Hormones and Behavior 119 (2020) 104619

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Hormones and Behavior

journal homepage: www.elsevier.com/locate/yhbeh

Review article

Hormones and behavior and the integration of brain-body science☆ T

Bruce S. McEwen
Laboratory of Neuroendocrinology, The Rockefeller University, 1230 York Avenue, New York, NY 10065, United States of America

A R T I C LE I N FO A B S T R A C T

Keywords: The investigation of hormones, brain function and behavior over the past 50 years has played a major role in
Hippocampus elucidating how the brain and body communicate reciprocally via hormones and other mediators and how this
Stress impacts brain and body health both positively and negatively. This is illustrated here for the hippocampus, a
Sex differences uniquely sensitive and vulnerable brain region, study of which as a hormone target has provided a gateway into
Steroids
the rest of the brain. Hormone actions on the brain and hormones generated within the brain are now recognized
Plasticity
to include not only steroid hormones but also metabolic hormones and chemical signals from bone and muscle.
Allostatic load
Moreover, steroid hormones, and some metabolic hormones, and their receptors, are generated by the brain for
specific functions that synergize with effects of those circulating hormones. Hormone actions in hippocampus
have revealed its capacity, and that of other brain regions, for adaptive plasticity, loss of which needs external
intervention in, for example, mood disorders. Early life experiences as well as in utero and transgenerational
effects are now appreciated for their lasting effects at the level of gene expression affecting the capacity for
adaptive plasticity. Moreover sex differences are recognized as affecting the whole brain via both genetic and
epigenetic mechanisms. The demonstrated plasticity of a healthy brain gives hope that interventions throughout
the life course can ameliorate negative effects by reactivating that plasticity and the underlying epigenetic
activity to produce compensatory changes in the brain with more positive consequences for the body.

1. Introduction other neural and systemic signals; yet the brain can become resistant to
insulin and leptin and this can lead to depression and later dementia
Because of the increasing attention to “brain health” (https:// along with systemic disorders such as Type 2 diabetes and cardiovas-
brainhealth.nia.nih.gov/), it is timely for the 50th Anniversary of cular disease (Biessels and Reagan, 2015; Rasgon and McEwen, 2016),
Hormones and Behavior to have a review summarizing how the study In this short review I shall recount phases of discovery and concepts,
and application of integrated brain-body science has evolved to a great albeit from the point of view of my laboratory and like-minded col-
extent from the study of hormone effects on behavior and behavioral leagues, that have been reviewed in more detail elsewhere (https://
effects on hormone secretion. This began with the pioneering work of www.sciencedirect.com/journal/frontiers-in-neuroendocrinology/vol/
hormone behaviorists like Young, Beach and Lehrman (e.g., see Young 49). Our work began with the hippocampus as a uniquely sensitive and
et al., 1964) and neuroendocrinologists like Harris, Scharrer, Guillemin, vulnerable brain region that has acted as a gateway to the rest of the
Schally and Vale (for review and one point-of-view see McEwen et al., brain. This review will also emphasize recent findings and novel con-
2015b). As information expands, we tend to be caught in silos of cepts that have grown out of this research path.
knowledge. Indeed, the traditional view of medicine has been to ignore
the brain above the hypothalamus and pituitary, while psychiatry, 2. Hormone actions in the hypothalamus and hippocampus
neurology and neuroscience, traditionally, have largely ignored the provided a gateway to the rest of the brain
influence of the body on the brain, However, it is now quite evident that
brain and body communicate reciprocally via hormones and other After the discovery of estrogen receptors in the hypothalamus with
mediators and in ways that promote brain and body health but which its implications for sexual behavior and neuroendocrine function (Pfaff,
can also accelerate disease processes when dysregulated. For example, 1980), the serendipitous discovery of adrenal steroid receptors in the
physical activity stimulates neurogenesis in the dentate gyrus and de- hippocampal formation provided a gateway to identifying hormone
pends upon circulating IGF-1 from the liver (Trejo et al., 2001), among receptors and hormone actions throughout the brain with implications

☆
This paper belongs to special issue 50th Anniversary of H&B
E-mail address: mcewen@mail.rockefeller.edu.

https://doi.org/10.1016/j.yhbeh.2019.104619
Received 1 November 2019; Accepted 1 November 2019
0018-506X/ © 2019 Elsevier Inc. All rights reserved.
B.S. McEwen Hormones and Behavior 119 (2020) 104619

Fig. 1. Glucocorticoids produce direct and indirect

genomic actions as well as nongenomic signaling
actions via glucocorticoid (GR) and miner-
alocorticoid (MR) receptors. These involve not only
direct and indirect 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 mi-
tochondria to affect Ca++ buffering and free ra-
dical 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 transcriptional
actions; this effect is synergistic with the ability of
glucocorticoids to activate, via a genomic me-
chanism, the phosphorylation of the Trk B receptor
independently of BDNF, thus creating a positive
feedback loop. From (McEwen et al., 2015a, 2015b)
with permission.

for influences upon cognitive function, mood and neurological pro- hippocampus (Fig. 2), cytoskeletal depolymerization and polymeriza-
cesses (McEwen et al., 2015b). tion is a feature not only of stress-induced shrinkage of dendrites in
In the case of steroid hormone, not only were the receptors found in hippocampus and post-stress recovery, but also of rapid shrinkage of
the cell nucleus with implications for gene regulation, receptors were dendrite in hibernation and rapid recovery when the animal is aroused.
also found with higher resolution methods in synapses, mitochondria Pores in the cell nucleus that allow two-way communication between
and glial cells (e.g., see Milner et al., 2001) that indicated both indirect the cytoplasm and genes in the nucleus contain at least one protein,
effects on gene expression as well as cellular signaling processes that Nup62, that is required for dendrite recovery after stress-induced
regulate second messenger formation and cytoskeletal polymerization shrinkage. And a cell surface molecular called PSA-NCAM is not only
leading for example to synapse formation (see Fig. 1). required for dendrite plasticity in hippocampus but also limits the
Indeed, one of the features of the brain that emerged from these dendrite regrowth that occurs after stress-induced shrinkage (Table 1).
findings is the dynamic nature of the healthy brain, referred to as Endocannabinoids are among the neurally-derived molecules that
“adaptive plasticity”, with synapse turnover, dendrite shrinkage and modulate stress-induced remodeling in amygdala and hippocampus.
growth and dentate gyrus neurogenesis, all regulated by circulating They are formed and released post-synaptically and act pre-synaptically
hormones along with endogenous growth factors and excitatory amino to inhibit either glutamate or GABA release and glucocorticoids sti-
acid neurotransmitters (McEwen et al., 2015a). Excessive stimulation mulate their formation and release (Balsevich et al., 2017). Blockade of
by excitatory amino acids in the presence of glucocorticoids, however, CB1 receptors during stress increases the stress-induced remodeling,
causes permanent damage as is the case with stroke, seizures and head whereas the inactivation or knock-out of the degradative enzyme,
trauma (Sapolsky, 1992), as well as involvement in the progression of FAAH, markedly blunts the effects of stressors in the amygdala (Hill
Alzheimer's pathology (Pereira et al., 2017) and major depressive ill- et al., 2013; Hill and Lee, 2016).
ness (Nasca et al., 2013). Another revelation due in part to the study of hormone action in the
A more subtle form of impaired brain health is loss of plasticity in brain is the recognition of the role of mitochondria with their own
the aftermath of stressful experiences, in which structural change pro- genetic information and ability to respond to hormones like estradiol
duced by those experiences cause the brain to “get stuck” and not adapt and glucocorticoids (Du et al., 2009; Nilsen et al., 2007; Picard and
when conditions improve. Such is the case with shrinkage of the hip- McEwen, 2018). Mitochondria generate free radicals and excess free
pocampus in major depression and overactivity of the amygdala in radicals increase inflammatory tone; yet, their normal function is pro-
anxiety disorders and depression where external behavioral and/or viding energy and carefully modulating free radical tone in the spirit of
pharmacological intervention are required (Sheline et al., 2019). allostasis (see below) (Picard et al., 2017). Mitochondria generate mi-
Recognizing adaptive plasticity of the adult as well as developing tokines that communicate with each other and with the cell nucleus (for
brain has led to more in depth knowledge of cellular mechanisms from review see Picard and McEwen, 2018).
the cell nucleus to the cell surface (see Table 1). Besides actin poly- The brain uses mitochondria to generate and use steroid hormones
merization leading to estrogen-induced synapse formation in and it also expresses other hormones normally associated with the
body. Besides progesterone generation by Schwann cells and oligo-
Table 1 dendrocytes (Schumacher et al., 2012), the brain is capable of making
Cellular mechanisms of adaptive plasticity: from nucleus to cell surface. estradiol and also androgens. Estradiol production “on demand” from
Nuclear pores – NUP62 – nuclear-cytoplasmic communication
cholesterol via aromatization in an ischemic brain has been docu-
Required for dendritic remodeling in CA3 neurons (Kinoshita et al., 2014) mented (Hojo et al., 2003), and knocking out aromatase in brain ex-
Cytoskeleton: Actin polymerization/depolymerization acerbates the damaging effects of ischemia (McCullough et al., 2003).
Dendrite length and branching changes within hours during hibernation and Furthermore, after ovariectomy estrogen level are detectable after
arousal (Arendt et al., 2003; Magarinos et al., 2006)
3 weeks of gonadectomy in the male or female amygdala and in the
Estradiol activates actin polymerization as part of synapse formation (Yuen et al.,
2011) female prefrontal cortex but not in hippocampus, suggesting a local
Cell surface: PSA-NCAM – limits and facilitates pasticity source (Barker and Galea, 2009). For androgens, the ability of exercise
Removal of PSA causes uncontrolled growth of CA3 dendrites and increases to stimulate neurogenesis in male rat hippocampus is dependent on
vulnerability to (McCall et al., 2013) extra-gonadal production of dihydrotestosterone (Okamoto et al.,

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B.S. McEwen Hormones and Behavior 119 (2020) 104619

Fig. 2. Non-genomic estradiol action: synapse formation. Estradiol activates LIMK-1 to promote actin polymerization and PI3kinase to activate translation of PSD95
mRNA. In the male hippocampus, androgens generate synapses and do so genomically at least in part via nuclear AR (Romeo et al., 2005; Yuen et al., 2011).

Table 2 by something unexpected, or get into an argument, or run to catch a

Systemic protein/peptide hormones expressed and/or acting in hippocampus. train. Some of these experiences we may refer to as “stressful” but other
Insulin – acts in hippocampus with neuroprotective and pro-cognitive effects we do not. So using the word stress does not really recognize all of the
different from promoting glucose transport (Biessels and Reagan, 2015) underlying biology. The “mediators” help us adapt as long as they are
IGF-1 – acts in hippocampus and required for exercise-induced neurogenesis (Trejo turned on in a balanced way when we need them and then turned off
et al., 2001) again when the challenge is over. When that does not happen, they can
Leptin –acts in hippocampus on cognitive function, neurogenesis, neuroprotection
cause unhealthy changes in brain and body. This is also the case when
and is also expressed in hippocampus (McGregor and Harvey, 2018; Yook et al.,
2019) the “mediators” are not produced in an orchestrated and balanced
Growth hormone –acts in hippocampus and expressed in hippocampus and responds manner – for example, too much or too little cortisol or an elevated or
to experience, aging and sex hormones; implicated in cognitive function and too low blood pressure. When this happens and continues over weeks
neuroprotection (Aramburo et al., 2014; Donahue et al., 2006)
and months, we call it “allostatic load” to refer to the wear and tear on
Ghrelin – acts in hippocampus but does not appear to be expressed in brain; it has
neuroprotective and pro-cognitive effects including neurogenesis in
the body that results from the chronic overuse and imbalance of the
hippocampus (Buntwal et al., 2019). Yet prolonged exposure to ghrelin has “mediators”. Accumulation of abdominal fat is an example as is the
negative effects related to fear memory (Yousufzai et al., 2018). development of chronic hypertension both of which can be called “al-
Prolactin – acts in hippocampus and may be expressed there; affects neurogenesis, lostatic overload” when they lead to disease (McEwen and Wingfield,
increases synaptogenesis and neuronal plasticity, promotes consolidates memory
2003). Note, however, that we are talking, not about one mediator, like
and acts as a neuronal protector against excitotoxicity (Carretero et al., 2019).
cortisol, but a host of mediators that are all released in allostasis in a
Note: Resistance to these hormones results in pathophysiology as well as vul- coordinated manner to help us adapt but which can also cause damage
nerability to damage. when overused and dysregulated as described above.

2012). The brain also has the capacity to generate neuroactive steroids 4. Epigenetics, genetics and the individual: example of sex
such as A-ring reduced metabolites of progesterone that are allosteric differences
modulators of the GABAa receptor that mediate its anaesthetic and
sedative effects (Baulieu and Robel, 1990; Gee et al., 1987). Thus experiences of the life course that are mediated in part via
Systemic hormones also act via receptors expressed in hippocampus hormones help to create each individual and do so epigenetically, as
and some are also expressed there and have neuroprotective and pre- seen for example in differences among identical twins (Fraga et al.,
cognitive effects on neuroplasticity. Leptin and growth hormone act in 2005) (see Box 1). Yet, the genome sets the limits on what is possible
hippocampus and are also expressed in hippocampus (Table 2). Ghrelin and sex differences are a complex example of the interaction between
acts in hippocampus as does prolactin via receptors expressed there and those genetic influences of the X and Y chromosome and mitochondrial
they do not appear to be expressed in that brain region; likewise, insulin DNA inherited primarily via the mother. As already noted, the entire
and insulin-like growth factor (IGF-1) also act in hippocampus to pro- brain has receptors for sex hormones, both genomic and non-genomic,
mote plasticity and protect against damage (Table 2). Moreover, factors and is able to generate sex hormones for local use. Three examples of
from bone and muscle have effects on neural activity and adaptive sex differences in relation to stressful experiences illustrate the diver-
plasticity, thus broadening what must be considered as systemic influ- gence of response due to genetic/epigenetic sex. First, exposure of male
ences on the nervous system (Khrimian et al., 2017; Moon and van and female rats to restraint plus intermittent tail shock has opposite
Praag, 2014). effects on classical eyeblink conditioning, inhibiting it in females and
enhancing it in males; in females, this effect is abolished by ovar-
3. Protection and damage – allostasis and allostatic load - biphasic iectomy and is therefore estradiol dependent (Shors et al., 2001; Wood
actions under rubric of “stress” and Shors, 1998). A morphological correlate of this in the hippocampus
is the finding that acute stress inhibits estradiol-depending spine for-
Because some of the mediators that affect brain and body are linked mation in CA1 neurons of the hippocampus, whereas the same acute
to negative as well as positive actions, another outcome of this line of stressors enhance spine density in male CA1 neurons, possibly by in-
research has led to the concepts of allostasis and allostatic load that creasing testosterone secretion (Shors et al., 2001) upon which spine
have broadened the definition of “stress” (McEwen, 1998; McEwen and formation in the male CA1 is dependent (Leranth et al., 2003). Neonatal
Gianaros, 2011; McEwen and Stellar, 1993). We know that “home- masculinizaton of females made them respond positively, like genetic
ostasis” means the physiological state which the body maintains to keep males, to the shock stressor (Shors, 2016) Moreover, in females, de-
us alive - that is, body temperature and pH within a narrow range and pending on reproductive status and previous experience, the negative
adequate oxygen supply. In order to maintain homeostasis, our body stress effect was epigenetically altered, e.g., it was absent in mothers
activates hormone secretion and turns on our autonomic and central and virgin females with experience with infants (Shors, 2016).
nervous system (we call these “mediators” like cortisol, adrenalin, the Second, in the hippocampus of male rats, 21 days of chronic re-
immune system and metabolism) to help us adapt, for example, when straint stress (CRS) causes apical dendrites of CA3 neurons to retract
we get out of bed in the morning, walk up a flight of stairs, have a and a loss of ~30% of the parvalbumin (PARV)-containing neurons in
conversation. These systems are also turned on when we are surprised the dentate gyrus; these changes do not occur following CRS in female

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B.S. McEwen Hormones and Behavior 119 (2020) 104619

Box 1
Epigenetics.

“Epigenetics” originally meant the emergence of developmentally-programmed characteristics as a fertilized egg develops into a living or-
ganism characteristic of that species (Waddington, 1942). This is programmed into each species, but the individual characteristics are in-
fluenced 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 retrotransposons (Griffiths and Hunter, 2014; Hunter et al., 2015) and
RNA editing (Mehler and Mattick, 2007). The repressive H3K9me3 histone mark is induced by acute stress in hippocampus of naïve rodents
and is chronically turned on by early life stress (ELS) and then, in those ELS mice, turned off by acute stress. Although the meaning of this is
unclear, it should be noted that the H3K9me3 mark represses DNA that includes transposon-like elements as well as non-coding regulatory
RNA's that may have important functions in gene regulation and gene stability, particularly in hippocampus that may be unique within the
brain (Hunter et al., 2015; Hunter et al., 2012).

rats (Galea et al., 1997; Milner et al., 2013). Moreover, female and male regions such as the hippocampus, amygdala and prefrontal cortex de-
rats show effects in the opposite direction of chronic stress on hippo- velop and function during childhood into young adulthood. (McEwen
campal dependent memory, with males showing impairment and fe- and McEwen, 2017; McEwen and Gregerson, 2019) Animal models are
males showing enhancement or no effect (Bowman et al., 2003; Luine useful, and, for the brain, the hippocampus, once again, provides a
et al., 1996; Luine et al., 1994). At the level of gene expression, using glimpse into what happens at the level of gene expression. As noted
RNA sequencing of ribosome-bound mRNA from hippocampal CA3 earlier, CA3 neurons that are crucially involved in cognitive function
neurons, we found remarkable sex differences and discovered that fe- and mood regulation as well as activation of glucocorticoid (CORT)
male mice displayed greater gene expression activation after acute secretion exhibit structural and functional changes after early-life stress
stress than males (Marrocco et al., 2017). Moreover, genes that were (ELS) as well as after chronic stress in adulthood. Exposed to a protocol
common to males and females in response to acute stress tended to go in of chronic ELS induced by limited bedding and nesting material fol-
the opposite direction, with the exception of the immediate early gene, lowed by acute-swim stress (AS) in adulthood, mice with a history of
c-fos, which was increased in both sexes by acute stress (see Fig. 3). ELS display a blunted CORT response to AS, despite exhibiting activa-
Moreover, having even one copy of the Met allele in BDNF tion of immediate early genes after stress similar to that found in
Val66Met mice, both sexes show a pre-stressed translational phenotype control mice (Marrocco et al., 2019). Yet acute stress increases the
that was not evident in mice with the BDNF Val/Val genotype where expression of the repressive histone H3 lysine 9 tri-methylation
the same genes were activated by an acute stressor. Behaviourally, only (H3K9me3) in hippocampal fields of control mice, including the CA3
heterozygous BDNF Val66Met females exhibit spatial memory impair- pyramidal neurons. Yet, ELS mice showed persistently increased ex-
ment, regardless of acute stress. Interestingly, this effect is not observed pression of H3K9me3 histone mark in the CA3 subfield at baseline that
in ovariectomized heterozygous BDNF Val66Met females, suggesting was subsequently decreased following AS. See BOX 1. Using translating
that circulating ovarian hormones induce cognitive impairment in Met ribosome affinity purification (TRAP) method to isolate CA3 translating
carriers. Cognitive deficits were not observed in males of either geno- mRNAs, we found that expression of genes of the epigenetic gene fa-
type. Thus, in a brain region not normally associated with sex differ- mily, GABA/glutamate family, and glucocorticoid receptors binding
ences, this work sheds light on ways that genes, environment and sex genes were decreased transiently in control mice by AS but showed a
interact to affect the transcriptome's response to a stressor (Marrocco persistent reduction in ELS mice and no response to an AS challenge. A
et al., 2017). stringent filtering of genes affected by AS in control and ELS mice re-
Third, males and females differ in response to stress in the medial vealed a remarkable decrease in gene expression change in ELS mice
prefrontal cortex – males show stress-induced shrinkage of dendrites elicited by acute stress compared to control. Fig. 4. Thus, ELS programs
that project cortically whereas females do not show that change but, a restricted translational response to stress in stress-sensitive CA3
rather, show stress-induced expansion of dendrites that project to the neurons leading to persistent changes in gene expression, some of
amygdala but only when there was estradiol in the circulation after which mimic the transient effects of AS in control mice, while leaving in
ovariectomy (Shansky et al., 2010). These differences may underlie sex operation the immediate early gene response to AS (Marrocco et al.,
differences in how male and female rats learn and extinguish fear 2019).
conditioning even though the outcome is similar (Gruene et al., 2015). While sex differences have so far not been studied in this model
The degree to which these differences are genetically, hormonally or after ELS, based upon the discussion above it is very likely that the
experientially determined is not yet known. response of CA3 neurons will be quite different in females. Moreover,
transgenerational transmission either by behavior (O'Donnell and
Meaney, 2017) or modifications of the germline DNA or epigenetic
5. Lasting epigenetic effects of early life adversity
changes in the fetus during pregnancy in the case of obesity are now
recognized (Bohacek and Mansuy, 2015; Donkin et al., 2016; Kral et al.,
Early life experiences are particularly potent in setting the direction
2006).
of the life course and increase the risk, in humans, of depression, sub-
stance abuse and suboptimal cognitive development later in life but also
allostasis and the propensity to develop allostatic load and overload in 6. Putting it all together
such disorders as cardiovascular disease and diabetes (Felitti et al.,
1998; McEwen and McEwen, 2017). Moreover, adverse early life ex- The unfolding of individuality within what the genetic endowment
perience in infancy and childhood involving poverty, abuse and ne- allows has led to a new view of the epigenetic changes over the life
glect, affect how genes are expressed and determine how well brain course that determine trajectories of health and disease. The plasticity

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B.S. McEwen Hormones and Behavior 119 (2020) 104619

Fig. 3. Acute stress affects CA3 neurons in a sex-dependent manner and alters a greater number of genes in females than in males. A histogram of mapped reads
showing expression of Arc and Fos, as genes representative of the immediate early gene transcription (IEG) cascade. Blue line represents the introns (thin) and exons
(thick). Shaded areas indicate the number of normalized reads for female controls (light pink), stressed female (dark pink), male controls (light blue), and stressed
male (dark blue). As expected, acute stress increases IEG expression in both males and females. b (Left) Venn diagram depicting the number of genes altered by acute
stress in females (pink circle), males (blue circle), and in both sexes (purple overlap) (Z-score < 0.001; absolute fold change > 1.5). (Right) Venn diagrams are
broken into up-regulated (red arrow) and down-regulated (blue arrow) genes. c Heat map representing the normalized read density of the 100 genes with the highest
variance across all groups. Genes were clustered based on similar expression profile: (i) Genes up-regulated by stress in females and down-regulated by stress in
males; (ii) Genes down-regulated by stress in females and unaffected by stress in males;(iii) Genes up-regulated by stress in females and unaltered by stress in males;
(iv) Genes down-regulated by stress in females and up-regulated by stress in males. C control, S stressed (Marrocco et al., 2017). (For interpretation of the references
to colour in this figure legend, the reader is referred to the web version of this article.)

of the brain offers opportunities for changing the trajectory (Halfon recovered after CRS. Each treatment group showed acute stress largely
et al., 2014). Indeed, we cannot “roll back the clock” and truly “re- unique gene expression responses, indicating that the brain is con-
verse” the effects of experiences, positive or negative. Rather, we must tinually changing with experience. Nevertheless, there is a set of genes
think of “recovery” and “redirection” and “resilience”, rather than that was always activated by FST (e.g., immediately early genes) (Gray
“reversal”. We therefore think about “changing trajectories” of function et al., 2014).
resulting in compensatory changes in the brain and body over the life Given the potency of early life experiences, both positive and ne-
course. One example of this is the remarkable differences in the qua- gative, and the substantial sex difference that exist at the level of gene
litative nature of gene expression in hippocampus after a bolus of expression and brain circuitry, interventions that change the trajectory
corticosterone compared to the effects of a novel acute forced swim of behavior and physiology should recognize these powerful influences
(FST) in naïve rats compared to FST effects in animals that were and take advantage of windows of opportunity when the likelihood of
chronically restrained (CRS) before or FST in animals that had change is increased (Halfon et al., 2014). Very early childhood is one

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B.S. McEwen Hormones and Behavior 119 (2020) 104619

Fig. 4. Translational repression in ELS mice fol-

lowing AS. Venn diagram depicting the number of
genes altered in stressed control mice vs. unstressed
control mice (dark blue), stressed ELS mice vs. un-
stressed ELS mice (yellow), and in both comparisons
(yellow-blue overlap; p < .05). AS induces a
markedly limited gene expression change in ELS
mice relative to control mice. We found that AS in-
duces 1698 genes in control mice and 34 genes in
ELS mice, with 16 genes common to both compar-
isons. Separating these AS-regulated genes based on
the direction of their fold change revealed that AS
upregulates 629 genes in control mice and 32 genes
in ELS mice, with 14 genes commonly upregulated in
both comparisons. In addition, 1069 genes are
downregulated in control mice and two genes
downregulated in ELS mice by AS, with no genes
common to both comparisons. ELS, early life stress;
AS, acute stress (Marrocco et al., 2019). (For inter-
pretation of the references to colour in this figure
legend, the reader is referred to the web version of
this article.)

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Research in the author's lab was supported by NIH grants NS07080 3543–3548.
Felitti, V.J., Anda, R.F., Nordenberg, D., Williamson, D.F., Spitz, A.M., Edwards, V., Koss,
and MH41256 and currently by the Hope for Depression Research M.P., Marks, J.S., 1998. Relationship of childhood abuse and household dysfunction
Foundation. The author acknowledges the many contributions of to many of the leading causes of death in adults. The adverse childhood experiences
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