Epigenetic Influence of
Social Experiences Across
Frances A. Champagne
Department of Psychology
Room 406 Schermerhorn Hall
1190 Amsterdam Avenue
New York, NY 10027
ABSTRACT: The critical role of social interactions in driving phenotypic variation
has long been inferred from the association between early social deprivation and
adverse neurodevelopmental outcomes. Recent evidence has implicated molecular
pathways involved in the regulation of gene expression as one possible route
through which these long-term outcomes are achieved. These epigenetic effects,
though not exclusive to social experiences, may be a mechanism through which the
quality of the social environment becomes embedded at a biological level.
Moreover, there is increasing evidence for the transgenerational impact of these
early experiences mediated through changes in social and reproductive behavior
exhibited in adulthood. In this review, recent studies which highlight the epigenetic
effects of parent–offspring, peer and adult social interactions both with and across
generations will be discussed and the implications of this research for under-
standing the developmental origins of individual differences in brain and behavior
will be explored. ? 2010 Wiley Periodicals, Inc. Dev Psychobiol
Keywords: epigenetic; maternal; social; transgenerational; development
relationship between the quality of the early social
environment and risk or resilience to subsequent physio-
logical, neurobiological, and behavioral outcomes has
been explored in longitudinal studies in humans and in
the developing brain. Classic examples of these associ-
ations can be found in the mother–infant attachment
literature, with a secure attachment relationship predict-
ing long-term resilience to physical and psychological
distress and insecure relationships predicting increased
risk of anxiety and depression (Sroufe, 2005). Maternal
sensitivity to infant behavioral cues is critical in the
formation of a secure attachment and low levels of
sensitivity are associated with increased fearfulness,
negative affect, and EEG asymmetry amongst 9-month-
old infants (Hane & Fox, 2006). The effects of variations
in parental care persist into adulthood with high parental
bonding associated with elevated self-esteem, reduced
trait anxiety, decreased salivary cortisol, and reduced
activation within theventral striatum in response to stress
(Lee, Gollan, Kasckow, Geracioti, & Coccaro, 2006;
Pruessner, Champagne, Meaney, & Dagher, 2004). These
consequences of early-life social deprivation (Fries,
Shirtcliff, & Pollak, 2008, 2005Fries, Ziegler, Kurian,
Jacoris, & Pollak, 2005; Harlow, Dodsworth, & Harlow,
1965; Seay & Harlow, 1965; Suomi, Harlow, & Kimball,
1971) and suggest that the social environment can lead to
divergent developmental pathways with implications for
the adult brain and behavior.
Study of the biological basis of these effects has relied
primarily on rodent models in which the quality of the
early social environment is characterized or manipulated
and then associated with specific neuroendocrine and
behavioral changes. A common theme that emerges from
these studies is the finding that environmentally induced
Received 4 November 2009; Accepted 22 December 2009
Correspondence to: F. A. Champagne
Contract grant sponsor: Office of the Director, National Institutes of
Contract grant number: DP2OD001674
Published online in Wiley InterScience
(www.interscience.wiley.com). DOI 10.1002/dev.20436
? 2010 Wiley Periodicals, Inc.
periphery can persist beyond infancy and be observed
in adulthood suggesting that there is an interplay between
genes and the environment that may be critical in
mediating the long-term effects of social experiences.
Exploration of the molecular mechanisms through which
these effects are achieved has provided exciting new
insights into dynamic nature of gene regulation and the
potential of these mechanisms to serve as an underlying
biological link between experiences of an organism and
individual differences in neurodevelopment, physiology,
gene regulation in response to experiences across the
lifespan. Thus, the quality of the social environment
beyond infancy is capable of shifting patterns of gene
expression with consequences for the functioning of the
individual within their social context. These epigenetic
and in mediating adaptive responses to environmental
conditions both within and across generations. In this
review, evidence for the influence of parent–offspring,
juvenile, and adult social interactions on epigenetic
mechanisms (see Fig. 1) will be explored and the
implications of these effects for transgenerational inher-
itance of environmentally induced changes in phenotype
will be discussed.
EPIGENETICS: LINKING GENES AND
ENVIRONMENT TO DEVELOPMENT
Historically, the term ‘‘epigenetic’’ was used to describe
2002). Broadly, this term is currently used to describe
phenotypic variation that is not attributable to genetic
variation with more specific definitions referring to the
molecular mechanisms that achieve these non-genomic
effects. Variation in gene expression rather than gene
sequence is the key concept within the study of
epigenetics. The molecular mechanisms through which
this regulation occurs are many and varied (Feng, Fouse,
& Fan, 2007; Razin, 1998; Turner, 2001). Ultimately, the
transcriptional activity of a gene is dependent on the
accessibility of the DNA to RNA polymerase and other
gene-specific transcription factors. In densely packed
chromatin, this accessibility is reduced and gene ex-
pression is repressed. Within the cell nucleus, DNA is
wrapped around a core of histone proteins which can
undergo multiple post-translational modifications includ-
ing methylation, acetylation, and ubiquination (Peterson
& Laniel, 2004; Zhang & Reinberg, 2001). These
modifications alter the dynamic interactions between the
histones and DNA which either reduce or enhance the
accessibility of DNA. In particular, histone acetylation is
histone deacetylation or methylation is associated with
transcriptional repression. Acetylation of histones is
mediated by the enzyme histone acetyltransferase
(HAT), whereas histone deacetylase (HDAC) promotes
removal of the acetyl group from the histone tails.
Thus, through alterations in the conformation of histones,
the accessibility of DNA can be rapidly and reversibly
what is generally considered a more stable and enduring
modification to the activity of genes. DNA methylation
occurs when cytosine nucleotides within DNA become
converted to 5-methylcytosine. This process is mediated
by methyltransferases which either promote maintenance
(i.e., DNMT1) or de novo DNA methylation (i.e.,
DNMT3) (Feng et al., 2007; Razin, 1998; Turner, 2001).
The conversion to 5-methylcytosine does not alter the
DNA sequence but does reduce the likelihood that that
sequence of DNA will be transcribed. Methylated
DNA attracts methyl-binding proteins, such as MeCP2,
which further reduce the accessibility of the gene and
is associated with transcriptional repression (Fan &
Hutnick, 2005). The stability of DNA methylation
patterns within the genome permits the stable regulation
of gene expression associated with cellular differentia-
tion. Importantly, during cell division, both DNA and
across the lifespan. Emerging evidence suggests that prenatal
environmental exposures, postnatal mother–infant interactions,
juvenile social rearing, and adult social stress can alter
epigenetic processes such as DNA methylation (red circles)
and histone acetylation (green circles)/methylation with long-
term consequences for gene expression, physiology, and
Epigenetic consequences of social experiences
thus allowing differentiated cells to transmit their
phenotype to the next generation of cells (Fukuda &
Epigenetic regulation of gene expression is particu-
larly important during the early stages of development.
The reorganization of maternal and paternal genetic
material immediately post-fertilization is associated
with decreased levels of 5-methylcytosine of the male
pronucleus with species-specificdifferences inthe degree
of demethylation (McLay & Clarke, 2003; Santos,
Hendrich, Reik, & Dean, 2002; Young & Beaujean,
2004). The male pronucleus is also subject to further
epigenetic modification through the replacement of
protamines with acetylated histone proteins in the
chromatin structure following fertilization (Nonchev &
Tsanev, 1990). Oocyte factors seem to be critical in the
chromatin remodeling that occurs during this phase and
there is evidence for species differences in the capacity of
oocytes to induce epigenetic change (Beaujean et al.,
2004). Zygotic genes are silenced through chromatin-
mediated suppression of transcription during the post-
fertilization phase and thus all protein synthesis is
mediated by maternal mRNAs and enzymes alone until
Sousa, Caveney, Westhusin, & Watson, 1998; Nothias,
Majumder, Kaneko, & DePamphilis, 1995). The impor-
tance of DNA methylation and histone acetylation for
studies in mice. Targeted deletion of the histone
acetyltransferase Gcn5 gene is lethal and even when
only delayed and associated with deficits in neural tube
closing (Bu, Evrard, Lozano, & Dent, 2007). Deletion of
whereas over-expression of this gene leads to DNA
induce embryonic lethality (Biniszkiewicz et al., 2002;
particular importance in maintaining the mono-allelic
expression of imprinted genes. Maternally and paternally
imprinted genes exhibit parent-of-origin expression
patterns that are maintained through epigenetic mecha-
nisms such as DNA methylation. These genes have a
the maternal or paternal allele is essential to establishing
normal patterns of growth and development (Reik,
Davies, Dean, Kelsey, & Constancia, 2001). Disruption
to the expression of DNMT1 or the de novo methyl-
transferases DNMT3a/3b can lead to altered genomic
imprinting (Biniszkiewicz et al., 2002; Okano, Bell,
Haber, & Li, 1999). Overall, it is evident that the fine
control of gene expression mediated through epigenetic
mechanisms determines the successful transition from
zygote to embryo to fetus and sets the stage for the
regulation of prenatal and postnatal developmental
MATERNAL EFFECTS DURING FETAL
ment does not typically include the prenatal period, there
is increasing evidence for the epigenetic influence of
of how the social and environmental experiences of the
mother can lead to divergent developmental pathways of
offspring.Thequalityof thematernal nutritional environ-
ment during pregnancy can have a significant impact
on the growth and development of the fetus, with long-
term consequences for brain development and metabo-
lism (Godfrey & Barker, 2001; Symonds, Stephenson,
Gardner, & Budge, 2007; Zeisel, 2009). Epidemiological
studies of cohorts exposed prenatally to conditions of
famine, suggest a heightened risk of schizophrenia,
affective disorders, antisocial personality, and other
neurodevelopmental abnormalities. Analysis of blood
samples from famine exposed versus non-exposed
siblings indicates that there is decreased DNA methyl-
ation of the insulin-like growth factor II (IGF2) gene as a
consequence of maternal periconceptual exposure to
famine (Heijmans et al., 2008). Laboratory studies in
rodents have subsequently identified specific nutritional
deficits, such as prenatal protein restriction or folic acid/
choline deficiency as having similar epigenetic conse-
quences. Offspring of female rats placed on a protein
deficient diet throughout gestation were found to
have elevated hepatic glucocorticoid receptor (GR) and
peroxisomal proliferator-activated receptor (PPAR) gene
expression associated with decreased DNA methylation
of these genes (Lillycrop, Phillips, Jackson, Hanson, &
Burdge, 2005; Lillycrop et al., 2008). Moreover, these
epigenetic effects are not observed when gestational
protein restriction is accompanied by folic acid supple-
mentation (Lillycrop et al., 2005). Dietary effects on
levels of DNMT1 may account for these observed
modifications in global and gene-specific methylation,
as DNMT1 expression is increased in hepatic (Lillycrop
et al., 2007) and brain tissue (Kovacheva et al., 2007) as a
function of protein/choline restriction. The impact of
dietary supplementation with methyl-donors during fetal
development is also clearly demonstrated by the con-
sequences for phenotype amongst mice with the Avyor
AxinFuepialleles. The expression of these alleles is
epigenetically regulated through levels of DNA methyl-
ation, with decreased methylation associated with yellow
Developmental Psychobiology Epigenetic Influence of Social Experiences
coat color and obesity amongst Avymice or a ‘‘kinky’’tail
phenotype amongst AxinFumice (Morgan, Sutherland,
Martin, & Whitelaw, 1999; Rakyan et al., 2003). Though
there is typically an epigenetic inheritance of these
phenotypes, gestational exposure to methyl donors
through dietary supplementation of the mother can
effectively silence the expression of these alleles with
the consequence of inducing a pseudo wild-type pheno-
type (Waterland et al., 2006; Wolff, Kodell, Moore, &
Cooney, 1998). Thus, the maternal nutritional environ-
The rapid period of cellular proliferation and differ-
entiation that occurs during fetal development provides a
critical window during which maternal gestational
exposure to toxins may lead to long-term disruptions in
offspring and there is increasing evidence for the
epigenetic basis of these effects. In utero methyl mercury
exposure in mice has been shown to lead to DNA
hypermethylation, increased histone tri-methylation, and
decreased histone acetylation within the IV promotor of
the brain-derived neurotrophic factor (BDNF) gene in the
hippocampus of offspring and is associated with depres-
sive-like behaviors (Onishchenko, Karpova, Sabri, Cast-
ren, & Ceccatelli, 2008). Prenatal exposure of pregnant
mice to inhaled diesel exhaust particles combined with
an allergen results in altered immunoglobulin (IgE)
levels associated with hypermethylation of the interferon
(IFN)-gamma promoter and hypomethylation of the
interleukin (IL)-4 promotor (Liu et al., 2008). Altered
DNA methylation within these immune pathways may
on offspring asthma risk (Li, Langholz, Salam, &
Gilliland, 2005). In rats, prenatal exposure to the anti-
androgenic fungicide vinclozolin or the estrogenic
pesticide methoxychlor results in increased rates of
prostate disease, kidney disease, immune system abnor-
malities, testis abnormalities, and tumor development
(Anway, Leathers, & Skinner, 2006). This exposure is
associated with altered DNA methylation patterns in
sperm and impairments in reproduction in male offspring
(Anway, Cupp, Uzumcu, & Skinner, 2005). In utero
exposure to the endocrine disruptor bisphenol-A (BPA)
has been demonstrated to induce widespread changes in
promoter methylation in the fetal mouse brain, with
consequences for neural development (Yaoi et al., 2008).
BPA-induced hypomethylation of the Avyallele in mice
leads to metabolic abnormality and obesity in adulthood.
Interestingly, these toxin-induced effects can be reversed
through folate supplementation in the mother’s diet
(Dolinoy, Huang, & Jirtle, 2007), suggesting that
abnormalities in DNA methylation can be ameliorated
through exposure to increased levels of methyl-donors.
The timing of dietary supplementation may be critical in
determining the ameliorating effects of folate, as recent
studies have indicated that the epigenetic effects of
prenatal protein restriction are not reversed when the diet
is subsequently enriched with folate during juvenile
development (Burdge et al., 2009).
Evidence for the epigenetic influence of antenatal
maternal mood has emerged from human cohort studies
and animal models; providing further support for the role
of epigenetic mechanisms in mediating developmental
outcomes. Analysis of cord blood samples from infants
the Hamilton Depression Scale) during the third trimester
of pregnancy indicates elevated GR 1F promotor DNA
methylation levels associated with maternal depressed
mood (Oberlander et al., 2008). Moreover, the level of
methylation within the neonatal GR 1F promotor predicts
increased salivary cortisol levels of infants at 3 months of
age and these effects are independent of exposure to
selective serotonin reuptake inhibitors during pregnancy.
The long-term consequences of prenatal stress for brain
and behavior have likewise been explored with recent
within the placenta and hypothalamus as possible
mediators of these maternal effects. In mice, chronic
variable stress during the first trimester is associated with
decreased DNA methylation of the corticotrophin-releas-
ing-factor (CRF) gene promotor and increased methyl-
ation of the GR exon 17promotor region in hypothalamic
tissue of adult male offspring (Mueller & Bale, 2008).
Gestational stress within these experiments was found to
exert sex-specific effects on the expression of DNMT1
in the placenta which may induce disruption of the
epigenetic status of genes within this critical interface
may be particularly sensitive to this disruption, leading
to impairments in placental growth and function with
development (Reik et al., 2003).
Epigenetic regulation during these early stages of
development and the implications for social behavior can
also be explored in insects, providing some intriguing
insights into the developmental origins of reproductive
behavior. Honeybees (Apis mellifera) have functional
DNA methyltransferases and the degree of methylation
of the genome varies during the course of development
(Wang et al., 2006). Amongst female honeybees, social/
reproductivecaste is determined through early nutritional
exposure to royal jelly (Laidlaw, 1992). Larvae provided
with a diet composed primarily of royal jelly grow more
bees. In contrast, worker bees are not provided with high
with only rudimentary ovaries. These caste differences in
development are associated with differential gene expres-
sion in queen bees versus workers (Evans & Wheeler,
1999). Manipulation of the activity of DNMT3 in honey
bee larvae through use of RNA interference provides
evidence that DNA methylation mediates these divergent
phenotypes (Kucharski, Maleszka, Foret, & Maleszka,
worker bees whereas inhibiting DNMT3 leads to the
majority of larvae developing morphologically as queen
bees. Thus, the capacity of royal jelly to induce caste
differences in this eusocial insect may be linked to the
presence of factors which inhibit DNA methylation.
EPIGENETIC MODIFICATION DURING
Though dynamic epigenetic modifications were once
thought to be limited to the very early stages of
development, evidence for continued parental influence
on DNA methylation beyond the prenatal period has
challenged this view. Studies of the effects of natural
mediating role of epigenetic factors in shaping individual
differences in brain and behavior (Meaney, 2001; Szyf,
maternal licking/grooming (LG) behavior, in particular,
has been found to induce increased hippocampal GR
expression leading to more efficient negative feedback of
the stress response with consequences for behavioral
response to novelty and cross-fostering studies have
confirmed that these effects are mediated by the level of
maternal care received during postnatal development
Liu et al., 1997). Analysis of the GR 17promotor region
suggests that variations in GR expression associated with
differential levels of maternal care are maintained though
altered DNA methylation (Weaver et al., 2004). Thus,
offspring who receive high levels of maternal LG during
the early postnatal period have decreased hippocampal
GR 17promotor methylation, increased GR expression,
and decreased stress responsivity. In contrast, low levels
of LG are associated with increased GR 17methylation,
decreased GR expression and an increased hypothala-
mic–pituitary–adrenal (HPA) response to stress. Time
course analysis has indicated that these maternally
induced epigenetic profiles emerge during the postnatal
period and are sustained into adulthood (Weaver et al.,
2004). The pathways through which these effects are
achieved are currently being elucidated and it appears
likely that maternal LG mediated up-regulation of nerve
growth factor inducible protein A (NGFI-A) in infancy
may be critical to activating GR transcription and
maintaining low levels of DNA methylation within the
GR 17promotor (Weaver et al., 2007). Though these
epigenetic effects can be stably maintained into adult-
hood, pharmacological targeting of the epigenome
through exposure to the HDAC inhibitor trichostatin-A
or to methionine (a methyl donor) can reverse the effects
of early maternal care on GR methylation and expression
(Weaver et al., 2004, 2005).
Though the exploration of these brain region-specific
maternal effects in humans is limited by the inaccessi-
bility of brain tissue, recent studies have illustrated the
long-term effects of childhood abuse on hippocampal
DNA methylation patterns of suicide victims (McGowan
et al., 2008, 2009). Analysis of hippocampal tissue from
decreased GR expression and elevated GR 1F promotor
methylation associated with disruptions of the early
environment. These studies also confirm the potential
roleof NGFI-Aas a mediator of differential GRpromotor
methylation (McGowan et al., 2009). Early life effects on
GR signaling pathways in humans are further illustrated
by a recent genome wide analysis of gene expression of
peripheral blood mononuclear cells from healthy adults
who had experienced conditions of low versus high
socioeconomic (SES) status during childhood, with low
childhood SES associated with a down-regulation of
genes containing GR response elements (Miller et al.,
The influence of maternal care during early postnatal
development is not limited to effects on stress responsiv-
ity/GR negative feedback. In rodents, exposure of female
neonates to low levels of LG leads to reduced expression
of estrogen receptor alpha (ERa) in the medial preoptic
area (MPOA) of the hypothalamus (Champagne, Weaver,
Diorio, Sharma, & Meaney, 2003). These effects on ERa
expression are sustained into adulthood with consequen-
ces for the estrogen sensitivity of these females. During
late gestation, there is typically increased levels of
circulating estrogen which serve to ‘‘prime’’ the mother
for the behavioral and physiological demands of parturi-
tion and lactation. Within the MPOA of female offspring
neural activation in response to estrogen and reduced
estrogen-mediated increases in levels of oxytocin recep-
tors (Champagne, Diorio, Sharma, & Meaney, 2001;
Champagne, Weaver, et al., 2003). As a consequence
of this reduced priming, female offspring who received
low levels of LG also provide low levels of this form of
maternal care to their own offspring. Analysis of the 1B
promotor region of the ERa gene in MPOA tissue
implicates DNA methylation as a potential mediator of
these maternal effects. At several sites within the ERa
promotor there is elevated DNA methylation associated
with exposure to low levels of LG (Champagne et al.,
Developmental Psychobiology Epigenetic Influence of Social Experiences
2006). Chromatin immunoprecipitation assays demon-
strate that this differential DNA methylation has con-
sequences for the binding of transcription factors such as
STAT5a to the 1B promotor. Maternal LG is associated
with increased levels of STAT5a during the postnatal
period and the increased levels of this factor may lead to
sustained activation of transcription and reduced DNA
Variations in mother–infant interactions can also be
induced in laboratory rodents with consequences for the
epigenetic regulation of genes involved in developmental
plasticity. Disruption to the nesting materials within a
female’s home cage can lead to abusive caregiving
characterized by increased frequency of rough handling,
dragging, dropping, and stepping on pups (Roth &
Sullivan, 2005). Daily exposure to this form of abusive
social interaction leads toreduced expression ofBDNF in
the prefrontal cortex in adulthood associated with
increased DNA methylation within the IV BDNF
promotor region (Roth, Lubin, Funk, & Sweatt, 2009).
The functional importance of DNA methylation in
mediating the long-term effects of abuse is further
supported by findings that central administration of
zebularine, a compound that reduces DNA methylation,
leads to increased BDNF expression in maltreated rats
non-abused offspring. Thus, as is the case for natural
variations in LG, there are persistent epigenetic con-
for gene expression and the adult brain.
BEYOND INFANCY: PLASTICITY DURING
Illustrations of the importance of the social environment
beyond early infancy in promoting species-specific
patterns of social behavior suggest the occurrence of
plasticity during later periods of development. Social
isolation of juvenile rhesus macaques leads to increased
cortisol and reduced immune responsiveness (Gordon
et al., 1992). Juvenile social isolation in rodents induces
what has been referred to as an ‘‘isolation syndrome’’
characterized by multiple behavioral and neuroendocrine
changes which can be attenuated by treatment with
antidepressants (Heritch, Henderson, & Westfall, 1990).
In contrast, social and physical enrichment during the
improved cognition, and reduced anxiety-like behavior
mental complexity during the juvenile period has also
been demonstrated to compensatefor deficitsinbrain and
behavior induced by exposures occurring during prenatal
and postnatal development. Prenatal stress-induced
reductions in social play behavior and increases in
corticosterone response to stress in rat offspring can be
reversed through post-weaning environmental enrich-
ment (Morley-Fletcher, Rea, Maccari, & Laviola, 2003).
Amongst offspring who experienced low levels of
maternal LG, social and physical environmental enrich-
exploratory behavior, and increase maternal care (Bredy,
Humpartzoomian, Cain, & Meaney, 2003; Bredy, Zhang,
Grant, Diorio, & Meaney, 2004; Champagne & Meaney,
Post-weaning environmental manipulations have been
demonstrated to delay onset of symptomatology in
genetic mouse models of Huntington’s and Alzheimer’s
disease (Jankowsky et al., 2005; van Dellen, Blakemore,
Deacon, York, & Hannan, 2000) and to promote
recovery following stroke (Buchhold et al., 2007) or
mechanismthrough which these effects are achievedmay
be dependent on the underlying neurobiological or
physiological deficit. For example, mutation of the
Huntingtin gene leads to reductions in BDNF transcrip-
with Huntington’s disease (Zuccato et al., 2005) and
environmental enrichment has been demonstrated to
delay the onset of motor deficits and decreases in brain
volume in mice with the Huntington’s transgene (Hockly
et al., 2002; van Dellen et al., 2000). This environmental
manipulation has been found to up-regulate BDNF levels
amongst Huntingtin-deficient mice, though these effects
(Zajac etal., 2009). Recoveryof memorydeficitsinduced
through p25-mediated neuronal loss can be achieved
through exposure to complex housing environments and
this enrichment is associated with increased histone (H3
and H4) acetylation in hippocampus and cortex (Fischer,
Sananbenesi, Wang, Dobbin, & Tsai, 2007). Moreover,
treatment with histone deacetylase inhibitors can mimic
the effects of environmental enrichment on learning and
synaptic plasticity. Though these studies do not differ-
entiate between aspects of the social versus physical
environment, it is clear that the quality of environmental
conditions beyond the postnatal period can have signifi-
cant implications for adult behavior.
SOCIAL INTERACTIONS IN ADULTHOOD:
EPIGENETIC CONSEQUENCES OF
The influence of adult social interactions on physiology
and behavior has been observed in humans, primates, and
rodents, suggesting continued plasticity in developmen-
tally mature organisms. The quality of the social stimuli
and the relationship of the subject to those stimuli are
of adult social interactions. One experimental model that
has been used to study the long-term consequences of
social defeat (Martinez, Calvo-Torrent, & Herbert, 2002;
aggression can be established such that when an
‘‘intruder’’ is introduced into a new territory, high levels
of agonistic behaviors (fighting and submissive postures)
will be observed, with the intruder typically being
exposed to repeated defeats during social encounters.
Socially defeated males manifest numerous behavioral
and neuroendocrine changes, including reduced locomo-
tion (Meerlo, Overkamp, Benning, Koolhaas, & Van den
Hoofdakker, 1996; Raab et al., 1986), decreased
social behavior (Meerlo, Overkamp, Daan, Van Den
Hoofdakker, & Koolhaas, 1996), increased drug self-
administration (Haney, Maccari, Le Moal, Simon, &
Piazza, 1995), and increased HPA activity (Blanchard,
Sakai, McEwen, Weiss, & Blanchard, 1993; Keeney
et al., 2006). This cascade of neurobehavioral change
induces a depression-like state that can be effectively
treated with antidepressants (Keeney & Hogg, 1999;
Rygula, Abumaria, Domenici, Hiemke, & Fuchs,
2006). These data are consistent with clinical and
epidemiological studies suggesting that chronic social
stress plays a significant role in the development of
The epigenetic basis of the effects of social defeat has
been exploredandsuggeststhat transcriptional activity of
BDNF may be a target of this environmental exposure.
BNDF gene expression is significantly decreased in the
hippocampus of socially defeated male mice and this
effect appears to be mediated by specific decreases in the
BDNF III and IV transcripts (Tsankova et al., 2006).
These effects are observeda monthfollowing exposure to
the social stress, indicating a persistent effect on gene
expression. Chromatin immunoprecipitation assay anal-
ysis indicates increased histone H3-K27 dimethylation at
males which may account for the reduced BDNF
expression. Histone deacetylase (HDAC5) mRNA levels
are also found to be decreased in socially defeated males
(Tsankova et al., 2006). HDAC5 appears to be important
in mediating the effects of anti-depressant treatment in
males exposed to chronic social stress (Renthal et al.,
2007). The differential levels histone H3-K27 dimethy-
lation observed in the hippocampus is also found across
thegenomeinthe nucleus accumbens,bothinresponse to
chronic social defeat and prolonged adult social isolation
the nucleus accumbens indicates that H3-K14 acetylation
is initially decreased and then increased following
as decreased social behavior, can be reversed with an
HDAC inhibitor infused into the nucleus accumbens
this pharmacological targeting of the histones is very
similar to that achieved using fluoxetine. Interestingly,
post-mortem analysis of brain tissue from depressed
patients indicates increases in H3-K14 acetylation
and decreased HDAC2 levels similar to those observed
in socially defeated mice (Covington et al., 2009),
suggesting that there may be an environmentally
induced-epigenetic substrate associated with human
TRANSGENERATIONAL EFFECTS OF THE
There is increasing evidence for the transgenerational
impact of early life experiences mediated either through
germline epigenetic inheritance or experience-dependent
epigenetic modifications. Laboratory studies in rodents
have demonstrated the transgenerational impact of
nutrition and indicate that prenatal protein restriction
can exert effects on growth and metabolism of offspring
and grand-offspring through changes in methylation
status of GR (Zambrano et al., 2005). When F0 female
mice are exposed to caloric restriction during late
gestation, F2 grand-offspring are found to have impaired
glucose tolerance and this effect is maintained even when
the F1 generation is provided with ad libitum food
throughout their lifetime. The consequences of in utero
exposure to endocrine disrupting compounds has also
been explored within a transgenerational model and
provides evidence for the pervasive effects on epigenetic
profiles of these early life exposures. In humans, matri-
lineal transmission of the effects of diethylstilbestrol
(DES)-induced hypomethylation and increased cancer
risk has been observed in daughters and granddaughters
(Newbold, Padilla-Banks, & Jefferson, 2006). In utero
exposure to vinclozolin in rats has been demonstrated to
disrupt DNA methylation in sperm and increase rates of
infertility and risk of prostrate and kidney disease in F1,
F2, and F3 offspring with the transmission though the
patriline (Anway et al., 2005). Vinclozolin-induced
alterations in gene expression within the hippocampus
and amygdala have also been observed for up to three
generations post-exposure with sex-specific effects on
Developmental Psychobiology Epigenetic Influence of Social Experiences
presented with F3 vinclozolin-exposed or non-exposed
males show a significant partner preference for non-
exposed males, indicating an additional measure of
decreased reproductive success as a consequence of
treatment with endocrine disruptors (Crews et al., 2007).
The persistence of these disruptions beyond the F2
generation suggests that the effects of these exposures
have become incorporated into the germline and there is
incomplete erasure of the associated epigenetic marks
during the process of gametogenesis, fertilization, and
embryogenesis (Skinner, 2008).
Across species, there is evidence for the transmission
of individual differences in maternal behavior from
mother to offspring and grand-offspring (Benoit &
Parker, 1994; Berman, 1990; Champagne & Meaney,
2001; Maestripieri, 2005; Miller, Kramer, Warner,
Wickramaratne, & Weissman, 1997). The epigenetic
mechanisms involved in this transmission has been
explored in laboratory rodents. Natural variations in
maternal LG observed in the F0 generation in rats are
associated with similar levels of LG in F1 and F2
generation females (Champagne, Francis, Mar, &
Meaney, 2003; Champagne & Meaney, 2007). As such,
under stable environmental conditions, offspring and
grand-offspring of Low LG females display low levels of
LG whereas offspring and grand-offspring of High LG
females display high levels of LG. Similar to the
transgenerational effects of abuse in macaques, cross-
fostering studies have demonstrated that the transmission
of maternal LG from mother to female offspring is
(Champagne, Francis, et al., 2003; Francis et al., 1999;
Maestripieri, 2005). Further evidence for the experience-
dependent nature of these effects comes from studies in
stress (Champagne & Meaney, 2006) or manipulation of
the juvenile environment (Champagne & Meaney, 2007),
leading to a disruption of the inheritance of the predicted
maternal phenotype. Studies of the effect of maternal
LG on DNA methylation within the ERa promotor
(Champagne et al., 2006) suggest that epigenetic
modifications to a gene that regulates several aspects of
reproduction, including postpartum maternal behavior,
results in differential levels of expression of ERa in
adulthood. Consequently, estrogen sensitivity is altered
2001; Champagne, Weaver, et al., 2003). The trans-
LG within this transgenerational framework is mediated
by the stability of brain region-specific epigenetic
in adulthood (Champagne, 2008). A similar experience-
dependent transmission of behavior is observed in
response to exposure to abuse. Female rat pups exposed
to abusive caregiving in infancy engage in abusive
caregiving toward their own offspring and F2 offspring
of these F1 females had elevated levels of methylation
within the BDNF promotor in the PFC and hippocampus
of F2 females to non-abusive dams did not reverse these
epigenetic effects, suggesting that there may be prenatal
factors that contribute to the generational transmission of
altered DNA methylation patterns.
Development is a dynamic process during which there is
and its environment. Emerging evidence suggests that
epigenetic modifications may serve as a critical mecha-
nism through which experiences occurring during the
lifespan of an organism can have sustained effects on
behavior. Though this may be true of numerous types of
experiences, including nutritional intake or exposure to
drugs/toxins, these mechanisms also appear to mediate
the effects of social experiences. The biologically
embedding of the quality of the social environment may
have adaptive versus maladaptive consequences depend-
ent on the context of the individual. For example, the
effects of low childhood SES on gene expression profiles
suggests the induction of a defensive phenotype, charac-
terized by heightened immune and HPA reactivity which
may better prepare an organism for conditions of threat
(Miller et al., 2009). However, long-term exposure to
these defensive responses may increase the likelihood of
physical andpsychiatric illness. The convergingevidence
in mediating the effects of social experiences may also
used to reverse the consequences of early or later-life
exposures. Though the appropriateness and feasibility of
such an approach in clinical populations has yet to be
provides support for the value of epigenetic therapy.
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considerable empirical support(Arai, Li,Hartley,&Feig,
2009; Curley, Champagne, Bateson, & Keverne, 2008).
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Developmental Psychobiology Epigenetic Influence of Social Experiences