Seymour 'Gig' Levine's

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neurotransmitters revealed that GABA and taurine levels were strongly ..... maternal deprivation on neurogenesis in male versus female rats. PLoS ONE. 2009 ...
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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

wileyonlinelibrary.com/journal/jne © 2018 British Society for Neuroendocrinology  |  1 of 17

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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

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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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SUCHECKI

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

|

SUCHECKI

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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      11 of 17

SUCHECKI

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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12 of 17      

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

|

      13 of 17

SUCHECKI

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