Neuroscience and Biobehavioral Reviews 33 (2009) 593–600

Contents lists available at ScienceDirect

Neuroscience and Biobehavioral Reviews

Review

Epigenetic mechanisms mediating the long-term effects of maternal care on

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

Keywords: The long-term consequences of early environmental experiences for development have been explored
Mother–infant extensively in animal models to better understand the mechanisms mediating risk of psychopathology in
Stress responsivity individuals exposed to childhood adversity. One common feature of these models is disruption of the
Maternal behavior mother–infant relationship which is associated with impairments in stress responsivity and maternal
Epigenetic
behavior in adult offspring. These behavioral and physiological characteristics are associated with stable
DNA methylation
changes in gene expression which emerge in infancy and are sustained into adulthood. Recent evidence
Psychiatry
suggests that these long-term effects may be mediated by epigenetic modification to the promoter
regions of steroid receptor genes. In particular, DNA methylation may be critical to maternal effects on
gene expression and thus generate phenotypic differentiation of offspring and, through effects on
maternal behavior of offspring, mediate the transmission of these effects across generations. In this
review we explore evidence for the influence of mother–infant interactions on the epigenome and
consider evidence for and the implications of such epigenetic effects for human mental health.
ß 2008 Elsevier Ltd. All rights reserved.

Contents

1. Deprivation, separation and variation: studying maternal influence on offspring development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 594
2. Maternal influence on the epigenome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 595
3. Pharmacological manipulations of the epigenome. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 596
4. Signalling pathways from maternal care to DNA methylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 596
5. Implications of the study of epigenetics for psychiatry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 597
6. Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 598
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 598

In humans, environmental adversity occurring early in devel- Gunnar, 2006; Gunnar and Fisher, 2006), most of our under-
opment is associated with an increased risk of both physical and standing of these effects comes from animal models in which the
psychiatric disorder in adulthood. Thus, the experience of child- relationship between variation in gene expression within the
hood abuse and neglect has been demonstrated to increase rates of central nervous system and behavioral patterns can be explored in
diabetes and cardiovascular disease (Baten et al., 2004; Goodwin response to discrete environmental events. These studies provide
and Stein, 2004) as well as increasing susceptibility to drug abuse evidence for the long-term impact of disruptions of the early
(Dube et al., 2003; Anda et al., 2006), depression (Baten et al., environment, particularly of the mother–infant relationship or of
2004), schizophrenia (Read et al., 2005; Rutter et al., 2006) and peer–peer interactions during the juvenile period, on the
anxiety-related disorders (Phillips et al., 2005). Though there has neuroendocrine systems regulating stress responsivity and social
been progress in determining the neurobiological consequences of behavior. Moreover, by altering social and reproductive behavior of
these experiences in humans (Teicher et al., 2006; Tarullo and offspring, these experiences have significant consequences for the
development and behavior of subsequent generations (Champagne
and Curley, 2005). One of the most intriguing questions to emerge
* Corresponding author. Tel.: +1 212 854 2589; fax: +1 212 854 3609. from this research involves the mechanism mediating these
E-mail address: [email protected] (F.A. Champagne). effects: How are early environmental effects sustained into

0149-7634/$ – see front matter ß 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.neubiorev.2007.10.009
594 F.A. Champagne, J.P. Curley / Neuroscience and Biobehavioral Reviews 33 (2009) 593–600

adulthood? Recent work suggests that the answer to this question quantity of care received. Similar effects have been demonstrated
involves understanding of epigenetic modifications of gene in rodents, either by imposing variable foraging demand (Bredy
expression in response to environmental cues. In this review, et al., 2007) or by inducing forced periods of physical separation
we will explore evidence from animal models for the long-term between mother and pups (Lehmann and Feldon, 2000). The
consequences of mother–infant interactions both within and maternal separation paradigm, involving hours of daily mother–
across generations, the emerging evidence for the role of infant separation has both short-and long-term effects on the
epigenetics in mediating these effects, and discuss the potential responsivity of the HPA axis (Lehmann and Feldon, 2000; Plotsky
relevance of these mechanisms to the pathophysiology of and Meaney, 1993; Plotsky et al., 2005; Rosenfeld et al., 1992) and
psychiatric disorders in humans. leads to a cascade of behavioral and neurobiological changes
though the consistency and direction of these changes has been
1. Deprivation, separation and variation: studying maternal debated (Pryce and Feldon, 2003; Macri and Wurbel, 2006). These
influence on offspring development manipulations are typically associated with decreased exploration,
behavioral inhibition, increased corticosterone releasing hormone
The profound effect of maternal deprivation on infant devel- (CRH) mRNA in the paraventricular nucleus (PVN), increased
opment that has been implied by longitudinal studies of orphans corticosterone response to stress and decreased levels of hippo-
reared in institutional settings (Kaler and Freeman, 1994; Gunnar campal glucocorticoid receptor (GR) mRNA (Plotsky and Meaney,
et al., 2001; Chugani et al., 2001; Roy et al., 2004) has been 1993; Meaney et al., 1996; Lehmann et al., 1999). Cognitive ability
investigated experimentally in both primates and rodents. is also modified by this experience as indicated by increased
Harlow’s artificial rearing paradigm in which infant rhesus performance latencies on the Morris Water Maze, decreased
macaques were socially isolated for periods of 3–12 months hippocampal synaptophysin levels and increased apoptosis
(Harlow and Suomi, 1971, 1974) illustrated that normal develop- (Lehmann et al., 2002). Females separated from their mothers
ment requires more than simply access to adequate nutrition. for 5 h per day during the pre-weaning period show reduced levels
Juveniles reared in this environment display marked deficits in of maternal licking/grooming toward their offspring (Fleming
play behavior, exhibit high levels of aggression with peers, perform et al., 2002) suggesting reproductive consequences of this
poorly on learning and cognitive discrimination tasks and are disruption to the early environment.
behaviorally inhibited associated with a heightened fear-response A third approach to studying the influence mother–infant
to novelty (Suomi et al., 1971; Seay et al., 1964; Seay and Harlow, interactions on neurobiology and behavior comes from the study of
1965). These behavioral patterns continue into adulthood and thus individual differences in maternal care. Amongst humans,
alter reproductive success, particularly of artificially reared primates and rodents, females display considerable variation in
females, who display high rates of infant abuse, neglect and the quantity and quality of care they provide for offspring
infanticide (Arling and Harlow, 1967; Harlow and Suomi, 1971; (Fairbanks, 1989; Berman, 1990; Fleming et al., 1997; Champagne
Seay et al., 1964). Maternally deprived macaques that are et al., 2003a) and this variability can be used in a longitudinal
permitted to interact with same-age same-sex peers also have design to predict phenotype in adulthood. Maternal behavior of
an elevated hypothalamic–pituitary–adrenal (HPA) response to vervet monkeys living in undisturbed social groups has been found
stress, impairments in learning and social behavior (Shannon et al., to vary along two-dimensions; (1) protectiveness, which consists
1998; Fahlke et al., 2000) and altered serotonergic systems (Ichise of high levels of ‘‘contact-seeking’’ by the mother and (2) rejection,
et al., 2006; Shannon et al., 2005) suggesting that it is disruption of which is associated with frequent attempts to break contact or to
the mother–infant relationship rather than the general conse- leave the infant (Fairbanks and McGuire, 1988). Behavioral
quences of social isolation that contribute to these effects. response to novelty in 1- and 2-year-old infants is associated
Likewise, complete maternal deprivation of rodent pups during with variation in maternal protectiveness, with increased latency
the postpartum period leads to increased HPA activity, reduces to enter a novel environment associated with having a more
exploratory behavior in adulthood and is associated with protective mother (Fairbanks and McGuire, 1988). Individual
locomotor hyperactivity, cognitive impairments and reductions differences in abusive behavior amongst postpartum rhesus and
in maternal care (Gonzalez and Fleming, 2002; Gonzalez et al., pigtail macaques are also associated with behavioral and
2001; Lovic and Fleming, 2004) with females displaying deficits in neurobiological characteristics of offspring (Maestripieri et al.,
hormonal priming of maternal behavior (Novakov and Fleming, 1999, 2005, 1997). Infant abuse occurring during the first 3 months
2005) and engaging in less maternal licking/grooming and contact is associated with an increased frequency of screaming, yawning,
toward their pups. and other indices of infant distress at 4–6 months (Maestripieri
Investigation of the consequence of prolonged periods of et al., 2005). The high levels of maternal rejection exhibited by
separation between mother and infant has also demonstrated the these females is correlated with increased solitary play and
long-term impact of disruptions of the maternal environment on decreased CSF levels of 5-HIAA of their offspring, implicating the
offspring development. In primates, this has been accomplished by role of serotonergic activity in mediating these effects (Maestri-
increasing the variability of foraging demand placed on mothers pieri et al., 2005, 2006). Cross-fostering of infants from abusive to
such that the time required to acquire food fluctuates randomly non-abusive mothers indicates that these effects are indeed
across days (Rosenblum and Paully, 1984). Offspring reared under mediated by the quality of care received rather than a genetic
these conditions exhibit behavioral inhibition, reduced social transmission (Maestripieri, 2005).
behavior associated with increased HPA activity, reduced levels of Postpartum maternal care exhibited by rodents has been found
growth factors, a compromised immune response, and altered to vary significantly between individuals and display the same
neurotransmitter metabolite levels in the anterior cingulate and level of stability over time illustrated by human and primate
medial temporal lobes (Andrews and Rosenblum, 1991, 1994; females. During the first week postpartum, lactating female rats
Coplan et al., 2005, 2001, 1998, 2000; Rosenblum et al., 2001). In and mice display high levels of nursing/contact with pups
addition to creating prolonged maternal separation, variable accompanied by bouts of licking/grooming with the frequency
foraging demand has been show to reduce the maternal of these behaviors varying both within and between strains (Shoji
responsivity of mothers when they are in contact with offspring and Kato, 2006; Champagne et al., 2003a). Strain differences in
(Rosenblum and Paully, 1984) suggesting that these effects may be adult blood pressure between offspring of spontaneously hyper-
mediated by changes in the quality rather than the simply the tensive (SHR) and Wistar Kyoto (WKY) rats have been correlated to
 F.A. Champagne, J.P. Curley / Neuroscience and Biobehavioral Reviews 33 (2009) 593–600 595

differences in the frequency of maternal licking/grooming, Francis et al., 1999). Thus, the offspring of High LG dams cross-
retrieval of pups, and nursing posture exhibited by these two fostered to Low LG dams are indistinguishable in phenotype from
strains (Myers et al., 1989b). Cross-fostering pups from a WKY the biological offspring of Low LG dams. Conversely, the offspring
mother to a SHR mother shifts the WKY phenotype to that of the of Low LG dams when reared by High LG dams resemble the
biological offspring of a SHR mother, suggesting the importance of biological offspring of High LG dams on measures of both gene
variation of the maternal environment in mediating these strain expression and behavior.
differences (Myers et al., 1989a). Strain differences in maternal
care of Balb/c and C57BL/6 mice have also been implicated as an 2. Maternal influence on the epigenome
influence on offspring stress reactivity (Francis et al., 2003; Priebe
et al., 2005). C57BL/6 embryos that are transferred prenatally to Converging evidence from primate and rodent studies support
Balb/c dams and reared by a Balb/c female develop characteristics the hypothesis that maternal environment has a profound
similar to Balb/c mice including decreased exploration of a novel influence on offspring phenotype and that this influence is
environment indicating increased anxiety (Francis et al., 2003). mediated by changes in gene expression. Consequently, under-
Though the characteristics that differentiate the prenatal environ- standing the mechanisms governing these effects requires an
ment of these strains is unknown, Balc/c females display decreased investigation of the molecular mechanisms which regulate gene
levels of postpartum licking/grooming compared to C57BL/6 dams transcription and thus exploration of the epigenetics of gene
which may contribute to the rearing effects observed (Francis et al., expression. The molecular mechanisms involved in the epigenetics
2003). of the genome are numerous and complex including RNA
The role of individual differences in maternal licking/grooming interference, chromatin remodelling, histone modification and
in modulating offspring gene expression, physiology and behavior DNA methylation (Turner, 2001) however, in this review we shall
has been explored extensively in Long Evans rats (Meaney, 2001). limit our focus to the modification of histone proteins and DNA
Amongst Long Evans lactating female rats there are considerable methylation. In order to fit within the nucleus of the cell, DNA must
variations in the frequency with which dams engage in maternal be very tightly coiled. This condensed structure is maintained by
licking/grooming of pups during the first week postpartum and complexes composed of four histone proteins: H1, H2, H3 and H4
licking/grooming behavior has been found to be a normally (Turner, 2001). The structure of these proteins includes a highly
distributed behavior (Champagne et al., 2003a,b). Thus by selecting positively charged region known as a histone ‘‘tail’’. It is this
females that engage in a frequency of licking/grooming that is positively charged histone tail that wraps around the negatively
either 1 standard deviation below (Low LG) or above (High LG) the charged DNA maintaining a very dense complex. In this state, DNA
cohort mean it is possible to compare two groups of offspring that will not be transcribed and gene expression will be inhibited.
experience a 2–3-fold difference in maternal care. Initial studies However, histone tails can undergo several post-translational
demonstrated an association between levels of LG and stress modifications that will alter this DNA–protein interaction. In
responsivity, with the adult male offspring of High LG females particular, acetylation can occur, where through an enzymatic
being more exploratory in a novel environment, having reduced reaction, an acetyl group is attached to the histone tail. When this
plasma adrenocorticotropin and corticosterone in response to occurs, the histone tail and DNA become more similar in electrical
stress, elevated hippocampal glucocorticoid receptor mRNA, change and hence repel each other allowing exposure of the DNA to
elevated hypothalamic CRH mRNA, and increased density of transcription factors. Thus, increases in acetylation of histone tails
benzodiazepine receptors in the amygdala compared to the promote gene expression whereas inhibition of this modification
offspring of Low LG dams (Caldji et al., 2000a; D.D. Francis will decrease gene expression (Verdone et al., 2005).
et al., 1999; Liu et al., 2000, 1997). Offspring of High LG dams also A second epigenetic process that has particular implications for
exhibit enhanced performance on tests of spatial leaning and long-term changes in phenotype is DNA methylation (Turner,
memory, elevated hippocampal brain derived neurotrophic factor 2001; Razin, 1998). Within the DNA sequence, there are specific
(BDNF) mRNA, and increased hippocampal choline acetyltransfer- sites where a methyl group can attach to a cytosine nucleotide
ase and synaptophysin (Liu et al., 2000). GABA subunit expression through an enzymatic reaction. The sites where this can occur
is altered by maternal LG with implications for benzodiazepine reside primarily within the regulatory regions of a gene, in the
binding (Caldji et al., 2000b). Neuronal survival in the hippocam- promoter area upstream from the transcription start site. At a
pus is increased and apoptosis decreased amongst the offspring of functional level, methylation prevents access of transcription
High LG dams associated with elevated levels of fibroblast growth factors and RNA polymerase to DNA resulting in silencing of the
factor (Bredy et al., 2003; Weaver et al., 2002). Dopaminergic gene. In addition to the gene silencing that occurs in the presence
release associated with stress responsivity in males and reward in of DNA methylation, these methyl groups attract other protein
females is also altered as a function of LG (Zhang et al., 2005; complexes which promote histone deacetylation, further inhibit-
Champagne et al., 2004). Natural variations in maternal care are ing the likelihood of gene expression (Strathdee and Brown, 2002;
also transmitted across generations. The offspring of High LG rat Turner, 2001). Unlike histone acetylation, which is a relatively
dams exhibit high levels of maternal LG toward their own offspring dynamic modification, the bond between the cytosine nucleotide
whereas the offspring of Low LG dams are themselves low in LG and methyl group is very strong, resulting in a stable yet
(Champagne et al., 2003a; D. Francis et al., 1999; Fleming et al., potentially reversible change in gene expression. DNA methylation
2002). Female offspring of Low LG dams exhibit decreased patterns are maintained after cell division and thus passed from
estrogen-mediated upregulation of oxytocin receptor binding parent to daughter cells and it is through this form of epigenetic
and c-fos immunoreactivity in hypothalamic regions implicated modification that cellular differentiation occurs (Turner, 2001;
in maternal care such as the medial preoptic area (MPOA; Taylor and Jones, 1985; Razin, 1998).
Champagne et al., 2001, 2003b; Francis et al., 2000). This sensitivity Previous studies have demonstrated that changes in DNA
may be mediated by decreased levels of estrogen receptor (ER) a methylation can be environmentally induced (Waterland, 2006;
mRNA in the MPOA that are found in offspring of Low compared to Jaenisch and Bird, 2003; Anway et al., 2005), however the question
High LG (Champagne et al., 2003b). Importantly, cross-fostering we would like to address is whether the changes in gene
studies have demonstrated that these changes in offspring expression that have been associated with postnatal mother–
phenotype are related to the level of postpartum care received infant interactions are likewise associated with these epigenetic
rather that genetic or prenatal factors (Champagne et al., 2003a; D. modifications. To address this question, initial research focused on
596 F.A. Champagne, J.P. Curley / Neuroscience and Biobehavioral Reviews 33 (2009) 593–600

the differences in hippocampal glucocorticoid receptor mRNA treatment has been found to specifically target the GR 17 promotor
observed in the offspring of High and Low LG dams (Weaver et al., and decrease DNA methylation of this region. Conversely, central
2004). Levels of hippocampal GR regulate the HPA response to administration of methionine, a methyl donor that promotes
stress though a negative feedback relationship with higher levels of methylation, to the adult offspring of High LG dams results in
GR mRNA associated with attenuated stress responsivity (Sapolsky increased anxiety, increased corticosterone response to stress,
et al., 1985; Jacobson and Sapolsky, 1991). Analysis of the level of decreased GR mRNA and decreased binding of NGFI-A to the
DNA methylation within the GR 17 promoter region suggests that hippocampal GR 17 promotor region (Weaver et al., 2005). Thus, by
elevated levels of maternal LG are associated with decreased GR 17 pharmacologically targetting low levels of GR 17 promotor
methylation corresponding to the elevated levels of receptor methylation it is possible to shift the phenotype of the offspring
expression observed in the hippocampus (Weaver et al., 2004). of a High LG dam to resemble that of the offspring of a Low LG dam.
Site-specific analysis of the methylation pattern in this region Evidence for the plasticity of the adult epigenome and phenotype
indicates that the binding site for NGFI-A, a transcription factor in response to pharmacological intervention is certainly not limited
induced by nerve growth factor, is differentially methylated in the to studies of mother–infant interactions. In rats, acute and chronic
offspring of High and Low LG dams and subsequent analysis cocaine administration induces distinct patterns of histone mod-
indicated that the binding of NGFI-A to this region is reduced in ification at specific gene promoters within the striatum. Acute
hippocampal tissue taken from the offspring of Low LG dams administration is associated with H4 acetylation and repeated
(Weaver et al., 2004). A temporal analysis of the methylation of the administration associated with H3 acetylation (Kumar et al., 2005).
GR 17 promoter indicates that differences between the offspring of Similar chromatin remodelling effects are observed in rat striatal
High and Low emerge during the postpartum period and are neurons following dopamine-2-like-antagonist administration (Li
sustained at weaning and into adulthood. Thus, the differences in et al., 2004). It has been proposed that such epigenetic modifications
gene expression and behavior that are observed in the adult could therefore be underlying some of the long-term stable gene
offspring associated with the quality of maternal care received expression and behavioral changes observed in drug abusers (Colvis
during the first week postpartum may be mediated by the long- et al., 2005). Moreover, DNA methylation can be altered through
term silencing of gene expression achieved through differential increasing dietary intake of the methyl donor S-adenosyl methio-
DNA methylation. nine. Examination of the reelin gene, which produces a protein
In addition to altering stress responsivity, maternal licking/ required for normal neuronal migration, axonal branching, synap-
grooming has consequences for the postpartum behavior of female togenesis and cell signaling (Forster et al., 2006) in rats placed on a
offspring associated with levels of ERa gene expression in the MPOA high-methionine diet indicates that this treatment results in
(D. Francis et al., 1999; Champagne et al., 2003a,b). Temporal hypermethylation at the reelin gene promoter, decreased reelin
analysis of ERa in the MPOA indicates that differential levels of ERa mRNA in the frontal cortex and deficits in social recognition and
mRNA are observed in infancy and maintained into adulthood prepulse inhibition (Tremolizzo et al., 2002, 2005). Significantly, this
suggesting a long-term suppression of gene expression in response hypermethylation can be prevented when rats were also treated
to low levels of LG (Champagne et al., 2006). Analysis of MPOA levels with valproate which, like TSA enhances H3 acetylation and
of DNA methylation within the ERa promoter indicate that low promotes demethylation (Tremolizzo et al., 2005). Finally, in mice
levels of maternal LG are associated with high levels of ERa with the ‘viable yellow’ Avy agouti allele, increasing the levels of
methylation whereas high levels of LG are associated with low levels methionine in the maternal diet causes an increase in the
of ERa methylation amongst female offspring (Champagne et al., methylation of the Avy allele in the offspring leading to a shift from
2006). This differential methylation occurs at multiple regions yellow to brown coat color (Wolff et al., 1998; Waterland, 2006;
within the ERa promoter including a binding site for signal Waterland and Jirtle, 2003). Maternal gestational dietary intake of
transducer and activator of transcription (STAT) protein Stat-5. genistein, the major phytoestrogen in soy, also leads to an increase in
Chromatin immunoprecipitation assay with Stat-5 antibody indi- the methylation of a retrotransposon upstream of the Agouti gene,
cates that the high levels of ERa promoter methylation observed in causing the same shift in coat color (Dolinoy et al., 2006). Thus,
the female offspring of Low LG dams results in less Stat-5 changes in gene expression and phenotype can be induced in
immunoreactivity indicating that differential methylation of the adulthood with pharmacological and dietary interventions that
ERa has functional consequences for the binding of factors that directly target the epigenome.
normally enhance gene expression (Champagne et al., 2006; Frasor
et al., 2001). Thus licking/grooming is associated with epigenetic 4. Signalling pathways from maternal care to DNA methylation
effects in female offspring that mediate long-term changes in the
expression of a gene involved in maternal behavior and as such In the maternal rat, licking/grooming may serve as a critical
mediates the transmission of maternal care across generations. source of tactile stimulation for the developing pup. The question is
how this physical stimulation leads to epigenetic changes to
3. Pharmacological manipulations of the epigenome specific genes within hippocampal and medial preoptic area cells
that have been observed in offspring of High compared to Low LG
The mediating role of epigenetic modifications in sustaining the dams. Pups provided with tactile stimulation in the form of
differences in gene expression and behavior of High and Low LG stroking with a paintbrush or maternal LG both exhibit increases in
offspring is supported by findings that these phenotypes can be hippocampal GR expression (Jutapakdeegul et al., 2003; Liu et al.,
altered through pharmacological manipulation of DNA methyla- 1997). In vitro studies suggest that these effects are mediated by
tion. ICV influsion of trichostatin-A (TSA), a histone deacetylase increases in NGFI-A which is dependent on serotonergic activation
inhibitor that promotes demethylation, has been demonstrated to of cAMP-coupled 5-HT7 receptors (Meaney et al., 2000; Mitchell
reverse the effects of low levels of maternal LG when administered et al., 1992, 1990). Thus, the effects on GR expression of tactile
to adult offspring (Weaver et al., 2006, 2004). Thus, the TSA-treated stimulation provided by mothers can be mimicked by adminis-
offspring of Low LG dams exhibit increased behavioral exploration, tration of a cAMP analogue and blocked by a 5-HT7 receptor
decreased levels of stress-induced corticosterone, and decreased antagonist (Laplante et al., 2002). Recent evidence highlights the
hippocampal GR mRNA expression compared to vehicle-treated importance of NGFI-A as a downstream target of this pharmaco-
offspring of Low LG dams and are indistinguishable from that of the logical or behavioral treatment (Weaver et al., 2007). Hippocampal
offspring of High LG dams (Weaver et al., 2006, 2004). This GR expression is not enhanced by 5-HT when an NGFI-A antisense
 F.A. Champagne, J.P. Curley / Neuroscience and Biobehavioral Reviews 33 (2009) 593–600 597

is co-administered and both cAMP and 5-HT have been found to Epigenetic marks are inherited mitotically from mother to
alter the methylation status of the NGFI-A binding site within the daughter cells (Zhou et al., 2005). Though these marks are stable
GR 17 promoter region. Furthermore, though increasing levels of over the long-term, studies in vitro using mammalian cells in tissue
NGFI-A are associated with decreased methylation of the GR 17 culture reveal that de novo methylation occurs in about 3–5%
promoter and thus increased GR expression, if the NGFI-A binding daughter cells per mitosis and methylation loss occurs in 0.1–3%
site within the GR 17 promoter is mutated, effects of NGFI-A are daughter cells per mitosis (Pfeifer et al., 1990; Riggs et al., 1998).
blocked. Though the exact role NGFI-A plays in the demethylation However, it is unlikely that the magnitude of difference in gene
of the GR 17 promoter is not known, these findings suggest that expression between 50-year-old MZ twins compared to 3-year-old
through the stimulation of specific factors that bind within steroid MZ twins is entirely accounted for by random stochastic effects
receptor promoter regions, maternal care can lead to a cascade of and thus may also be related to the degree of discordance in
events that alter offspring development and result in stable environmental variables between the twins. The significance of
patterns of adult gene expression and behavior. This same such epigenetic divergence has been investigated in other studies
principle of activation may be applicable to the relationship of MZ twins. Using restriction landmark genome scanning,
between Stat-5 interactions with the ERa promoter and estrogen genomic DNA extracted from leukocytes of male MZ twins
receptor gene expression, however this particular cascade has not discordant for schizophrenia was found to have significant
yet been investigated. differences between twins at NotI methylation sites (Tsujita
et al., 1998). Using bisulfite mapping, differential methylation in
5. Implications of the study of epigenetics for psychiatry the 5’-regulatory region of the dopamine D2 receptor gene (DRD2)
in lymphocytes of MZ twins discordant for schizophrenia has also
Epigenetic modification in response to early environmental been reported (Petronis et al., 2003). Using fine detail methylation
conditions provides an elegant mechanism to explain the effects of mapping technology on buccal cell samples, 5-year-old MZ twins
childhood adversity on increasing risk of psychopathology in have been shown to vary in the degree of discordance in
adulthood. However, studying the role of epigenetic modifications methylation status at two CpG islands of the promoter region of
in mediating these effects in humans is limited by several the catechol-O-methyltransferase (COMT) gene. Some MZ twin
methodological constraints. Nevertheless, recent studies in pairs showed a high degree of discordance whereas others were
humans suggest that similar epigenetic processes to those very similar in their epigenetic status (Mill et al., 2006). This
observed experimentally in the rat may play a significant role in finding is intriguing given the implications of COMT and DRD2 in
shaping human behavioral plasticity. the risk of psychopathology due to their role in dopamine
One approach to studying environmentally induced epigenetic catabolism (Shifman et al., 2004), a risk that is enhanced when
effects in humans is to compare monozygotic (MZ) twins. A recent interacting with environmental variables such as drug use (Thapar
study compared the gene expression of 3-year-old and 50-year-old et al., 2005; Caspi et al., 2005). Indeed, though most previous work
MZ twins and found a 4-fold discordance amongst older twins has focused upon how different genetic polymorphisms of genes
which was associated with increasing differences in DNA such as COMT and DRD2 may be associated with gene expression
methylation and histone H3 and H4 acetylation of genes in and psychopathology (Kukreti et al., 2006; Shifman et al., 2004;
peripheral blood lymphocyte and other non-neural tissues (Fraga Bray et al., 2003), these recent epigenetic studies suggest that the
et al., 2005). One potential explanation of these findings is that accumulation of epigenetic variation in gene promoters through
epigenetic modification of the genome is induced through random environmental or stochastic means may account for changes in
stochastic accumulation or ‘‘epigenetic drift’’ (Martin, 2005). brain development and risk of mental illness.

Fig. 1. The epigenetic modification of DNA. ‘‘Silenced’’ DNA is heavily methylated (red circles) with deacetylated histone tails (green bands). Thus the DNA (blue bands) is tightly
bound to the histone proteins (brown cylinders) preventing transcription by RNA polymerase (RNAp). ‘‘Active’’ DNA is demethylated with acetylated histone tails (green ‘A’s)
allowing transcription by RNA polymerase. The expression of genes can be adjusted by stochastic variation and environmental triggers such as maternal care, drugs, dietary
factors and pharmacological agents. In the rat, high levels of tactile stimulation by dams leads to the long-term stable reduction in methylation of both GR and ERa gene
promoters in the hippocampus and MPOA, respectively. This is believed to occur through the stimulation of transcription factors such as NGFI-A and Stat-5. Low levels of
tactile stimulation by rat dams leads to the methylation and deacetylation of the same gene promoters. These environmentally induced epigenetic modifications can be
partially reversed in adult animals through central administration of pharmacological agents such as the histone deacetylase inhibitor trichostatin A (TSA) and methyl donor
methionine.
598 F.A. Champagne, J.P. Curley / Neuroscience and Biobehavioral Reviews 33 (2009) 593–600

One limitation to studying the influence of epigenetic effects on Andrews, M.W., Rosenblum, L.A., 1991. Attachment in monkey infants raised in
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