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Received: 30 October 2017 Revised: 13 May 2018 Accepted: 13 May 2018 DOI: 10.1111/jne.12610
REVIEW ARTICLE
Maternal regulation of the infant’s hypothalamic-pituitary- adrenal axis stress response: Seymour ‘Gig’ Levine’s legacy to neuroendocrinology D. Suchecki Departamento de Psicobiologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil Correspondence Deborah Suchecki, Departamento de Psicobiologia, Universidade Federal de São Paulo, São Paulo, Brazil. Email:
[email protected] Funding information Conselho Nacional de Desenvolvimento Científico e Tecnológico, Grant/Award Number: 303449/2015-2; Coordenação de Aperfeiçoamento de Pessoal de Nível Superior; Associação Fundo de Incentivo à Pesquisa; Fundação de Amparo à Pesquisa do Estado de São Paulo, Grant/Award Number: 2015/26364-4
Thirty years ago, Seymour ‘Gig’ Levine published a serendipitous, yet, seminal finding with respect to the regulatory role of maternal presence on the corticosterone stress response of neonatal rats during the developmental period known as the stress hyporesponsive period. At the same time, his group of students also investigated the stress response of infant monkeys with respect to maternal separation, as a means of understanding the stress to the primary caregiver resulting from disruptions of attachment. Gig and his group of students and collaborators, mainly in the USA and the Netherlands, investigated how initial social relationships buffer the stress response of nonhuman primates and rodent infants. His work in rodents involved determining how prolonged deprivation of maternal care disinhibits the stress response of neonates and how maternal behaviours regulate specific aspects of the hypothalamic- pituitary-adrenal axis. Maternal deprivation for 24 hours was useful for determining the importance of nutrition in suppressing the corticosterone stress response, whereas anogenital licking and grooming inhibited stress-induced adrenocortoctrophic hormone release, with the combination of both behaviours preventing the effects of maternal deprivation on the central hypothalamic stress response. Levine’s group also studied the consequences of maternal deprivation on basal and stress- induced activity of the hypothalamic-pituitary-adrenal axis in juveniles and the persistent effects of the replacement of maternal behaviours on these parameters. Gig’s legacy allowed many groups around the world to use the 24-hour maternal deprivation paradigm as an animal model of vulnerability and resilience to stress-related psychiatric disorders, as well as in studies of the neurobiological underpinnings of disruption of the mother-infant relationship and loss of parental care, a highly prevalent condition in humans. This review pays homage to a great scientist and mentor, whose discoveries paved the way for the understanding of how early social relationsships build resilience or lead to susceptibility to emotional disorders later in life. KEYWORDS
development, HPA axis, maternal deprivation, stress, stress hyporesponsive period
Journal of Neuroendocrinology. 2018;30:e12610. https://doi.org/10.1111/jne.12610
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If there is one principle that I have communicated to the
fall in body temperature and the nest disturbance when pups were
many students who have passed through my laboratory,
removed, which might have affected the mother. In an elegant study
it is that the neonate plays by different rules than the
designed to test which of these factors was involved in the effects
adult
of infantile stimulation on the stress response, it was shown that
(Seymour Levine)
CORT levels of all animals previously separated from the mother for 10 minutes (regardless of changes in body temperature) were lower
1 | I NTRO D U C TI O N
than those of undisturbed animals, strongly suggesting that maternal factors contributed to the observed long-lasting effects.3 In most mammalian species, the mother represents a strong (if
Seymour ‘Gig’ Levine was a visionary and one of the greatest psy-
not the strongest) attachment figure for the neonate6; therefore, it
chobiologists of the 20th century. His work about the inhibitory role
is not unexpected that separation from the mother results in signifi-
of parental care on the infant’s physiological and behavioural stress
cant changes in behavioural and physiological phenotypes.
response has been demonstrated in rodents, humans and nonhuman primates. His pioneering work on the effects of neonatal stimulation in the late 1950s and early 1960s set the grounds for modern epigenetic studies and the neurobiology of individual differences of the adult stress response. In the 1970s and 1980s, Levine and his group
2 | TH E I M P O RTA N C E O F TH E M OTH E R- I N FA NT R E L ATI O N S H I P I N S TR E S S A N D CO PI N G
published a series of studies in monkeys and rats that would be the seed of useful animal models for the investigation of the impact of
In human beings, the most impacting adversities during infancy can
disruption of the mother-infant relationship on the stress response.
be classified into 3 categories: disruption, deprivation, and neglect
This review pays homage to a great scientist and unforgettable men-
and/or abuse. In most cases, these adversities are likely to be inter-
tor, who is still remembered fondly for his insightful remarks and
twined or to occur in contingency. Disruption involves long periods
ingenious ideas and is missed by those who had the privilege to work
of separation from the main caregiver, as a result of death, aban-
with him.
donment and removal from the home. Deprivation is a condition in which the infant is reared under limited or inexistent attachment
1.1 | Initial contributions
with an adult. This situation is well exemplified by foster homes, to which children are sent because of parental neglect and/or sexual
Sixty years have elapsed ever since Gig Levine first published 2 stud-
and psychological abuse.7 The seminal work by John Bowlby on the
ies about the effects of chronic infantile handling (ie, removal of the
impact of family relationships on children’s mental health 8 and that
infant from the nest for approximately 3 minutes) on the adult stress
of Myron Hofer on the maternal regulation of the neonate’s physiol-
reactivity. In these classical studies, Gig showed that handling ap-
ogy 9,10 paved the grounds for the scientific investigation of the im-
peared to accelerate the maturation of stress-induced adrenal re-
portance of mother-infant bonding for adequate physiological and
sponse in infants, as measured by the depletion of ascorbic acid. This
psychological development.
effect appeared to be evident within a critical period from postnatal
Epidemiological and clinical studies confirm that a less than ideal
day (PND)2 to 51 and it was shown to reduce the stress effects on
upbringing of human infants has devastating psychological conse-
adrenal weight of adult animals. 2 Using a direct hormonal measure-
quences that manifest in adolescence and adulthood. These adversi-
ment, it was possible to demonstrate that a period of 10 minutes
ties interact with the individual’s genetic background,11 as has been
away from the mother, either in a warm or cold environment, from
shown with a polymorphism of the corticotrophin-releasing hor-
PND2 to 7, resulted in lower corticosterone (CORT) levels in adult
mone (CRH) receptor 1, which moderates the impact of childhood
offspring in response to open field exposure.3 These findings chal-
abuse on adulthood depression only in men, clearly indicating a sex-
lenged the current knowledge on the infant rat’s stress response be-
specific interaction between genes and environment.12 Studies car-
cause it was accepted that they were not capable of secreting CORT
ried out by Megan Gunnar’s group with Romanian orphans, exposed
in response to stressors during the first days of life, a phenomenon
to all kinds of deprivation when in the orphanages and later adopted
coined the ‘stress nonresponsive period’ by Schapiro.4 Furthermore,
by American and Canadian families, show that the endocrine and
the data demonstrated, unequivocally, that stimulation during devel-
psychological outcomes of this early-life adversity depend on the
opment had enduring positive effects on physiological stress reac-
length of institutionalisation13 and can be moderated by a polymor-
tivity. Subsequent studies were conducted to confirm the influence
phism of the FKBP5 gene, a regulator of the glucocorticoid receptor
of neonatal stimulation and maternal factors, such as fostering and
(GR) affinity for cortisol.14 Another impressive finding concern-
brief separations from the mother, on the maturation of the stress
ing the impact of disrupted mother-infant interaction comes from
response, as measured by adrenal ascorbic acid, CORT content and
a study in which 6-year-old children raised by depressive mothers
CORT plasma levels.5 In the studies of early stimulation, there were
display more unstable emotional behaviours, are less empathic and
2 factors intrinsically associated with the experimental protocol that
exhibit lower plasma oxytocin levels than children raised by healthy
might have contributed to the observed changes in adulthood: the
mothers.15 Loss of parental care, by means of death or abandonment,
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causes dysregulation of hypothalamic-pituitary-adrenal (HPA) axis
baseline and 30 minutes. 23 In this study, mother-infant dyads were
activity16 and a greater incidence of depression in adulthood, espe-
housed individually; if, however, they were group-housed, the re-
cially when the loss occurs at an earlier age (eg, before the age of
moval of the mother from the cage elicited a cortisol response lower
5 years).17
than that of individually-housed dyads, but no behavioural agitation,
Below, a historic perspective is provided of the remarkable work
in infants tended by “aunts” living in the same group. 22,24 Conversely,
carried out by Gig Levine and his group of students and collaborators.
removal of surrogate mothers resulted in behavioural distress signs
Although the main focus of this review relies on the effects of mater-
but no elevation of plasma cortisol, 27 suggesting that the behav-
nal deprivation (MD) paradigm on the physiological and behavioural
ioural and physiological responses to separation were dissociable.
stress response in rats, a brief review of the results obtained in non-
The time course of behavioural and physiological responses of in-
human primates is also presented in an attempt to disclose the im-
fants to separation from their mothers supports this notion, as
portance of the mother-infant relationship in a broader sense. The
indicated by the increase in cortisol levels and a decrease of vocali-
findings discussed in this review intend to show the importance of
sations as a function of the lengthening of the separation period. 25
early social relationships for the adequate development of emotion-
Interestingly, the infant response to removal of the mother depends
related behaviours and stress response. In Gig’s own words, as re-
on the experimental conditions because placement of the mother
cently quoted by Dr Christopher Coe: “You can learn as much from
in a nearby cage results in negligible elevations in the infant’s corti-
the ways that animals differ as from the ways they are similar”. The
sol levels, whereas removal to another room, even in the presence
review concludes by discussing how the 24-hour MD paradigm is a
of peers, elicits a much more pronounced hormonal response. 28,29
suitable animal model of early deprivation, providing a template for
Certainly, the mother is the strongest anti-stress social stimulus for
the study of pathophysiological aspects of psychiatric disorders and
the infant; nonetheless, the presence of peers can attenuate some
for the proposal of therapeutic strategies to treat these disorders.
behavioural distress signs, such as agitation and movements, but not protest calls.30
3 | CO N S EQ U E N C E S O F D I S RU P TI O N O F TH E M OTH E R- I N FA NT R E L ATI O N S H I P I N PR I M ATE S
Repeated separations (4 to 6 separations lasting 4 to 6 hours each) in 3.5-5.5 month-old squirrel monkeys result in lower cortisol, 3-methoxy-4-hydroxyphenylglycol (noradrenaline metabolite) and vocalisation responses to social separations 1.5 to 2.5 years later. These results were interpreted as being the consequence of
Classic laboratory studies by Harry Harlow demonstrate that early
increased contact between mother and infant upon reunion,31,32 and
social relationships are able to shape the behaviour of adult ani-
are in agreement with reports of maternal separation in rats.33,34 By
mals, including symptoms of depression in motherless reared infant
contrast, protracted separation, consisting of 12 days away from the
18
For monkeys, as well as for human beings, the
mother, results in an initial elevation of cortisol release at 30 min-
bond between mother and infant is critical for the formation of
rhesus monkeys.
utes and 3 hours of separation, followed by a reduction of hormone
social skills. The primate infant spends most of its time clinging to
levels by 24 hours, even though the hormone levels remain above
or in close proximity with the mother, who represents a source of
pre-separation values for the entire study period. Infant monkeys
emotional stability.19 Infants raised in total isolation for extended
also show intense signs of protest, with persistent movements in the
periods of time display antisocial and aggressive behaviour towards
cage and an initial increase of vocalisations; correlating with corti-
age-matched conspecifics. 20
sol levels, these signals also reduce throughout the separation period,35 suggesting that infants partially habituate to this situation. In
3.1 | Physiological and behavioural responses to separation from the mother
a study designed specifically to investigate the habituation capacity of squirrel monkey infants to multiple 2-hour separations from their mothers from 11 to 32 weeks of age, Hennessy36 clearly showed
Brief periods of separation of infant monkeys from their mothers
that behavioural and physiological responses to separation are more
elicit signs of protest and agitation in the infant and reunion increases
intense at the beginning of the procedure. Interestingly, those ani-
the interaction. 21 In Levine’s first study of the pituitary-adrenal re-
mals that had been submitted to the multiple separations displayed
sponse to disruption of the mother-infant relationship, 30 minutes
no vocalisations but exhibited a higher cortisol response to a further
of separation resulted in a robust elevation of cortisol plasma levels
separation session than nonseparated counterparts by 35 weeks,
in the mothers and infants, as well as in infants raised by surrogate
which is an age when these animals are completely independent of
mothers, indicating that separation is as disturbing to the infant as it
their mothers.36
is to the mother; however, it should be noted that, although basal lev-
To summarise, the studies discussed above show that the mother
els of cortisol are similar between mothers and infants, the response
and infant function as social buffer to each other, preventing the rise
to separation is far greater in the infants. 22-25 In addition, separation
of cortisol levels under stressful situations. The response of infant
and immediate reunion of infants with their mothers prevents this
monkeys to separation and to other types of stress is fast, indicating
cortisol response, 26 although periods of separation-reunion shorter
that the HPA axis in this species is mature and that maternal pres-
than 30 minutes produce cortisol levels intermediate between
ence is not a regulator of this physiological system (discussed below),
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rather being a secure attachment figure. Still, the infant stress re-
for VFD-induced changes in CRF secretion.45 These results were
sponse of monkeys to separation from the mother does not habit-
considered to be in agreement with a study in a small cohort of de-
uate completely, regardless of how many separations the infant is
pressed patients and healthy volunteers whose CSF CRF levels were
exposed to.
elevated in those reporting having experienced early-life stress in preschool-, but not in preteen years.46 These findings demonstrate that, if on one side, increased effort
3.2 | Physiological and behavioural consequences of distinct foraging demands
to find food represents a stressful condition to the mother, on the
A more subtle and ecological paradigm designed to induce dis-
predictability of the VFD condition fosters unstable mother-infant
ruptions in the monkey mother-infant relationship is the foraging
relationships, which results in altered activity of the infant’s HPA axis
demand. In this procedure, mother-infant dyads are exposed to envi-
in an age-dependent fashion (ie, in early infancy, it leads to increased
ronments that vary in the effort that the mother has to make to find
CRF levels, whereas, in late infancy, it has the opposite effect).
other, it speeds the infant’s independence and maturation. The un-
food. Importantly, in any of these environments, food supply is more
Findings from studies on infant monkeys are easier to extrapo-
than sufficient to meet the mother’s and the growing infant’s caloric
late to humans, given the similarity between these species regarding
needs. In the low foraging demand (LFD) food is abundantly avail-
the maturation of the HPA axis activity. Not surprisingly, many of
able and can easily be found (600% supply based on the mother’s
the physiological and behavioural alterations seen in adolescent and
daily food intake); in the high foraging demand (HFD), mothers are
adult monkeys exposed to early-life stress are equivalent to what is
required to seek for food, which is not so readily available (120%
observed in human beings.47
supply based on daily food intake). Finally, in the variable foraging
The findings described from studies on monkeys are summarised
demand (VFD), LFD and HFD are alternated every 2 weeks, for 12
in Table 1, where more details of the main outcomes of each study
to 16 weeks, in an attempt to mimic a chaotic environment, which in
are provided.
humans, is assumed to influence normal mother-infant relations.
37
In
ovariectomised female squirrel monkeys, social behaviour and cortisol levels were determined during 12 weeks of VFD (2 weeks of LFD alternated with 2 weeks of HFD) to establish the stressful nature of this manipulation. The results of this study showed that VFD dis-
4 | CO N S EQ U E N C E S O F D I S RU P TI O N O F TH E M OTH E R- I N FA NT R E L ATI O N S H I P I N R AT S
rupted social behaviours and enhanced cortisol levels, mainly during the HFD periods, but, towards the end of the protocol, these altera-
Most animal models that have been developed to study the out-
tions were also seen during LFD.38 Assessment of affiliative behav-
comes of disruption of the mother-infant relationship use the rat to
iour in adolescent female monkeys raised, during infancy, under VFD
replicate the variety of early-life adversities to which human infants
reveals less sociability and more subordination than animals raised
can be submitted, with good construct and face validity. These mod-
under LFD39 (ie, unstable contact with mothers results in disturbed
els are related to maternal neglect,48 maternal abuse,49 repeated
social behaviour years after the stress event).
separations50 and deprivation of maternal care51 and all of them re-
Using this paradigm to evaluate the effects of feeding demands
sult in immediate and/or long-term alterations of the HPA axis. Even
on the development of infant squirrel monkeys and the cortisol se-
though they provide an important framework for the study of the
cretion in both mothers and infants, Lyons et al.4 reported an earlier
outcomes of stress impact during sensitive developmental periods, it
independence in HFD infants from their mothers, who initiated self-
should be noted that major differences exist in brain maturation be-
transport (instead of clinging to the mother) approximately 4 weeks
tween rats and humans. Although these are altricial species (eg, they
before LFD infants. Furthermore, compared to LFD counterparts,
are born immature and completely dependent on maternal care),
HFD led to much higher cortisol levels in mothers and a modest,
the newborn human brain is more mature than the rat’s. As a rough
albeit significant, elevation of the hormone in infants.40 Although
comparison, the newborn rat’s brain corresponds to a 23-week-old
VFD represents a more uncertain and unpredictable condition and,
human foetus; by PND7, the rat’s brain is similar to a human new-
hence, a more stressful situation,41 elevation of cortisol levels was
born and, by 2 weeks of life, the infant rat’s brain corresponds to a
not sustained during the protocol but, instead, reflected the current
preschool child.52
foraging demand, both in mothers and infants. 43
term effects, adolescent
44
and adult
42
Regarding long-
bonnet macaques whose
mothers were exposed to VFD when they were, respectively, 17
4.1 | The HPA axis of the neonatal rat
and 8- 10 weeks old, were found to exhibit higher cerebrospinal
The HPA axis undergoes major changes in secretory capacity and
fluid (CSF) corticotrophin-releasing factor (CRF) levels than the
activation by stressors throughout the lifespan of many animal spe-
LFD and HFD counterparts. Interestingly, however, the opposite
cies.47 Particularly, in some species, the maturation of the HPA axis
was found when VFD took place when infants were 18-20 weeks
occurs mostly during the gestational period, including guinea pigs,
old, where CSF CRF values were lower in VFD- than in LFD-reared
sheep, nonhuman primates and humans; in contrast, completion of
adolescents, suggesting the existence of windows of vulnerability
the HPA axis maturation process in rats and mice takes place during
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TA B L E 1 Studies on disruption of the mother-infant relationship in primates. Main findings refer only to results in infants Reference
Experimental condition
Species (n)
Age of the infant
Endpoint and main findings
Coe et al. Mendoza et al. 26
Separation for 30 min
Squirrel monkey (4 dyads) (17 dyads)
2-2.5 mo 3 mo
Cortisol levels Removal of the mother or the infant increases hormone levels above basal
Levine et al. 23
Separation for 30 min
Squirrel monkey (7 dyads)
3 mo
Cortisol levels Levels increased at 5, 10 and 15 min of separation and continued elevated 30 min after reunion
Wiener et al. 24
Separation for 1 or 6 h Reunion at home or novel cage
Squirrel monkey (26 dyads)
3.5 mo
Infant vocalisation 1 h of separation increased vocalisation in group-and reduced in individual-separated infants in novel cage 6 h of separation in a novel cage increased vocalisation Cortisol levels 1 h: elevated above basal in all separated infants 6 h: infants raised in group dyads showed lower levels than those raised in individual dyads
Levine et al. 25
Separation for 1, 3 or 6 h
Squirrel monkey (5 dyads)
3 mo
Infant vocalisation and activity Decreased with lengthening of separation Cortisol levels Increased with lengthening of separation
Hennessy et al. 27
Separation for 30 min, in familiar or unfamiliar environment
Squirrel monkey 4 males and 5 females reared on inanimate surrogates
4.5-5 mo
Cortisol levels Infants in unfamiliar cages have greater cortisol levels than all other groups
Levine et al. 28
Separation for 24 h
Rhesus monkeys (8 dyads)
4-6 mo
Cortisol levels Levels were higher in isolation or with peers than when the mother was in an adjacent cage or in tactile contact
Wiener et al. 29
Separation for 24 h
Squirrel monkeys (5 dyads)
3.5 mo
Cortisol levels Total separation led to the highest response, whereas at home led to the lowest response Vocalisation Level of vocalisation was the highest when the mother was in an adjacent cage
Gunnar et al.30
Separation for 24 h
Rhesus monkeys (9 dyads)
1 y (9-16 mo)
Behaviours Infants were more agitated when alone than when with peers Whoo calls were greater when the mother was away Cortisol levels 30 min: separated infants kept with unknown peers showed higher levels than with familiar peers and mother 24 h: similar for all groups and lower than at 30 min
Levine and Mody31
4-6 separations lasting 4-6 h
Squirrel monkeys 18 dyads, 9 previously separated and 9 never separated
3.5-5.5 mo at separation and tested when aged 2 and 3 y
Cortisol and liquor monoamine levels Previous separation led to lower cortisol and noradrenaline metabolite levels to 6 h of social isolation in adolescence
22
(Continues)
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TA B L E 1 (Continued) Reference
Experimental condition
Species (n)
Age of the infant
Endpoint and main findings
Separation for 12 days in visual contact
Rhesus monkeys (9 dyads, 5 separated and 4 nonseparated infants)
7.2 mo on average
Behavioural outcomes Increased movements throughout the separation period, although more intense in the first 4 days More whoo calls in the first 2 days of separation Cortisol levels Highest levels in the first 30 min of separation, with a subsequent decrease, which never equalled basal or nonseparated levels
Hennessy36
80 separations, 2 h long
Squirrel monkeys (11 dyads, 5 separated and 6 nonseparated infants
12-31 weeks Challenging separation at 35 weeks of age
Vocalisations Very intense in the first separation, subsequent decline to baseline values Cortisol levels The greatest response on the first separation, followed by reduction, although values were still higher than basal Challenge results Nonseparated infants vocalised more and cortisol levels were lower than in previously separated ones
Champoux et al.38
12 weeks of LFD or VFD: LFD alternated with HFD, every 2 weeks
10 ovariectomised female squirrel monkeys
7-8 y
Behavioural outcomes Reduction of social contact and proximity and increased activity during HFD periods Cortisol levels Elevated during HFD periods
Andrews and Rosenblum39
12 weeks of LFD or VFD: LFD alternated with HFD, every 2 weeks
Bonnet macaques 6 LFD and 6 VFD
11 weeks when LFD and VFD took place 2.5-3.5 y at testing
Behavioural outcomes VFD animals avoided passive contact, physical proximity and social grooming with unfamiliar individuals After 9 mo living together, VFD animals made less afilliative approach than LFD
Lyons et al.40
12 weeks of LFD or HFD
Squirrel monkeys (7 dyads in LFD and 7 dyads in HFD)
10-21 weeks of age
Behavioural outcomes HFD infants engaged less in clinging to the mother’s back and more in self-transport sooner than LFD infants HFD infants made more contact attempts with their mothers, who opposed more often to these attempts LFD infants made more break-contact attempts with the mother, who rejected this behaviour more often than HFD animals Cortisol levels Throughout the 12 weeks of the protocol, cortisol levels of HFD mothers were higher than those of LFD mothers, whereas the levels in HFD infants were slightly elevated above LFD ones
Champoux et al.42
12 weeks of HFD, LFD or VFD
Squirrel monkeys (5 dyads/group)
3-6 mo 1 separation from the mother (for 24 h) on the week following the end of the protocol
Cortisol levels Mothers: HFD and VFD sustained elevation above LFD Infants: HFD and VFD inconsistent and slighter elevation above LFD Response to maternal separation was similar among the 3 groups
Gunnar et al.
35
(Continues)
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TA B L E 1 (Continued) Reference Coplan et al.
43
Mathew et al.45
Experimental condition
Species (n)
Age of the infant
Endpoint and main findings
12 weeks of HFD, LFD or VFD
Bonnet macaques 8 HFD, 7 LFD and 15 VFD
Protocols began when infants were aged 17 weeks and CSF sampling: 2 y (VFD) and 4 y (HFD and LFD)
CSF CRF and cortisol levels CRF was higher in VFD than in LFD and HFD CSF cortisol was lower in VFD than LFD and HFD
16 weeks of VFD or LFD
Bonnet macaques 11 VFD and 9 LFD
Protocols began when infants were aged 18 weeks and CSF sampling when they were 2.4 y
CSF CRF and monoamine metabolites VFD increased serotonin metabolite and reduced CRF levels VFD increased aggressive behaviour, which was positively correlated with levels of serotonin metabolite
CRF, corticotrophin-releasing factor; CSF, cerebrospinal fluid; HFD, high foraging demand; LFD, low foraging demand; VFD, variable foraging demand.
the postnatal period. An excellent and comprehensive review on
its mediators, CRH, arginine vasopressin (AVP) and ACTH, although
developmental aspects of the HPA axis is provided by Wood and
they increase steadily throughout the postnatal development.59,60
Walker.
53
Nonetheless, more recent studies have shown that, during the SHRP,
An especially relevant developmental period that has been described in rats, 54 mice,54 mandarin voles
55
and humans
56
is the
stress hyporesponsive period (SHRP).57 For the purpose of the
the hypothalamus is responsive to light or mild stressors, which increase CRH61 and AVP mRNA62 in the paraventricular nucleus (PVN) of 6-, 12-and 18 day-old rats.
present review, much emphasis is given to the neonatal rat stress
In CD1 mice, the SHRP extends from PND1-9, when almost no
response, although a brief description in mice and human is also
CORT and ACTH responses to 30 minutes novelty stress are ob-
presented. In rats, the adrenal glands are perfectly capable of re-
served, followed by a robust increase in hormone levels from PND12
sponding to its trophic hormone, adrenocorticotrophic hormone
until PND16. During this period (PND1- 9), CRH mRNA expression
(ACTH), from birth to PND3, yet this capacity is greatly diminished
in the PVN is higher than between PND12 and 16 and a gradual in-
from PND4 until, approximately, PND1458 (Figure 1). The SHRP was
crease in GR mRNA expression takes place in the hippocampal CA1
found to be not only restricted to the adrenals, but also to extend
field and in mineralocorticoid receptor (MR) mRNA levels in the den-
to all components of the HPA axis, with a reduced production of all
tate gyrus (DG).54
50 Saline
45
ACTH
F I G U R E 1 Corticosterone (CORT) plasma levels induced by saline or adrenocorticotrophic hormone (ACTH) i.p. injection in animals at different ages, before, during and after the stress hyporesponsive period. PND, postnatal day. Data were integrated based on Witek-Janucek58
CORT plasma levels (µg dL–1)
40 35 30 25 20 15 10 5 0
PND 1
PND 2
PND 5
PND 10 Age
PND 14
PND 21
Adult
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Studies in human babies have shown that such a hyporespon-
hypothesis of an increased efficiency of the negative-feedback
sive period may also occur in humans. At birth, babies respond to
to explain the SHRP, which is further reinforced by evidence that
stress in a discriminative way, with much higher secretion to a painful
treatment of 9-day-old mice with a GR antagonist reduces hypo-
stimulus than to routine physical examination.63,64 The cortisol re-
thalamic CRH mRNA and elevates pituitary pro-opiomelanocortin
sponse to vaccination is strong in 2-month-old babies but decreases
mRNA expression, leading to greater ACTH and CORT plasma lev-
There is
els, causing the infant to emerge from the SHRP.78 However, it
a further reduction in the cortisol response intensity by 15 months,
is irreconcilable with findings demonstrating that CORT adminis-
with almost no changes from baseline to post-vaccination levels,66
tration to 9-and 12 day-old adrenalectomised pups does not re-
as well as by 18 months of age.67 Importantly, this cortisol response
store ACTH back to basal levels.79 Moreover, once the pup is made
pattern is seen in infants with secure attachment, whereas children
capable of mounting a robust stress response, ACTH and CORT
with insecure or disorganised attachment show high cortisol release
levels remain elevated for at least 2 hours, 80-82 which is far longer
by 4 and 6 months, although it is still above basal values.
to a standard test,
52
65
recollecting the results described with infant
monkeys raised in a VFD environment.42 Therefore, the stress response is modulated by the quality of care provided to the infant.
than any adult stress response. The ontogenetic profile of GR expression, including high receptor density in the PVN and hippocampus, as associated with low
This period of low, stable CORT levels is extremely adaptive be-
CBG levels, neatly explains the SHRP at the central level. However,
cause glucocorticoids are catabolic and their excessive production
it does not justify why and how the adrenal becomes unresponsive
impairs optimum neonatal brain and physical development, 68,69 al-
to ACTH and to stress in general during this period. Gig devoted part
though the mechanisms involved in the initiation of the SHRP are
of his life to answering this question, exploring the fact that primary
still a matter of debate. The first hypothesis put forward to explain
social relationships have major shielding effects against stress.
this unique period was based on reports of extremely low levels of corticosterone binding globulin (CBG) until PND12.70,71 Because CORT-b ound CBG is unable to activate the high affinity MR and the low affinity GR, low CBG levels would leave CORT almost
4.2 | Maternal inhibitory regulation of the neonatal stress response
free to bind these receptors, leading to very efficient negative-
Almost 50 years ago, Myron Hofer discovered that different aspects
feedback.72,73 In this regard, it is also important to consider the
of the maternal care regulated, somehow specifically, different
ontogenetic profile of these receptors; in the hippocampus, MR
physiological systems of the neonates. He reached this conclusion
are undetectable until PND4 but, by PND8, these receptors reach
by separating pups from their mothers for 24 hours and observing
adult-like concentrations; GR, in contrast, are present at birth with
a constellation of physiological and behavioural changes that could
high affinity to CORT in the first week of life, decreasing thereaf-
be reversed by replacement of specific aspects of the maternal care,
ter towards adult values. Regarding receptor density, by 3 weeks
such as warmth, milk infusion and contact, even with a nonlactating,
of life, the GR concentration was only 65% of that of the adult.74
foster mother. These processes were coined “hidden regulators” of
During the SHRP (eg, at PND4, 8 and 12), increased MR density
the infant behaviour and physiology and could be either stimulatory
in the hippocampus and pituitary was confirmed by autoradiog-
or inhibitory.10 Therefore, maternal presence and aspects of mater-
raphy, with maximum uptake of tracer doses of CORT, suggesting
nal care could be implicated in the appearance and maintenance of
that these receptors were involved with physiological CORT ef-
the SHRP. The strategy used to understand the regulatory role of
fects.75 In a more detailed study, it was shown that localisation
maternal care on the infant’s stress response was to submit rat neo-
of GR-immunoreativity decreased progressively and irreversibly
nates to long periods of MD, usually 24 hours, and assess the im-
throughout the first 3 weeks of life in the CA3-4 hippocampal fields
mediate outcomes. With this simple methodology, it became clear
and suprachiasmatic nucleus of the hypothalamus (SCN), when
that, indeed, the infant rat’s pituitary-adrenal activity was regulated
intense synaptogenesis is taking place. It was hypothesised that
by maternal care.
the effects of maternal CORT on the synchronisation of the pup’s circadian rhythms could be mediated by GR in the SCN, prior to entrainment by the light/dark cycle.76 A comparative analysis of MR and GR mRNA expression in different hippocampal fields at PND2, 8, 12 and adulthood indicates greater MR expression at
4.3 | Immediate effects of MD on the activity of the HPA axis Curiously, the first MD study conducted by Gig Levine’s group was
all ages in the CA3 hippocampal subfield and DG. In the infant,
not designed to investigate the consequences of MD on the stress
GR mRNA is expressed in the amygdala, PVN and arcuate nu-
response but rather comprised an entirely different question. Gig
cleus of the hypothalamus; in the neonatal dorsal hippocampus,
was interested in the role of feeding on the activity of the pituitary-
GR expression is greater in CA1 than in CA3 and DG, whereas, in
adrenal axis of developing rats (after all, he was a developmental psy-
the adult, it is lower than MR expression in all 3 fields.
77
This pat-
chobiologist). Based on the knowledge that, in adult animals, feeding
tern of expression contrasts with the previous study published
reduces the activation of the HPA axis,83 12-, 16-and 20 day-old
by the same group, where very low GR expression was detected
pups, previously maternally-deprived for 24 hours (DEP11, DEP15
in CA3 compared to CA1 and DG fields.76 These data support the
and DEP19, respectively; note that the number corresponds to the
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age of the pup at the beginning of MD and this notation is used
augmented further. Reunion with the mother was capable of reset-
throughout this review), were artificially fed or exposed to an anaes-
ting the system in such a way that testing of pups in various ages
thetised mother (unable to lactate) in a novel cage. There were 2
within and immediately after the end of the SHRP did not lead to
surprising results: (i) although DEP11 pups were in the SHRP, they
differences between deprived and nondeprived mice.89
displayed higher basal and novelty-induced CORT levels than non-
During the MD period, the infant is subjected to a number of
deprived (NDEP) counterparts and (ii) contact with an anaesthetised
conditions, including separation from littermates, absence of mater-
mother, but not milk infusion, inhibited the adrenocortical response
nal contact, fasting and a lack of transmission of hormones from the
to novelty at all ages.84 Subsequently, it was shown that, on PND12
mother. All of these instances could somehow influence, alone or in
and 16, MD for 24 hours, but not for 1 or 8 hours, produced a major
combination, the regulation of the stress response. One of the first
increase in basal CORT levels and also in the sensitivity of the adrenal
studies designed to investigate these possibilities in DEP7, DEP11
gland to ACTH.85 Interestingly, the adrenal response of DEP3, DEP7,
and DEP15 pups showed that the presence of littermates did not
DEP11 and DEP15 pups to 2 doses of ACTH (1 and 4 IU 100 g-1 body
mitigate the effects of maternal absence. Although contact with an
weight) was more or less the same, regardless the age. Albeit the
anaesthetised mother was sufficient to reset a previously stimulated
CORT output of DEP pups was much higher than those of NDEP, the
CORT stress response,85 contact with a thelectomised dam did not
hormone response showed a similar age-dependent pattern seen in
prevent MD-induced adrenal sensitisation,90 nor did contact with
the SHRP, such that the lowest ACTH-induced CORT levels were
an intact dam that was fully capable of providing all maternal care
obtained at PND886 (Figure 2), indicating that maternal presence is,
to pups which were, themselves incapable of suckling, as a result
indeed, necessary, to maintain the low adrenal sensitivity to ACTH
of a cannula implanted in their tongues.91 These studies suggested
typifying this period, although there must be maturational factors
that lack of nourishment could be one factor involved in the MD-
acting upon the adrenal as well.
induced adrenal response. This hypothesis was supported by stud-
Although, at certain ages, 8 hours of maternal separation was
ies showing that milk replacement during MD at various ages was
sufficient to release the adrenal gland from the maternal inhibitory
sufficient to reset basal CORT levels, albeit the stress response was
influence, a much larger basal and stress-induced CORT response
still slightly higher in DEP than in NDEP animals.91,92 More recent
was observed after 24 hours of MD, both in rats
87
and mice.
88
For
studies have been conducted aiming to understand how nutrition
example, at PND8 and 12, the CORT response to novelty, saline in-
influences adrenal steroidogenic activity. Fasting reduces leptin and
jection and exogenous ACTH was maximal after 24 hours compared
increases ghrelin concentrations.93 These peripheral hormones ap-
to NDEP and to 2, 4 and 8 hours of separation. At PND4, in contrast,
pear to regulate, at least in part, the adrenal quiescence to ACTH. On
NDEP pups showed a major response to ACTH administration, as
the one hand, incubation of adrenal cells of DEP10 pups with leptin
would be expected from animals outside the SHRP,58 and maternal
inhibits ACTH-induced steroidogenesis.94 On the other hand, treat-
separation as short as 4 hours induced a strong CORT response.87
ment with glucose or with a ghrelin antagonist partly suppresses
In the mouse, DEP3 pups exhibited a robust increase in CORT basal
MD-induced increased ACTH and CORT secretion.95
levels and a further elevation in response to novelty stress. Basal
The increased capacity of deprived pups to secrete CORT both
ACTH secretion was also elevated, although stress levels were not
under basal or stress-induced conditions could be the consequence of MD inducing a greater ACTH release because this peptide has trophic effects at the adrenal cortex, resulting in ACTH receptor up-
45 NDEP
CORT plasma levels (µg dL–1)
40
DEP
regulation96 and increased activity of the enzymes involved in steroidogenesis.97 With this idea in mind, we began to investigate the
35
consequences of MD on basal and stress (saline injection)-induced
30
ACTH levels of DEP5, DEP8 and DEP11 pups. At all ages tested, sa-
25
line produced a slight stress response in NDEP pups but, surprisingly, ACTH levels in DEP5 pups did not differ from those of NDEP ani-
20
mals. Basal ACTH levels in DEP8 and DEP11 pups were not different
15
from NDEP counterparts, although the stress response was higher
10
and remained elevated up to 30 minutes after the stress.82 These results indicated that (i) the time-course of the ACTH stress response
5 0
differed from that observed in adult rats, which, by 30 minutes, PND4
PND8
PND12
PND16
Age F I G U R E 2 Corticosterone (CORT) plasma levels obtained 60 minutes after an i.p. adrenocorticotrophic hormone injection (4 IU) in nondeprived (NDEP), as well as maternally-deprived (DEP) pups, at different ages. Data were integrated based on Rosenfeld et al86
show a return to basal levels, and (ii) not only the adrenal cortex, but also the pituitary was under the inhibitory regulation of maternal presence. If nutritional aspects were responsible for maintenance of the adrenal quiescence, this maternal factor might also be involved in inhibition of the ACTH stress response. Accordingly, we deprived pups of their mothers at PND8 and 11 and some litters were picked up, turned over and stroked in the anogenital area 3 times during the
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10 of 17
deprivation period (ie, to mimic anogenital licking provided by the
DEP8 and DEP11 neonates, MD reduces the expression of MR,
mother), whereas others were handled the same way, except for the
but not of GR, mRNA in the CA1 subfield, leading to reduction of
stroke. These litters were compared with the NDEP and DEP coun-
hippocampal MR:GR ratio. The increased CORT basal levels and
terparts and the results obtained showed that deprived pups stroked
the insensitivity of ACTH regulation by CORT were attributed to
in the anogenital area did not differ from NDEP pups, demonstrating
this change in the receptor subtype ratio in the CA1 hippocampal
that the stress response at the pituitary level was regulated not by 91
feeding, but by anogenital licking.
field.103
Remarkably, maternal presence
Not only are the different components of the HPA axis stimu-
has such a strong influence on the adrenal gland that even 2 admin-
lated by stress in distinct ways, but also their actual response to MD
istrations of ACTH to NDEP animals during 24 hours fail to increase
takes place following a particular time-course. Evaluation of CORT,
basal and stress-induced CORT response, suggesting that high levels
ACTH, CRH, MR and GR values throughout MD in DEP8 mice shows
of ACTH are not sufficient to overcome the effect of maternal care
that the adrenal gland is the only element of the HPA axis that ex-
on this organ.98
hibits a linear response to MD, whereas the pituitary responds in a
Having now determined the impact of MD on peripheral stress
bimodal fashion and the PVN shows little correlation with the length
hormones, it was only natural that researchers would investigate
of MD. In the CA1 hippocampal subfield, levels of MR and GR mRNA
its consequences at the level of the central nervous system (CNS).
do not show a clear pattern of change, except that they are lower at
Thus, it was demonstrated that, at the end of 24 hours of MD,
the end of 24 hours of deprivation.88 A schematic representation of
DEP9 neonates exhibited lower CRH concentration in the median
the integrated data from this study is provided in Figure 3.
eminence (a likely indicator of augmented CRH release), without
A summary of the main data presented here is as follows: (i) the
alteration of CRH pituitary receptors.99 In a subsequent study,
SHRP exists at the central and at the adrenal levels, with different
however, CRH mRNA abundance in the PVN was not different
developmental patterns, and MD alters the response of each level
among DEP8 pups submitted to MD, individually or as a group, and
of the HPA axis in a unique way; (ii) even though the MD renders
NDEP pups, although CORT levels were higher in both deprived
the adrenal responsive to ACTH, the age-dependent profile seen
groups compared to NDEP ones,100 suggesting the possibility that
in the SHRP is maintained, albeit at greater magnitude (as shown in
the activities of the PVN and the adrenal gland may not be well
Figure 2); (iii) nutritional aspects of maternal behaviour regulate the
correlated during the SHRP.101 To test whether MD activates the
adrenal responsiveness, whereas, at the pituitary level, anogenital
central component of the HPA axis, immediate early genes, c-fos
stroking is the main regulatory maternal behaviour, and both are
and nerve growth factor I (NGFI-B), were determined in DEP11
necessary to reverse the effects of MD at the central component of
and DEP19 neonates, 30 minutes after saline injection, whereas
the HPA axis. Interestingly, natural variations of maternal care in rats
CRH mRNA was determined 120 minutes after the stimulus. The
result in distinct phenotypes in adult animals. Pups raised by mothers
stressor increased c-fos and NGFI-B in the PVN of NDEP pups and
engaging in a higher frequency of anogenital licking and grooming,
MD augmented this response even further in DEP11 but not in
as well as arch-backed nursing (considered to be more careful mater-
DEP19 pups, indicating that maternal inhibition of the stress re-
nal behaviours), display a lower stress response and less anxiety-like
sponse is also exerted at the hypothalamic level.101 However, be-
behaviours.104,105 Epigenetic studies revealed that this high-quality
cause stress is capable of inducing a fast CRH mRNA expression in
maternal care reduces the methylation of the GR promoter region,
NDEP pups, without resulting in elevated ACTH levels, 61 this might
thus increasing this receptor’s expression, and, consequently, im-
suggest that AVP, a co-s ecretagogue, could play a role in the ACTH
proving the negative-feedback regulation of the HPA axis.106
stress response of deprived neonates. This was indeed the case in DEP11, but not DEP5 or DEP17 neonates, for which a greater AVP and CRH mRNA expression was exhibited, together with elevated ACTH plasma levels, in response to restraint stress. 62 Such as that
4.4 | Middle-term effects of MD on the HPA axis and stress response
observed peripherally, at the level of the CNS, feeding and ano-
If reunion of the pups with their mothers resets the adrenal stress
genital stroking were also able to reverse the effects of MD on GR
response, as had been shown in the first MD study,84 this could
mRNA in the CA1 subfield of the hippocampus, as well as c-fos and
mean that changes in stress responsiveness induced by MD did not
CRH mRNA in the PVN of DEP11 neonates.102
persist over time. However, in the rat, the answer to this question is
One of the most replicable effects of MD is the prolonged re-
a resounding no. More intriguingly, the outcome depends on the age
lease of CORT and ACTH in response to mild stressors. As noted
when pups are deprived of their mothers. Thus, juveniles challenged
above, when the neonate becomes responsive to stressors at the
at PND20 with a saline injection displayed lower ACTH secretion
end of MD, ACTH and CORT levels remain elevated for, at least,
when MD occurred on PND11 and higher ACTH secretion if MD
2 hours, suggesting that loss of maternal care alters MR and/or
took place on PND3, whereas there were no differences in CORT re-
GR-m ediated CORT negative-feedback. The hippocampus plays an
sponse between deprived and age-matched NDEP pups.107 Another
important role in the basal tone of the HPA axis and in the mag-
study in Wistar rats showed the same result for the CORT stress
nitude and duration of the stress response, being a main target of
response when pups were tested at PND16 and 22 but, surprisingly,
CORT as a result of high density of both corticoid receptors. In
30-day-old juveniles exhibited lower basal and stress-induced CORT
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To determine whether the persistent effects of MD are also de-
(A)
pendent on the genetic background of the rat, the basal and stress-
100
HPA axis activity of 18-day-old Brown Norway rats, submitted to MD on PND3, was investigated. The SHRP was confirmed in this
Hormone values
80
rat strain and MD resulted in greater ether-induced CORT levels on PND3, 6, 14 and 18, but not on PND10.110 Similar to the mix-bred Sprague-Dawley and Long Evans pups,107 DEP3 Brown Norway rats
60
showed a hyperactive ACTH stress response, without changes in CORT levels, at PND18.110
40
In summary, these findings demonstrate that the age of the neonate when submitted to MD determines the profile of stress-
CORT (ng/mL–1)
20
induced HPA axis activation and this effect appears to be indepen-
ACTH (pg/mL–1)
dent of the rat strain. This pattern of stress response is similar to
CRH mRNA
the effects of VFD in bonnet macaques 46 (ie, higher CRF levels in
0 0h
(B)
2h
4h
8h
12 h
16 h
20 h
24 h
adolescents exposed to VFD in early childhood and lower levels in animals exposed to VFD in later childhood). Furthermore, replace-
90
ment of specific aspects of maternal care is capable of preventing
MR mRNA
not only the immediate, but also the middle-term effects of MD at all
GR mRNA
85
Arbitrary units
1h
levels of the HPA axis.
80
4.5 | Middle-term effects of MD on emotion- related behaviour
75
In addition to the well-characterised MD outcomes on basal and
70
stress-induced activity of the HPA axis, several groups aimed to investigate whether adrenal disinhibition in the early developmental stage
65
leads to altered behaviour and neurobiology. This is specially alluring because this paradigm models an ecological early-life adversity, in
60 0h
addition to favouring the choice of time-points that represent land-
2 h 4 h 8 h 12 h 16 h 20 h 24 h Length of maternal deprivation
marks of ontogenetic development of specific neural systems. For
F I G U R E 3 Different lengths of maternal deprivation-induced changes in corticosterone (CORT) and adrenocorticotrophic hormone (ACTH) plasma levels, as well as corticotrophin-releasing hormone (CRH) mRNA in the paraventricular nucleus (A) and mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) mRNA expression in the hippocampus (B), of DEP8 mice. Data were integrated based on Schmidt et al88
example, MD on PND3 reduces, in juvenile females, and increases, in juvenile males, the number of immature hippocampal cells, even in the absence of changes in neurone and astrocyte proliferation.111 Moreover, it has been reported that MD reduces the DG granule cell layer and increases freezing behaviour in tone fear conditioning, an amygdala-related emotional memory.112 These results on neuronal fate have important implications for humans, considering that mood disorders are twice as prevalent in women than in men113 and that
108
secretion than NDEP animals.
The distinctive effects of MD in
early- life adversity triggers adulthood depression, mainly associ-
different phases of the SHRP also extend to the expression of hip-
ated with a smaller hippocampal volume.114 Furthermore, increased
pocampal MR and GR in a sex-dependent way; thus, DEP3 males
amygdala-related fear conditioning is in line with altered emotional-
displayed greater MR expression in CA3 and CA4 subfields, whereas
regulation and an increased amygdala volume in orphanage-dwelling
DEP11 females exhibited lower MR expression in all hippocampus
children subsequently adopted by foreign families.115
subfields compared to NDEP counterparts. As for GR, there was a
There are only a few studies on the effects of MD on the be-
reduced expression in all hippocampal subfields of DEP7 and DEP11
haviour of adolescent rats and these studies suggest an age-
(but not of DEP3) males and females.80 This age-dependent effect
dependent effect. For example, DEP9 male and female rats tested
of MD extends to the PVN, revealing a pattern similar to that seen
on PND30 show increased immobility in the forced swimming test,
in the peripheral hormones (eg, DEP 3 increases and DEP11 reduces
suggestive of a passive coping style,116 in addition to reduced explor-
107
CRH mRNA expression to saline injection in 20-day-old juveniles).
atory activity in the centre of the open field and less interest in in-
The ACTH hyporeactivity, as well as the reduction of GR mRNA ex-
vestigating an unfamiliar conspecific during late adolescence.117 MD
pression in the hypothalamus and hippocampal CA1, CA4 and DG
on PND11, in contrast, increases central exploration and reduces
fields, in 20-day-old DEP11 rats is reversed by feeding and stroking
grooming in the open field (ie, reduces anxiety-like behaviours) in
the pups during the deprivation period.109
30-day-old male and female rats.118
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Thus, these data indicate that MD at earlier ages (even if out-
schizophrenia involves, at least in part, changes in the dopaminergic
side the SHRP) increases the likelihood of adolescent male and fe-
system and results from neurodevelopmental disturbance,122 the
male rats displaying increased emotionality, whereas, at a later age
influence of MD was investigated with respect to the prepulse in-
within the SHRP, MD appears to increase resilience to this type of
hibition of the acoustic startle response, a phenomenon that is dis-
behaviour.
rupted in schizophrenic patients.123 MD was employed at different ages (DEP3, DEP6, DEP9 and DEP13) and prepulse inhibition was
4.6 | Long-term effects of MD on the HPA axis and stress response
altered in DEP6 and, more strongly, in DEP9 males and females, being normalised with haloperidol and quetiapine, which are classical and atypical neuroleptics, respectively.51 A subsequent study
The first studies on the long-term consequences of MD were car-
also revealed that NDEP pups raised by mothers deprived of their
ried out with DEP3 Brown Norway rats, tested at PND60, showing
9-day-old pups had disrupted prepulse inhibition and, conversely,
that these animals exhibited lower basal CRH mRNA expression in
DEP9 pups raised by undisturbed mothers behaved as NDEP rats,
the PVN, although the ACTH and CORT basal plasma levels were
implicating an altered behaviour to circumstances beyond the depri-
higher than in NDEP rats; hippocampal GR and MR mRNA were simi-
vation period.124 In addition to changes in prepulse inhibition, DEP9
lar between DEP3 and NDEP animals but, in the PVN and pituitary,
males were also shown to be more anxious than NDEP counterparts
expression was lower in DEP3 animals, suggesting a less efficient
in the open field test, demonstrating a reduced exploration of the
negative-feedback system.119 At 12 months of age, DEP3 animals dis-
centre and more peripheral parts of the apparatus. In agreement
played a slower return to basal CORT levels and no difference in the
with this behavioural phenotype, these animals had a greater sero-
ACTH values from NDEP in response to novelty. After exposure to
tonin hypothalamic turnover rate, which has been implicated in the
restraint stress, however, senescent (age 30 months) Brown Norway
neurobiological substrate of stress and anxiety.125
DEP3 rats presented lower reactivity than NDEP counterparts. This
The effects of MD on prepulse inhibition were replicated by
hyporesponsiveness was more evident in CORT levels, especially
Husum and Mathé,126 who also showed that DEP9 male rats ex-
from 30 to 150 minutes after the stressor, and might be explained
hibited lower levels of neuropeptide Y (NPY) in the occipital cortex
by the lower CRH mRNA expression in the PVN.120 Such a pattern of
and hippocampus; whether or not the changes in prepulse inhibi-
CORT secretion was not observed in Wistar rats previously submit-
tion and NPY are related still needs clarification, although this could
ted to MD on PND4, 9 or 18 and exposed to 30 minutes of restraint
be a possibility because dopamine negatively regulates NPY levels.
stress at 5 or 20 months of age. At 5 months, all maternally-deprived
NPY levels were also shown to be reduced in the hypothalamus,127
rats exhibited higher CORT levels than NDEP counterparts, whereas
as well as in the amygdala and hippocampus (unpublished data, A. S.
older rats did not show group differences in the stress response.
Miragaia, G. S. Wertheimer, A. C. Consoli, R. Cabbia, B. M. Longo, C.
Moreover, in both age groups, CORT levels were back to baseline by
E. Girardi, D. Suchecki) of male and female DEP3 and DEP11 rats.
60 minutes post-stress,121 confirming the lack of MD effect on the
Therefore, the NPY system may be a particularly interesting end-
efficiency of the negative-feedback system, at least in Wistar rats.
point worthy of investigation, giving its involvement with mood and
The discrepancy between these studies105,106 may be a result of the
anxiety disorders.128
animal strain or the type of stressor used to challenge the system.
As noted previously, an advantage of using MD is the opportu-
The ACTH and CORT responses to hypertonic saline in adult
nity to investigate its impact on specific stages of neonatal develop-
Wistar rats were dependent on the sex and age of deprivation; DEP3
ment. The effects of MD at PND4, 9 and 18 on conditioned (classical
males showed a hyperactive ACTH response, whereas, in DEP11
fear conditioning, active avoidance) and unconditioned (open field
males, there was a hypoactive response (very much like the results
and elevated plus maze) fear tests were examined in male and fe-
reported in another study107). As for the CORT levels, there were
male Wistar rats. Regardless of the age when MD was imposed,
no group differences in stress-induced hormone release, although
females were more exploratory in the open field and elevated plus
basal levels were lower in DEP11 than in DEP3 rats. Likewise, no
maze, whereas males displayed greater freezing behaviour in fear
group differences were demonstrated in the dexamethasone sup-
conditioning tasks. MD produced an age-dependent effect on ac-
pression test, indicating that MD does not alter the functionality of
tive avoidance in males, with impairment in DEP4 (less avoidance
the negative-feedback system in adult Wistar rats.98
response) and improvement in DEP9 rats.129 A comparison of DEP3 and DEP11 adult male and female rats (in diestrous) indicated that MD induces anxiety-like behaviour, as measured in the light/dark
4.7 | Long-term effects of MD on emotion- related behaviour
transition box, in both groups and sexes.98 This result was confirmed
Maternal deprivation as an animal model of vulnerability to devel-
in dioestrous) showed increased risk assessment behaviour; neuro-
opment of psychiatric disorder was first employed by Ellenbroek
chemical evaluation of hippocampal monoamines and amino acid
in the elevated plus maze, in which DEP11 males and females (also
et al., 51 based on the fact that DEP3 animals present greater tyrosine
neurotransmitters revealed that GABA and taurine levels were
hydroxylase mRNA in the substantia nigra and are more responsive
strongly reduced in DEP11 females and males, respectively, with no
to apomorphine, a dopaminergic D2 receptor agonist.119 Given that
changes in monoamine concentrations.130 Interestingly, in a recent
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study carried out by our group, NDEP and DEP11 adult females
of development of the tertiary matrix of granular cells of the DG.138
tested in the oestrous phase of the oestrous cycle displayed greater
This feature provides a unique opportunity to investigate how early
exploratory activity in the open arms of the elevated plus maze (ie,
adversity impacts the specific behavioural and neurobiological as-
reduced anxiety-like behaviour) than male rats, adding another ele-
pects that can be selected for the elaboration of animal models of
ment to the already complex myriad of behavioural effects of this
psychiatric disorders.129 At the very least, we can affirm that MD
early-life manipulation.
fulfils the construct validity criterion of animal models, in as much
Cognitive decline is a common, but not an inevitable, conse-
as epidemiological studies undisputedly demonstrate that loss of
quence of the ageing process. Cognitive preservation in the elderly
maternal care leads to a higher prevalence of schizophrenia,139 de-
population is extremely variable both in humans and rats and ap-
pression17 and anxiety disorder.140 Face validity has also been met,
pears to be dependent on individual features of stress responsive-
as discussed earlier in this review, with several neuroendocrine and
ness.131,132 A good example of such modulatory role comes from a
neurobiological changes emulating the clinical features observed in
study using the neonatal handling procedure, shown by Gig Levine
psychiatric patients. Therefore, it is only a matter of time before re-
to result in smaller stress response in adult animals,133 and to reduce
searchers propose better and more efficient treatments for these
134
the impairment of hippocampus-dependent memory in aged rats.
devastating conditions.
Maternal deprivation on PND3, in contrast, increases the number
Although it was not Gig’s primary purpose, he was well aware
of animals displaying cognitive impairments compared to nonde-
of the enormous potentiality of the MD paradigm as a model of
prived counterparts.135 Remarkably, the distribution of animals in
vulnerability (or perhaps resilience under certain circumstances) of
3 categories: no impairment, partial or severe impairment, demon-
stress-and emotion-related psychopathologies. The studies pre-
strates that, among senescent NDEP animals, there is a bell-shaped
sented in this review demonstrate not only that the MD protocol
distribution of cognitive performance, with most animals displaying
established by Gig Levine is a suitable and valuable animal model of
partial impairment of hippocampus-dependent memory, whereas, in
early-life adversity, but also that this model provides an interesting
DEP3 senescent rats, the distribution follows a U-shaped pattern,
template for the study of the impact of a loss of maternal care on
with most animals showing either severely impaired or no cognitive
the development of the CNS, within specific time constraints.
problems.136 As described previously,120 adult DEP3 Brown Norway
Gig’s brilliant work has provided subsequent generations of sci-
rats showed greater and longer novelty-induced CORT secretion
entists with a perfect background enabling an indepth examination
than control rats, a likely mechanism involved in the shift in devel-
of the pathophysiological consequences of disruption of the mother-
opmental trajectory, from mildly to fully-impaired cognitive function
infant relationship, with respect to the use of epigenetic, neurophys-
expressed in senescence. Another likely mechanism that was also
iological, neuroendocrine and molecular tools.
investigated was the expression of brain-derived neurotrophic factor (BDNF) in different hippocampal fields. In cognitively unimpaired senescent rats, training in the spatial task produced an increase in
AC K N OW L E D G E M E N T S
BDNF expression in CA1 and DG, which did not occur with memory
This work is supported by grants from Fundação de Amparo à
impaired animals.137 This, certainly is some of the strongest evidence
Pesquisa do Estado de São Paulo (FAPESP, grant # 2015/26364-4),
in support of the permanent effects of MD on brain function in rats.
Conselho Nacional de Desenvolvimento Científico e Tecnológico
The findings presented here suggest that some of the long-term
(CNPq), Associação Fundo de Incentivo à Pesquisa and Coordenação
effects of MD are dependent on the age when the pup was deprived
de Aperfeiçoamento de Pessoal de Nível Superior (CAPES). Deborah
and that these effects appear to be modulated by environmental
Suchecki is the recipient of a research fellowship from CNPq.
factors. Another important aspect is related to the test and/or apparatus employed to evaluate the behaviour of an animal, which may generate contrasting data. The studies evaluating spatial memory in maternally-deprived rats strongly support the hypothesis that this
ORCID D. Suchecki
http://orcid.org/0000-0003-1697-8663
early manipulation induces permanent changes in cognitive function. Finally, sex is a major issue, given that males and females may display distinct outcomes, depending on the phase of the oestrous cycle when females are tested.
5 | CO N C LU D I N G R E M A R K S The MD paradigm is an extremely useful template for studying the impact of a transient loss of maternal/paternal care during sensitive periods in development, when several structures of the CNS are maturing, such as, for example, on PND3, which represents the onset
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How to cite this article: Suchecki D. Maternal regulation of the infant’s hypothalamic-pituitary-adrenal axis stress response: Seymour ‘Gig’ Levine’s legacy to neuroendocrinology. J Neuroendocrinol. 2018;30:e12610. https://doi.org/10.1111/jne.12610