Download Impact of early-life stress on the medial prefrontal cortex functions

Pharmacological Reports
Copyright © 2013
2013, 65, 1462–1470
by Institute of Pharmacology
ISSN 1734-1140
Polish Academy of Sciences
Review
Impact of early-life stress on the medial prefrontal
cortex functions – a search for the pathomechanisms
of anxiety and mood disorders
Agnieszka Chocyk, Iwona Majcher-Maœlanka, Dorota Dudys,
Aleksandra Przyborowska, Krzysztof Wêdzony
Laboratory of Pharmacology and Brain Biostructure, Department of Pharmacology, Institute of Pharmacology,
Polish Academy of Sciences, Smêtna 12, PL 31-343 Kraków, Poland
Correspondence: Agnieszka Chocyk, e-mail: [email protected]
Abstract:
Although anxiety and mood disorders (MDs) are the most common mental diseases, the etiologies and mechanisms of these psychopathologies are still a matter of debate. The medial prefrontal cortex (mPFC) is a brain structure that is strongly implicated in the pathophysiology of these disorders. A growing number of epidemiological and clinical studies show that early-life stress (ELS) during
the critical period of brain development may increase the risk for anxiety and MDs. Neuroimaging analyses in humans and numerous
reports from animal models clearly demonstrate that ELS affects behaviors that are dependent on the mPFC, as well as neuronal activity and synaptic plasticity within the mPFC. The mechanisms engaged in ELS-induced changes in mPFC function involve alterations in the developmental trajectory of the mPFC and may be responsible for the emergence of both early-onset (during childhood
and adolescence) and adulthood-onset anxiety and MDs. ELS-evoked changes in mPFC synaptic plasticity may constitute an example of metaplasticity. ELS may program brain functions by affecting glucocorticoid levels. On the molecular level, ELS-induced programming is registered by epigenetic mechanisms, such as changes in DNA methylation pattern, histone acetylation and microRNA
expression. Vulnerability and resilience to ELS-related anxiety and MDs depend on the interaction between individual genetic predispositions, early-life experiences and later-life environment. In conclusion, ELS may constitute a significant etiological factor for
anxiety and MDs, whereas animal models of ELS are helpful tools for understanding the pathomechanisms of these disorders.
Key words:
early-life stress, maternal separation, prenatal stress, medial prefrontal cortex, synaptic plasticity, anxiety, mood disorders,
epigenetics
Abbreviations: 11B-HSD2 – 11b-hydroxysteroid dehydrogenase type 2, BDNF – brain-derived neurotrophic factor, ELS –
early-life stress, GDNF – glial cell-derived neurotrophic factor,
GFAP – glial fibrillary acidic protein, GR – glucocorticoid receptor, ILC – infralimbic cortex, LTD – long-term depression,
LTP – long-term potentiation, MDs – mood disorders, miRNA
– microRNA, mPFC – medial prefrontal cortex, MS – maternal
separation, NCAM – neural cell adhesion molecules, PLC –
prelimbic cortex, PTSD – post-traumatic stress disorder, SHRP
– stress hyporesponsive period, vmPFC – ventromedial prefrontal cortex
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Introduction
Anxiety and mood disorders (MDs) are the most
prevalent mental disorders and the leading causes of
years lived with disability all over the world [68].
They affect all age groups, from children and adolescents to adults [27]. Despite numerous research attempts and existing theories, the pathogenesis of anxiety and MDs is still poorly understood.
Early-life stress, anxiety and mood disorders
Agnieszka Chocyk et al.
Clinical and epidemiological data from the past
decade markedly point toward early-life stress (ELS)
as a relevant risk factor for the development of anxiety and MDs. Early-life adversity in the maladaptive
family functioning cluster (family violence, physical
abuse, sexual abuse, neglect, parental mental illness
and substance abuse) is most strongly correlated with
mental disorder onset [30]. A recent World Mental
Health Survey revealed that ELS is associated with
59.5% of childhood-onset MDs and 32.6% and 13.6%
of adolescence- and later adulthood- (age 30+) onset
MDs, respectively. In the case of anxiety disorders,
ELS is generally responsible for approx. 30% of onsets, regardless of age group [30]. The neurobiological substratum for associations between ELS and the
development of anxiety and MDs is widely studied
with advanced in vivo neuroimaging technologies and
preclinical studies, which apply various animal models [20, 56].
The medial prefrontal cortex as the key
brain structure implicated in the
pathophysiology of anxiety and mood
disorders
The medial prefrontal cortex (mPFC) is a forebrain
structure known to regulate a variety of cognitive and
emotional processes. Specifically, the ventral part of
the mPFC (vmPFC) has been shown to be involved in
such processes as (1) fear and anxiety, (2) risk taking,
(3) decision making, and (4) attentional processes
[25]. On the basis of evidence from neuroimaging, lesion analyses and post-mortem studies, the mPFC was
recognized as a key brain structure, along with the
amygdala, hippocampus and ventromedial parts of the
basal ganglia, that is affected by anxiety and MDs
[20, 44]. It was shown that patients suffering from
MDs and anxiety disorder, e.g., post-traumatic stress
disorder (PTSD), had reduced gray matter volume of
the mPFC [20, 67]. Moreover, histopathological examinations showed several morphological abnormalities, such as reductions in synapses and synaptic proteins and elimination of glial cells in the mPFC of MD
subjects [20]. Changes in neural and metabolic activities of the mPFC were also reported in patients with
anxiety and MDs. In this respect, most neuroimaging
studies demonstrated a decrease in neural activity of
the vmPFC in PTSD patients [24]. In the case of MD
patients, several reports showed elevated vmPFC activity and its modification during antidepressant
medication [44].
As a frontal lobe structure, the mPFC exhibits
a prolonged developmental trajectory. It is one of the
last brain regions to mature during development [10].
Thus, it is not surprising that the mPFC is especially
vulnerable to early-life insults (e.g., ELS). Several
neuroimaging studies in humans revealed reduced
mPFC volume in children, adolescents and adults
with a history of ELS [23, 53, 63]. Moreover, a loss of
sustained activity in the vmPFC in response to stress
has recently been found in individuals who experienced early-life emotional abuse [65]. Therefore, it is
postulated that adverse early-life experiences may
constitute a significant etiological factor for anxiety
and MDs. Despite the numerous advantages of advanced neuroimaging technologies applied to humans, the search for the specific pathomechanisms of
the abovementioned disorders within the mPFC is
possible only in preclinical studies that use (1) animal
models of ELS, (2) behavioral tests reflecting some
symptoms of anxiety and MDs and (3) a variety of
biochemical and electrophysiological techniques [56].
ELS-induced dysfunction of the mPFC –
implications from the behavioral studies
in animal models
There are many different experimental procedures
that model ELS in animals (mostly in rodents). They
can be divided simply into prenatal and early postnatal procedures, according to the developmental time
when the stressful event is applied (for review, see:
[38, 51]). Prenatal stress can be evoked in pregnant
dams by various stressors, such as (1) lipopolysaccharide injection and viral infection (both cause maternal
immune activation), (2) unpredictable psychological
stress (restraint stress) or (3) malnutrition [38]. Early
postnatal procedures are strongly represented by maternal separation (MS) paradigms, which are usually
conducted during the first three weeks of rodent life.
MS procedures are applied in many ways, such as
a single 24-h-long MS or a prolonged repeated everyday MS (e.g., 3 h /day, on postnatal days 1–14) [51].
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As previously mentioned, the vmPFC is strongly
engaged in fear and anxiety processes. It regulates
both unconditioned (innate) fear responses and conditioned fear responses, based on associative learning
(fear learning and memory, fear extinction) [25]. In
general, neural circuits engaged in fear behaviors are
evolutionarily conserved; therefore, the mechanisms
underlining fear and anxiety can be successfully studied both in humans and laboratory animals. The
vmPFC modulates fear behavior by its impact on the
activity of the amygdala and periaqueductal gray [13].
The vmPFC is subdivided into distinct parts, including the ventral prelimbic cortex (PLC), infralimbic
cortex (ILC) and medial orbital cortex [25]. The roles
of specific parts of the vmPFC in the regulation of innate fear are still a matter of debate; both the PLC and
ILC seem to exert a unique impact [13, 35]. However,
the roles of the distinct parts of the vmPFC in the
modulation of the different phases of fear memory
consolidation are well established [37, 58]. The PLC
is involved in the consolidation and recall of fear
memory, whereas the ILC is required for the consolidation of extinction memory [37, 58].
Numerous animal studies consistently reveal that
ELS enhances anxiety-like behaviors in tests that
measure innate fear, such as the elevated plus maze or
light/dark exploration test [15, 48, 62]. In contrast,
when fear conditioning procedures are applied, earlylife-stressed animals display a reduction in fear expression [29, 61, 64]. Interestingly, both types of behavioral phenotypes present in animals with a history
of ELS point toward a specific dysfunction of the
vmPFC. A recent study supporting this idea showed
that chemically induced synaptic inhibition of both
the PLC and ILC produced similar changes in fear
and anxiety responses, namely an increase in innate
fear and a decrease in the expression of fear conditioning [35]. The reason for the different roles of the
vmPFC in modulating innate and learned fear is still
unknown. It is speculated that this phenomenon could
be associated with differences in the vmPFC projection systems that regulate these distinct types of fear
behavior and involve different neurotransmitters [35].
It is also unknown how ELS affects specific vmPFC
functions to produce distinctive behavioral phenotypes in different fear-inducing paradigms. Resolving
this complex problem may bring us closer to understanding the pathomechanisms of anxiety disorders.
Another behavioral indication that ELS may affect
the mPFC comes from studies showing that prenatally-stressed and MS animals display impairments in
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cognitive functions governed by the mPFC, measured
by the temporal order memory task, the attentional
set-shifting task and the delayed alternation task [3,
38]. It is worth mentioning that cognitive deficits are
important hallmarks of MDs [12].
It should be stressed that animal models of ELS do
not show consistent results concerning depressivelike symptoms, as measured by the forced swim test
or sucrose preference test [38, 56, 62]. However, these
tests are not specific for mPFC function [54].
The impact of ELS on structural and
functional synaptic plasticity of
the mPFC
In addition to strong behavioral data implicating
mPFC dysfunction in animals exposed to ELS, numerous biochemical, morphological and electrophysiological reports have shown that ELS affects
neural activity and synaptic plasticity within the
mPFC [3, 14–16, 60, 62]. Synaptic plasticity underlies the continuous ability of the brain to adapt to specific experiences in a changing environment. It can be
divided into structural and functional plasticity [36].
Structural plasticity refers to the morphological remodeling of dendrites and synapses and synapse turnover, whereas functional synaptic plasticity is best
characterized by the long-term potentiation (LTP)
phenomenon [36]. An abundance of experimental
data has accumulated concerning the effects of ELS
on the structural plasticity of the mPFC [5, 15, 39, 40,
48]. ELS affects the morphology of the dendritic tree,
the length of dendritic processes and spine/synapse
density in pyramidal neurons of the mPFC [5, 15, 39,
40, 48]. Moreover, ELS influences the expression of
neural cell adhesion molecules (NCAMs) in the
mPFC [14, 16]. NCAM proteins belong to the immunoglobulin superfamily of cell adhesion molecules
and are engaged in neural plasticity processes, such as
(1) neurite outgrowth, (2) axon fasciculation and
guidance, and (3) synapse stabilization [14, 16]. It is
worth emphasizing that both impairments [5, 15, 39,
48] and intensifications [5, 40] in structural plasticity
are observed in animals subjected to ELS. The direction and magnitude of ELS-induced morphological
changes depend on several factors, such as the severity of ELS and the developmental stage of the brain
Early-life stress, anxiety and mood disorders
Agnieszka Chocyk et al.
during the aversive experience and during the final
morphological assessments [4].
In contrast, there are very few research reports concerning the impact of ELS on the neural activity and
functional plasticity of the mPFC, especially on LTP
processes. It was found that ELS decreased the metabolic activity of the mPFC in juveniles [6]. It was also
shown that in adult rats, MS reduced basal unit activity and basal local field potential activity in the right
and left mPFC cortex, respectively. Moreover, MS attenuated the hemispheric synchronization of the basal
local field potential activity of the mPFC [60]. Recent
data have shown that MS causes impairment of LTP
processes in the mPFC of adolescent rats, which also
displayed increased anxiety-like behavior [15]. These
functional changes were accompanied by increased
expression of the key proteins engaged in LTP (e.g.,
glutamate receptors 1 and 2, Ca2+/calmodulin-dependent
protein kinase II, postsynaptic density protein 95) in
the mPFC and by the atrophy of dendritic trees and reduced spine density in layer II/III pyramidal neurons
of the mPFC [15]. Interestingly, in adult animals subjected to ELS, Baudin et al. (2012) revealed an upregulation of LTP processes in the mPFC and deficits
in mPFC-dependent cognitive tasks [3].
The latest hypotheses and data suggest that glial
cells play an important role in the process of synaptic
plasticity [47]. It is well known that in addition to performing neural housekeeping functions, glial cells
(mostly astrocytes) modulate synaptogenesis, synaptic efficacy and strength. These modulatory functions
involve the release of specific neurotrophins, such as
brain-derived and glia cell line-derived neurotrophic
factors (BDNF and GDNF, respectively), as well as
gliotransmitters (e.g., glutamate, ATP and D-serine)
from astrocytes [47]. In experimental animals, glial
ablation in the mPFC was able to induce depressivelike behaviors [2]. Moreover, numerous post-mortem
studies revealed a clear reduction in glial cell number
and density in the mPFC of depressive patients [20].
Interestingly, it was shown that ELS in animal models
affected the number of S-100b- and GFAP-immunoreactive glial cells in the mPFC [8, 33, 41]. Additionally, functional genomic and proteomic analyses revealed strong effects of ELS on gene and protein
markers related to oligodendrocyte maturation and
myelination in the mPFC [7].
It is worth mentioning that ELS-induced changes
in synaptic plasticity within the mPFC may be considered as the phenomenon of the brain plasticity per se.
Moreover, ELS-induced plasticity interferes with nor-
mal experience-induced plasticity throughout an individual’s life span. In other words, one experience alters the effect of others and induces “plasticity of synaptic plasticity” [1]. This vision of the effects of ELS
is similar to the concept of the metaplasticity, originally proposed by Abraham and Bear [1]. This concept postulates that some conditions that occur,
known as “priming” or “preconditioning”, may (after
some period of time) modify the subsequent induction
of synaptic plasticity [1]. The concept of metaplasticity initially referred to LTP and long-term depression
(LTD) processes; however, it has recently been used
to describe and understand stress-induced changes in
synaptic plasticity [31, 55].
ELS-induced alterations in the
developmental trajectory of the mPFC and
emergence of early-onset mental disorders
As previously mentioned, the mPFC is characterized
by a prolonged maturation time and is one of the last
brain structures to develop [10]. Within its developmental trajectory, adolescence is recognized as a time
of a particularly intensive morphological and functional remodeling of the mPFC [10]. During adolescence,
many relevant processes occur, including (1) a reduction in gray matter volume, (2) intensive myelination,
(3) synapse pruning and (4) dynamic changes in receptor systems [10]. The processes of brain remodeling
and maturation during adolescence may easily unmask malfunctions that originated earlier in life. Thus,
it is not surprising that many early-onset psychopathologies emerge during this period [10]. Although
the adolescent period has not been extensively studied
in animal models of ELS, recent reports have revealed
the effects of ELS on mPFC function and specific behaviors in adolescent animals [15, 32, 48, 71]. More
importantly, some data show a correlation of depressive-like behavior and increased anxiety-like behavior
with specific aberrations of the mPFC, such as impairments in structural and functional plasticity (as
discussed previously) [15, 48], reduced GABA-ergic
markers [32], and reduced glutamate metabolites [71]
in adolescent rats subjected to ELS. Moreover, a few
recent reports, both biochemical and behavioral,
clearly documented that ELS alters the developmental
trajectory of the mPFC [9, 11]. First, it was shown
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that MS increases the specific adolescent peak in dopamine D1 receptor expression and blunts the adolescent peak in D2 receptor expression in projection neurons of the mPFC [9]. Second, another group of
authors studying the fear extinction procedure linked
specific behavioral phenotypes present in infant, juvenile and adolescent animals subjected to ELS to aberrations of mPFC development [11]. The abovementioned study was based on the fact that the effectiveness of fear extinction varies across development
[49]. Less effective extinction is seen during adolescence, reflecting the specific stage of mPFC maturation [49]. It was revealed that MS leads to the emergence of a fear extinction phenotype typical for older
animals. In other words, juvenile rats subjected to MS
displayed an extinction phenotype usually observed in
adolescents (poor extinction), whereas adolescent animals behaved like adults (good extinction retention)
[11]. The functional role of the vmPFC (particularly
the ILC) in fear extinction allows for the postulation
that MS significantly interferes with mPFC maturation [11]. Taking into account the above cited data and
the epidemiological estimation that early-life adversity is responsible for approx. 30% of adolescenceonset anxiety and MDs, 30% of childhood-onset anxiety disorders and 59.5% of childhood- onset MDs,
ELS may constitute a very important etiological factor for early-onset psychopathology.
The mechanisms mediating ELS-induced
changes in brain function – a search
for the epigenetic signature of early-life
experiences
The question then arises, how does ELS change/program brain functions and how is this programming
registered? First, it should be noted that ELS acts during the critical period of brain development and maturation. In rodents, this period extends from gestation
through the first three weeks of postnatal life [38, 51].
There are some specific mechanisms, both in humans
and rodents, that protect the developing brain from
harmful stress-induced elevation of glucocorticoid
levels during this time period. For example, during
gestation, placental 11b-hydroxysteroid dehydrogenase type 2 (11b-HSD2) controls fetal glucocorticoid
access. 11b-HSD2 is an enzyme that converts corti-
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sol/corticosterone to inactive metabolites and, in this
way, constitutes a physiological barrier that protects
the fetus from the detrimental effects of maternal glucocorticoids [26]. Moreover, during the early postnatal stage (on postnatal days 2–14 in rodents), the
stress hyporesponsive period (SHRP) occurs. During
the SHRP, mild stressors do not elicit an increase in
corticosterone levels, and therefore, the maturating
brain is protected [19]. A comparable SHRP is also
found in humans during postnatal months 6–12 [22].
However, when confronted with severe and/or prolonged stress such as early-life adversity, the abovementioned protective mechanisms are not sufficient.
Paradoxically, ELS specifically affects these processes and diminishes their effectiveness [26, 46, 59].
It was revealed that prenatal stress and anxiety downregulate placental 11b-HSD2 both in humans and
laboratory animals [26, 46], whereas a MS procedure
abolishes the SHRP [59]. As a consequence, animals
subjected to ELS display persistent enhancement in
hypothalamic-pituitary-adrenal (HPA) axis reactivity
(for review, see [18]). The substantial role of glucocorticoids in brain development, maturation and everyday function is well known. During neurodevelopment, glucocorticoids regulate neurogenesis, differentiation, and migration [21, 28, 70]. Acting through
their specific receptors, glucocorticoid and mineralocorticoid receptors (GR and MR, respectively) affect
transcription of specific genes or exert non-genomic
effects by directed action on membrane lipids and
proteins [52]. Thus, ELS-induced changes in glucocorticoid levels may permanently program brain functions [52].
A growing number of studies show that ELSinduced programming of brain functions is registered
through epigenetic mechanisms [26, 42, 43, 50]. Epigenetic mechanisms regulate gene transcription without altering DNA sequence and involve (1) DNA
methylations, (2) histone modifications, and (3) microRNAs (miRNAs). All of these processes are responsible for the normal pattern of expression typical
of a specific cell and tissue. DNA methylation in the
promoter region of a gene is usually associated with
gene silencing. Histone modifications regulate the accessibility of chromatin to the transcription machinery, whereas miRNAs are ~22 nucleotide-long RNA
molecules that can regulate gene expression at the
post-transcriptional level, e.g., by repression of specific mRNA [17].
Early-life stress, anxiety and mood disorders
Agnieszka Chocyk et al.
The first clear evidence that early-life experiences
program the brain by epigenetic mechanisms was
shown by Weaver et al. in a model of the naturally occurring variation of maternal care [66]. The authors
demonstrated that the quality of maternal care received by Long Evans rats in their first week of life
regulates hippocampal GR expression through
changes in DNA methylation levels in the GR promoter region [66].
Data showing the epigenetic signature of ELS are
rapidly accumulating. It was revealed that prenatal
stress downregulates placental 11b-HSD2 mRNA by
increasing DNA methylation within the 11b-HSD2
gene promoter [26]. Other work has shown that prenatal stress increases global DNA methylation and
changes the expression pattern of over 700 genes in
the mPFC [42, 43]. In the case of postnatal ELS models, many studies showed changes in DNA methylation in the hippocampus (for review, see [18]). However, Provencal et al. [50] have recently demonstrated
that different rearing methods (maternal vs. inanimate
surrogate) produced different DNA methylation patterns in the mPFC of rhesus [50]. The epigenetic signature of ELS is also accomplished by histone modification. It was revealed that MS increases histone H4
acetylation at lysine K12 in the forebrain neocortex of
adult Balb/c mice [34]. Additionally, Xie et al.,
showed an elegant correlation between MS-induced
elevation in histone H4 acetylation and increased expression of two immediate early genes underlying
experience-induced synaptic plasticity, Arc and Egr1,
in the mouse hippocampus [69]. Moreover, these epigenetic changes were accompanied by increases in
dendritic complexity and spine number in hippocampal CA3 pyramidal neurons [69]. To the best of our
knowledge, this is the first report that links ELSinduced epigenetic changes with synaptic plasticity.
Knowledge of miRNA functions is increasing rapidly. It is now known that miRNAs are enriched at
synapses, where they quickly regulate the translation
of specific proteins in response to synaptic activity
[57]. Thus, miRNAs may be directly engaged in synaptic plasticity. Individual miRNAs are involved in
the regulation of dendritic spine size and morphology,
as well as in postsynaptic density protein 95 and
NMDA receptor subunit NR2A mRNA expression
[57]. Interestingly, a few reports have shown that prenatal [72] and early postnatal stress (MS) [62] change
the expression profile of miRNAs in the whole brain
and the mPFC, respectively [62].
Toward understanding vulnerability
and resilience to ELS-related mental
disorders – the main concepts
Indisputably, ELS produces profound changes in brain
function; however, not all subjects with a history of
ELS develop psychopathologies. There are few promising concepts that try to explain this phenomenon. The
more “classic” and traditional concept is the cumulative stress hypothesis [18, 45]. It postulates that the effects of stress are cumulative across an individual’s
lifetime, and after passing a certain threshold, the probability of developing a psychopathology is increased.
Thus, ELS may increase an individual’s vulnerability
to aversive challenges in future life and may lead to
a disease. The cumulative stress model assumes that
the effects of cumulative adversity during development
do not have advantageous aspects, such as providing
a source of adaptation [18, 45].
In contrast, the match/mismatch hypothesis postulates that ELS may induce adaptation to certain (aversive) conditions and may prepare the individual for
similar aversive events in the future (a match between
early-life and late environments) [54]. In this way,
ELS may induce specific coping mechanisms and
promote resilience. However, if a mismatch occurs
between early-life and later environments/experiences, coping strategies are compromised and vulnerability to psychopathology develops [54]. Therefore,
in the match/mismatch model, the potential benefits
or costs of adaptive plasticity depend on the environmental context.
Both concepts (cumulative stress and match/mismatch hypotheses) are still being tested in animal
models and in epidemiological studies; however, the
results of these tests have so far been ambiguous. The
main disadvantage of the above hypotheses is that
they both say nothing about individual predispositions
to aversive events [18, 45]. Attempts to integrate both
hypotheses together with an individual/genetic background perspective were undertaken independently by
Nederhof and Schmidt [45] and Daskalakis et al. [18],
and a model of individual sensitivity to early programming in concurrence with the three-hit concept
was proposed [18, 45].
The authors of the first concept used the term
“a sensitivity to early programming”, defined as the
ability of an individual to induce adaptive plasticity in
response to aversive conditions that enhances fitness
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under similar conditions in the future [45]. Subjects
with high programming sensitivity will benefit from
the match between early and late environments, and
in this situation, the match/mismatch hypothesis will
be applied and will promote resilience. On the other
hand, a cumulative stress hypothesis will be applied
to individuals who display low programming sensitivity and who are unable to induce adequate adaptation.
They may accumulate the effects of stressful events
during their lifetime and, in consequence, develop
a disease [45].
The three-hit concept (i.e., hit-1: genetic predisposition, hit-2: early-life environment and hit-3: laterlife environment) adds the genetic background and
completes the model of individual sensitivity to early
programming described by Nederhof and Schmidt
[18, 45]. The three-hit hypothesis of vulnerability and
resilience proposes that during the critical time period
of brain development, individual genetic factors interact with the early-life environment and experiencerelated factors. In consequence, these interactions
(which constitute the genetic and epigenetic signatures of early-life experiences) program gene expression patterns and create specific phenotypes. Then,
these “programmed phenotypes” meet specific laterlife environments/experiences, and depending on the
interplay between them, vulnerability or resilience
may occur [18]. The integrated models cited above
need to be thoroughly tested; however, they definitely
bring us closer to an understanding of the phenomenon of vulnerability and resilience, not only to ELS
but also to stress events in general.
Conclusions
Altogether, clinical and epidemiological studies as
well as advanced neuroimaging techniques and numerous preclinical studies in animal models strongly
implicate that (1) early-life adversity is a relevant
etiological factor for anxiety and MDs and (2) ELSinduced changes in synaptic plasticity within the
mPFC may underlie the pathomechanisms of these
psychopathologies. Given that early-life adversity has
the potential to program brain function and behavior
for the rest of an individual’s life, public awareness
and sensitivity to child abuse and neglect should be
increased.
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Acknowledgments:
This work was supported by grant no. POIG.01.01.02-12-004/09-00
(assignment 2.1), co-financed by the EU European Regional
Development Fund (Poland) within the framework of the Innovative
Economy Programme, 2007–2013.
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Received: July 24, 2013; in the revised form: September 26, 2013;
accepted: October 3, 2013.