Maternal programming of defensive responses through sustained effects on gene expression.
ABSTRACT There are profound maternal effects on individual differences in defensive responses and reproductive strategies in species ranging literally from plants to insects to birds. Maternal effects commonly reflect the quality of the environment and are most likely mediated by the quality of the maternal provision (egg, propagule, etc.), which in turn determines growth rates and adult phenotype. In this paper we review data from the rat that suggest comparable forms of maternal effects on defensive responses stress, which are mediated by the effects of variations in maternal behavior on gene expression. Under conditions of environmental adversity maternal effects enhance the capacity for defensive responses in the offspring. In mammals, these effects appear to 'program' emotional, cognitive and endocrine systems towards increased sensitivity to adversity. In environments with an increased level of adversity, such effects can be considered adaptive, enhancing the probability of offspring survival to sexual maturity; the cost is that of an increased risk for multiple forms of pathology in later life.
- SourceAvailable from: onlinelibrary.wiley.com[Show abstract] [Hide abstract]
ABSTRACT: Objective Early stress events severely impact brain and behaviour. From a neurobiological point of view early stress influences neuroanatomical structures and is associated with a dysregulation of the hypothalamic‐pituitary‐adrenal axis. The objective of this article is to review the epigenetic alterations implicated in brain adaptation to early stress events. MethodA review of empirical research of epigenetic alterations associated to early stress events was performed. ResultsNeuroanatomic and epigenetic alterations have been observed after early stress events. Epigenetics alterations include DNA methylation, histones modifications and microRNA (miRNA) expression. The most studied is largely the former, affecting genes involved in neuroendocrine, neurotransmission and neuroplasticity regulation after early stress exposition. It includes glucocorticoid receptor, FK506‐binding protein 5, arginine vasopressin, oestrogen receptor alpha, 5‐hydroxy‐tryptamine transporter and brain‐derived neurotrophic factor. Conclusion Epigenetic regulation is critical in the interplay between nature and nurture. Alterations in the DNA methylation as well as histones modifications and miRNA expression patterns could explain abnormal behaviours secondary to early stress events.Acta Neuropsychiatrica 10/2012; 24(5). · 0.61 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: We review studies with human and nonhuman species that examine the hypothesis that epigenetic mechanisms, particularly those affecting the expression of genes implicated in stress responses, mediate the association between early childhood adversity and later risk of depression. The resulting studies provide evidence consistent with the idea that social adversity, particularly that involving parent-offspring interactions, alters the epigenetic state and expression of a wide range of genes, the products of which regulate hypothalamic-pituitary-adrenal function. We also address the challenges for future studies, including that of the translation of epigenetic studies towards improvements in treatments.Dialogues in clinical neuroscience 09/2014; 16(3):321-33.
- [Show abstract] [Hide abstract]
ABSTRACT: Children of low socioeconomic status (SES) are at elevated risk for health problems across the lifespan. Observational studies suggest that nurturant parenting might offset some of these health risks, but their design precludes inferences about causal direction and clinical utility. Here we ask whether a psychosocial intervention, focused improving parenting, strengthening family relationships, and building youth competencies, can reduce inflammation in low-SES, African Americans from the rural South. The trial involved 272 mothers and their 11-y-old children from rural Georgia, half of whose annual household incomes were below the federal poverty line. Families were randomly assigned to a 7-wk psychosocial intervention or to a control condition. When youth reached age 19, peripheral blood was collected to quantify six cytokines that orchestrate inflammation, the dysregulation of which contributes to many of the health problems known to pattern by SES. Youth who participated in the intervention had significantly less inflammation on all six indicators relative to controls (all P values < 0.001; effect sizes in Cohen's d units ranged from -0.69 to -0.91). Mediation analyses suggested that improved parenting was partially responsible for the intervention's benefits. Inflammation was lowest among youth who received more nurturant-involved parenting, and less harsh-inconsistent parenting, as a consequence of the intervention. These findings have theoretical implications for research on resilience to adversity and the early origins of disease. If substantiated, they may also highlight a strategy for practitioners and policymakers to use in ameliorating social and racial health disparities.Proceedings of the National Academy of Sciences 07/2014; · 9.81 Impact Factor
J Psychiatry Neurosci 2007;32(4)
© 2007 Canadian Medical Association
There are profound maternal effects on individual differences in defensive responses in species ranging from plants to insects to birds. In
this paper, we review data from the rat that suggest comparable forms of maternal effects on defensive responses to stress, which are
mediated by the effects of variations in maternal behaviour on gene expression. Under conditions of environmental adversity, maternal
effects enhance the capacity for defensive responses in the offspring. These effects appear to “program” emotional, cognitive and en-
docrine systems toward increased sensitivity to adversity. In environments with an increased level of adversity, such effects can be con-
sidered adaptive, enhancing the capacity for responses that have immediate adaptive value; the cost is an increased risk for multiple
forms of pathology in later life.
Il y a de profonds effets maternels sur les différences individuelles au niveau des réactions défensives chez des espèces allant des
végétaux aux insectes et aux oiseaux. Dans cet article, nous étudions des données sur le rat qui indiquent des formes comparables d’ef-
fets maternels sur les réactions défensives face au stress, dont les facteurs médiateurs sont les effets des variations du comportement
de la mère sur l’expression génique. Dans des conditions d’adversité environnementale, les effets maternels améliorent la capacité de
réaction défensive chez les rejetons. Ces effets semblent «programmer» les systèmes affectif, cognitif et endocrinien pour les rendre
plus sensibles à l’adversité. Dans des environnements où l’adversité est plus importante, on peut considérer que ces effets sont adaptat-
ifs et améliorent la capacité de produire des réactions ayant une valeur adaptative immédiate, ce qui se fait au prix d'un risque accru de
multiples formes de pathologies plus tard dans la vie.
Maternal programming of defensive responses
through sustained effects on gene expression
Josie Diorio, BSc; Michael J. Meaney, PhD
McGill Program for the Study of Behaviour, Genes and Environment, Douglas Hospital Research Centre, Departments of
Psychiatry and Neurology and Neurosurgery, McGill University, Montréal, Que.
The quality of family life influences the development of indi-
vidual differences in vulnerability to illness throughout life.1
Such effects include vulnerability for obesity, metabolic dis-
orders and heart disease as well as affective disorders and
drug abuse.2–4Recent findings from epidemiological studies5–9
as well as from primate models10suggest that developmen-
tally determined vulnerability emerges from the interaction
between genotype and early environmental events, including
early life adversity. Critical questions concern the identity of the
relevant genomic targets, the nature of the gene–environment
interactions and their relation to phenotype.
Stress diathesis models are proposed as explanations for the
effects of early life on health in adulthood and suggest that
adversity in early life alters the development of neural sys-
tems in a manner that predisposes individuals to disease in
adulthood. Chronic illness is thought to emerge as a function
of the altered responses to environmental demand (stressors)
in conjunction with an increased level of prevailing adversity.
These models11–14are supported by research showing that low-
LG prolonged activation of neural and hormonal responses to
stressors can promote illness, and early environmental events
influence the development of stress responses. In humans,
physical or sexual abuse (or both), poor parental bonding and
family dysfunction in early life increase endocrine and auto-
Correspondence to: Dr. Michael J. Meaney, Douglas Hospital Research Centre, 6875 Boul. LaSalle, Montréal QC H4H 1R3;
fax 514 762-3034; firstname.lastname@example.org
J Psychiatry Neurosci 2007;32(4):275-84.
Medical subject headings: corticotrophin-releasing factor; gene expression; hippocampus; postnatal care.
Submitted Sept. 27, 2006; Accepted Oct. 5, 2006.
2005 CCNP Heinz Lehmann Award Paper
nomic responses to stress in adulthood14–19as well as cognitive
processing of potentially threatening stimuli.20There is evi-
dence for comparable developmental effects in primates10,21,22
and rodents,23–27albeit with models that rely on prolonged pe-
riods of separation of parent and offspring. Moreover,
sustained exposure to elevated levels of stress hormones, in-
cluding corticotrophin-releasing factor (CRF); catecholamines,
most notably norepinepherine; and glucocorticoids can ac-
tively promote the development of a diverse range of high-
risk conditions, such as visceral obesity, hypertension and
insulin intolerance, or overt pathology, including diabetes, de-
pression, anxiety disorders, drug addiction and multiple
forms of coronary heart disease.28–32It is not difficult to under-
stand the appeal of stress diathesis models. Because stress
hormones regulate such a wide range of physiological
processes, a very real strength lies in their ability to explain in-
dividual differences in vulnerability for specific diseases and
the high level of comorbidity between brain-based disorders
and cardiovascular/metabolic illness.
The relation between the quality of the early environment
and health in adulthood appears to be mediated by parental
influences on the development of neural systems that under-
lie the expression of behavioural and endocrine responses to
stress.33There is strong evidence for such parental mediation
in developmental psychology. For example, the effects of
poverty on emotional and cognitive development are medi-
ated by variations in parent–offspring interactions: if parental
care factors are statistically controlled, there no longer re-
mains any discernible effect of poverty on child develop-
ment.34,35Such findings are not surprising. Poverty imposes
considerable stress on the family unit, and stressors seriously
compromise the quality of parental care.1,36In humans, high
levels of maternal stress during the transition to parenthood
are associated with depressed or anxious mood states and
less sensitive parent–child interactions that, in turn, influence
the quality of parent–child attachment.37–39Unstable or stress-
ful environments, such as those prevailing under conditions
of poverty, are associated with greater variability in the qual-
ity of infant–mother attachments.40Parents who experience
poverty or other environmental stressors more frequently ex-
perience negative emotions such as irritability, depressed or
anxious moods or both, which can lead to more punitive
forms of parenting.34,41,42Reduced parental education, low in-
come, multiple children, the absence of social support and
single parenthood predict forms of parenting (verbal threats,
pushing or grabbing, emotional neglect, overt physical abuse,
and more controlling attitudes toward the child) that com-
promise cognitive development and result in more anxious
and behaviourally inhibited children. In this review, we con-
sider environmental effects occurring during the early post-
natal period. There is, of course, considerable evidence for
the effects of adversity on the mother and offspring during
the prenatal period43–47; thus, the influence of adversity is best
seen as being continuous, with effects through development
at multiple genomic targets and influences on a wide range
of functional outcomes. Prenatal adversity is also associated
with increased hypothalamic-pituitary-adrenal (HPA) and
autonomic responses to stressors.43–51
Support for the basic elements of stress diathesis models is
compelling. Adversity during perinatal life alters develop-
ment in a manner that seems likely to promote vulnerability,
especially for stress-related diseases. Diathesis describes the
interaction between development, including the potential in-
fluence of genomic variations, and the prevailing level of
stress in predicting health outcomes. Such models could iden-
tify both the origins and the nature of vulnerability.
Maternal care in the rat: behavioural and HPA
responses to stress
CRF systems furnish the critical signal for the activation of
behavioural, emotional, autonomic and endocrine responses
to stressors. There are 2 major CRF pathways regulating the
expression of these stress responses. One is a CRF pathway
from the parvocellular regions of the periventricular nucleus
of the hypothalamus (PVNh) to the hypophysial–portal sys-
tem of the anterior pituitary, which serves as the principal
mechanism for the transduction of a neural signal into a pitu-
itary–adrenal response.52–56In response to stressors, CRF, as
well as cosecretagogues such as arginine vasopressin, are re-
leased from the PVNh neurons into the portal blood supply
of the anterior pituitary, where the pituitary stimulates the
synthesis and release of adrenocorticotropin hormone
(ACTH). Pituitary ACTH, in turn, causes the release of gluco-
corticoids from the adrenal gland. CRF synthesis and release
is subsequently inhibited through a glucocorticoid negative-
feedback system mediated by both mineralocorticoid and
glucocorticoid receptors in a number of brain regions includ-
ing, and perhaps especially, the hippocampus.57,58For exam-
ple, selective disruption of the glucocorticoid receptor gene in
the hippocampus and cortex that is unique to adulthood re-
sults in negative feedback impairments and increased HPA
CRF neurons in the central nucleus of the amygdala project
directly to the locus coeruleus and increase the firing rate of
locus coeruleus neurons, resulting in increased noradrenaline
release in the vast terminal fields of this ascending noradren-
ergic system. Thus, intracerebroventricular (icv) infusion of
CRF increases extracellular noradrenaline levels.60–63The
amygdaloid bed nucleus of the stria terminalis (BNST) CRF
projection to the locus coeruleus63–67is also critical for the ex-
pression of behavioural responses to stress.68–75Hence, the
CRF neurons in the PVNh and the central nucleus of the
amygdala are important mediators of both behavioural and
endocrine responses to stress.
We examine the relation between maternal care and the
development of behavioural and endocrine responses to
stress in the Long-Evans rat, using a model of naturally oc-
curring variations in maternal behaviour over the first 8 days
after birth.76We characterize individual differences in mater-
nal behaviour through direct observation of mother–pup
interactions in normally reared animals. These observations
reveal considerable variation in pup licking (L) and groom-
ing (G)77that includes both anogenital and nonanogenital
licking. For the studies described here, high- and low-LG
mothers are females whose scores on LG measures were
Diorio and MeaneyDiorio and Meaney
Rev Psychiatr Neurosci 2007;32(4)
Maternal programming of defensive responses
J Psychiatry Neurosci 2007;32(4)
above (high) or below (low) 1 standard deviation above the
mean for their cohort. High- and low-LG mothers do not dif-
fer in the amount of contact time with pups; therefore, differ-
ences in the frequency of LG do not occur simply as a func-
tion of time in contact with pups. High- and low-LG mothers
raise a comparable number of pups to weaning, and there are
no differences in the weaning weights of the pups, suggest-
ing an adequate level of maternal care across the groups.
These findings also suggest that we are examining the conse-
quences of variations in maternal care that occur within a
normal range. Indeed, the frequency of pup LG is normally
distributed across large populations of lactating female rats.76
These variations in maternal care are associated with stable
individual differences in behavioural and neuroendocrine re-
sponses to stress in the offspring.78–81As adults, the offspring
of high-LG mothers show reduced plasma ACTH and corti-
costerone responses to acute stress, compared with those of
low-LG mothers. As mentioned above, circulating glucocorti-
coids act at glucocorticoid and mineralocorticoid receptor
sites in corticolimbic structures, such as the hippocampus, to
regulate HPA activity. Indeed, in several rodent models,
downregulation of hippocampal glucocorticoid receptor (GR)
levels is associated with increased HPA activity.58Such gluco-
corticoid feedback effects commonly target CRF synthesis
and release at the level of the PVNh.53The high-LG offspring
showed significantly increased hippocampal glucocorticoid
receptor messenger ribonucleic acid (mRNA) expression, en-
hanced glucocorticoid negative feedback sensitivity and de-
creased hypothalamic CRH mRNA levels. Moreover, Liu and
colleagues79found that the magnitude of the corticosterone
response to acute stress was significantly correlated with the
frequency of both maternal licking and grooming (r = –0.61)
during the first week of life, as was the level of hippocampal
glucocorticoid receptor mRNA and hypothalamic CRH
mRNA expression (all r > 0.70). Although such studies more
commonly focus on adult male offspring, the maternal effect
on HPA responses to stress is also apparent in the adult fe-
An earlier study82reveals that the selective downregulation
of GR levels in the hippocampus is sufficient to eliminate dif-
ferences in HPA responses to acute stress derived from varia-
tions in early experience. Indeed, the results of recent studies
suggest a direct relation between the effects of maternal care
on hippocampal GR expression and those on HPA responses
to acute stress. Direct infusion of RU38486, a GR antagonist,
into the hippocampus eliminates the differences in corticos-
terone responses to acute stress in the offspring of high- and
Apparently, the maternal effect on HPA function is not
limited to stress-induced activity.83The HPA axis shows a
well-defined circadian rhythm, with the peak in activity oc-
curring in the hours before the most active phase of the
light–dark cycle. The adult offspring of low-, compared with
high-, LG mothers show increased levels of both ACTH and
corticosterone at the time of the normal circadian peak in ac-
tivity (the latter portion of the light phase and early portion
of the dark phase). HPA activity over the diurnal period is
regulated by both mineralocorticoid and glucocorticoid re-
ceptors, depending on the phase of the cycle.57The adult off-
spring of high- and low-LG mothers differ in hippocampal
expression of glucocorticoid but not mineralocorticoid recep-
tor expression. Interestingly, influence of the GR activity is
most apparent during the diurnal peak in basal HPA activity,
which corresponds to the time when differences in basal
HPA activity as a function of maternal care are apparent.
Mineralcorticoid receptor influence prevails during the nadir
in HPA activity, a time when there are no differences in basal
Prolonged periods of maternal separation in the neonatal
rat result in sustained alterations in the CRF system, includ-
ing increased CRF expression in the PVNh and the amyg-
dala, and enhanced behavioural responses to stress.24,84The
CRF system of the BNST/amygdala–locus coeruleus is also
altered as a function of normal variations in maternal care in
the rat. The offspring of the high-LG mothers showed de-
creased CRF receptor levels in the locus coeruleus and in-
creased gamma amino butyric acid (GABAA)/benzodiazepine
(BZ) receptor levels in the basolateral and central nuclei of
the amygdala, and in the locus coeruleus78,85and decreased
CRF mRNA expression in the central nucleus of the amyg-
dala. BZ agonists suppress CRF expression in the amygdala,86
and the GABA system is an important modulator of activity
within the amygdala in tests of fear conditioning.87Pre-
dictably, stress-induced increases in PVNh levels of nora-
drenaline that are normally stimulated by CRF were signifi-
cantly higher in the low-LG offspring.88 The offspring of the
high- and low-LG mothers also differ in behavioural
responses to novelty.85,89As adults, the offspring of the high-
LG mothers showed decreased startle responses, increased
open-field exploration and shorter latencies to eat food pro-
vided in a novel environment. The offspring of low-LG
mothers also show greater burying in the defensive burying
paradigm,90which involves an active response to a threat.
Maternal care during the first week of life is associated
with stable individual differences in GABAAreceptor sub-
unit expression in brain regions that regulate stress reactivity.
The adult offspring of high-LG mothers show significantly
higher levels of GABAA/BZ receptor binding in the basolat-
eral and central nuclei of the amygdala and the locus
coeruleus. These findings provide a mechanism for increased
GABAergic inhibition of amygdala–locus coeruleus activity.
More recent studies85illustrate the molecular mechanism for
these differences in receptor binding and suggest that varia-
tions in maternal care might actually permanently alter the
subunit composition of the GABAAreceptor complex in the
offspring. The offspring of high-LG mothers show increased
levels of mRNAs for the γ1 and γ2 subunits that contribute to
the formation of a functional BZ binding site. Such differ-
ences are not unique to the γ subunits. Levels of mRNA
for the α1 subunit of the GABAA/BZ receptor complex are
significantly higher in the amygdala and locus coeruleus of
offspring of high, compared with low, LG mothers. The α1
subunit appears to confer higher affinity for GABA, provid-
ing the most efficient form of the GABAAreceptor complex,
through increased receptor affinity for GABA. A direct effect
of maternal care is revealed in the results of cross-fostering
studies85showing that the expression of the γ2 or α1 subunits
in the amygdala or the locus coeruleus of animals born to
low-LG mothers but reared by high-LG dams is comparable
with that of the normal offspring of high-LG mothers; the
converse is also true.
Adult offspring of the low-LG mothers actually show in-
creased expression of the mRNAs for the α3 and α4 subunits
in the amygdala and locus coeruleus. Interestingly,
GABAA/BZ receptors composed of the α3 and α4 subunits
show a reduced affinity for GABA, compared with those
bearing the α1 subunit. Moreover, the α4 subunit does not
contribute to the formation of a BZ receptor site. These differ-
ences in subunit expression are tissue specific; no such differ-
ences are apparent in the hippocampus, hypothalamus or
cortex. Thus, differences in GABAA/BZ receptor binding are
not simply caused by a deficit in subunit expression in the
offspring of the low-LG mothers, but are apparently an active
attempt to maintain a specific GABAA/BZ receptor profile in
selected brain regions.
The critical question concerns the relation between these
profiles and fear-related behaviour. Studies with animals
bearing mutations of various GABAA/BZ receptor subunits
suggest that mutations of the γ2 subunit do indeed lead to de-
creased BZ receptor binding and increased fearfulness. Mice
that are heterozygous for the γ2 null mutation (γ 2+/− mice)
are viable and fertile (the homozygous null mutation is
lethal) and display enhanced behavioural inhibition toward
aversive stimuli and heightened responsiveness in fear con-
ditioning.90,91However, among the alpha subunits, it is α2 and
not α1 that has been more directly linked to the anxiolytic ef-
fects of BZ treatment; the α1 subunit is linked to the hypnotic
effects (see Rudolph and Mohler92for a review). Thus, the
precise cause–effect relation between the effects of maternal
care on GABAA/BZ receptor subunits and fear remains to be
clearly defined. Here, and throughout this area of research,
an understanding of the importance of the effects of early en-
vironment on gene expression requires a more precise defini-
tion at the level of function. However, a recent study92reveal-
ing differences in BZ sensitivity between the adult offspring
of high- and low-LG mothers suggests that maternal effects
on the expression of GABAA/BZ receptor subunits are of
functional importance. In this study, there was a significantly
greater anxiolytic effect of BZ treatment in the adult offspring
of high, compared with low, LG mothers.
Individual differences in behavioural and neuroendocrine
responses to stress in the rat are associated with naturally oc-
curring variations in maternal care. Such effects might serve
as a possible mechanism by which selected traits are trans-
mitted from one generation to another. Indeed, low-LG
mothers are more fearful and show increased HPA responses
to stress compared with high-LG dams.89Individual differ-
ences in stress reactivity are apparently transmitted across
generations: fearful mothers beget more stress-reactive off-
spring. The obvious question is whether the transmission of
these traits occurs only as a function of genomic-based inheri-
tance. If this is the case, then the differences in maternal be-
haviour may simply be an epiphenomenon and not causally
related to the development of individual differences in stress
responses. The issue is not one of inheritance, but mode of
The results of cross-fostering studies provide evidence for
a nongenomic transmission of individual differences in stress
reactivity.89The critical groups of interest are the biological
offspring of low-LG mothers fostered onto high-LG dams
and vice versa. The results are consistent with the idea that
variations in maternal care are causally related to individual
differences in the behaviour of the offspring. The biological
offspring of low-LG dams reared by high-LG mothers are
significantly less fearful under conditions of novelty than are
the offspring reared by low-LG mothers, including the bio-
logical offspring of high-LG mothers.89Subsequent studies re-
veal similar findings for hippocampal glucocorticoid receptor
expression and for the differences in both the α1 and γ2
GABAAreceptor subunit expression in the amygdala.85These
findings suggest that individual differences in patterns of
gene expression and stress responses can be directly linked to
maternal care in the first week of life.
Maternal care and hippocampal development
Maternal care influences the activity of endocrine systems
that determine metabolic states and growth in neonates. Tac-
tile stimulation from the mother stimulates the release of
growth hormone. Kuhn and colleagues93showed that pro-
longed separation from the dam resulted in a dramatic de-
crease in plasma growth hormone levels. Such effects were
reversed with experimental stroking with a brush, mimicking
the tactile stimulate derived from maternal LG. Suchecki and
colleagues94found a comparable effect on pup HPA activity.
Separation increases glucocorticoid levels in the pup, and
these effects attenuated with stroking and were completely
eliminated when stroking was combined with feeding. Un-
der conditions of regular maternal contact, the nutritional
and thermoregulatory demands of the pup are met by the
mother. In her absence, the pup increases HPA activity, acti-
vating a catabolic state that serves to mobilize energy re-
serves. Resources that would otherwise be directed toward
growth, under the direction of growth hormone, are now re-
quired for survival. A comparable situation occurs in the
brain. Maternal deprivation decreases the expression of
brain-derived neurotrophic factor (BDNF) expression in
neonates.25The results of these studies suggest that tactile
stimulation derived from maternal LG can promote an en-
docrine or paracrine state that fosters growth and develop-
ment. Indeed, Huot and colleagues26reported decreased
mossy fibre density in the hippocampus of adult animals as a
function of repeated and prolonged maternal separation in
infancy. Similarly, Mirescu and others95reported that mater-
nal separation in early life alters hippocampal neurogenesis.
A decrease in neuron proliferation characteristic of the adult
hippocampus is significantly reduced in adult animals as a
function of maternal separation over the first weeks of life.
Studies of maternal separation reveal a potential influence
of variations in mother–offspring interactions on neural de-
velopment. To examine the effects of natural variations in
maternal LG, we examined hippocampal gene expression us-
Diorio and Meaney
Rev Psychiatr Neurosci 2007;32(4)
Maternal programming of defensive responses
J Psychiatry Neurosci 2007;32(4)
ing complementary DNA (cDNA) rays.96The analyses of the
array data revealed major classes of maternal effects on hip-
pocampal gene expression in postnatal day 6 offspring, in-
cluding 1) genes related to cellular metabolic activity (glucose
transporter, cFOS, cytochrome oxidase and low-density
lipoprotein receptor; 2) genes related to glutamate receptor
function, including effects on the glycine receptor and those
mentioned for the N-methyl-D-aspartic acid (NMDA) receptor
sub-units; and 3) genes encoding for growth factors,
including BDNF, basic fibroblast growth factor (bFGF) and
β-NGF. In each case, expression was > 2-fold higher in hip-
pocampal samples from offspring of high, compared with low,
LG mothers. A subsequent cDNA array analysis comparing ex-
pression profiles in the hippocampus from the adult offspring of
high- and low-LG mothers97found that constuitive expression of
genes associated with synaptic plasticity, such as the subunits of
the various glutamate receptors and those involved in the mito-
gen-activated protein kinase (MAPK) pathways, were elevated
in the offspring of high-LG mothers (i.e., > 1.5-fold increases).
Essentially, maternal care increases genes that provide
metabolic support, mediates experience-dependent neuronal
activation and supports the growth and survival of synapses.
Not surprisingly, variations in maternal care are associated
with individual differences in the synaptic development of
the hippocampus, including neural systems that mediate
learning and memory. As adults, the offspring of high-LG
mothers show enhanced spatial learning or memory or both
in the Morris water maze and in object recognition.98–100Per-
formance in both tasks is dependent on hippocampal func-
tion,101–103and maternal care alters the synaptic development
of the hippocampus. At either day 18 or day 90, there are sig-
nificantly increased levels neural cell adhesion molecule (N-
CAM) or synaptophysin-like immunoreactivity on Western
blots in hippocampal samples from the offspring of high,
compared with low, LG mothers, suggesting increased
synapse formation or survival. Subsequent studies provided
evidence for a maternal effect on neuron survival in the hip-
pocampus.104Bromodeoxyuridine (BrdU) injections made on
day 7 of life revealed group differences in neuronal prolifera-
tion. However, at 21 and 90 days of life, there were signifi-
cantly more BrdU-labelled cells in the offspring of high-,
compared with low-, LG mothers.
Recently, Champagne and colleagues105reported on the re-
sults of a golgi-staining study of the morphology of hip-
pocampal neurons in adult animals. Although the branch
length of individual dendrites was comparable, the number
of dendritic branches was significantly greater in the adult
offspring of high-LG mothers. The enhanced dendritic ar-
borization suggests an increased capacity for synaptic plastic-
ity in the adult offspring of high-LG mothers. Long-term
potentiation is an electrophysiological model of synaptic
plasticity and was assessed for 60 minutes in response to
tetanic stimulation in the Schaffer collateral pathway. The re-
sults show a significantly lower percentage of long-term
potentiation (LTP) in low-LG offspring relative to high-LG
offspring. These findings are in line with previous findings of
defective synaptic plasticity in low-LG offspring99and extend
this phenomenon to another subfield of the hippocampus.
The influence of the hippocampus in spatial learning is
thought to involve, at least in part, cholinergic innervation
emerging from the medial septum.106In the adult offspring of
the high-LG mothers, there was increased hippocampal
choline acetyltransferase (ChAT) activity and acetyl-
cholinesterase staining, as well as increased hippocampal
basal and K+–stimulated acetylcholine release.98These find-
ings suggest increased cholinergic synaptic number in the
hippocampus of the offspring of high-LG mothers. Hip-
pocampal BDNF mRNA levels are elevated in the high-LG
offspring on day 8 of life.98BDNF is commonly associated
with the survival of cholinergic synapses in the rat fore-
brain107–109; for example, there is decreased hippocampal
ChAT activity in BDNF knockdown mice.
The expression of BDNF is regulated by NMDA receptor
activation, and tactile stimulation increases NMDA receptor
expression in the barrel cells of mice.110There is increased
mRNA expression of both the NR2A and NR2B subunits of
the NMDA receptor in the offspring of high, compared with
low, LG mothers at day 8 of life,98and these effects on gene
expression are associated with increased hippocampal
NMDA receptor binding.
Naturally occurring variations in maternal LG and arched-
back nursing are associated with the development of cholin-
ergic innervation to the hippocampus, as well as differences
in the expression of NMDA receptor subunit mRNAs. There
is also increased hippocampal NR1 mRNA expression in the
adult offspring of high-LG mothers. These findings provide a
mechanism for the differences observed in spatial learning
and memory in adult animals. In the adult rat, spatial learn-
ing and memory is dependent on hippocampal integrity; le-
sions of the hippocampus result in profound spatial learning
impairments. Moreover, spatial learning is regulated by both
cholinergic or NMDA receptor activation or NR1 subunit
knockout.111–113These findings suggest that maternal care
increases hippocampal NMDA receptor levels, resulting in
elevated BDNF expression and increased hippocampal
synaptogenesis and, thus, enhanced spatial learning in adult-
hood. These results are also consistent with the idea that
maternal behaviour actively stimulates hippocampal synap-
togenesis in offspring through systems known to mediate
experience-dependent neural development.
An NR2B-specific receptor antagonist, ifenprodil, infused
directly into the CA1 region of the hippocampus completely
eliminates the group differences in the Morris water maze.100
The NMDA receptor complex, and the NR2B subunit in par-
ticular, is interesting because of its importance in synaptic
plasticity and hippocampal-dependent learning and mem-
ory,102and ifenprodil blocks the effects of postweaning envi-
ronmental enrichment on spatial learning and memory.
Transgenic mice overexpressing the NR2B subunit exhibit
enhanced hippocampal LTP and improved learning and
memory compared with wild-type controls. After exposure
to environmental enrichment, wild-type mice show an over-
all improvement in contextual and cued conditioning, fear
extinction and novel object recognition learning, with little or
no effect of enrichment on the performance of the NR2B
transgenic mice.103One explanation for these findings is that,
in animals where there is an overexpression of the NR2B sub-
unit, environment provides no further “gain of function.”
The adult offspring of low-LG mothers reared under condi-
tions of environmental enrichment show increased hip-
pocampal NR2B expression and synaptic density as well as
performance in the Morris water maze test or object-
recognition test that is comparable to that of the adult off-
spring of high-LG mothers. Predictably, the adult offspring
of high-LG mothers, which normally exhibit increased NR2B
expression, are unaffected by environmental enrichment.
These findings suggest that maternal care in the rat directly
influences hippocampal development by effecting the expres-
sion of genes involved in both neuron survival and synaptic
development. The group differences in performance in the
Morris water maze are consistent with a maternal effect on
cognitive performance in adulthood. However, the Morris
water maze is a model of escape learning that, by definition,
involves an aversive component, which provides the motiva-
tion for escape. The water maze is an interesting task for this
discussion because it provides an opportunity to examine
cognitive performance under stressful conditions. In se-
quence, the animal must contend with removal from the
home cage; transport to the testing area; placement into the
pool of water, murky at that; and the uncertainty at each
stage of testing. Initially, most animals behave in a manner
similar to that of an open-field test, circling the perimeter and
remaining close to the walls (i.e., thigmotaxis). There is little
opportunity for learning so long as the animal refuses to en-
ter the centre area of the swim maze where the platform is
located. The tendency to remain close to the walls and reluc-
tance to enter the centre area is commonly associated with a
fear response to the environment. Not surprisingly, thigmo-
taxis is significantly more prevalent in the offspring of low,
compared with high, LG mothers. The difference in thigmo-
taxis is reversed with postweaning environmental enrich-
ment.104Moreover, Smythe and colleagues114,115show that
blockade of hippocampal cholinergic input results in in-
creased fear behaviour under conditions of novelty. The ef-
fect is blocked with acute benzodiazepine administration.
The offspring of low-LG mothers show decreased hippocam-
pal cholinergic innervation, which might explain the in-
creased thigmotaxis and thus the impaired performance in
the Morris water maze. These findings underscore the com-
plex relations between emotional and cognitive systems in
determining the behaviour of animals in stressful conditions.
Maternal effects on gene expression
These studies reflect the potential consequences for neurode-
velopment of maternal regulation of gene expression in the
pup. An obvious question here concerns how early experi-
ence might serve to program gene expression. Variations in
maternal care over the first week of life alter hippocampal
glucocorticoid receptor expression and HPA responses to
stress. These effects endure well beyond weaning and sug-
gest a stable influence of maternal care on the development
of individual differences in stress responses. The critical
question concerns the mechanisms whereby these maternal
effects, or other forms of environmental programming, are
sustained over the lifespan of the animal. The effect of mater-
nal care on glucocorticoid receptor expression in the hip-
pocampus appears to involve an epigenetic modification of
the DNA and, specifically, at the exon 17promoter of the glu-
cocorticoid receptor. The neural-specific exon 17promoter is
significantly more active in the hippocampus of adult off-
spring of high, compared with low, LG mothers.116,117The
exon 17promoter contains a consensus-binding sequence for
nerve growth factor-induced protein-A (NGFI-A) and NGFI-
A can activate transcription through the 17promoter.
The NGFI-A consensus sequence contains 2 CpG dinu-
cleotides, and maternal care is associated with an alteration
in the methylation of the 5′ CpG site of the NGFI-A site.80The
5′ cytosine is heavily methylated in the offspring of low-LG
mothers and rarely in those of high-LG dams. This pattern is
reversed with cross-fostering, suggesting a direct effect of
maternal care. Methylation of the 5′ CpG significantly de-
creases NGFI-A binding to the exon 17promoter in gel shift
assays, and the results of chromatin immunoprecipitation as-
says reveal greater in vivo NGFI-A binding to the exon 17
promoter sequence in the hippocampus of high, compared
with low, LG mothers.80,117The findings suggest that maternal
care alters the methylation status of the NGFI-A consensus
sequence and, thus, the NGFI-A binding to the exon 17
DNA methylation inhibits transcription factor binding
through alterations in chromatin structure, which gates the ac-
cessibility of promoters to transcription factors.118,119Histone
acetylation at lysine (K)-9 residue of H3 and H4 histones is a
well-established marker of active chromatin, transcription fac-
tor binding and gene expression. Acetylation of the histone
tails neutralizes the positively charged histones, which dis-
rupts histone binding to negatively charged DNA, opens up
the histone–DNA complex and thus promotes transcription
factor binding. Weaver and others80,117found that maternal ef-
fect on DNA methylation is associated with increased histone
acetylation at the lysine 9 residue of histone 3 (H3) associated
with the exon 17glucocorticoid receptor promoter and in-
creased interaction of NGFI-A with the promoter sequence.
Cytosine methylation can stably silence gene expression
through the binding of methylated DNA binding proteins,
which bind with a complex that includes histone deacetylase
(HDAC). HDAC, in turn, prevents histone acetylation, stabi-
lizing the tight histone–DNA relation and preventing tran-
scription factor binding. Thus, in the adult offspring of low-
LG mothers, central infusion of trichostatin-A, a potent
HDAC inhibitor, permits greater H3 acetylation and increased
NGFI-A binding to the exon 17promoter. Predictably, the in-
creased NGFI-A binding to the exon 17promoter results in
greater glucocorticoid receptor expression and, most impor-
tantly, eliminates the group difference in HPA responses to
These findings suggest that sustained effects of maternal
care on gene expression are caused by alterations of DNA
methylation and chromatin structure at relevant promoter
sites. A simple developmental time course study80reveals
that the difference in cytosine methylation of the NGFI-A
Diorio and Meaney
Rev Psychiatr Neurosci 2007;32(4)
Maternal programming of defensive responses
J Psychiatry Neurosci 2007;32(4)
consensus sequence actually involves a process of demethy-
lation.118,119On the day after birth, methylation of the NGFI-A
consensus sequence is comparable in the offspring of high-
and low-LG mothers. Between postnatal days 1 and 6, the
difference at the 5′, but not the 3′ cytosine becomes apparent,
suggesting an active demethylation process.118,120It is over the
same period that the high- and low-LG mothers differ in ma-
The dissolution of epigenetic marks, such as cytosine methy-
lation, through processes such as demethylation reflects a
costly energy investment. Demethylation requires specific en-
zymatic machinery and breaking carbon-carbon bonds. The
end point appears to be that of sustained changes in gene ex-
pression that reflect variations in maternal care. So the obvi-
ous question is — why bother? We think that maternal effects
represent a developmental strategy whereby the defensive
responses of the offspring are refined in response to the pre-
vailing level of environmental demand. In mammals, the rel-
evant signal that predicts the level of environmental demand
is the behaviour of the parent. Indeed, we use the term “de-
velopmental strategy” here in a descriptive sense, since the
strategy may be seen as emerging from a strategy on the part
of the offspring (i.e., use the signals of the parent to forecast
environmental demand121) or the parent (i.e., signal the off-
spring in a manner that influences the development of defen-
sive responses). These need not be considered as mutually
exclusive options. The crucial assumption is that the result
confers some advantage onto the offspring with respect to
survival and reproduction.
We propose that adversity in mammals alters parent–
offspring interactions in a manner that is designed to increased
endocrine, cognitive and emotional responses to stress. In the
rat, gestational stress is associated with decreased maternal
LG122,123and increased stress reactivity in the offspring.122In the
macaque, stress imposed on lactating females decreases the
quality of mother–infant interactions124and increases endocrine
and behavioural responses to stress.125,126In the rat, decreased
maternal LG is associated with increased fearfulness, en-
hanced HPA responses to stress and impaired performance on
attentional tasks and tests of declarative learning or memory
under stressful conditions. These effects appear to be mediated
by maternal effects on gene expression in relevant brain re-
gions. We suggest that such effects produce an increased state
of preparedness of defensive systems. This could be of particu-
lar importance in the time after weaning and independence
from the parent when mortality rates are extremely high in
most mammals. Considering the adaptive value of behav-
ioural and endocrine responses to stress, such a bias may be
especially important for an individual functioning under con-
ditions of increased adversity. If this is the case, then we are
better to consider functional differences in developmental out-
comes under conditions of adversity as reflecting alternative
phenotypes rather than impairments in development.
1. Repetti RL, Taylor SE, Seeman TE. Risky families: family social en-
vironments and the mental and physical health of offspring. Psy-
chol Bull 2002;128:330-66.
2. Felitti VJ, Anda RF, Nordenberg D, et al. Relationship of childhood
abuse and household dysfunction to many of the leading causes of
death in adults. Am J Prev Med 1998;14:245-58.
3. Lissau I, Sorensen TIA. Parental neglect during childhood and in-
creased risk of obesity in young adulthood. Lancet 1994;343:324-7.
4. McCauley J, Kern DE, Kolodner K, et al. Clinical characteristics of
women with a history of childhood abuse: unhealed wounds.
5. Brookes K-J, Mill J, Guindalini C, et al. A common haplotype of
the dopamine transporter gene associated with attentiondeficit
/hyperactivity disorder and interacting with maternal use of alco-
hol during pregnancy. Arch Gen Psychiatry 2006;63:74-81.
6. Caspi A, Sugden K, Moffitt TE, et al. Influence of life stress on
depression: moderation by a polymorphism in the 5-HTT gene.
7. Caspi A, Moffitt TE, Cannon M, et al. Moderation of the effect of
adolescentonset cannabis use on adult psychosis by a functional
polymorphism in the COMT gene: longitudinal evidence of a gene
X environment interaction. Biol Psychiatry 2005;57:1117-27.
8. Thapar A, Langley K, Fowler T, et al. Catechol-O-methyltransferase
gene variant and birth weight predict early-onset antisocial behavior
in children with attention-deficit/hyperactivity disorder. Arch Gen
9. Manuck SB, Bleil ME, Petersen KL, et al. The socio-economic status
of communities predicts variation in brain serotonergic responsivity.
Psychol Med 2005;35:519-28.
10. Bennett AJ, Lesch KP, Heils A, et al. Early experience and sero-
tonin transporter gene variation interact to influence primate CNS
function. Mol Psychiatry 2002;7:118-22.
11. Seckl JR, Meaney MJ. Early life events and later development of is-
chaemic heart disease. Lancet 1993;342:1236.
12. Chrousos GP, Gold PW. The concepts of stress and stress system
disorders. Overview of physical and behavioral homeostasis.
13. Higley JD, Hasert MF, Suomi SJ, et al. Nonhuman primate model
of alcohol abuse: effects of early experience, personality, and stress
on alcohol consumption. Proc Natl Acad Sci U S A 1991;88:7261-
14. McEwen BS, Steller E. Stress and the individual. Mechanisms lead-
ing to disease. Arch Intern Med 1993;153:2093-101.
15. De Bellis MD, Chrousos GP, Dorn LD, et al. Hypothalamic-pituitary-
adrenal dysregulation in sexually abused girls. J Clin Endocrinol
16. Essex MJ, Klein MH, Cho E, et al. Maternal stress beginning in in-
fancy may sensitize children to later stress exposure: effects on
cortisol and behavior. Biol Psychiatry 2002;52:776-84.
17. Heim C, Newport DJ, Heit S, et al. Pituitary-adrenal and auto-
nomic responses to stress in women after sexual and physical
abuse in childhood. JAMA 2000;284:592-7.
18. Luecken LJ, Lemery KS. Early caregiving and physiological stress
responses. Clin Psychol Rev 2004;24:171-91.
19. Pruessner JC, Champagne FA, Meaney MJ, et al. Dopamine release
in response to a psychological stress in humans and its relation-
ship to early life maternal care: a positron emission tomography
study using [11C]raclopride. J Neurosci 2004;24:2825-31.
Competing interests: None declared.
Contributors: Dr. Meaney designed the study and wrote the article,
which Ms. Diorio critically reviewed. Ms. Diorio acquired the data,
which was analyzed by Dr. Meaney. Both authors gave final ap-
proval for the article to be published.
Diorio and Meaney
Rev Psychiatr Neurosci 2007;32(4)
20. Pollak SD, Pawan S. Effects of early experience on children’s recog-
nition of facial displays of emotion. Dev Psychol 2002;38:784-91.
21. Higley JD, Hasert MF, Suomi SJ, et al. Nonhuman primate model
of alcohol abuse: effects of early experience, personality and stress
on alcohol consumption. Proc Natl Acad Sci U S A 1991;88:7261-5.
22. Suomi SJ. Early determinants of behaviour: evidence from primate
studies. Br Med Bull 1997;53:170-84.
23. Plotsky PM, Meaney MJ. Early, postnatal experience alters hypo-
thalamic corticotropin-releasing factor (CRF) mRNA, median emi-
nence CRF content and stress-induced release in adult rats. Brain
Res Mol Brain Res 1993;18:195-200.
24. Plotsky PM, Thrivikraman KV, Nemeroff CB, et al. Long-term con-
sequences of neonatal rearing on central corticotropin-releasing
factor systems in adult male rat offspring. Neuropsychopharmacol-
25. Roceri M, Hendriks W, Racagni G, et al. Early maternal depriva-
tion reduces the expression of BDNF and NMDA receptor sub-
units in rat hippocampus. Mol Psychiatry 2002;7:609-16.
26. Huot RL, Plotsky PM, Lenox RH, et al. Neonatal maternal separa-
tion reduces hippocampal mossy fiber density in adult Long Evans
rats. Brain Res 2002;950:52-63.
27. Newport DJ, Stowe ZN, Nemeroff CB. Parental depression: animal
models of an adverse life event. Am J Psychiatry 2002;159:1265-83.
28. Arborelius L, Owens MJ, Plotsky PM, et al. The role of corticotropin-
releasing factor in depression and anxiety disorders. J Endocrinol
29. Chrousos GP, Gold PW. The concepts of stress and stress system
disorders. JAMA 1992;267:1244-52.
30. Dallman MF, Akana SF, Strack AM, et al. The neural network that
regulates energy balance is responsive to glucocorticoids and in-
sulin and also regulates HPA axis responsivity at a site proximal
to CRF neurons. Ann N Y Acad Sci 1995;771:730-42.
31. Dallman MF, la Fleur SE, Pecoraro NC, et al. Mini review: gluco-
corticoids–food intake, abdominal obesity, and wealthy nations in
2004. Endocrinology 2004;145:2633-8.
32. McEwen BS. Protective and damaging effects of stress mediators.
N Engl J Med 1998;338:171-9.
33. Meaney MJ. Maternal care, gene expression, and the transmission
of individual differences in stress reactivity across generations.
Annu Rev Neurosci 2001;24:1161-92.
34. Conger RD, Ge X, Elder G, et al. Economic stress, coercive family
process and developmental problems of adolescents. Child Dev
35. McLoyd VC. Socioeconomic disadvantage and child development.
Am Psychol 1998;53:185-204.
36. Hart B, Risley TR. Meaningful differences in the everyday experience of
young American children. Baltimore: Paul H. Brookes Publishing;
37. Fleming AS. Factors influencing maternal responsiveness in hu-
mans: usefulness of an animal model. Psychoneuroendocrinology
38. Fleming AS. The neurobiology of mother-infant interactions: expe-
rience and central nervous system plasticity across development
and generations. Neurosci Biobehav Rev 1999;23:673-85.
39. Goldstein LH, Diener ML, Mangelsdorf SC. Maternal characteris-
tics and social support across the transition to motherhood: associ-
ations with maternal behavior. J Fam Psychol 1996;10:60-71.
40. Vaughn B, Egeland B, Sroufe LA, et al. Individual differences in
infant-mother attachment at twelve and eighteen months: stability
and change in families under stress. Child Dev 1979;50:971-5.
41. Belsky J. Attachment, mating, and parenting: an evolutionary in-
terpretation. Hum Nat 1997;8:361-81.
42. Grolnick WS, Gurland ST, DeCourcey W, et al. Antecedents and
consequences of mothers’ autonomy support: an experimental in-
vestigation. Dev Psychol 2002;38:143-55.
43. Glover V, O’Connor TG. Effects of antenatal stress and anxiety:
Implications for development and psychiatry. Br J Psychiatry 2002;
44. Matthews SG. Early programming of the hypothalamo-pituitary-
adrenal axis. Trends Endocrinol Metab 2002;13:373-8.
45. McCormick CM, Smythe JW, Sharma S, et al. Sex-specific effects of
prenatal stress on hyppthalamic-pituitary-adrenal responses to
stress and brain glucocorticoid receptor density in adult rats. Brain
Res Dev Brain Res 1995;84:55-61.
46. Seckl JR. Glucocorticoid programming of the fetus; adult phenotypes
and molecular mechanisms. Mol Cell Endocrinol 2001;185:61-71.
47. Weinstock M. Does prenatal stress impair coping and regulation of
hypothalamic-pituitary-adrenal axis. Neurosci Biobehav Rev 1997;21:
48. Amiel-Tison C, Cabrol D, Denver R, et al. Fetal adaptation to
stress: part II. Evolutionary aspects; stress-induced hippocampal
damage; long-term effects on behavior; consequences on adult
health. Early Hum Dev 2004;78:81-94.
49. Chapillon P, Patin V, Roy V, et al. Effects of pre- and postnatal
stimulation on developmental, emotional, and cognitive aspects in
rodents: a review. Dev Psychobiol 2002;41:373-87.
50. Maccari S, Darnaudery M, Morley-Fletcher S, et al. Prenatal stress
and long-term consequences: implications of glucocorticoid hor-
mones. Neurosci Biobehav Rev 2003;27:119-27.
51. Wadhwa PD, Sandman CA, Garite TJ. The neurobiology of stress
in human pregnancy: implications for prematurity and develop-
ment of the fetal central nervous system. Prog Brain Res 2001;133:
52. Antoni FA. Vasopressinergic control of pituitary adrenocorticotropin
secretion comes of age. Front Neuroendocrinol 1993;14:76-122.
53. Herman JP, Figueiredo H, Mueller NK, et al. Central mechanisms of
stress integration: hierarchical circuitry controlling hypothalamic-
pituitary-adrenocortical responsiveness. Front Neuroendocrinol
54. Rivier CL, Plotsky PM. Mediation by corticotropin-releasing factor
of adenohypophysial hormone secretion. Annu Rev Physiol 1986;48:
55. Plotsky PM. Hypophysiotropic regulation of stress-induced ACTH
secretion. Adv Exp Med Biol 1988;245:65-81.
56. Whitnall MH. Regulation of the hypothalamic corticotropin-releas-
ing hormone neurosecretory system. Prog Neurobiol 1993;40:573-629.
57. De Kloet ER, Vregdenhil E, Oitzl MS, et al. Brain corticosteroid re-
ceptor balance in health and disease. Endocr Rev 1998;19:269-301.
58. Sapolsky RM, Romero LM, Munck AU. How do glucocorticoids in-
fluence stress responses? Integrating permissive, suppressive,stim-
ulatory, and preparative actions. Endocr Rev 2000;21:55-89.
59. Boyle MP, Brewer JA, Funatsu M, et al. Acquired deficit of fore-
brain glucocorticoid receptor produces depression-like changes in
adrenal axis regulation and behavior. Proc Natl Acad Sci U S A
60. Emoto H, Yokoo H, Yoshida M, et al. Corticotropin-releasing
factor enhances noradrenaline release in the rat hypothalamus
assessed by intracerebral microdialysis. Brain Res 1993;601:286-8.
61. Lavicky J, Dunn AJ. Corticotropin-releasing factor stimulates cate-
cholamine release in hypothalamus and prefrontal cortex in freely
moving rats as assessed by microdialysis. J Neurochem 1993;60:602-12.
62. Page ME, Valentino RJ. Locus coeruleus activation by physiologi-
cal challenges. Brain Res Bull 1994;35:557-60.
63. Valentino RJ, Curtis AL, Page ME, et al. Activation of the locus
coeruleus brain noradrenergic system during stress: circuitry, con-
sequences, and regulation. Adv Pharmacol 1998;42:781-4.
64. Gray TS, Bingaman EW. The amygdala: corticotropin-releasing
factor, steroids, and stress. Crit Rev Neurobiol 1996;10:155-68.
65. Koegler-Muly SM, Owens MJ, Ervin GN, et al. Potential corti-
cotropin-releasing factor pathways in the rat brain as determined
Maternal programming of defensive responses
J Psychiatry Neurosci 2007;32(4)
by bilateral electrolytic lesions of the central amygdaloid nucleus
and paraventricular nucleus of the hypothalamus. J Neuroen-
66. Moga MM, Gray TS. Evidence for corticotropin-releasing factor,
neurotensin, and somatostatin in the neural pathway from the cen-
tral nucleus of the amygdala to the parabrachial nucleus. J Comp
67. Van Bockstaele EJ, Colago EE, Valentino RJ. Corticotropin-releasing
factor-containing axon terminals synapse onto catecholamine den-
drites and may presynaptically modulate other afferents in the
rostral pole of the nucleus locus coeruleus in the rat brain. J Comp
68. Bakshi VP, Shelton SE, Kalin NH. Neurobiological correlates of de-
fensive behaviors. Prog Brain Res 2000;122:105-15.
69. Butler PD, Weiss JM, Stout JC, et al. Corticotropin-releasing factor
produces fear-enhancing and behavioural activating effects fol-
lowing infusion into the locus coeruleus. J Neurosci 1990;10:176-83.
70. Davis M, Whalen PJ. The amygdala: vigilance and emotion. Mol
71. Koob GF, Heinrichs SC, Menzaghi F, et al. Corticotropin-releasing
factor, stress and behavior. Semin Neurosci 1994;6:221-9.
72. Liang KC, Melia KR., Miserendino MJ, et al. Corticotropin releas-
ing factor: long-lasting facilitation of the acoustic startle reflex.
J Neurosci 1992;12:2303-12.
73. Schulkin J, McEwen BS, Gold PW. Allostasis, the amygdala and
anticipatory angst. Neurosci Biobehav Rev 1994;18:385-96.
74. Stenzel-Poore MP, Heinrichs SC, Rivest S, et al. Overproduction of
corticotropin-releasing factor in transgenic mice: a genetic model
of anxiogenic behavior. J Neurosci 1994;14:2579-84.
75. Swiergiel AH, Takahashi LK, Kahn NH. Attenuation of stress-
induced by antagonism of corticotropin-releasing factor receptors
in the central amygdala in the rat. Brain Res 1993;623:229-34.
76. Champagne FA, Francis DD, Mar A, et al. Naturally-occurring
variations in maternal care in the rat as a mediating influence for
the effects of environment on the development of individual
differences in stress reactivity. Physiol Behav 2003;79:359-71.
77. Stern JM. Offspring-induced nurturance: animal-human parallels.
Dev Psychobiol 1997;31:19-37.
78. Caldji C, Tannenbaum B, Sharma S, et al. Maternal care during in-
fancy regulates the development of neural systems mediating the
expression of behavioral fearfulness in adulthood in the rat. Proc
Natl Acad Sci U S A 1998;95:5335-40.
79. Liu D, Tannenbaum B, Caldji C, et al. Maternal care, hippocampal
glucocorticoid receptor gene expression and hypothalamic-pituitary-
adrenal responses to stress. Science 1997;277:1659-62.
80. Weaver ICG, Cervoni N, D’Alessio AC, et al. Epigenetic program-
ming through maternal behavior. Nat Neurosci 2004;7:847-54.
81. Zhang TY, Chrétien P, Meaney MJ, et al. Influence of naturally oc-
curring variations in maternal care on prepulse inhibition of
acoustic startle and the medial prefrontal cortical dopamine re-
sponse to stress in adult rats. J Neurosci 2005;25:1493-502.
82. Meaney MJ, Aitken DH, Viau V, et al. Neonatal handling alters
adrenocortical negative feedback sensitivity and hippocampal
type II glucocorticoid receptor binding in the rat. Neuroendocrinol-
83. Dhir SK, Sharma S, Parent CP, et al. Natural variations in maternal
care influence basal stress hormone levels and potentially alter cir-
cadian activity. 459.7/DD9 [abstract]. 2006 Neuroscience Meeting
Planner. Atlanta: Society for Neuroscience; 2006. Available:
www.abstractsonline.com (accessed 2007 Jun 8).
84. Ladd CO, Owens MJ, Nemeroff CB. Persistent changes in corti-
cotropin-releasing factor neuronal systems induced by maternal
deprivation. Endocrinology 1996;137:1212-8.
85. Caldji C, Diorio J, Meaney MJ. Variations in maternal care alter
GABA(A) receptor subunit expression in brain regions associated
with fear. Neuropsychopharmacology 2003;28:1950-9.
86. Owens MJ, Vargas MA, Knight DL, et al. The effects of alprazo-
plam on corticotropin-releasing factor neurons in the rat brain:
acute time course, chronic treatment and abrupt withdrawal.
J Pharmacol Exp Ther 1991;258:349-56.
87. Stutzmann GE, LeDoux JE. GABAergic antagonists block the in-
hibitory effects of serotonin in the lateral amygdala: a mechanism
for modulation of sensory inputs related to fear conditioning.
J Neurosci 1999;19:RC8.
88. Caldji C, Diorio J, Meaney MJ. Maternal behavior in infancy regu-
lates the development of GABAAreceptor levels, its subunit
composition and GAD. Soc Neurosci Abtsr 2000;26:489.
89. Francis D, Diorio J, Liu D, et al. Nongenomic transmission across
generations in maternal behavior and stress responses in the rat.
90. Menard JL, Champagne D, Meaney MJ. Variations of maternal
care differentially influence ‘fear’ reactivity and regional patterns
of cFos immunoreactivity in response to the shock-probe burying
test. Neuroscience 2004;129:297-308.
91. Crestani F, Keist R, Fritschy JM, et al. Trace fear conditioning in-
volves hippocampal alpha5 GABA(A) receptors. Proc Natl Acad Sci
U S A 2002;99:8980-5.
92. Rudolph U, Mohler H. Analysis of GABAA receptor function and
dissection of the pharmacology of benzodiazepines and general
anesthetics through mouse genetics. Annu Rev Pharmacol Toxicol
93. Kuhn CM, Pauk J, Schanberg SM. Endocrine responses to mother-
infant separation in developing rats. Dev Psychobiol 1990;23(5):395-
94. Suchecki D, Rosenfeld P, Levine S. Maternal regulation of the hy-
pothalamic-pituitary-adrenal axis in the infant rat: the roles of
feeding and stroking. Brain Res Dev Brain Res. 1993;75(2):185-92.
95. Mirescu C, Peters JD, Gould E. Early life experience alters re-
sponse of adult neurogenesis to stress. Nat Neurosci 2004;7:841-6.
96. Dorio J, Weaver ICG, Meaney MJ. A DNA array study of hip-
pocampal gene expression regulated by maternal behavior in in-
fancy. Soc Neurosci Abstr 2000;26:1366.
97. Weaver ICG, Meaney MJ, Szyf M. Maternal care effects on the hip-
pocampal transcriptome and anxiety-mediated behaviors in the
offspring that are reversible in adulthood. Proc Natl Acad Sci U S A
98. Liu D, Diorio J, Day JC, et al. Maternal care, hippocampal synapto-
genesis and cognitive development in rats. Nat Neurosci 2000;3:
99. Bredy TW, Humpartzoomian RA, Cain DP, et al. Partial reversal of
the effect of maternal care on cognitive function through environ-
mental enrichment. Neuroscience 2003;118:571-6.
100. Bredy TW, Zhang T-Y, Grant RJ, et al. Peripubertal environmental
enrichment reverses the effects of maternal care on hippocampal
development and glutamate receptor subunit expression. Eur J
101. Morris RG, Anderson E, Lynch GS, et al. Selective impairment of
learning and blockade of long-term potentiation by an N-methyl-D-
aspartate receptor antagonist, AP5. Nature 1986;319:774-6.
102. Mumby DG, Tremblay A, Lecluse V, et al. Hippocampal damage
and anterograde object-recognition in rats after long retention in-
tervals. Hippocampus 2005;15:1050-6.
103. Whishaw IQ. Place learning in hippocampal rats and the path inte-
gration hypothesis. Neurosci Biobehav Rev 1998;22:209-20.
104. Bredy TW, Diorio J, Grant R, et al. Maternal care influences hip-
pocampal neuron s urvival in the rat. Eur J Neurosci 2003;18:2903-9.
105. Champagne D, Rochford J, Poirer J. Effect of apolipoprotein E defi-
ciency on reactive sprouting in the dentate gyrus of the hippocam-
pus following entorhinal cortex lesion: role of the astroglial re-
sponse. Exp Neurol 2005;194(1)31-42.
106. Quirion R, Wilson A, Rowe WB, et al. Facilitation of acetylcholine re-
lease and cognitive performance by an M2 muscarinic receptor an-
Diorio and Meaney
Rev Psychiatr Neurosci 2007;32(4)
tagonist in aged memory-impaired rats. J Neurosci 1995;15:1455-62.
107. Alderson RF, Alterman AL, Barde Y-A, et al. Brain-derived neu-
rotrophic factor increases survival and differentiated functions of
rat spetal cholinergic neurons in culture. Neuron 1990;5:297-306.
108. Friedman B, Klienfeld DP, Ip NY, et al. BDNF and NT-4/5 exert
neurotrophic influences on injured spinal motor neurons. J Neu-
109. Thoenen H. Neurotrophins and neuronal plasticity. Science 1995;
110. Jablonska B, Kossut M, Skangiel-Kramska J. Transitent increase of
AMPA and NMDA receptor binding in the barrel cortex of mice
after tactile stimulation. Neurobiol Learn Mem 1996;66:36-43.
111. McHugh TJ, Blum KI, Tsien JZ, et al. Impaired hippocampal repre-
sentation of space in CA1-specific NMDAR1 knockoutmice. Cell
112. Tang YP, Shimizu E, Dube GR, et al. Genetic enhancement of
learning and memory in mice. Nature 1999;401:63-9.
113. Tang YP, Wang H, Feng R, et al. Differential effects of enrichment
on learing and memory function in NR2B transgenic mice. Neu-
114. Smythe JW, Murphy D, Costall B. Benzodiazepine receptor stimu-
lation blocks scopolamine-induced learning impairments in a wa-
ter maze task. Brain Res Bull 1996;41:299-304.
115. Smythe JW, Bhatnagar S, Murphy D, et al. The effects of intrahip-
pocampal scopolamine infusions on anxiety in rats as measured by
the black-white box test. Brain Res Bull 1998;45:89-93.
116. McCormick JA, Lyons V, Jacobson MD, et al. 5′-heterogeneity of
glucocorticoid receptor messenger RNA is tissue specific: differen-
tial regulation of variant transcripts by early-life events. Mol En-
117. Weaver IC, Champagne FA, Brown SE, et al. Reversal of maternal
programming of stress responses in adult offspring through
methyl supplementation: altering epigenetic marking later in life. J
118. Bird A. Methylation talk between histones and DNA. Science
119. Hashimshony T, Zhang J, Keshet I, et al. The role of DNA methyla-
tion in setting up chromatin structure during development. Nat
120. Bhattacharya SK, Ramchandani S, Cervoni N, et al. A mammalian
protein with specific demethylase activity for mCpG DNA. Nature
121. Hinde RA. Some implications of evolutionary theory and compar-
ative data for the study of human prosocial and aggressive behav-
iour. In: Block J, Olweus D, Radke-Yarrow M, editors. Development
of antisocial and prosocial behavior. Orlando: Academic Press; 1986.
122. Champagne FA, Meaney MJ. Stress during gestation alters post-
partum maternal care and the development of the offspring in a
rodent model. Biol Psychiatry 2006;59:1227-35.
123. Smythe JW, Seckl JR, Evans AT, et al. Gestational stress induces
post-partum depression-like behaviour and alters maternal care in
rats. Psychoneuroendocrinology 2004;29:227-44.
124. Rosenblum LA, Andrews MW. Influences of environmental de-
mand on maternal behavior and infant development. Acta Paediatr
125. Coplan JD, Andrews MW, Rosenblum LA, et al. Persistent elevations
of cerebrospinal fluid concentrations of corticotropin-releasing
factor in adult nonhuman primates exposed to early-life stressors:
implications for the pathophysiology of mood and anxiety disor-
ders. Proc Natl Acad Sci U S A 1996;93:1619-23.
126. Coplan JD, Trost RC, Owens MJ, et al. Cerebrospinal fluid concen-
trations of somatostatin and biogenic amines in grown primates
reared by mothers exposed to manipulated foraging conditions.
Arch Gen Psychiatry 1998;55:473-7.
JPN’s Top Ten Articles, June 2007
(based on Web views on PubMed Central)
1. Efficacy of escitalopram in the treatment of major
depressive disorder compared with conventional
selective serotonin reuptake inhibitors and
venlafaxine XR: a meta-analysis
Kennedy et al
J Psychiatry Neurosci 2006;31(2):122-31
2. Platelet serotonin levels support depression scores
for women with postpartum depression
Maurer-Spurej et al
J Psychiatry Neurosci 2007;32(1):23-9
3. Treatment of primary insomnia with melatonin: a
double-blind, placebo-controlled, crossover study
Almeida Montes et al
J Psychiatry Neurosci 2003;28(3):191-6
4. “Missing” links in borderline personality disorder:
loss of neural synchrony relates to lack of emotion
regulation and impulse control
Williams et al
J Psychiatry Neurosci 2006;31(3):181-8
5. Citalopram - a review of pharmacological and
Bezchlibnyk–Butler et al
J Psychiatry Neurosci 2000;25(3):241-54
6. Eating disorder and obsessive–compulsive
disorder: neurochemical and phenomenological
Jarry and Vaccarino
J Psychiatry Neurosci 1996;21(1):36-48
7. Electroconvulsive shock enhances striatal
dopamine D1and D3receptor binding and
improves motor performance in 6-OHDA-
Strome et al
J Psychiatry Neurosci 2007;32(3):193-202
8. Depression in acute stroke
Caeiro et al
J Psychiatry Neurosci 2006;31(6):377-83
9. Reduced hippocampal volume correlates with
executive dysfunctioning in major depression
Frodl et al
J Psychiatry Neurosci 2006;31(5):316-25
10. Vulnerability for apoptosis in the limbic system after
myocardial infarction in rats: a possible model for
human postinfarct major depression
Wann et al
J Psychiatry Neurosci 2007;32(1):11-6