Pediatrics and Neonatology (2011) 52, 122e129

available at www.sciencedirect.com

journal homepage: http://www.pediatr-neonatol.com

REVIEW ARTICLE

Effects of Early Life Stress on Neuroendocrine and

Neurobehavior: Mechanisms and Implications
Ming-Chi Lai a, Li-Tung Huang b,*

a
Department of Pediatrics, Chi Mei Medical Center, Yong Kang Campus, Tainan, Taiwan
b
Department of Pediatrics, Chang Gung Memorial HospitaldKaohsiung Medical Center, Chang Gung University College
of Medicine, Kaohsiung, Taiwan

Received Aug 10, 2010; received in revised form Nov 30, 2010; accepted Dec 23, 2010

Key Words
early life stress;
epileptogenesis;
hypothalamic-pituitary-
adrenal axis;
learning and memory;
psychiatric disorders
Evidence continues to mount that adverse experiences early in life have an impact on brain
functions. Early life stress can program the development of the hypothalamic-pituitary-
adrenal axis and cause alterations of neurochemistry and signaling pathways involved in regu-
lating neuroplasticity, with resultant neurobehavioral changes. Early life experiences and
genetic factors appear to interact in determining the individual vulnerability to mental health
disorders. We reviewed the effects of early life stress on neuroendocrine regulation and the
relevance to neurobehavioral development.
Copyright ª 2011, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. All rights
reserved.

1. Introduction disorder.1e3 Talge et al2 revealed a large body of research

An adverse environment in early life has been demon-
strated to be one of the most important factors affecting
long life health. In humans, early adverse experiences, such
as abuse, neglect, or loss of a parent, have an impact on
cardiometabolic risk profile and increase the risk of
developing mental health disorders, including attention
deficit/hyperactivity disorder, conduct disorders, anxiety,
depression, suicide, drug abuse, and posttraumatic stress
* Corresponding author. Department of Pediatrics, Chang Gung
Memorial HospitaldKaohsiung Medical Center, 123 Ta Pei Road,
Niao Sung Hsiang, Kaohsiung Hsien 833, Taiwan.
E-mail address: huang_li@pie.com.tw (L.-T. Huang).
relating stress to health and found an attributable load of
emotional/behavioral problems and language delay
because of prenatal stress and/or anxiety in approximately
15% of subjects. Animal studies have also suggested that
exposure to stressors or steroids during early life alters
the programming of neuroendocrine and neuroimmune
systems.4 For example, maternal separation of rodent pups
during the first 2 weeks of life has been shown to induce
alterations in behavior and hypothalamic-pituitary-adrenal
(HPA) axis reactivity to stress that persists throughout life.
The long-term effects of early life stress on vulnerability to
neurological events, such as seizures or stroke, are well
documented.5,6 These findings provide evidence that early
life stress modifies the development of the HPA axis, brain
function, and neurobehavior.7e16

1875-9572/$36 Copyright ª 2011, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. All rights reserved.
doi:10.1016/j.pedneo.2011.03.008
Early life stress
2. The Concept of Stress
A generally accepted concept of stress is still elusive;
however, a useful operational definition is anything that
induces activation of the autonomic nervous system and HPA
axis and promotes catabolism.12,17 Stress response aims to
restore homeostatic control and facilitate adaptation. When
encountering acute physical or psychological stress, input to
the higher brain centers is connected synaptically with the
hypothalamus to increase the production of hypothalamic
corticotrophin-releasing hormone (CRH) and vasopressin.
CRH is transported by means of the hypophyseal portal
system to the pituitary, where it elicits the release of
adrenocorticotropic hormone (ACTH) from the anterior lobe
of the pituitary gland, which finally stimulates the secretion
of glucocorticoids (GCs), principally cortisol in humans and
corticosterone (CORT) in rodents, from the adrenal glands.
GCs then interact with their receptors in multiple target
tissues, including the HPA axis and hippocampus, where they
exert an inhibitory negative feedback effect over the
synthesis of hypothalamic releasing factors for ACTH,
notably CRH and vasopressin (Figure 1).18e21 The neuroen-
docrine system acts in close cooperation with vegetative
centers in the brain and in regulating metabolism, psychical
and physical development, and the necessary adaptations in
the performance of the organism, and the internal milieu
(homeostasis).20 The increase in circulating levels of both
Figure 1 Response of the hypothalamus-pituitary-adrenal
axis to stress and negative feedback. CRH is transported by
means of the hypophyseal portal system to the pituitary
gland, where it elicits the release of ACTH from the anterior
lobe of the pituitary gland, which finally stimulates the
secretion of glucocorticoids from the adrenal glands. In each
of these steps, the original signal can not only be amplified
but can also undergo modulation, e.g., feedback regulation.
Glucocorticoids in turn act back on the hypothalamus and
pituitary (to suppress CRH and ACTH production) in a negative
feedback cycle. CRH Z corticotrophin-releasing hormone;
ACTH Z adrenocorticotropic hormone.
123
catecholamines and GCs also promotes the increase in
cardiovascular tone, and these reactions serve to enhance
the availability and distribution of energy substrates to meet
the metabolic demands posed by the stressor. However,
these responses to stress are a double-edged sword.
Elevated GCs actually help to terminate fight/flight physio-
logical and behavioral responses. However, when the
elevation of GCs and/or CRH remains for a prolonged period,
it threatens neuronal viability and increases the risk of
stress-related disorders. Relevant studies have shown that
individuals with long-term or frequent stress-induced exag-
geration of HPA activity and sympathetic reaction are at risk
of vulnerability to diseases over a life span, including
cognitive dysfunction, hypertension, diabetes, anxiety,
depression, and drug addiction.13,22
3. Spectrum of Early Life Stress
Early life stress in humans can originate from prenatal
stress, including negative birth perception, provider dis-
affirmation, perinatal trauma symptoms, or postnatal
stress, including premature steroid use, maternal post-
partum depression, family conflict, or childhood physical/
sexual abuse, usually involving economic hardship, marital
strife, and a lack of social and emotional support.1,2,23e29
Relevant animal research has mostly investigated the
effects of restraint stress,3,30 maternal separation
(neonatal isolation),31e34 and infant paired odor-shock
conditioning.35 These findings, in particular, indicate the
importance of parental care as a mediator of the effects of
early environmental adversity on neural development.
4. Early Life Programming of Neuroendocrine
System
The hypothalamus is intimately connected with the limbic
system, formatio reticularis, and (by means of the thal-
amus) cerebral cortex. Hormone balance is thus not only
concerned with purely vegetative regulation but is also
connected with the sleeping-waking rhythm and with
psychic-emotional factors. The end hormone, GC, not only
acts on target cells but also inhibits the HPA axis. In each of
these steps, the original signal can be amplified and also
undergoes modulation (e.g., feedback regulation), and the
hippocampus, a region rich in glucocorticoid receptors
(GRs), has been strongly implicated in GC negative feed-
back regulation.36,37 Exposure of the developing brain to
severe and/or prolonged stress can result in enduring
hyperactivation of the HPA axis: upregulation of CRH mRNA
expression in the hypothalamus and amygdala,38e41
reduced GR gene expression in the hippocampus, and
increased CORT release in response to acute stress.11,32
4.1. Effects during the stress hyporesponsive
period
Previous studies in rodents have demonstrated that during
the first 2 weeks of life, normal maternal behavior ensures
a quiescent stress response in the pup, the so-called stress
hyporesponsive period (SHRP), when neonatal rats have
very low basal levels of CORT, and the CORT response to
124
stressors is blunted.8,16,42 An important question is which
factor contributes substantially to the stress hypores-
ponsiveness of the HPA axis during the SHRPdcentral
inhibition or peripheral inhibition of HPA axis activity?
Although the expression of CRH in the paraventricular
nucleus (PVN) of the hypothalamus is high, CRH expression
decreases at the end of the SHRP when basal CORT levels
increase, indicating very sensitive negative feedback
regulation of CRH gene expression in the neonate.43,44 GR
expression in the hippocampus is low at birth but increases
significantly during the SHRP, with the highest level at
a postnatal age (P) of 12 days in rat pups.45 The animals
with GR knockouts have massive basal CORT levels during
the first postnatal week, and the homozygous knockout
offspring ultimately die.46 Furthermore, Levine et al47
demonstrated a smaller increase in CORT secretion after
ACTH secretion in neonatal pups compared with older
animals outside the SHRP. Taken together, these results
suggest an important role of peripheral inhibition at the
level of the pituitary gland by means of a high GR feedback
signal and the adrenal gland by means of a low sensitivity to
ACTH during the SHRP.48
4.2. Influences of maternal care
Based on the fact that mother is a substantial provider of
psychosocial stimulation for infants, normal mother-infant
interaction appears to be a key regulator during SHRP.
Different maternal separation paradigms have been
demonstrated to influence the sympatho-adrenal system, as
well as long-term physiological and behavioral conse-
quences for the offspring. For example, 24-hour isolation of
rat pups from the dam (neonatal isolation) can result in
a 40% decline in heart rate, and repeated daily 1-hour
neonatal isolation from P2 to P9 can increase CORT release
after seizure without changing baseline circulating levels of
CORT. Regarding the central effects of maternal separation,
prior studies have also demonstrated an increase in c-fos
expression in the PVN in P12 rat pups after 24-hour maternal
deprivation, indicating an activation of the PVN cells,49 and
downregulated expressions of GR and mineralocorticoid
receptors (MRs) in the hippocampus in maternally deprived
pups at P9.50,51 In contrast, compared with nonhandled rats,
postnatally handled animals showed a decrease of mRNA
and immunoreactivity for CRH and vasopressin in the hypo-
thalamus, as well as an increase of hippocampal GR gene
expression, which is considered to mediate the enhanced GC
negative feedback sensitivity of the handling effect on the
HPA axis. The most intriguing question is how maternal care
or early life stress affects long-term HPA responses to stress.
Weaver et al16 demonstrated that maternal behavior
produces enduring alterations of DNA methylation at the GR
gene promoter (GR exon 17 promoter) and that the adult
offspring of less licking-grooming dams showed a decrease
of GR gene expression in the hippocampus and an increase of
plasma CORT in response to acute stress. Cross-fostering
reverses the differences in the methylation of the GR exon
17 promoter. Accordingly, epigenetic modifications in GR
gene promoters in response to environmental demands may
contribute to the dynamic regulation that mediates persis-
tent changes in neurobiology and behavior through life.52
M.-C. Lai, L.-T. Huang
4.3. Roles of GCs
The elevation of GCs is thought to be the primary candidate
for programming of the fetal HPA axis during early life
experience.10 GCs operate in concert with other humoral
and nervous signals that mediate the stress response. In
general, stress is assumed to cause initial acute effects
through the actions of monoamines (noradrenaline, dopa-
mine, and serotonin) and peptides (CRH and vasopressin).
The latter effects are mainly mediated by GRs acting as
regulators of gene transcription53 and by CRH receptor 2
signaling, which exerts inhibition on the initial stress
effects for restoring allostasis.54e56 The actions of GCs
depend on the functionality of the balance of MRs and GRs
in the brain and their effects involve interactions with
other neurochemical systems, including serotonin, g-ami-
nobutyric acid (GABA), and excitatory amino acids (mainly
glutamate). GRs have lower affinity compared with MRs,
thus GRs are more occupied as CORT increases. The MR:GR
balance is altered by gene variants of these receptor
complexes and experience-related factors, which can
induce lasting epigenetic changes in the expression of these
receptors.16,52,57
5. Effects on Neuroplasticity in Later Life
The term “neuroplasticity” refers to the ability of the
nervous system to adapt its structural and functional
organization to altered circumstances arising from de-
velopmental or environmental changes.58 Psychological
stressors primarily engage stress mediators in their
preferred brain regions that subserve emotion (the amyg-
dala and prefrontal cortex), learning and memory (the
hippocampus), and decision making (the prefrontal cortex),
and the functional contributions to the stress response act
through convergence on interconnected networks.5
Because of the importance of the limbic system in the
regulation of HPA axis responses to psychological stressors,
limbic-HPA axis is usually used in discussions of the stress
response system. Activation of the HPA axis to psycholog-
ical stressors involves the amygdala, whereas inhibition of
the HPA response involves the hippocampus and medial
prefrontal cortex. Several lines of evidence suggest that
early life stress has detrimental effects on the developing
central nervous system and destabilizes homeostatic neu-
rosynaptic plasticity on the hippocampus and amygdala in
particular.12,59,60 Chronically, early life stress can suppress
dentate gyrus neurogenesis, induce dendritic remodeling in
CA3 and mossy fiber sprouting, and lead to an abnormal
abundance of mossy fiber terminals in CA3 and marked
dendritic atrophy of CA1 pyramidal cells.12,39,61 The adult
offspring of abundant maternal care (high levels of licking
and grooming and arched-back nursing) have been shown to
have an increased expression of N-methyl-D-aspartic acid
(NMDA) receptor subunits and brain-derived neurotrophic
factor (BDNF) mRNA in the hippocampus, suggesting
increased synapse formation,62 whereas neonatal isolation
from the dam has been shown to cause decreased BDNF and
synaptophysin mRNA density in the hippocampus and lower
neural cell adhesion molecule expression after water maze
learning.63
Early life stress
6. Effects on Neurobehavior in Later Life
Early life stress appears to disrupt the HPA axis and the
limbic system (mainly the hippocampus and amygdala),
both of which are considered as critical mediators of early
life stress on compromised mental health in humans and
animal models in later life, such as fear reaction (amygdala
hyperfunction),13,64 impaired spatial learning and memory
(hippocampal functionedependent task),9,12,63 and
increased seizure vulnerability (Figure 2).5,31e33
6.1. Effects on learning and memory in later life
The major concern is how hippocampus-dependent memory
and synaptic plasticity are modulated by stress hormone.
Stress modulates intrinsic hippocampal excitability and
activity-dependent synaptic plasticity, which are involved
in transferring immediate or short-term memories into
long-term memories. If a stressor is physical or cognitive,
the central nervous system mediates the synergistic acti-
vation of the neuroendocrine and autonomic nervous
systems. In doing so, it optimizes physiological parameters
that help subserve short-term coping needs, e.g., gluco-
neogenesis, enhanced oxygen delivery, increased heart
rate, and effective vigilance. The limbic forebrain circuits
are activated to immediately cope with the threat
stressors. Prominent in the stress circuitry of the brain are
the amygdala, for regulation of emotional responses and
modulating the consolidation of memory,66 and the hippo-
campus, for context memory in terms of time and
place.67,68 However, inappropriate stress or GC exposure
impairs spatial learning and memory,63 contextual fear
conditioning (hippocampus implicated)69 and fear condi-
tioning (amygdala implicated).35,70 Likewise, early life
stress or exposure to GCs can result in long-term alterations
of several molecules important to synaptic plasticity during
memory processing, such as a decrease in hippocampal
Figure 2 Long-term effects of early life stress on neurobehavior. The early environment modifies the interplay between the
limbic system and hypothalamic-pituitary-adrenal axis and influences long-term neurobehavioral development (modified from
Fig. 1 in Ref. 65). LHPA Z limbic-hypothalamic-pituitary-adrenal axis.
125
BDNF63 and pCREBSer-133,71 pivotal in the switch from short-
term to long-term memory,72 and an alteration in hippo-
campal NMDA receptor expression.73,74
6.2. Effects on emotional reactivity in later life
Early life perturbations induce persistent changes in the
CRH system, including increased CRH expression in the PVN
and the amygdala and alterations of CRH receptor levels,
increased a2 adrenoreceptor density in the locus ceruleus,
as well as decreased GABAA/benzodiazepine receptor
binding in the basolateral and central nuclei of the amyg-
dala and in the locus ceruleus. Considering the importance
of the amygdala for the behavioral responses to stress,
particularly the anxiogenic influence of CRH projections
from the amygdala to the locus ceruleus and the anxiolytic
actions of GABAA/benzodiazepine receptors, such effects
may contribute to the enhanced stress-related behavior,
such as open-field exposure, and fearfulness in response to
novelty.64 Inappropriately increased exposure to CORT or
stress alters specific gene patterns, with the greatest
implication on the 5-hydroxytryptamine 1A receptor sys-
tem.75e77 In one study, disruption of the 5-hydroxytrypta-
mine 1A receptor gene in early postnatal life produced
a more anxious mouse, an effect not observed when
mutagenesis was postponed until adulthood.53Furthermore,
prior work has also demonstrated a critical role of BDNF in
mediating the effects of early life stress in mood disor-
ders.15,78 BDNF is involved in adaptive brain plasticity, in
particular neuronal growth, differentiation, and synapto-
genesis, and is highly expressed in the neocortex and
hippocampus, critical to HPA axis activity, as well as being
involved in mood disorders. It is reasonable to speculate
that BDNF plays an important role in the modulation of
neural plasticity changes in the pathogenesis of psychiatric
disorders after early life stress. Roceri et al15 showed
long-term depression of BDNF gene expressions in the
126 M.-C. Lai, L.-T. Huang

prefrontal cortex and hippocampus after early maternal
deprivation.
6.3. Effects on increased incidence
of epileptogenesis
Seizures are one of the most common pediatric emergen-
cies with the highest incidence in the first year of life.
Notwithstanding the higher susceptibility to seizures, the
immature brain is less vulnerable to seizure-induced
injuries than the mature brain.79,80 However, temporal lobe
epilepsy, the most common focal intractable epilepsy, is
thought to be a multistage process of increasing epilepto-
genesis commencing in early life, and epidemiological data
implicate early life stress in the aggravation of limbic
epilepsy.81 Epileptogenesis is a process by which a normal
brain develops epilepsy, and the hippocampus is implicated in
the pathogenesis of both the initiation phase and propagation
phase. Seizure-induced neural injuries are a kind of excito-
toxicity, mainly mediated by excessive calcium influx into
cells by means of overactivation of excitatory neurotrans-
mitter (glutamate) receptors (NMDA receptor and a-amino-
3-hydroxyl-5-methyl-4-isoxazole-propionate receptor) and
subsequent activation of a number of enzymes, including
phospholipase, endonucleases, and proteases. These
enzymes go on to damage cell structures. Excessive GCs
increase extracellular glutamate levels,82,83 calcium
conductance, either voltage- or ligand-gated,82 and alter
expressions of NMDA receptor subunits,84 as well as reduce
the uptake of glutamate by glia (Figure 3).65,85 It is reasonable
to speculate that stress or excessive GC exposure will
potentiate the excitotoxic effect of concurrent neurological
insults.22,65 Several lines of evidence have demonstrated that

Figure 3 Model of glucocorticoid effects on excitotoxicity. Glutamate is the major excitatory neurotransmitter in the
mammalian central nervous system and activates both ionotropic receptors and G protein-coupled (mGlu) receptors. Activation of
these receptors evokes cellular responses by means of increased iCa2þ and is responsible for basal excitatory synaptic transmission
and many forms of synaptic plasticity such as LTP and LTD. The iCa2þ level varies with Ca2þ influx through both the glutamate-
operated Ca2þ channel and VSCC and with the mGlu receptor-mediated calcium release from intracellular stores. However, high
concentrations of glutamate cause cell death through the excessive activation of these receptors. Overactivation at NMDA
receptors triggers an excessive entry of Ca2þ, initiating a series of cytoplasmic and nuclear processes that promote neuronal cell
death, such as activating NOS, lipases, proteases, and endonucleases. All these mechanisms, together with enhanced oxidative
stress can induce cell death through necrosis as well as apoptosis. Glucocorticoids seem to enhance the postsynaptic response by
inhibiting the glutamate uptake by glial cells and by preferentially stimulating the genomic expression of the NMDA receptor
subunit, NR2B, that increases Ca2þ influx. Furthermore, glucocorticoid receptor activation increases Ca2þ current through
VSCCs65,82e85 (modified from Fig. 2 in Ref. 65). VSCC Z voltage-sensitive Ca2þ channel; NMDA Z N-methyl-D-aspartic acid;
AMPA Z a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; iCa2þ Z intracellular Ca2þ; mGlu Z metabotropic glutamate;
LTP Z long-term potentiation; LTD Z long-term depression; NOS Z nitric oxide synthase.
Early life stress
early life stress impacts on epileptogenesis by accelerating
kindling epileptogenesis,86 changing seizure propensity,87,88
and potentiating early life seizure-induced epilepto-
genesis.33 Prior steroid treatment has been shown to result in
an acceleration of seizure behavior and a significant increase
in the amplitude of voltage-gated Ca2þ currents in kindled
rats89 and increases in the magnitude of the glutamate
response to kainic acid-induced seizures, exacerbating NMDA
receptor-mediated toxicity.90,91 Repeated parental separa-
tion has been shown to result in an elevated excitatory spine
density,92 and alteration of numbers of hippocampal
GABAergic neuronal subpopulations, reflecting reduced
inhibitory activity in the CA1 region.93 Frye et al87 demon-
strated that prenatal stress reduces the effectiveness of the
neurosteroid 3a,5a-tetrahydroprogesterone, a GABA-active
metabolite of progesterone, to prevent kainic acid-induced
seizures. Thus, early life stress changes the balance of
excitatory and inhibitory synaptic connectivity in the hippo-
campus, a critical region for epileptogenesis.
7. Conclusions
Optimal regulation of the stress response is a prerequisite
for adaptation, homeostasis, and health. Stress can elicit
an immediate response mode to protect an individual
against threats, and a slower mode, which facilitates
behavioral adaptation, promotes recovery, and reestab-
lishes homeostasis. GC hormones are implicated in both
system modes. As highlighted in this review, adverse
experiences during development contribute to deficits in
the maturity of stress response systems. Early life stress
programs HPA axis development and exerts profound
effects on neural plasticity, with resultant long-term
influences on neurobehavior. In humans, early life stress,
including persistent emotional neglect, family conflict, or
excessive exposure to steroids, is one of the most robust
risks for mental illness and increases vulnerability to
diseases throughout life.
Acknowledgments
This work was supported by grant 99-2314-B-182A-003-MY3
from the National Science Council, Taiwan to Dr Li-Tung
Huang, and by grants of 96CM-KMU-03 and 96CM-KMU-04 to
Ming-Chi Lai.
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