Journal of Neuroendocrinology, 2014, 26, 707–723

© 2014 British Society for Neuroendocrinology

REVIEW ARTICLE

The Consequences of Early-Life Adversity: Neurobiological, Behavioural

and Epigenetic Adaptations
S. Maccari†, H. J. Krugers§, S. Morley-Fletcher†, M. Szyf¶ and P. J. Brunton**
†LIA, International Laboratory Associated, UMR 8576 CNRS Neural plasticity Team, University of Lille 1, France and Sapienza University of Rome, IRCCS
NEUROMED, Italy.
§Swammerdam Institute for Life Sciences, SILS-CNS, University of Amsterdam, Amsterdam, The Netherlands.
¶Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada.
**Division of Neurobiology, The Roslin Institute and R(D)SVS, University of Edinburgh, Midlothian, UK.

Journal of
Neuroendocrinology
Correspondence to:
P. J. Brunton, Division of
Neurobiology, The Roslin Institute and
R(D)SVS, University of Edinburgh,
Easter Bush, Midlothian EH25 9RG,
UK
(e-mail: p.j.brunton@ed.ac.uk).
During the perinatal period, the brain is particularly sensitive to remodelling by environmental
factors. Adverse early-life experiences, such as stress exposure or suboptimal maternal care, can
have long-lasting detrimental consequences for an individual. This phenomenon is often referred
to as ‘early-life programming’ and is associated with an increased risk of disease. Typically,
rodents exposed to prenatal stress or postnatal maternal deprivation display enhanced neuroen-
docrine responses to stress, increased levels of anxiety and depressive-like behaviours, and cog-
nitive impairments. Some of the phenotypes observed in these models of early-life adversity are
likely to share common neurobiological mechanisms. For example, there is evidence for impaired
glucocorticoid negative-feedback control of the hypothalamic-pituitary-adrenal axis, altered glu-
tamate neurotransmission and reduced hippocampal neurogenesis in both prenatally stressed
rats and rats that experienced deficient maternal care. The possible mechanisms through which
maternal stress during pregnancy may be transmitted to the offspring are reviewed, with special
consideration given to altered maternal behaviour postpartum. We also discuss what is known
about the neurobiological and epigenetic mechanisms that underpin early-life programming of
the neonatal brain in the first generation and subsequent generations, with a view to abrogating
programming effects and potentially identifying new therapeutic targets for the treatment of
stress-related disorders and cognitive impairment.
Key words: cognition, DNA methylation, hippocampus, HPA axis, maternal behaviour, mood dis-
orders, prenatal stress
doi: 10.1111/jne.12175

this programming is maladaptive, increasing the susceptibility of

Introduction
It is widely accepted that the physiological and behavioural traits
of an individual are determined by complex interactions between
their genes (‘nature’) and their experiences/environment (‘nurture’).
The perinatal period, infancy, childhood and puberty are periods
of increased neuroplasticity and therefore the brain is particularly
sensitive to remodelling by environmental factors at these times.
Exposure to adversity (such as stress or maternal deprivation) in
early-life can ‘programme’ or ‘imprint’ persistent neuroendocrine,
behavioural and metabolic changes (1–4). These programming
effects may be considered adaptive, permitting an organism to
adapt to cope with unfavourable conditions (5). However, often
an individual to adulthood pathologies such as cardiovascular
disease, metabolic syndrome, cognitive impairments and affective
disorders (6). The idea that adult vulnerability to disease may be
programmed or imprinted during the foetal period (i.e. foetal
programming) was first proposed by Barker et al. (7,8) and is
now widely accepted. This idea has subsequently been extended
to also include the early postnatal period, termed ‘perinatal pro-
gramming’, where nongenetic factors act in early life (pre- or
postnatally) to permanently organise or imprint physiological sys-
tems.
Early adverse experiences can programme adult health in two
ways: either by cumulative damage over time or by the biological
708 S. Maccari et al.
embedding of adversities during sensitive developmental periods.
For example, according to the developmental hypothesis of mood
disorders, stressful events occurring during critical periods of brain
development trigger a maladaptive programme that alters mecha-
nisms of resilience to stress across the entire lifespan. Along this
line, major depression can be seen as a latent outcome of stressful
early-life events (9–15).
This review will focus on adversity in the perinatal period. We
first discuss the consequences of prenatal stress on the offspring’s
brain and behaviour (taking into account sex differences), the possi-
ble central mechanisms underpinning these altered phenotypes and
how prenatal stress effects may be transmitted to the developing
foetus. Next, we consider the importance of the early postnatal
environment, in particular the quality of maternal care on brain
development of the neonate. Finally, we review the evidence for
early-life adversity in transgenerational programming of future gen-
erations and discuss the epigenetic mechanisms involved.
Consequences of prenatal stress on the brain and
behaviour in later life
The use of early-life environmental manipulations in animal models
has spawned the study of individual vulnerability to stress-related
disorders, which should aid the development of new therapies and
enhance our understanding in such a way as to improve prevention
strategies. A plethora of studies have investigated the consequences
of manipulating the prenatal environment (e.g. by maternal stress
exposure, maternal glucocorticoid administration, maternal nutrient
restriction) on the developing offspring. The majority of these stud-
ies have been performed in rodents and multiple paradigms of
‘adversity’ have been reported in the literature. Pregnant rats, mice
or guinea pigs are typically repeatedly exposed to a either a psy-
chological stressor (e.g. repeated restraint, noise or strobe lighting)
(16–18), a physical stressor (e.g. hypoxia or immune challenge)
(19,20) or a combined psychological and physical stressor (e.g.
social stress) (1,21) either throughout or during a specific period of
gestation. Alternatively, chronic variable stress paradigms are also
commonly utilised that involve exposing pregnant animals to a
combination of different stressors on an unpredictable basis
(22–24).
Here, we focus on two prenatal stress paradigms in the rat, with
which we have most experience: the prenatal restraint stress (PRS)
model and the prenatal social stress (PSS) model. Both are well-
documented models of early-life stress (ELS) (4,25). The PRS model
(26) involves restraining a pregnant rat in a transparent Plexiglas
cylinder, three times a day for 45 min under bright light: from day
11 of pregnancy until term (4,27) (Fig. 1), whereas the PSS model
involves transferring a pregnant rat to the cage of an unfamiliar
(and hence aggressive) lactating rat for 10 min/day for 5 consecu-
tive days (gestation days 16–20) during the last week of pregnancy
(1). The advantage of the PSS model is that it is considered etho-
logically relevant and, because of the ‘social’ aspect, it perhaps bet-
ter reflects the types of stress pregnant women are likely to
experience. However, because this model relies on the behaviour
exhibited by lactating rats (e.g. aggression), more animals are
© 2014 British Society for Neuroendocrinology
required and the intensity of the stress is more difficult to maintain
at a consistent level between animals and across time, in contrast
to the PRS model.
Prenatal stress and hypothalamic-pituitary-adrenal (HPA)
axis dysfunction in the offspring
A key feature of both of these models is a permanent impairment
of HPA axis functioning in the offspring (Table 1). PRS offspring
exhibit prolonged corticosterone responses to stress in both male
and female PRS rats (4,26,28). Similarly, both male and female PSS
offspring display enhanced and prolonged HPA axis responses to
physical (Fig. 2) and psychological stressors in adulthood (1).
Prenatal restraint stress (PRS) also affects age-related alterations
in HPA axis function. For example, the HPA axis period of hypore-
sponsiveness typically observed in the early postnatal period (29)
is abolished in newborn PRS rats (16) and circulating glucocorti-
coid levels in middle-aged PRS animals are similar to those found
in aged nonstressed animals (30). Moreover, PRS alters not only
reactive adaptation, but also predictive adaptation by altering cir-
cadian rhythmicity. Both male and female PRS rats have greater
levels of corticosterone at the end of the light period, and females
display elevated corticosterone levels over the entire diurnal cycle
(31). The sleep–wake cycle is also dramatically modified by PRS
(32,33), with a significant increase in the amount of rapid eye
movement sleep over a 24-h recording session, which is positively
correlated with plasma corticosterone concentrations. Significant
phase advances are also observed in the circadian rhythms of
locomotor activity relative to the entrained light/dark cycle in both
male and female PRS rats. Furthermore, when subjected to an
abrupt shift in the light/dark cycle, PRS rats resynchronise their
activity rhythm to a new light/dark cycle slower than control rats
(34).
Prenatal stress and affective behaviour in the offspring
The hyperactivity of the HPA axis observed in PRS and PSS off-
spring is accompanied by increased anxiety- and depressive-like
behaviour during the life span (Table 1). This is evidenced in male
PRS offspring (females were not studied) by increased ultrasonic
vocalisations (USVs) in infancy (35), reduced social play during ado-
lescence (36), reduced exploration in the elevated-plus maze test
and open field test (30,37) and increased immobility in the forced-
swim test during adulthood (27,38–40). Rats subjected to PRS emit
significantly more USVs in response to isolation at postnatal day 10
compared to controls. In addition, PRS pups do not show the phe-
nomenon of ‘maternal potentiation’ (i.e. the increase in USVs in
response to a brief maternal reunion after isolation), normally seen
at postnatal day 10 and postnatal day 14 (35).
Adult male PSS offspring also display increased anxiety-related
behaviour on the elevated plus maze (1). However, PSS does not
appear to affect anxiety-type behaviour in the female offspring
(1). A distinct sex difference in anxiety-like behaviour is also
observed in offspring of the PRS model, with males appearing to
be more susceptible than females (41). Taken together, these data
Journal of Neuroendocrinology, 2014, 26, 707–723
 Consequences of early-life adversity 709

Reduced
Prenatal
maternal
restraint stress
behaviour Anxiety and glutamate
35
CON r = 0.9
PRS P < 0.01
30

Time spent in open arms (%)

25

20

15

10

0
100 200 300 400
Depolarisation-stimulated glutamate release
(pmol/mg prot.)

E11 P0 P21 3 months

Pregnancy Birth Weaning Adulthood

Fig. 1. Prenatal restraint stress (PRS) in the rat: a model of early programming of stress-related diseases from molecules to behaviour. During the second half
of gestation, the dam is restrained (45 min 9 3 times/day) under bright light. The procedure is not painful but the dam cannot escape. The offspring and the
mother are then left undisturbed until weaning (P21). Gestational stress reduces subsequent maternal behaviour and the adult PRS offspring are characterised
by enhanced anxiety and reduced glutamate release in the ventral hippocampus. Based on data from Marrocco et al (54). CON, control; E, embryonic day; P,
postnatal day; PRS, prenatal restraint stress.

offer a clear demonstration that prenatal stress exposure causes
anxiety and depression-like behaviour in the male offspring, which
is already evident early in development, but also depression-like
behaviour in female PRS rats (40). Chronic treatment with anti-
depressants in adulthood can fully reverse the key alterations
induced by PRS (33,38,39), indicating that models of prenatal
stress, such as the PRS paradigm, can replicate the developmental
factors involved in the etiology of anxious/depressive disorders
(14), and have predictive and face validity as an experimental ani-
mal model of anxiety and depression in humans (10).
Prenatal stress, impaired cognition and related
neuroplasticity in the offspring
Studies in nonhuman primates and rodents have reported altera-
tions in the structure and function of the hippocampus as a conse-
quence of prenatal stress (42,43) and several studies have shown
learning and/or memory impairment in the offspring of dams
stressed during pregnancy (41,44). However, the timing of the pre-
natal stress (early versus mid- or late-gestation) (44), the type and/
or the severity of the prenatal stress, the sex of the offspring (41)
and the age of the offspring at time of memory assessment (e.g.
juvenile, adult or aged) appear to be critical. PRS during late gesta-
tion generally has little effect on cognitive performance in the
Morris water maze and Y-maze in young male adults (30,41)
(Table 1) but exacerbates memory impairment observed during age-
ing in these tests (30,45,46). Cognitive deficits induced by PRS are
linked to a reduction in hippocampal neurogenesis (42,47). In
particular, these effects are sex-dependent, with males being more
vulnerable than females, and this effect is observed mainly in the
ventral hippocampus (41). However, in addition to a sex-dependent
effect, alterations in neuroplasticity may also depend on the genetic
background of the individual. Indeed, prenatal stress has been
shown to differentially alter the consequences of a genetic predis-
position to either high- or low-anxiety-related behaviour on neuro-
plasticity. Prenatal stress results in reduced neurogenesis in rats
with genetically determined high emotionality but not those with
low emotionality (48,49). The PRS-induced deficit in neurogenesis
can be restored by chronic treatment with antidepressants such as
fluoxetine and agomelatine (39) or the neurotrophin, insulin-like
growth factor-1 (45).
Central mechanisms underlying altered phenotypes in
prenatally stressed offspring
Because the brain is particularly sensitive to programming by pre-
natal stress exposure and programming of the brain is associated
with several negative phenotypes (e.g. anxiety, depression, impaired
cognition), understanding the central mechanisms involved is
important to pave the way for new therapeutic strategies and iden-
tify potential pharmacological targets.
Increased forward drive and impaired negative-feedback
control of the HPA axis
Enhanced adrenocorticotrophic (ACTH) and corticosterone responses
to stress in PSS offspring are associated with elevated expression
of mRNA for the ACTH secretagogues, corticotrophin-releasing

Journal of Neuroendocrinology, 2014, 26, 707–723 © 2014 British Society for Neuroendocrinology
710 S. Maccari et al.

Table 1. Comparison of Neuroendocrine and Behavioural Effects of the Pre-

natal Restraint Stress (PRS) and Prenatal Social Stress (PSS) Models. Control PSS

PRS PSS

Parameter Male Female Male Female References

pPVN CRH
Basal corticosterone ↑* ↑ ↔ ↑ 1,28 mRNA
levels
Stress-induced ↑ ↑ ↑ ↑ 1,16,26
corticosterone levels
Hippocampal GR ↓† NA ↔‡ ↔‡ 1,16,26 300
Hippocampal MR ↓† NA ↓‡ ↓‡ 1,16,26

Δ ACTH 30 min post-IL-1β (pg/ml)

Anxiety-type ↑ ↓ ↑ ↔ 1,30,35–37,41 *
250
behaviour
Depressive-like ↑ ↑ NA NA 27,38–40 200
behaviour
Spatial memory ↔ NA ↔ ↔ 30,37, Brunton PJ Anterior 150 ACTH
(young rats) and Lai Y-T, pituitary
unpublished 100
data
Working memory ↔ NA NA NA 30,37 50
(young rats)
Working memory ↓ NA NA NA 30 0
(aged rats) CON PSS

Δ Corticosterone 60 min post-IL-1β (ng/ml)

The neuroendocrine and behavioural effects of the PRS and PSS models on
the male and female offspring compared to age-matched control offspring
(mothers undisturbed during pregnancy). ↑, increase; ↓, decrease or ↔, no
significant effect. GR, glucocorticoid receptor, MR, mineralocorticoid recep-
tor; *Only at end of light phase; †receptor binding; ‡mRNA expression. NA,
no data available.
hormone (CRH) and vasopressin in the paraventricular nucleus
(PVN), indicating increased excitatory drive to the anterior pituitary
by the hypothalamus (Fig. 2). Whether this is a result of enhanced
drive to the PVN CRH neurones, reduced inhibitory input to the
CRH neurones or a combination of both is not clear.
The HPA axis is under negative-feedback control by glucocortic-
oids, acting via glucocorticoid (GR) and mineralocorticoid (MR)
receptors. Prolonged corticosterone responses to stress in PRS
offspring occur concomitant with reduced levels of both MR and
GR in the hippocampus, which is evident in the neonate, adoles-
cent and adult (16,26). Similarly, expression of MR mRNA is
reduced in the hippocampus in adult male and female PSS off-
spring (1). Together, these findings indicate impaired glucocorti-
coid negative-feedback control of the HPA axis in prenatally
stressed offspring.
The mechanisms through which hippocampal GR and/or MR may
be down-regulated are not fully understood, although they likely
involve epigenetic changes, as has been previously demonstrated
for altered GR gene expression in the hippocampus of rats exposed
to varying degrees of postnatal maternal care (discussed below)
(50) and in mice exposed to prenatal stress (23).
Glutamate neurotransmission in the hippocampus
Therapeutic strategies aimed at restoring the balance between
excitatory and inhibitory neurotransmission in the hippocampus
250
*
200
150
Adrenal
CORT
cortex
100
50
0
CON PSS
Fig. 2. Enhanced stress-induced hypothalamic-pituitary-adrenal (HPA) axis
responses in prenatally stressed rats. HPA axis responses in adult male off-
spring born to control (CON) dams or dams exposed to social stress (PSS)
from days 16–20 of gestation. Rats were blood sampled before and after
treatment with the cytokine, interleukin-1b (IL-1b; 0.5 lg/kg i.v.) and then
killed 4 h later. Neurones located in the parvocellular region of the paraven-
tricular nucleus (pPVN) in the hypothalamus express corticotrophin-releasing
hormone (CRH) mRNA (detected by in situ hybridisation). IL-1b-induced
CRH mRNA levels are significantly greater in the PSS rats compared with
controls, resulting in a three-fold greater secretion of adrenocorticotrophic
hormone (ACTH) from the anterior pituitary and corticosterone (CORT) secre-
tion from the adrenal cortex. *P < 0.001, Student’s t-test. Based on data
from Brunton and Russell (1).
may be effective in correcting the pathological phenotype caused
by ELS. Alterations in glutamate neurotransmission are assumed to
play a role in the pathophysiology of stress-related disorders
(51–53). Indeed, a long-term alteration in glutamate transmission
lies at the core of the neuroplastic programming and anxious
phenotype induced by PRS. PRS induces a selective reduction in

© 2014 British Society for Neuroendocrinology Journal of Neuroendocrinology, 2014, 26, 707–723

glutamate release in the ventral hippocampus that is causally
related with the enhanced anxiety-like behaviour displayed by PRS
animals (Fig. 1). Furthermore, pharmacological enhancement of
glutamate release in the ventral hippocampus abolishes this
behavioural pattern (54). PRS rats also show reduced expression
and function of group-I and group-II hippocampal metabotropic
glutamate (mGlu) receptors, with a marked reduction of mGlu1
and mGlu5 observed selectively in males and a reduction in mGlu
2/3 in both males and females (35,41,46). The alterations in mGlu
receptors in the hippocampus induced by PRS can be detected at
infancy with mGlu5 and mGlu1 receptors reduced in PRS rats by
postnatal day 10, whereas expression of mGlu2/3 receptors
declines only after weaning (35).
Thus, glutamatergic transmission in the ventral hippocampus, a
key brain region involved in the (mal)adaptive programming caused
by ELS, represents an attractive pharmacological target for novel
therapeutic strategies in the treatment of depression and anxiety
(10,54,55). Indeed, chronic treatment with fluoxetine or agomelatine
can reverse the depressive-like phenotype induced by PRS by
enhancing glutamatergic transmission in the ventral hippocampus
(56).
Anxiety and altered CRH receptor expression in the
amygdala
The amygdala CRH system plays a key role in mediating anxiety-
like behaviours (57–59). Increased levels of CRH mRNA are
observed in the central nucleus of the amygdala (CeA) of both
male and female PSS offspring (1). This increase in CRH is probably
facilitated by glucocorticoids because glucocorticoids up-regulate
CRH gene expression in the amygdala (60) and central GR facilitate
anxiety-type behaviours. Indeed, GR mRNA expression is also up-
regulated in the CeA in PSS rats (1). However, this is unlikely to
explain the anxiety-like behaviour in PSS male rats because both
sexes show elevated CRH and GR mRNA expression in the CeA,
whereas only the males exhibit an anxious phenotype (1). Never-
theless, there are sex differences in CRH receptor expression in the
amygdala in PSS offspring indicating that these changes may be
critical in the expression of an anxious phenotype (61). Two dis-
tinct receptors mediate the actions of CRH: the type 1 receptor
(CRH-R1) mediates anxiogenic behavioural responses, whereas the
type 2 receptor (CRH-R2) mediates the anxiolytic actions of
urocortins 2 and 3 (62). In PSS males, CRH-R1 is increased in the
CeA and basolateral amygdala, whereas CRH-R2 is decreased in
the basomedial amygdala; however this effect is not seen in PSS
females (61). This altered ratio of CRH-R1 to CRH-R2 expression in
the amygdala in PSS males may contribute to increased anxiogenic
actions of CRH, and decreased anxiolytic actions of urocortins 2
and/or 3, thus explaining the anxious-like behaviour observed in
PSS males. Indeed, heightened anxiety has been associated with
increased CRH-R1 mRNA expression in the PVN (63) and reduced
CRH-R2 expression in the amygdala (64) in other models of prena-
tal stress in rats, and forebrain CRH-R1 signalling is necessary for
the expression of anxiogenic behaviour in a mouse model of ELS
(65).
Journal of Neuroendocrinology, 2014, 26, 707–723
Consequences of early-life adversity 711
Transmission of prenatal stress effects from mother to
foetus
Glucocorticoids
The mechanisms responsible for transmitting the effects of maternal
stress to the foetus(es) remain unclear; however, given that an
important feature of the stress response is the secretion of glucocor-
ticoids, these steroids have become the preferred candidate
‘programming factor’ conveying maternal stress effects to the foetus
(es) (66,67). The evidence is as follows: (i) pregnant rodents treated
with the synthetic glucocorticoid, dexamethasone, produce offspring
with phenotypes similar to prenatally stressed offspring (18,68) and
(ii) maternal adrenalectomy (to remove the source of maternal gluco-
corticoids) abrogates some of the effects of PRS in the offspring (69).
Nevertheless, a role for maternal glucocorticoids in transmitting
the effects of maternal stress to the foetus is not clear-cut. First, the
placenta expresses 11b-hydroxysteroid dehydrogenase type-2
(11b-HSD2), which serves to limit foetal exposure to maternal gluco-
corticoids by metabolising corticosterone into inactive 11-dehydro-
corticosterone (70). However, repeated stress exposure in pregnancy
significantly reduces activity of this barrier enzyme and placental
gene expression for 11b-HSD2 (71,72), which means potentially
increased exposure of the foetuses to maternal glucocorticoids. Sec-
ond, maternal HPA axis responses to stress are dramatically reduced
in late pregnancy, which is assumed to minimise foetal exposure to
maternal glucocorticoids (73). Indeed, PSS offspring display pro-
grammed phenotypes despite the maximal maternal corticosterone
response during the PSS exposure not exceeding the concentrations
observed at the diurnal peak in gestation (74). However, it may be
that repeated stress, in combination with reduced effectiveness of
placental 11b-HSD2, leads to exposure of the foetus(es) to maternal
glucocorticoids at levels sufficient to programme the offspring.
Finally, it should be noted that, in foetal rats, the adrenal glands
are capable of corticosterone secretion from embryonic day 16.
Because maternal stress in late pregnancy results in activation of
the foetal HPA axis (75,76), it is plausible that glucocorticoids of
foetal origin may also contribute to programming the foetal brain.
Catecholamines
Maternal adrenalectomy not only removes the source of glucocor-
ticoids, but also removes the source of other hormones (e.g. cate-
cholamines, sex steroids, mineralocorticoids), which could
potentially contribute to foetal programming. By contrast to stress-
induced adrenaline secretion from the adrenal medulla, which is
attenuated in late pregnancy, noradrenaline responses to stress are
maintained in pregnancy (77,78). Elevated levels of circulating
maternal catecholamines have the potential to negatively influence
foetal development: vasoconstriction of placental blood vessels will
reduce placental blood supply, thus impairing the delivery of oxy-
gen and nutrients to the foetuses. Given that both hypoxia and
nutrient restriction activate the foetal HPA axis (79,80) and the foe-
tal sympathetic-adrenomedullary system (81), these responses may
also contribute to programming of the offspring (19,63,82,83).
© 2014 British Society for Neuroendocrinology
712 S. Maccari et al.
Altered placental function
Foetal growth and development relies on adequate placental nutri-
ent transfer; thus, placental dysfunction could also be implicated in
programming the offspring. A key nutrient for the developing foe-
tus is glucose, which crosses the placental barrier via transporters
(84). Glucose transporter type 1 (GLUT1) is the most abundantly
expressed of the glucose transporters in rodent placentas (85) and
is considered rate limiting for glucose transport from mother to
foetus. Placental expression of GLUT1 is decreased by PRS and is
associated with reduced levels of glucose and growth hormone in
the foetal circulation (72). As noted above, placental expression and
activity of 11b-HSD2 is also strongly reduced by PRS (72), which
would be expected to lead to increased transfer of maternal gluco-
corticoids to the foetal compartment (70).
Interestingly, placental expression of 11b-HSD2 is selectively
increased in rats with genetically determined low anxiety-related
behaviour (49) but not in rats with high anxiety-related behaviour,
thus indicating that the gene 9 early environment interaction con-
tributes to shape placental function. Together, these changes in pla-
cental function induced by ELS may underlie reduced birth weight
observed in PRS and PSS offspring and contribute to programming
of metabolism, inflammatory responses, the brain and behaviour
(1,2,72,86).
Epigenetic mechanisms are critically involved in determining pla-
cental functioning and a recent study by Howerton et al. (86) has
identified O-linked-N-acetylglucosamine (O-GlcNAc) transferase
(OGT), as a promising placental biomarker of maternal stress expo-
sure (early gestation PRS in mice). OGT is an X-linked gene impor-
tant in regulating proteins involved in chromatin remodelling.
Levels of both OGT and its biochemical marker, O-GlcNAcylation,
are significantly lower in males than females and are further
reduced by prenatal stress exposure (86). Moreover, examination of
human placental tissue has found similar patterns related to X
chromosome dosage (86). Hypothalamic gene expression and the
broad epigenetic microRNA environment in the neonatal brain of
placental-specific hemizygous OGT mice are markedly altered, high-
lighting the importance of placental OGT in neurodevelopment (86).
Interestingly, OGT interacts with the GR to repress gene expression
(87), thus strengthening the epigenetic role played by placental OGT
in the programming induced by prenatal stress.
Altered maternal behaviour
The early postnatal environment is known to influence the activity
of the HPA axis and anxiety-like behaviour in later life (88,89).
Given that stress exposure during gestation can alter subsequent
maternal behaviour (90,91) and increase anxiety-related behaviour
postpartum (92), it is important to take this into account when
considering how the effects of maternal stress during pregnancy
are transmitted from the mother to the offspring. Although the
importance of maternal care for offspring development is discussed
in detail below, it is important to note that prenatal stress-related
outcomes on HPA axis function in the offspring can be reversed by
early postnatal manipulation such as adoption (26). Indeed,
© 2014 British Society for Neuroendocrinology
adoption modifies maternal behaviour, increasing pup-directed
behaviour in foster mothers, and decreasing stress-induced cortico-
sterone secretion in adult PRS offspring (26). Moreover, stress-
induced impairments in subsequent maternal behaviour (following
repeated restraint stress during the second half of pregnancy) can
be reversed by treating the lactating dam with oxytocin receptor
agonists (Mairesse J, Gatta E, Reynaert ML, Marrocco J, Morley-
Fletcher S, Soichot M, Deruyter L, Van Camp G, Bouwalerh H, Fagioli
F, Pittaluga A, Allorge D, Nicoletti F, Maccari S; unpublished data),
highlighting the possibility of targeting the central oxytocinergic
system in the treatment of stress-related disorders both in the
adult offspring and in the mothers during the postpartum period
(93, Mairesse J, Gatta E, Reynaert ML, Marrocco J, Morley-Fletcher
S, Soichot M, Deruyter L, Van Camp G, Bouwalerh H, Fagioli F, Pit-
taluga A, Allorge D, Nicoletti F, Maccari S; unpublished data). There
are, however, some important considerations that should be taken
into account when manipulating the oxytocin system, particularly
in the peripartum period (94).
Consequences of postnatal stress on the brain and
behaviour in later life
In rodents, the presence of the mother during the initial weeks
after birth is of fundamental importance for the offspring. During
this time, the interaction between mother and pups is highly rele-
vant for nutrition, body temperature and physiological homeostasis
(95). Postnatally, the brain is still developing and disturbances of
the early postnatal mother–pup relationship can have major and
long-lasting consequences for neuroendocrinology, neuronal func-
tion, behaviour and adaptation of the offspring. Moreover, there is
increasing evidence from studies in biparental species that paternal
deprivation can have similar adverse neurobiological and behaviour-
al consequences for the offspring (96).
Postnatal stress and HPA axis dysfunction in the offspring
The presence of the dam during the early postnatal period is crucial
for maintaining activity of the HPA axis (88,89). In general, the
presence of the dam results in lower levels of HPA axis activity in
the offspring (97–101). During the first 2 weeks of life, pups show
diminished reactivity of the HPA axis in response to mild–moderate
stressors (stress hyporesponsive period; SHRP) (29,102). Disruption
of the early-life environment and the SHRP by separating pups
from the dam has substantial and long-lasting neuroendocrine and
behavioural consequences. In general, maternal deprivation and
maternal separation result in phenotypes similar to those observed
in prenatally stressed offspring (described above), including HPA
axis hyperactivity (103–108), as well as altered social behaviour and
increased aggression (109).
Postnatal stress, impaired cognition and related
neuroplasticity in the offspring
Postnatal stress also results in cognitive impairments (110–112)
and higher levels of anxiety (109,113–115). Moreover, hippocampal
Journal of Neuroendocrinology, 2014, 26, 707–723

structure is affected: maternal separation and deprivation has been
found to decrease mossy fibre density (116), reduce neurogenesis
(112,117–119), reduce brain-derived neurotrophic factor expression
(120,121) and alter the number of primary dendrites in dentate
gyrus granule cells in a sex-dependent manner (an increase is
found in females and a decrease in males) (112,122). Similar
findings are observed in mice that were exposed to chronic ELS
evoked by reducing nesting and bedding material between P2 and
P9 (123,124). ELS results in elevated plasma corticosterone levels in
adult animals as a result of enhanced excitatory glutamatergic
transmission in the PVN (125), together with reduced spatial learn-
ing, impaired object recognition, reduced hippocampal dendritic
arborisation and disrupted hippocampal long-term potentiation
(LTP) (123,124,126). These cognitive deficits and structural changes
in the hippocampus induced by ELS appear to be dependent, at
least in part, on forebrain CRH-R1 signalling (126,127).
Maternal care, cognition and neuroplasticity in the
offspring
Maternal deprivation and maternal separation disturb mother–
infant interactions in a complex way. During separation and depri-
vation, the offspring are deprived of maternal care (such as licking/
grooming, nutrition, warmth) for a shorter or longer period of time.
However, upon reunion with the mother, the pups may actually
receive enhanced levels of maternal care (112). Because maternal
separation and deprivation are accompanied by alterations in
maternal behaviour (88,128–130), it is highly relevant to understand
how naturally occurring variations in maternal care provided by the
dam affects the offspring (131).
Studies have explored this behavioural variability in a normal,
undisturbed population of Long Evans rats. It was confirmed that
substantial differences in maternal care exist between dams (88) and
that this trait was stable over time and over multiple litters (132).
More specifically, licking and grooming (LG) and arched-back nursing
(ABN) of the pups by the dam were shown to predict later-life phe-
notypic outcome (88,133–135). The offspring of low LG-ABN dams
exhibit enhanced HPA axis responses to stress in adulthood,
increased CRH mRNA levels in the hypothalamus and reduced hippo-
campal GR levels (88,135). Hippocampal GR expression is epigeneti-
cally programming via maternal care as discussed later. Importantly,
these neuroendocrine effects of variations in maternal care are
reversed by cross-fostering, thereby directly implying the relevance
of maternal care in neuroendocrine regulation of the HPA axis (88).
Different levels of maternal care during the early postnatal per-
iod can also regulate hippocampal structure. Neuronal survival in
the adult dentate gyrus (136), dendritic length of hippocampal CA1
pyramidal cells and dentate gyrus granular cells, the spine number
of hippocampal CA1 pyramidal cells (135) and dentate gyrus granu-
lar cells (137) and synaptophysin and neural cell adhesion molecule
levels (88) are all increased in adult offspring from high LG-ABN
dams. However, dendritic complexity and spine density in layer II/III
neurones of the somatosensory cortex were found to be reduced in
high LG-ABN offspring (138) indicating that maternal care can have
different effects on dendritic complexity in different brain areas.
Journal of Neuroendocrinology, 2014, 26, 707–723
Consequences of early-life adversity 713
In parallel with increased dendritic complexity, LTP can easily be
induced in the CA1 area and dentate gyrus in high LG-ABN off-
spring but not in low LG-ABN offspring (135,137,139). Recent stud-
ies have also described that synaptic currents are altered by
maternal care. NMDA currents are enhanced in the dentate gyrus
of offspring of low LG-ABN animals and maternal deprivation
affects synaptic expression of NMDA receptors (140). Interestingly,
application of NMDA receptor antagonist enabled synaptic plasticity
in offspring of low LG-ABN animals. Although paradoxical, these
studies may suggest that enhanced NMDA receptor function under-
lies the reduced ability to elicit hippocampal LTP in low LG-ABN
offspring. In agreement with an impaired ability to express synaptic
plasticity, low LG-ABN animals show spatial learning deficits in the
Morris water maze (134) and impaired object recognition memory
(141) compared to high LG-ABN offspring.
Not only neuroendocrine regulation and synaptic plasticity are
affected by maternal care, but also the synaptic function of low
LG-ABN and high LG-ABN animals appears to be differently regu-
lated by stress hormones. Thus, synaptic plasticity in low LG-ABN
animals is facilitated by bath-application of corticosterone and/or
noradrenaline to the slices (135,137,139). This indicates that synapses
of low LG-ABN animals do have the ability to express synaptic plas-
ticity and that the sensitivity of synapses is determined by variations
in postnatal maternal care (Fig. 3). Accordingly, memory formation in
a highly emotional contextual fear conditioning task is markedly
improved in low LG-ABN animals compared to high LG-ABN off-
spring (135). Similar effects have been found after maternal depriva-
tion (112). These observations indicate that low levels of postnatal
maternal care renders synapses more efficient under stressful condi-
tions and enhances memory formation for emotionally arousing
events, which may be an example of behavioural adaptation (142).
Interestingly, recent studies have demonstrated that there is con-
siderable variation in maternal care even within a litter, which also
250 Vehicle
Cort
Synaptic potentiation (% of baseline)
200
*
150
*
100
50
0
L-LG H-LG
Fig. 3. Maternal care determines sensitivity to corticosterone (Cort). Synap-
tic potentiation is enhanced in high licking/grooming (H-LG) animals com-
pared to low licking/grooming (L-LG) animals. However, corticosterone
enhances synaptic potentiation in L-LG animals at the same time as sup-
pressing synaptic plasticity in H-LG animals. *P < 0.05, Student’s t-test.
Based on data from Champagne et al. (135).
© 2014 British Society for Neuroendocrinology
714 S. Maccari et al.

has long-lasting consequences for brain and behaviour (143–145). Early-life programming of the genome: the role of
In the hippocampus, the pup LG-ABN score positively correlates epigenetics
with GR mRNA expression (145). In addition, the ability to evoke
There is a strong body of data supporting the hypothesis that ELS
synaptic plasticity in the dentate gyrus correlates positively with
results in long-term and stable phenotypic changes that involve per-
high LG-ABN scores although dendritic morphology in the dentate
sistent alterations in gene function. This begs the question of what
gyrus correlates less well with LG-ABN scores and differs between
comprises the mechanism that embeds the effects of early-life
males and females (145). Moreover, LG-ABN scores result in slight
adversity in the genome. Although much attention in understanding
effects on adult CA1 structure and function, which appear to be
how malfunctioning genes are involved in neuropathology in the last
sex-dependent (144).
decades has focussed on rare or common sequence alterations, the
Within-litter variations of maternal care also correlate with
data reviewed above indicate the possibility that gene function might
behaviour in adult animals. Thus, LG-ABN scores during early life
also be stably altered by the early environment and particularly by
correlates positively with behavioural expressions of social play
behavioural exposure. The classical idea of gene–environment inter-
(143) and decision making and correlates negatively with anxiety in
action focussed on how risk alleles affect the phenotype under dif-
rats (146).
ferent environments. However, these studies do not offer a
In conclusion, there is considerable evidence that maternal care
mechanism for this ‘magical’ interaction of environment and genes
during the early postnatal period can have long-lasting conse-
and the focus on polymorphic risk alleles might lead to the idea that
quences for brain structure, synaptic function, responsiveness of
‘gene–environment’ effects are limited to polymorphic genes (154).
synapses and behaviour.
Both the persistence and commonality of the effects of early-life
adversity suggest that physiological mechanisms must exist that
Transgenerational effects of early-life adversity translate these exposures to persistent gene function differences and
that they act on the common genetic landscape.
In recent years, research on the influence of early-life adversity has
The challenge to the idea that genotype exclusively defines phe-
been extended to include not only the first-generation offspring,
notypes was first addressed in the field of embryology when it
but also subsequent generations. It has become increasingly clear
became clear that, in multicellular organisms, such as mammals,
that the detrimental effects of early-life adversity (described above)
the same genetic heritage common to all different tissues expresses
can be transmitted to future generations, apparently via nonge-
numerous different phenotypes. Waddington (155) was the first to
nomic mechanisms (discussed below). Maternal under- or over-
coin the term ‘epigenetics’ to describe the persistent differentiation
nutrition during pregnancy has been most extensively studied. In
of gene function during embryonic development. The idea was that
guinea pigs, the effects of maternal under-nutrition during preg-
the genes undergo ‘nongenetic’ changes in their mode of function
nancy on HPA axis activity in the offspring are transmitted to both
that would define both the spatial and temporal profile of gene
the first- and second-generation offspring (147) and, in mice, phe-
function in the developing organism (155). Several decades of
notypes resulting from maternal high-fat diet (e.g. body length and
research have unravelled the epigenetic mechanisms that differenti-
insulin insensitivity) can be passed to subsequent generations
ate gene function during embryonic development. However, these
(148,149). Moreover, in rats, the effect of maternal administration
mechanisms respond to the innate signals of embryonic develop-
of dexamethasone during pregnancy on glucose tolerance is trans-
ment. It is easy to see how exposure to chemicals that intervene
mitted to the second-generation offspring via either the maternal
with epigenetic processes during embryonic development will dis-
(i.e. where prenatally dexamethasone-exposed F1 females are bred
rupt the generation of the epigenetic profile and will result in long-
with na€ıve males) or paternal line (i.e. where prenatally dexametha-
term changes in the expression of genes in the brain and other tis-
sone-exposed F1 males are bred with na€ıve females) (150). Recent
sues. The main question with response to early-life adversity is
studies have demonstrated that paternal stress exposure prior to
whether the same mechanism that differentiates gene function
conception can programme altered stress responsivity (151) and
during embryology in response to ‘innate’ signals will also respond
behaviour (152,153) in the subsequently conceived adult offspring,
to ‘external’ signals from the environment and whether behavioural
and this is associated with epigenetic reprogramming of the sperm
exposures rather than chemical exposure could impact ‘epigenetic’
(151,153). Furthermore, paternal nutritional status, drug/toxin expo-
programming. It was recently proposed that the same mechanism
sure and the social environment have been demonstrated to influ-
that provides different tissue-specific identities to identical genes
ence the offspring’s brain and behaviour (via epigenetic
could operate in conferring ‘experience-specific’ identities to genes.
mechanisms) and these effects persist across multiple generations
These mechanisms are proposed to be adaptive/maladaptive physio-
(96). To date, very few published studies have investigated trans-
logical mechanisms that prepare the genome for anticipated life-
generational inheritance of phenotypes induced by prenatal stress
long social and physical environments based on cues received dur-
exposure; however, research in this field is now gathering momen-
ing the perinatal period (156).
tum and our understanding of the mechanisms involved in trans-
generational programming following maternal stress exposure is
Epigenetic mechanisms
likely to increase considerably in the next few years. Epigenetic
reprogramming of the germ cells is a likely mechanism that There are a number of processes acting on different levels of prox-
requires investigation. imity with the DNA molecule itself, which stably alter the accessi-

© 2014 British Society for Neuroendocrinology Journal of Neuroendocrinology, 2014, 26, 707–723

bility of the gene to the transcription machinery and define its
state of activity. The covalent chemistry of the DNA molecule itself
is altered by DNA methylation (157) and hydroxymethylation (158).
Histone proteins in chromatin are modulated by a large set of
chemical modifications such as acetylation (159), methylation (160),
phosphorylation ubiquitination (161) and sumoylation (162). Chro-
matin structure is modulated through altering the positioning of
nucleosomes. In addition, epigenetic regulation of gene function
can occur downstream to transcription by involving noncoding and
microRNAs, which act on mRNA stability and translation arrest
(163–165). These mechanisms are highly inter-related; for example,
alterations in histone acetylation can result in demethylation and
DNA methylation triggers hypoacetylation (166).
DNA methylation provides differential identity to DNA during
embryonic development and recent studies have used genome wide
methods to map the changes in DNA methylation during brain
development (167). Similarly the ENCODE project has mapped many
of the tissue specific chromatin modifications; thus, it is well estab-
lished that epigenetic marks participate in cell type specific expres-
sion.
DNA methylation and the DNA methylation enzymatic
machinery
In vertebrates, DNA methylation occurs mainly in CG dinucleotide
in DNA (168). Recent evidence suggests that non-CG methylation
(methylation occurring in CA, CT and CC sequences) is prevalent in
the brain mostly in nondividing neurones, where there is no
requirement for maintaining a DNA methylation pattern during cell
division. Non-CG methylation occurs in promoters in the brain and
might be involved in epigenetic responses of the brain after birth
(167,169). DNA methylation is the most proximal epigenetic modifi-
cation to DNA because it is part of its chemical structure and has
been well established to silence gene expression when occurring in
50 regulatory regions of genes directly through interference with
transcription factors binding to their binding recognition element in
DNA (170) or indirectly through attracting methylated DNA binding
protein, which in turn recruits chromatin inactivating complexes
(171). DNA methylation is catalysed by DNA methyltransferases
(DNMT) (Fig. 4). DNMT1 is a maintenance DNMT that copies the
pattern of methylation in the palindromic CG dinucleotide sequence
from the parental strand to the daughter strand during DNA syn-
thesis in dividing cells. DNMT3a and DNMT3b are de novo methyla-
tion enzymes because they do not require a methylation template
for methylating DNA. They can therefore methylate non-CG
sequences in nondividing cells, which is important in neurones, par-
ticularly after birth (167). DNMT3a most probably plays an impor-
tant role in this particular brain-specific DNA methylation (169);
however, the role of DNMT3a in ELS has not yet been explored.
For DNA methylation to play a role in post-mitotic reprogram-
ming in response to stress, it must be reversible. Ramchandani
et al. (172) previously proposed that DNA methylation is a bona
fide reversible DNA methylation signal and that a demethylase
methylated DNA binding protein 2 (MBD2b) removes the methyl
group from DNA (173). One mechanism that has recently been
Journal of Neuroendocrinology, 2014, 26, 707–723
Consequences of early-life adversity 715
shown to facilitate demethylation is hydroxylation of the methyl
group by ten-eleven translocation enzymes (174). 5-hydroxymethyl-
cytosine is a poor substrate for DNMT1-mediated maintenance
methylation (the copying of methylation from the parental to
daughter strand) (175). During replication, the hydroxyl methylation
on the parental strand is not copied by DNMT1 to the daughter
strand and hence the methylation is lost (175). Such a mechanism
was recently proposed to be responsible for the loss of DNA meth-
ylation early after fertilisation in the male pronucleus (176). How-
ever, such a mechanism cannot operate in post-mitotic neurones
because they do not synthesise new DNA. To address this problem
of demethylation in post-mitotic cells, it has recently been proposed
that DNA hydroxymethylation is removed by ‘passive’ repair mecha-
nisms and then an unmethylated cytosine is reintroduced by repair
DNA synthesis in the absence of DNMT (Fig. 4); thus, the repaired
base remains unmethylated (177–181). The identity of the enzymes
involved in demethylation in response to ELS are still unknown;
nevertheless, the fact that demethylation occurs in post-mitotic
neurones implies the feasibility of dynamic DNA methylation states
in response to stress.
DNA methylation provides a heritable ‘epigenetic’ mechanism
that confers cell type identity during embryonic development, thus
explaining how the same DNA sequence could perform different
tasks in differentiating cells in a stable and persistent manner. An
increasing body of data has lent support to the idea that a similar
mechanism occurs in response to postnatal and prenatal stressful
experience (Fig. 4). Epigenetic modifications could thus confer upon
similar genes a different stable functional state in response to
stress and mediate the long-term effects of early-life adversity.
Involvement of DNA methylation and histone acetylation in
the response to early-life adversity
The first evidence for an epigenetic mechanism mediating exposure
to ELS was provided by examining the epigenetic effects of differ-
ences in maternal care in the rat. In this model (discussed above),
low licking and grooming by the mother triggers a stable reduction
in expression of NR3C1 in the hippocampus and heightened stress
responsivity in the adult offspring. Examining the mechanisms that
might mediate such a persistent change in gene expression in
response to maternal behaviour demonstrated that differences in
maternal care behaviour resulted in differences in histone acetyla-
tion DNA methylation at the NR3C1 (GR exon 17 promoter) (133).
The differences in DNA methylation emerged early after birth in
response to maternal care and remained stable into adulthood, pro-
viding a feasible mechanism for environment programming gene
expression. One of the principal differences between epigenetic and
genetic changes in gene function is that genetic differences are
fixed and cannot be changed; however, because DNA methylation
and histone acetylation are reversible biochemical reactions (as dis-
cussed above), they should be amenable to pharmacological and
possibly behavioural interventions. Interestingly, the differences in
adult behaviour in response to maternal rearing were reversible in
both directions by agents that stimulate DNA methylation such as
the amino acid, methionine (182) and by agents that increase
© 2014 British Society for Neuroendocrinology
716 S. Maccari et al.

Adversity Neurotransmitters Signalling pathways

Repair: AID, GADD45B, MBD4, BER

Demethylase (MBD2?)

NH2 NH2 NH2

DNMT TET
CH3 CH2OH
N N N

O N O N O N
H SAM SAH H H

Cytosine 5-Methylcytosine 5-Hydroxy-Methylcytosine

Fig. 4. DNA methylation mechanisms targeted by early-life adversity. Cytosine bases in DNA are methylated by DNA methyltransferase (DNMT) enzymes that
catalyse the transfer of a methyl moiety from the methyl donor S-adenosylmethionine (SAM), which is converted to S-adenosylhomocysteine (SAH). Methyla-
tion of cytosine at critical position silences (X) transcription initiation (horizontal green arrow), thus converting an active gene to an inactive gene. The
5-methylcytosine could be further modified by the ten-eleven translocation (TET) oxidases to 5-hydroxymethylcytosine. The epigenetic role of 5-hydroxymethyl-
cytosine is unknown (?). DNA methylation is reversible and could therefore respond to signals from early-life experience. A direct mechanism of demethylation
might involve a demethylase such as MBD2. The widely accepted model is that hydroxymethylated cytosine serves as a substrate for repair-based demethyla-
tion whereby the hydroxymethylated base is removed and replaced with an unmethylated cytosine. This process involves several proteins such as the deami-
nase AID, the repair protein GADD45B and base excision repair enzymes (BER). Demethylation will turn on a silenced gene and thus change its programming.
Early-life experience turns on neuronal pathways, which in turn activate signalling pathways that can potentially act on the multiple methylation and deme-
thylation processes and trigger either DNA methylation or hydroxymethylation and demethylation, thus altering programmes of gene expression.

histone acetylation through inhibition of histone deacetylase with
trichostatin A (133).
A critical question remains: what is the mechanism that mediates
interactions between early-life experience (e.g. maternal care) and
changes in DNA methylation at particular addresses in the genome?
Weaver et al. (183) proposed that maternal care leads to activation
of a transcription factor, nerve growth factor inducible gene-A
(NGFI-A) in response to serotonin receptor activation, which in turn
targets the NR3C1 promoter for DNA demethylation. This provides
a feasible paradigm of a conduit leading from exposure to stress to
changes in DNA methylation at particular sites in the genome.
These results have been translated to humans. By examining hip-
pocampi from humans who were exposed to child abuse and com-
paring the DNA methylation at the same NR3C1 promoter,
McGowan et al. (184) showed that child abuse is associated with
hypermethylation of several sites, including the NGFI-A recognition
element that was implicated in targeting demethylation in response
to maternal care licking and grooming in rats. The changes in DNA
methylation are associated with differences in expression of the
NR3C1 receptor, linking child abuse and hippocampal regulation of
stress responses (184).
Several other studies support the hypothesis that ELS results in
particular changes in DNA methylation in candidate genes. For
example, exposure of infant rats to stressed caretakers that display
abusive behaviour produces persistent changes in methylation of
the Bdnf gene promoter in the adult prefrontal cortex (185). Simi-
larly, ELS in mice causes sustained DNA hypomethylation of an
important regulatory region of the arginine vasopressin gene (186).
More recently, it has been shown that a post-traumatic stress dis-
order risk allele of the proximal regulator of GR, FKBP5, is demethy-
lated in peripheral lymphocytes in children who were exposed to
trauma early in life (187). This study elegantly demonstrates a
methylation-dependent ‘gene–environment’ interaction (187).
Initial studies exploring an epigenetic mechanism for ELS focused
on candidate genes and on specific brain regions where well estab-
lished physiological stress regulation circuitries are positioned.
However, it is clear, as discussed above, that ELS is associated with
multiple adult phenotypes. Therefore, it has been hypothesised that
the changes in DNA methylation triggered by ELS should not be
limited to several candidate genes and instead must be system-
wide involving multiple physiological systems. Furthermore, it is
proposed that an integrated response of the methylome to physical,
social and biosphere cues occurs early in life as an adaptation of
the genome to anticipated life-long experiences (188). These adap-
tations could become maladaptive if social and other environmental
contexts are altered later in life (188).

© 2014 British Society for Neuroendocrinology Journal of Neuroendocrinology, 2014, 26, 707–723

Consistent with this hypothesis, McGowan et al. (189) have
shown that child abuse is associated with an alteration in the state
of methylation of the ubiquitous promoters of ribosomal RNA
(rRNA) genes, which are critical for general protein synthesis but
were not previously implicated in responses to ELS. This change in
DNA methylation is associated with differences in the expression of
rRNA (189). Similarly, in rats, a transcriptome analysis of the hippo-
campus from adult offspring of high and low licking/grooming
dams revealed differences in hundreds of transcripts (190). Broad
changes in DNA methylation, histone acetylation and transcription
covering a few megabytes around the NR3C1 locus in the hippo-
campus were revealed in adult rats that received differential mater-
nal care postnatally (191) and in humans that were abused as
children (192).
Recent studies examining the impact of exposure of guinea pig
foetuses to glucocorticoids prenatally showed changes in overall
DNA methylation in the adult offspring in several tissues that per-
sisted for two generations, as well as genome wide changes in
DNA methylation states, histone acetylation and transcription in
exposed foetal hippocampi (193,194).
A critical question for the study of behavioural epigenetics, par-
ticularly in humans, is whether DNA methylation associated with
exposure to ELS is limited to the brain or whether they are system
wide (188). This obviously has important implications because the
primary target of stress regulation, the brain, is not accessible in
living humans or animals. Provencal et al. (195) examined the
impact of differential rearing in nonhuman primates (rhesus maca-
ques) in parallel with DNA methylation in the prefrontal cortex and
peripheral T cells. Differences in DNA methylation were detected in
both tissues; however, it is important to note that the changes in
DNA methylation are not surrogate markers of the prefrontal cor-
tex, although they most probably reflect the response of the
immune system to ELS. Nevertheless, several differences are com-
mon in both tissues.
The idea that the epigenomic response to ELS is not limited to
the brain and could be studied in peripheral lymphocytes has
gained support from several other tissues. The early-life trauma
associated demethylation of FKBP5 is detected in peripheral white
cells (187) and the same group have recently shown a DNA meth-
ylation signature of early-life adversity in peripheral blood cells
(196). Moreover, Borghol et al. (197) have demonstrated a broad
DNA methylation signature associated with socioeconomic position-
ing in whole blood DNA from 45-year-old adults. Other studies
have correlated DNA methylation of the NR3C1 gene in DNA from
neonatal cord blood mononuclear cells with maternal depression
(198) and childhood adversity and maltreatment (199–201).
Together, these findings give rise to the potential for longitudinal
studies investigating possible environmental or pharmacological
interventions.
Summary and outlook
In summary, adverse experiences occurring in early life, be it pre-
or postnatally, can have life-long detrimental consequences, which
are associated with an increased propensity for disease. The brain is
Journal of Neuroendocrinology, 2014, 26, 707–723
Consequences of early-life adversity 717
particularly susceptible to early-life programming and this is mani-
fested as stress hyper-reactivity, increased susceptibility to affective
disorders (e.g. anxiety and depression) and cognitive deficits. In the
case of prenatal stress, the mechanisms underlying how the effects
are transmitted from the mother to the offspring are not fully
understood but, given that stress in gestation can negatively affect
subsequent maternal care, and, moreover, maternally-deprived off-
spring display similar phenotypes to prenatally stressed animals,
disrupted maternal care postpartum is one possibility.
Studies aimed at reversing the negative effects of early-life
adversity by exploiting findings from what we understand about
the neurobiological and epigenetic mechanisms underpinning some
of the phenotypes observed in programmed offspring should pro-
vide insights for developing new therapeutic strategies for the
treatment of mood disorders and cognitive decline. Moreover, the
finding that the negative phenotypes arising from early-life adver-
sity may potentially be transmitted to subsequent generations has
wide-ranging implications for disease susceptibility in humans and
further research in this area is warranted.
Although data are limited, evidence is emerging to support the
hypothesis that DNA methylation is a potential mediator of the
long-term response to early-life adversity. These responses are pro-
posed to be an adaptive response of the genome to anticipated
integrated stressful environment that is predicted by early-life cues.
The response is not limited to a few candidate genes; it involves
several gene pathways and occurs in both central and peripheral
tissues. The fact that changes in DNA methylation also occur in
peripheral tissues indicates that it might be possible to study the
immune facet of stress in living humans in longitudinal cohorts, as
well as in response to behavioural and pharmacological interven-
tions.
Acknowledgements
Research performed in the laboratory of SM and SMF is funded by the Fon-
dation de France and the International Associated Laboratory for prenatal
stress and neurodegenerative diseases (LIA-PSND). Research by HJK is finan-
cially supported by the Netherlands Organization for Scientific Research
(NWO), Cognitive Science Center Amsterdam, Internationale Stitchting Alz-
heimer Onderzoek (ISAO). Studies performed in MS’s laboratory are sup-
ported by the Canadian Institute for Health Research and the Sackler
program in Epigenetics and Psychobiology. PJB receives funding from the
Biotechnology and Biological Sciences Research Council (BBSRC) and the
British Society for Neuroendocrinology.
Received 16 January 2014,
revised 9 July 2014,
accepted 10 July 2014
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