 2007). Moreover, the systemic metabolic
state plays a role in the brain, in that fatty Zucker rats have poorer
hippocampal dependent memory than lean Zucker rats, as well as im-
paired translocation of an insulin-dependent glucose transporter to
hippocampal membranes (Winocur et al., 2005). Moreover, a diet rich
in fat has been shown to impair hippocampal-dependent memory
(Winocur and Greenwood, 1999) and a combination of a high fat diet
and a 3 week predator exposure causes retraction of dendrites in the
CA3 hippocampus, even though neither treatment alone had this effect
(Baran et al., 2005).
Indeed systemic metabolism, particularly triglycerides and leptin
resistance in the hippocampus, has turned out to be very important, as a
mild food restriction paradigm both prevented and reversed the obesity
phenotype in the rats in which hypothalamic insulin receptors had been
inactivated by antisense (Grillo et al., 2014). The food restriction
paradigm restored long-term potentiation (LTP) in the CA1 region and
reversed the decreases in the phosphorylated/total ratio of GluA1
Ser845 AMPA receptor subunit expression observed in the hippo-
campus of hypo-IRAS rats. Because regulation of GluA1 Ser845 AMPA
receptor subunit phosphorylation is a key feature of leptin action, the
impairment of insulin action in hypo-IRAS rats is mediated through the
impairment of hippocampal leptin activity (Grillo et al., 2014).
However, while glucose uptake is important and impaired leptin
signaling by elevated triglycerides can impair insulin action, it is not
the dominant feature of insulin action and insulin resistance in the
hippocampus (Fadel and Reagan, 2016). Antisense inactivation of
hippocampal insulin receptors produced impaired long-term potentia-
tion and hippocampal dependent learning without any systemic meta-
bolic disturbance (Grillo et al., 2015). While antisense inactivation of
insulin receptors is not a likely mechanism in pathophysiology, it has
been shown that excessive stimulation of NMDA receptors by glutamate
and sustained calcium influx stimulates the activity of tyrosine phos-
phatases on insulin receptors and attenuates insulin signal transduction
and this is a process that may lead to a cascade resulting in dementia
(De Felice et al., 2014). Another processes that may be involved in brain
insulin resistance is the active transport of IGF-1 into the brain, which is
activated by neural activity (Nishijima et al., 2010); impairment of this
has not yet been demonstrated in insulin resistance but the requirement
of neural activity may be one of the reasons that exercise is beneficial
for cognitive function and against insulin resistance.
Role of astrocytic glycogen: While muscle glycogen fuels exercising
muscles to sustain endurance capacity, the brain also stores glycogen in
astrocytes to produce lactate as an energy source transported to active
neurons via the monocarboxylate transporter MCT2. Disrupting the
expression of the neuronal lactate transporter, MCT2, leads to failure of
long-term memory and amnesia; in particular, glycogenolysis and as-
trocytic lactate transporters are also critical for the molecular changes
required for memory formation, including the induction of phospho-
CREB, Arc and phospho-cofilin (Suzuki et al., 2011). A collaboration
with Hideyaki Soya at Tsukuba University has shown that MCT2 is also
important for the effects of exercise and the feeling of exhaustion
B.S. McEwen
(Matsui et al., 2017). Using a rat model of prolonged exhaustive ex-
ercise, microwave irradiation of brains, metabolomics, and in-
tracerebroventricular injection of inhibitors of glycogenolysis and
MCT2 showed that lactate derived from astrocytic glycogen fuels the
prolonged exercising brain to maintain endurance capacity. Further
studies of this process are needed in relation to hippocampal insulin
resistance.
Metabolic factors, depression, dementia and aging: But there is a lot
more to this story, as shown by important work of Antonio Convit at
NYU and Natalie Rasgon at Stanford. Metabolic factors involving glu-
cose regulation and insulin resistance play a role in hippocampal vo-
lume change in the human hippocampus in mild cognitive impairment
with aging (Convit et al., 2003; Rasgon et al., 2001). Poor glucose
regulation is associated with smaller hippocampal volume and poorer
memory function in individuals in their 60s and 70s who have “mild
cognitive impairment” (MCI) (McIntyre et al., 2010), and both MCI and
Type 2, as well as Type 1, diabetes are recognized as risk factors for
depression and dementia as will now be described (de Leon et al., 2001;
Haan, 2006; Ott et al., 1996; Rasgon et al., 2001) .
Within the life course perspective of epigenetic effects of a pro-
gression of lifetime experiences and health-related behaviors operating
on different genotypes (Halfon et al., 2014), there is growing evidence
for a relationship between insulin resistance and risk for cognitive de-
cline and dementia, as first described by Natalie Rasgon who has be-
come a collaborator and has catalyzed the formation of PALS (https://
www.pals-network.org/) (Rasgon and Jarvik, 2004; Rasgon et al.,
2011). Hippocampal shrinkage is reported in women with insulin re-
sistance who are at risk for Alzheimer’s disease (Rasgon et al., 2011),
and in men as well as women with Type 2 diabetes (Gold et al., 2007).
Hippocampal shrinkage is an index of early Alzheimer’s Disease (de
Leon et al., 2004; Hampel et al., 2008). We have seen that elevated
glucocorticoid levels can also shut off glucose and endanger survival of
hippocampal neurons (Sapolsky, 1992). As noted, the normal, physio-
logical regulation apparently does not happen in the Alzheimer brain in
which input and output of hippocampus is damaged (de Leon et al.,
1997; DeLeon et al., 1988). An oxidative stress and inflammatory cas-
cade has been suggested as a pathway from insulin resistance to Alz-
heimer’ pathology (Gold et al., 2013; Manolopoulos et al., 2010) re-
presenting an example of an allostatic overload.
Possible interventions including hormone therapy, particularly un-
opposed estradiol (Rasgon et al., 2014), and PPARγ agonists such as
pioglitazone (Gold et al., 2013; Lin et al., 2015) along with lifestyle
changes leading to increased physical activity. Given the occurrence of
obesity and Type 2 diabetes already in adolescent youth, as shown by
Convit’s group at NYU (Yau et al., 2012), early life intervention is im-
perative wherever possible to redirect the progression of the allostatic
load towards a healthier path. The involvement of my laboratory and
former fellows led unexpectedly to a new direction involving a mole-
cule, carnitine, that was the subject of my first co-authored paper in
1959 (Fritz and Mcewen, 1959).
19. Depressive-like behavior and insulin resistance associated
with acetyl-L-carntine (LAC) deficiency
As explained above, the arrival of Carla in our laboratory for the
final year of her Ph.D. thesis introduced us to the role of acetyl-L-car-
nitine (LAC) in ameliorating depressive-like behavior in animal models
(Nasca et al., 2013). In one animal model, the FSL rat, continuing a
collaboration with Aleksander Mathe and Per Svenningsson of Kar-
olinska Institute, Stockholm, LAC deficiency is associated with depres-
sive-like behavior and, more recently, it is accompanied by elevated
insulin, leptin and triglycerides in serum; LAC supplementation not
only reduces the depressive like behavior within 3–5 days, but it also
treats the metabolic dysregulation in a study led by Benedetta Bigio
(Bigio et al., 2016), In human MDD, Carla Nasca, Natalie Rasgon,
Francis Lee, Jim Kocis and James Murrough find that LAC is
22
Frontiers in Neuroendocrinology 49 (2018) 8–30
significantly lower in individuals with MDD compared to healthy con-
trols. Low LAC levels in individuals with MDD are associated with
greater severity and earlier onset, and a treatment resistant course of
illness. Consistent with lower LAC in more severe forms of MDD, there
is an association between low LAC levels and childhood trauma in pa-
tients with a treatment resistant course of illness. Together with the
association between reduced LAC and insulin resistance (IR) in animal
models, LAC is potential a biomarker to delineate, diagnose and treat a
novel biologically-defined MDD subtype that may associate LAC with
insulin resistane.
20. Transgenerational influences and brain development
Another important element so far in this discussion of stress is the
influence of events early in life and their epigenetic effects on brain and
body development. Michael Meaney, a former postdoctoral fellow and
now Professor at McGill University, has led the way in demonstrating
the important role of postnatal maternal care in emotional and cogni-
tive development. In my lab, Meaney and Robert Sapolsky investigated
ontogeny of glucocorticoid receptors in the neonatal rat brain (Meaney
et al., 1985a, 1985b), which led them to later investigate the ability of
neonatal “handling” of infant rats to slow down brain aging (Meaney
et al., 1988, 2013). Meaney went on to show that “handling” (Levine
et al., 1967), i.e., separating pups from the mother for 10–20′, increases
maternal care when the pups are returned. Going on to explore the role
of maternal care, Meaney and Darlene Francis showed that infant rats
raised with a nurturing mom develop less emotionality and great ability
to explore novel places and things, while pups raised with an anxious
mom that provides inconsistent care shows the opposite outcome
(Francis et al., 1999). This was done by Francis switching embryos in
the womb (Francis et al., 2003) and also by cross-fostering pups post-
natally between mothers of two mouse strains by Wayne Brake, Russ
Romeo and Helen Sisti together with Darlene Francis (Priebe et al.,
2005).
Later, Akaysha Tang’s group working with Russ Romeo and me
showed that it was the consistency of maternal care and not the amount
that has the most positive effect (Tang et al., 2014). Indeed, chaos in the
nest has negative effects on the offspring as it does in humans (Evans
and Wachs, 2010; Molet et al., 2014). Cross-fostering of infants between
good and bad moms alters the outcome, pointing to what is now re-
ferred to as epigenetic transgenerational behavioral transmission
(Francis et al., 1999).
John Kral at Downstate Medical Center, Brooklyn, introduced us to
other forms of transgenerational transmission of traits: even before
conception and during life in the womb, paternal and maternal obesity
can affect the child (Donkin et al., 2016; Kral et al., 2006). These may
involve “epigenetic” changes of the DNA of the sperm and egg that do
not alter the genetic code per se, but, rather, how it is read. In the case
of parental obesity, this increases the risk that the child will also be-
come obese. Moreover, adverse early life experience in infancy and
childhood involving poverty, abuse and neglect, affect how genes are
expressed and determine how well brain regions such as the hippo-
campus, amygdala and prefrontal cortex develop and function during
childhood into young adulthood. Indeed, as we have seen, the brain is
continually changing with experiences, creating memories and alerting
brain architecture via mechanisms that are facilitated in part by cir-
culating sex, stress and metabolic hormones and chemicals produced by
the immune system.
This has led to a new view of the epigenetic changes over the life
course that determine trajectories of health and disease and the plas-
ticity of the brain offers opportunities for changing the trajectory
(Halfon et al., 2014). Indeed, we cannot “roll back the clock” and
“reverse” the effects of experiences, positive or negative. Rather, we
must think of “recovery” and “redirection” and ”resilience”, rather than
“reversal” (Gray et al., 2014). See Fig. 2. We therefore think about
“changing trajectories” of function resulting in compensatory changes
B.S. McEwen
in the brain and body over the life course. A pediatrician researcher at
UCLA, Neal Halfon, has written and spoken about “life course health
development”, or LCHD as the most up-to-date overview of medicine,
contrasting that with the view of “magic bullets” like penicillin that
revolutionized treatment of infectious disease but does not apply to
antidepressants or drugs, like statins, that help but do not “cure” the in
principle preventable diseases of modern life (Halfon et al., 2014).
Going beyond the psychosocial model of how health behaviors and
toxic stress cause those diseases (Engel, 1977), LCHD notes the im-
portance of events pre-conception, prenatally and throughout the life-
course in which income and education have a huge influence. The de-
terminants of diabetes, depression and dementia are a good example of
this (Rasgon and McEwen, 2016).
21. Life course health development for an ever-changing brain
What does this mean for prevention and treatment? In the spirit of
integrative medicine, it seems to me that it is important to let the
“wisdom of the body” prevail and to focus upon 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 interventions
(McEwen, 2012). This is because a major challenge throughout the life
course is to find ways of redirecting future behavior and physiology in
more positive and healthy directions (Halfon et al., 2014). We do not
mean “reversibility” as in “rolling back the developmental clock” but
rather “redirection” of those features of a species that can be modified
by experiences.
Even in adulthood, gene expression continually changes with ex-
perience (see Fig. 2 (Gray et al., 2014)) and there is loss of resilience
with aging (Bloss et al., 2010) that can be redirected by exercise
(Erickson et al., 2011) and possibly by pharmacological intervention
(Pereira et al., 2014). Even chronic anxiety, possibly resulting from
adverse childhood experiences, can respond to a behavioral interven-
tion in adulthood (Holzel et al., 2010). Indeed mindfulness based stress
reduction and meditation increases functional connectivity within the
brain and benefit fluid intelligence as well as improving function in
aging (Gard et al., 2014a, 2014b) and meaning and purpose in life also
has benefits for overall health and cognitive function (Carlson et al.,
2009; Fredrickson et al., 2013).
The response of the brain to stressors is a complex process involving
multiple interacting mediators that utilizes both genomic and non-
genomic mechanisms from the cell surface to the cytoskeleton to epi-
genetic 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 experience (McEwen et al., 2015a).
Resilience may be thought of as an active process that implies ongoing
adaptive plasticity without external intervention (Russo et al., 2012).
Therefore recovery of stress-induced changes in neural architecture
after stress is not a “reversal” but a form of neuroplastic adaptation and
resilience that may be impaired in mood disorders, when the brain “gets
stuck” and needs external intervention. Loss of resilience may also
occur with aging and need external intervention such as exercise (Bloss
et al., 2010).
On the other hand, resilience is decreased and vulnerability is in-
creased by adverse childhood experiences (ACE) and poverty that lead
to “biological embedding” of trajectories of response to stressful life
events (Shonkoff et al., 2009) throughout the life course (Halfon et al.,
2014) which contribute disproportionately to allostatic overload in the
form of physical and mental health disorders over the life course and
impaired brain development (Felitti et al., 1998; Hanson et al., 2013).
Evidence from CpG methylation of DNA indicates the embedded in-
fluence of early adversity (McGowan et al., 2009). From hereon in this
review, we move into the domain started for me by the MacArthur
Foundation networks and continued for me in the National Scientific
Council on the Developing Child (http://developingchild.harvard.edu/
23
Frontiers in Neuroendocrinology 49 (2018) 8–30
science/national-scientific-council-on-the-developing-child/).
22. Interventions
Based on this, what are the implications of this line of research for
interventions that help individuals and societies deal with the stresses
of modern life and their health consequences? We shall consider in-
dividuals, first, and then the role of societies and how groups of in-
dividuals, differing in income and education are affected, and can be
affected by programs of government and the private sector.
Personalized medicine: Regarding individuals, the term “persona-
lized medicine” has become very popular, but it has generally focused
on the individual genetic constitution and not the influence of epige-
netics. However, I was very fortunate to meet and establish a long-
distance collaboration with Linn Getz Professor in Behavioural Sciences
in Medicine of the Department of Public Health and General Practice at
Norwegian University of Science and Technology in Trondheim,
Norway. In a joint paper (McEwen and Getz, 2013) we wrote: “The aim
of personalized medicine is to base medical prevention and therapy on
the unique health and disease susceptibility profile of each individual.
From a medical perspective, knowledge of a person encompasses both
biological and biographical perspectives. The latter includes significant
events and experiences throughout the person's lifespan, from concep-
tion to the present, in which epigenetic influences play an important
role. In practice, personalized medicine should emphasize the devel-
opment and maintenance of a healthy nervous system. The neurobio-
logical processes for that depend heavily on the psychosocial environ-
ment, in particular the presence of responsible, caring adults and
integration in a reasonably fair society. A healthy brain subsequently
promotes good health throughout life, both through direct, favorable
influences on the body's intrinsic biological pathways, and indirectly by
enabling the person to engage in supportive relationships, make wise
decisions and take good care of him/ herself. From a public health
perspective, hi-tech personalized medicine based on detailed bio-mo-
lecular mapping, monitoring and tailored drug interventions holds
promise only as part of a wider, socio-culturally informed approach to
the person.”
So what can we do to change trajectories and alleviate the many
stressors in our lives? At the individual level, prevention of early life
adversity for children and families is key via programs like the Nurse-
Family Partnership (http://www.nursefamilypartnership.org/) that
pave the way for strong attachment between mother and child and good
child-rearing practices. Yet, when bad things have happened to a child
from adverse prenatal, gestational and early life influences, our in-
creasing knowledge of the plasticity of the brain gives hope for thera-
pies that utilize brain-body interactions while enhancing a sense of self-
regulation and control to reduce toxic to at least more tolerable stress.
Along with a healthy diet, positive social interactions and support,
adequate sleep and attention to maintaining a normal sleep waking
cycle, regular physical activity is vitally important not only for meta-
bolic and cardiovascular function but also for memory, mood and for
prevention of dementia. We think of this as using healthy behaviors to
“open a window” of plasticity and allow the wisdom of the body to
exert itself as well as to allow targeted behavioral interventions to
shape brain circuits in a more positive direction. Examples of the tar-
geted interventions include compensatory repair of damage from a
stroke by intensive physical therapy (Chollet et al., 2011) and how
“lazy eye”, i.e., abnormal development of a visual field that responds
abnormally to the input of both eyes, is ameliorated by binocular visual
stimulation (Vetencourt et al., 2008).
Policy and Practice: At the level of societies, income and education
are hugely important as determinants of longievity and health span as
shown in 2 publications from the MacSES Network (see http://www.
macses.ucsf.edu/downloads/Reaching_for_a_Healthier_Life.pdf and
more in depth: http://onlinelibrary.wiley.com/doi/10.1111/nyas.
2010.1186.issue-1/issuetoc). As noted at the beginning of this article
B.S. McEwen
and in Box 1, my experience with MacArthur Foundation Research
Networks brought me together with social scientists, physicians, and
epidemiologists who were interested in a common problem, namely,
how to measure “stress” from our social and physical environments and
how it affects our health behaviors and our disease vulnerability. A
major focus was and still is the influence of income and education,
referred to as “socioeconomic status”, and how it “gets under the skin”.
In so doing, it provided the impetus and the collegial environment to
develop the concepts of allostasis and allostatic load and overload and
begin to measure them and then try to find ways to alleviate toxic stress
and reduce allostatic overload. This I have done and in the process
came to know and admire another colleague, Teresa Seeman, Professor
of Epidemiology in Medicine at UCLA, who has played major role in
measuring and using allostatic load/overload to predict health out-
comes (McEwen and Seeman, 1999; Seeman et al., 2010a, 2010c; Wiley
et al., 2016).
One additional perspective became clear from the MacSES Network:
the most important contributor to poor adult health is childhood pov-
erty as well as abuse, neglect and chaos in the home (Caspi et al., 2016;
Evans and Wachs, 2010). Since the MacSES Network ended, I have
continued this interest and contributed my expertise as a member of the
National Scientific Council on the Developing Child, which provides the
best current scientific knowledge in a digestible form for policy makers
as well as the pediatric community and the general public to both
prevent and alleviate the effects of adversity in childhood. The National
Scientific Council web site is very useful (http://developingchild.
harvard.edu/science/national-scientific-council-on-the-developing-
child/) .
One of the most influential studies in this area is that conducted in
Dunedin, New Zealand, by Avshalom Caspi and Terrie Moffitt. Early life
adversity, including poverty, impair brain development, particularly
the development of self-regulatory behaviors that determine childhood
self control, and poor self control predicts physical health, substance
dependence, personal finances, and criminal offending outcomes, fol-
lowing a gradient of self-control (Moffitt et al., 2011). In this study,
“effects of children’s self-control could be disentangled from their in-
telligence and social class as well as from mistakes they made as ado-
lescents. In another cohort of 500 sibling-pairs, the sibling with lower
self-control had poorer outcomes, despite shared family background.
Interventions addressing self-control might reduce a panoply of societal
costs, save taxpayers money, and promote prosperity (Moffitt et al.,
2011) Going further, the same group wrote in a recent paper (Caspi
et al., 2016): “A segment comprising 22% of the cohort accounted for
36% of the cohort’s injury insurance claims; 40% of excess obese
kilograms; 54% of cigarettes smoked; 57% of hospital nights; 66% of
welfare benefits; 77% of fatherless child-rearing; 78% of prescription
fills; and 81% of criminal convictions. Childhood risks, including poor
brain health at three years of age, predicted this segment with large
effect sizes. Early-years interventions that are effective for this popu-
lation segment could yield very large returns on investment.”
Finally, what can be done to improve the outcome? Societies differ
in the degree to which they promote an environment that encourages
equality and harmony or inequality and discord (Wilkinson and Pickett,
2010). Virtually all policies of government and the private sector affect
health, whether they deal with housing, transportation, health care,
education, flexible working hours, and vacations (Acheson, 1998).
Thus, policies that are forward-looking by government and the private
sector are vitally important to promote better health and to increase
“healthspan”, as opposed to “lifespan”. They can do so by providing
opportunities for individuals to experience better working and living
environments and to learn and practice healthy behaviors, recognizing
the “the wisdom of the body”. We must give the body and brain, which
work together and know what to do, a chance to do so!. For business,
such policies also improve employee morale, loyalty and productivity.
From such policies, there is enormous benefit to society to reduce ex-
penses for health care and, most importantly, to reduce human misery!
24
Frontiers in Neuroendocrinology 49 (2018) 8–30
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