Received: 2 November 2020

| Revised: 6 April 2021

| Accepted: 9 April 2021

DOI: 10.1111/ejn.15238

SPECIAL ISSUE REVIEW

How early maternal deprivation changes the brain and behavior?

Maša Čater1,2 | Gregor Majdič1,2

1
Veterinary Faculty, Laboratory for Animal
Genomics, Institute for Preclinical Studies,
Abstract
University of Ljubljana, Ljubljana, Slovenia Early life stress can adversely influence brain development and reprogram brain
2
Faculty of Medicine, Institute of function and consequently behavior in adult life. Adequate maternal care in early
Physiology, University of Maribor, Maribor,
childhood is therefore particularly important for the normal brain development, and
Slovenia
adverse early life experiences can lead to altered emotional, behavioral, and neuroen-
Correspondence docrine stress responses in the adulthood. As a form of neonatal stress, maternal dep-
Gregor Majdič, Veterinary Faculty,
rivation/separation is often used in behavioral studies to examine the effects of early
Laboratory for Animal Genomics, Institute
for Preclinical Studies, University of life stress and for modeling the development of certain psychiatric disorders and
Ljubljana, Gerbičeva ulica 60, 1000 brain pathologies in animal models. The temporary loss of maternal care during the
Ljubljana, Slovenia.
Email: [email protected]
critical postpartum periods remodels the offspring's brain and provokes long-­term ef-
fects on learning and cognition, the development of mental disorders, aggression, and
Funding information an increased tendency for the drug abuse. Early life stress through maternal depriva-
Slovenian Ministry of Education, Science
and Sport, Grant/Award Number: tion affects neuroendocrine responses to stress in adolescence and adulthood by dys-
C3330-­17-­529039; European Regional regulating the hypothalamic–­pituitary–­adrenal axis and permanently disrupts stress
Development Fund
resilience. In this review, we focused on how improper maternal care during early
postnatal life affects brain development resulting in modified behavior later in life.

KEYWORDS
behavior, brain, development, maternal deprivation, programming, stress

1 | IN T RO D U C T ION environment (Alyamani & Murgatroyd, 2018). An import-

ant influence of maternal deprivation has even been found at
Maternal care plays a significant role in the development of the DNA level, as maternal behavior towards their children
children in the postnatal period, and includes care and affection, may control neuroendocrine responses to stress in adulthood
as well as physical, emotional, and social support. Its impor- through permanent epigenetic changes in children's DNA
tance was first described in 1950s by psychiatrists and psy- (van Bodegom et al., 2017; Linnér & Almgren, 2020).
choanalysts John Bowlby, René Spitz, and William Goldfarb The stress response in the adulthood is controlled by the
(Bowlby, 1951; Goldfarb, 1943; Spitz, 1945). Increased ma- hypothalamic–­pituitary–­adrenal (HPA) axis, representing the
ternal care is known to reduce anxiety and improve life-­long main neuroendocrine stress pathway. During stressful events,
stress resilience. Epigenetics and early life environment seem the paraventricular nucleus of the hypothalamus releases two
to program the stress-­related genes for responses to the future neuropeptides, corticotropin-­releasing hormone (CRH), and

Abbreviations: ACTH, adrenocorticotrophic hormone; AVP, arginine vasopressin; BDNF, brain-­derived neurotrophic factor; CRH, corticotropin-­releasing
hormone; GR, glucocorticoid receptor; HPA, hypothalamic–­pituitary–­adrenal axis; NGF, nerve growth factor; NMDAR, N-­methyl-­D-­aspartat receptor;
NPY, neuropeptide Y; OXT, oxytocin; PND, postnatal days; SHRP, stress hyporesponsive period; TH, tyrosine hydroxylase; THDOC,
tetrahydrodeoxycorticosterone.
Edited by: Dr. Mathias Schmidt

© 2021 Federation of European Neuroscience Societies and John Wiley & Sons Ltd

Eur J Neurosci. 2021;00:1–18.  wileyonlinelibrary.com/journal/ejn | 1

2
|    ČATER and MAJDIČ

F I G U R E 1 Schematic overview
of how early life maternal deprivation
causes alterations in brain function in the
adolescence and adulthood

arginine vasopressin (AVP). These two neuropeptides stim- although the exact role of such a developmental period is not
ulate the release of adrenocorticotrophic hormone (ACTH) yet understood.
from the pituitary, which stimulates the adrenal cortex to Stress hypo-­ responsiveness cannot completely prevent
release glucocorticoid hormones (corticosterone in some exposure to glucocorticoids. For example, early separation
animals, cortisol in humans and some animals). When the from the mother from 1 up to several hours is a stressful event
stressor is no longer present, the system returns to a homeo- for neonate animals, especially if it occurs repeatedly, and
static balance via negative feedback loop, involving gluco- it significantly alters ACTH and corticosterone levels (Kuhn
corticoid and mineralocorticoid receptors (Brunton, 2015; et al., 1990). Although dependent on various factors, such trau-
Vazquez et al., 1996). matic events permanently shape neurochemical phenotype of
The neonatal period is a sensitive period of life around the newborns and, consequently, behavior in the adulthood
the time of birth when active neuroplasticity takes place in (Figure 1). Thus, the infant's HPA system is under maternal
the developing brain and stress can affect it through various regulation and is directly influenced by behavioral patterns
mechanisms. The HPA axis is carefully modulated through- of maternal care (Levine et al., 1992; Rosenfeld et al., 1992a;
out life. However, early life events can permanently alter Stanton & Levine, 1988). Numerous studies confirmed the
the responsiveness of HPA axis. The presence of mother negative impact of maternal deprivation on various behaviors
during early life period is of outmost importance to pups. It and on long-­lasting dysregulation of the HPA axis in differ-
reduces anxiety-­like behavior and impairment of short-­term ent species (Brunton, 2015; Miragaia et al., 2018). Rodents
memory later in life, which would otherwise be induced in are often used as a model to investigate the effects of early
pups by early life social stress (Rajan et al., 2019). Weaver emotional attachment disruption on the brain development
et al., (2004) reported that enhanced maternal care during the and consequently on the behavior in adult life (Benmhammed
early life of rats has positive effects on establishing a reduced et al., 2019). Similar consequences of reduced maternal care
stress response later in life. Adult rats exposed to neonatal have also been observed in monkeys and humans (Hegde
stress had higher expression of glucocorticoid receptors in & Mitra, 2020; Kundakovic & Champagne, 2015; Seay
the hippocampus, suggesting a life-­long reduced activity of et al., 1962). In humans, the most severe early-­childhood
the HPA axis. stressful events are usually deprivation, disruption, neglect or
Some publications suggest that the time period from post- abuse (Nemeroff, 2016; Suchecki, 2018).
natal days (PND) 1–­12 in mice and PND 3–­14 in rats is a In this review, we summarized the current literature on
stress hyporesponsive period (SHRP) and is an important de- the molecular mechanisms about the effects of early life ma-
velopmental phase (Levine, 1994; Sapolsky & Meaney, 1986; ternal deprivation on the neonatal brain development, stress
Walker et al., 1986). During this period, adrenal glands have resilience, and vulnerability to develop cognitive deficits and
reduced sensitivity to ACTH and to most stressors. Proper psychiatric disorders in adulthood. Effects on the neuroendo-
maternal care also down regulates the secretion of the ACTH crine system, brain remodeling, and permanent, even trans-
and corticosterone in pups (van Bodegom et al., 2017; generational epigenetic modulation of stress-­sensitive genes
Hofer, 1994; van Oers et al., 1998). Consequently, levels of are presented, comparing results from preclinical studies on
corticosterone are stable and low, and brain development rodents and other laboratory animal models with studies in
proceeds normally in developing mouse and rat pups. With humans. Furthermore, differences in the results from studies
the increasing age of pups, corticosterone levels increase. about early maternal separation are discussed. These likely
Because high corticosterone levels can have deleterious reflect different protocols used, and various factors influenc-
effects on the brain development, it has been proposed the ing the results of such studies must be carefully considered
SHRP period has a protective role in the developing brain for a successful translation of the preclinical results. Recent
(Meaney et al., 1991; Sapolsky & Meaney, 1986). It seems successful approaches to reversing the effects of early mater-
that similar mechanisms of stress resistance are present also nal deprivation are also discussed. Finally, the father's role in
in other animals and perhaps in humans (Schmidt, 2019), the neonatal brain development is also discussed.
ČATER and MAJDIČ   
| 3

2 | M ATE R NA L D E P R IVAT ION Maternal separation has become a collective term de-
AN D S E PA R AT ION MOD E L S scribing a variety of protocols in which pups are removed
from their dams for different time periods before weaning.
Two models of early life stress based on the lack of mater- Procedures vary widely in manipulation, duration, frequency,
nal care are in use (Figure 2). The term “maternal separa- and age of pups at separation (Ellebroek & Cools, 1998;
tion” is commonly used to refer to the daily separation of Levine et al., 1992; van Oers et al., 1998; Rosenfeld et al.,
the pups from the dam, but not from other littermates, while 1992a, 1992b). Separations are usually daily repeated sepa-
“maternal deprivation” refers to the separation of the pups rations from the dam from 1 up to 16 hr, with different num-
from both the dam and littermates and is thus a model of bers of daily repeats. Separations can also be one-­time events,
a social isolation in addition to the stress due to separation but such one-­time events usually last longer, up to 24 hr.
from the mother (Tata, 2012; Zimmerberg & Sageser, 2011). Artificial rearing of the pups and limited bedding/nesting are
Gandelman (1992) described the definition of deprivation as also used as a maternal separation/deprivation models (Rice
the opposite of privation. When the neonates have not been in et al., 2008). The lack of consistency in procedures, the use
contact with their mothers from birth, this is called privation. of different control groups and the use of incorrect statistical
Deprivation, on the other hand, is defined when neonates that methods when related animals are used, makes comparison
live with their mothers are either temporarily or permanently of different studies very difficult (Lehmann & Feldon, 2000;
separated from their mothers. Murthy & Gould, 2018). The genetic background of the ex-
Zimmerberg and Sageser (2011) compared the effects of perimental animals is also important as some effects of early
maternal separation and maternal deprivation on juvenile so- maternal separation might be strain specific. For example,
cial behavior in rats. They showed that maternal separation C57Bl/6 mouse strain is known as one of the most resistant
produces greater stress in dams, resulting in greater maternal to stress, while BALB/c strain is known to be more stress
mediation when reunited with pups, while maternal depriva- sensitive and anxious (Millstein & Holmes, 2007; Savignac
tion causes greater stress on pups, leading to different behav- et al., 2011; Wei et al., 2010). The sex of the animals must
ioral consequences (Miyazaki et al., 2012). In both maternal also be considered, as stress affects males and females dif-
separation and maternal deprivation, pups are separated from ferently (Altemus et al., 2014; Eklund & Arborelius, 2006),
their mother and/or from each other for 1 or more hours each and behavioral tests are not always equally suitable for
day during the first 2 or 3 weeks of life (Aisa et al., 2008; both sexes (Clayton & Collins, 2014). The timing and the
Chen et al., 2012). Both models, maternal deprivation and duration of the stressful event(s) in early life are extremely
separation, are used, sometimes interchangeably, in animal important factors (Murthy & Gould, 2018), and this is espe-
studies to mimic the transient loss of maternal care (licking/ cially important in translational studies as the timing of the
grooming, nursing) during first postnatal days and the SHRP stressful postnatal events in rodents does not always corre-
period. spond to the timing of child abuse, which mostly extends for

F I G U R E 2 Maternal deprivation
and maternal separation are used to model
maternal care absence in the early life in
animal models
4
|    ČATER and MAJDIČ

several years of the childhood (Gunnar & Donzella, 2002). 4 | EFFECTS OF M ATERNAL
Therefore, this aspect arises questions about the direct trans- DEPRIVATION ON THE
lational validity of some early life stress models in rodents NEUROENDOCRINE SYSTEM
(Dunn et al., 2018).
The brain undergoes important structural changes during
perinatal period that include neurogenesis, synaptogenesis,
3 | S E X D I F F E R E NC E S A N D arborisation of the dendrites and axons, myelinization of the
EA R LY LIF E ST R E SS nerve cells, and programmed cell death. Stressful events dur-
ing this period lead to neuroanatomical alterations, changes
The sex of the neonate obviously plays an important role as in physiology and modifications in neuroendocrine func-
different neurobiological vulnerability has been observed tion and behavior later in life (Maccari et al., 2014; Paris &
in males and females in rodents and humans (Barbosa Neto Frye, 2011). Maternal separation has been shown to stimulate
et al., 2012; Bondi et al., 2008; Farrell et al., 2016; Gobinath various brain regions in different ways depending on the tim-
et al., 2015; Kunzler et al., 2015; Miragaia et al., 2018; ing and duration of separation (Fabianova et al., 2018). Early
Oomen et al., 2009). However, the negative effects of early chronic stress has been shown to affect the development of
life stress on neurogenesis and plasticity of the hippocampus, the paraventricular nucleus of the hypothalamus, the amyg-
as well as the prevalence of psychopathologies and behav- dala, the hippocampus, and the excitatory feed-­forward and
ioral abnormalities are often studied in only one sex which the negative feedback loop of the HPA axis (van Bodegom
needs to be changed in the future studies that will include et al., 2017; Brunton, 2015; Holsboer, 2000; Murgatroyd
both sexes. & Bradburn, 2016). Maternal deprivation in young mouse
Early life stress affects the maturation of the catechol- pups triggers CRH mRNA overexpression in the parvocel-
aminergic system. It induces a reduction of the tyrosine lular neurons in the paraventricular nucleus, increasing their
hydroxylase (TH)-­immunoreactive fibers in the prefrontal excitatory input and resulting in the exaggerated ACTH and
cortical regions and in prelimbic cortex and an increase in corticosterone responses (Gunn et al., 2013). Maternal dep-
the TH positive fibers' density in the orbitofrontal cortex. rivation also reduces hippocampal expression of glucocor-
These effects are more pronounced in male rodents than in ticoid and mineralocorticoid receptors through a disturbed
females and are long lasting, with the sex difference being glucocorticoid negative feedback. In our experiments with
preserved in adult life (Kunzler et al., 2015). The sex dif- early maternal deprivation in mice, a reduction in glucocor-
ference in the density of TH-­positive fibers could explain ticoid receptor mRNA expression in the hippocampus has
the differences in sensitivity of males and females to the been observed in adult males but not in females (Cater and
neonatal stress. Majdic, manuscript in preparation).
Sex-­related differences after neonatal stress have also Neuroactive steroids have an important role in the regu-
been reported for the hippocampal volume and plasticity and lation of stress response in adult animals, as they modulate
in the density of hippocampal neurons in rodents and hu- the HPA axis function. Their levels are altered differently
mans. Maternal deprivation results in reduced cell prolifer- during acute or chronic stress. In adulthood, allopregnano-
ation in the dentate gyrus and reduced number of immature lone and tetrahydrodeoxycorticosterone (THDOC) levels in
neurons in the ventral hippocampus in adult male rats, but the brain and blood normally increase after acute stress. This
not in females. This suggests that hippocampal neurogenesis negatively affects the activated HPA axis, resulting in the ter-
is more sensitive to neonatal stress in male than in female mination of the stress response and homeostasis restoration.
rats (Gobinath et al., 2015). However, the existence of sex-­ However, adult chronic stress usually reduces allopregnano-
related differences in hippocampal volume reduction due to lone levels and 5α-­reductase expression in the hippocampus,
early maternal deprivation is controversial. While the study amygdala and prefrontal cortex (Agis-­Balboa et al., 2007).
by Buss et al., (2007) reported a smaller hippocampal size in Gunn et al., (2013) showed that allopregnanolone was inef-
women following a lack of maternal care during early child- fective at suppressing CRH neuronal expression in adult mice
hood, Frodl et al., (2002) reported that smaller hippocampus that were exposed to stress as pups. This was likely caused by
is more commonly observed in men. permanent insensitivity of the CRH neurons due to increased
In humans, lack of maternal care in the early childhood glutamergic excitation of CRH neurons in the paraventricular
causes cognitive and emotional behavioral disorders, as ob- nucleus of the hypothalamus. This indicates the importance
served in children growing up in orphanages (Hostinar & of neuroactive steroids for modulation of neuronal activity
Gunnar, 2013). Interestingly, psychopathologies related to during neonatal period for a normal development of the HPA
early life stress are reported to be twice as common in fe- axis and for its normal responses to stress later in life.
males as in males, although the exact reason for this is still Neuropeptide Y (NPY) plays an important role in stress
unknown (Goodwill et al., 2019). response, in addition to its anxiolytic and neuroprotective
ČATER and MAJDIČ   
| 5

properties (Heilig, 2004; Miragaia et al., 2018; Thorsell & in the postnatal period are sensitive to experience-­dependent
Mathe, 2017). Adult stress alters the biosynthesis of the NPY modifications. Brain development is highly dependent on
in brain regions like the brainstem, hypothalamus, and limbic the regulation by neurotrophins such as nerve growth factor
system, affecting emotional-­affective behavior, food-­intake, (NGF) and brain-­derived neurotrophic factor (BDNF). These
and stress response (Reichmann & Holzer, 2016). NPY ex- neurotrophins regulate proliferation, survival, and differen-
pression is reduced in several brain areas involved with mo- tiation of some neuronal populations in both the central and
tivational and emotional behaviors (amygdala, hippocampus) in the peripheral nervous system. Neurotrophins also act as
in animal models of posttraumatic stress disorder. NPY defi- mediators of synaptic and morphological plasticity (Cirulli
ciency is therefore thought to be one of the additional triggers et al., 2003; McAllister et al., 1999). The expression of NGF
for the development of vulnerability to later psychopathol- and BDNF is localized to the hippocampus and neocortex
ogy, leading to behavioral disorders (Cohen et al., 2012; and is developmentally regulated. Their expression increases
Miragaia et al., 2018). significantly when maximal neuronal growth, differentiation
Early maternal separation affects other neuroendocrine and synaptogenesis occur (Davies, 1994), suggesting neuro-
pathways. It is well documented that neuropeptides AVP and trophins are involved in the postnatal brain modifications and
oxytocin (OXT) expression is altered in stressed rodent pups play a role in the development of complex behaviors.
(Riveros-­Barrera & Dueñas, 2016; Veenema et al., 2006). As It is now well established that neurogenesis continues after
both are involved in the regulation of various social behav- postnatal development in rodents, although it is not yet clear
iors and emotions, different behavioral disorders can conse- whether neurogenesis also occurs in adult humans. Several
quently occur during adolescence or in adulthood in stressed studies demonstrated that the mammalian brain retains the
pups (Doreste-­ Mendez et al., 2019; Lesse et al., 2017). ability to generate new neurons in adulthood. Adult neural
Neonatal stress increases AVP receptor binding in the lateral stem cells or progenitor cells have been localized in the adult
septum, ventromedial hypothalamus, piriform cortex, and brain, mainly in the subventricular zone of the lateral ven-
hippocampus and decreases AVP binding in the arcuate nu- tricles and in the dentate gyrus of the hippocampus (Braun
cleus. OXT receptor binding is reduced in the lateral septum, & Jessberger, 2014; Gage, 2000). Therefore, the mammalian
caudate putamen and agranular cortex and increased in the brain appears to have the ability to undergo functional ad-
medial preoptic area and ventromedial hypothalamus (Lukas aptations to changes in the internal or external environment.
et al., 2010). Veenema et al., (2006) reported that mater- Although several studies suggested that adult neurogenesis is
nal separation of rat pups triggered long-­lasting changes in present also in the human brain (Boldrini et al., 2018), a re-
AVP expression and altered the behavior of stressed animals. cent study (Sorrells et al., (2018) reported that neurogenesis
Neonatally stressed rats had increased AVP expression in the in the human brain declines rapidly after the first year of life
paraventricular nucleus of the hypothalamus and altered ag- and is not common in adolescents and adults. This study sug-
gressive and depression-­like behaviors in adulthood. Riveros-­ gests that hippocampal neurogenesis is rare in adult humans.
Barrera and Dueñas (2016) also reported sex differences OXT Interestingly, the same study suggests that adult neurogenesis
and AVP expression as a stress response. They observed in- is also absent in the hippocampi of aquatic mammals, which
creased OXT levels in the brain of neonatally stressed adult are known for their human-­like features such as large brains,
female rats, whereas OXT levels were reduce in neonatally longevity, and complex behavior. The controversy over
stressed adult male rats. In contrast, AVP levels were reduced human adult neurogenesis has been broadly discussed in the
in adult male and female rats that were exposed to neonatal paper by Danzer (2018) and by Kempermann et al., (2018).
stress. The potential connection between early life stress and Many questions remain unanswered due to the difficulty of
OXT was reported also in humans. Women who were abused assessing adult neurogenesis in humans. There is a clear need
in childhood had lower cerebrospinal OXT levels than non-­ to direct research towards a more quantitative analysis that
abused women (Heim et al., 2008). Therefore, the observed aims at relating parameters of neurogenesis to other features
deficits in social behaviors could be connected to alterations of plasticity and behavior.
in OXT/AVP action in the central nervous system. Adult neurogenesis plays an important role in the brain
homeostasis. However, early life stress can cause perturba-
tions of this homeostasis. Postnatally, the developing brain
5 | E F F E C TS ON B R A IN is very sensitive to various influences from the environment.
RE M O D EL ING Adverse experiences during early life can hinder brain mat-
uration, leading to permanent brain damage and psychiatric
Neonatal mammalian nervous system is immature. During the disorders later in life (Cirulli et al., 2003). Studies with rats
early postnatal period, the connectivity within the cerebral cor- exposed to early life maternal separation suggest that stress
tex as well as between cortex and other brain areas is increas- increases NGF expression in the hypothalamus, cerebral
ing. However, accelerated neurogenesis and synaptogenesis cortex, and hippocampus of stressed pups, while an increase
6
|    ČATER and MAJDIČ

of cell death was observed in the neocortex, white matter, most likely has an important role. Postnatal stress can trigger
and dentate gyrus (Cirulli et al., 2000; Zhang et al., 2002). epigenetic changes such as alterations in DNA methylation
The expression of BDNF and NMDA receptors was signifi- and hydroxymethylation, posttranslational histone modifi-
cantly reduced in the hippocampus of adult rats which were cations, and microRNA activity (Stankiewicz et al., 2013;
maternally deprived during postanatal development (Roceri Weaver et al., 2004; Zannas & West, 2014), resulting in
et al., 2002). Interestingly, changes in the levels of neuro- permanent changes in gene expression patterns. These modi-
trophins and in the expression of NMDA receptor have also fications alter the epigenetic programming of the genes
been observed in human patients with some psychiatric dis- involved in HPA axis regulation. The type and magnitude
orders (Akbarian et al., 1996; Gao et al., 2000; Takahashi of epigenetic changes caused by environmental factors are
et al., 2000), although it is not known whether these alter- highly dependent on the developmental stage at which they
ations are anyhow connected to stress. occur (Provencal & Binder, 2015). Maternal care during
Cognitive brain networks, especially in the hippocam- early life in laboratory mice and rats and childhood trauma
pal and prefrontal cortex regions, which are involved in in humans have been shown to be linked to long-­term altera-
emotional processes and social behaviors, appear to be es- tions in global as well as regional DNA methylation and his-
pecially vulnerable to the effects of stress. Early life ma- tone modification profiles (Klengel et al., 2013; Murgatroyd
ternal deprivation causes brain remodeling with abnormal et al., 2009; Weaver et al., 2004). Maternal separation could
maturation or rewiring of neuronal connectivity (Kartsen reduce or increase methylation of promotor regions of dif-
& Baram, 2013). An increased quantity, and consequently ferent genes. However, some DNA methylation differences
function, of excitatory synapses to stress-­sensitive neurons are now known to be strain-­specific, as shown by Kember
have been observed in the murine hypothalamus (Gunn et al., (2012), suggesting that epigenetic responses to an ad-
et al., 2013). However, in the prefrontal cortex, amygdala verse environment in early life might also differ due to ge-
and hippocampus, reduced hypertrophic dendritic trees, as netic background.
well as altered number and reduced function of synapses Maternal separation sustains the methylation of the
and overall reduction of hippocampi were observed after glucocorticoid receptor (GR) exon I7 promoter, which de-
chronic early life stress in rodents and humans (Chen & creases expression of GR in the hippocampus of rat pups.
Baram, 2016; Ivy et al., 2010; Reshetnikov et al., 2020). In Hypermethylation of the GR promoter results in decreased
our studies, we also found that early maternal deprivation transcription and altered reactivity of the stress hormone sys-
caused reduced size of the hippocampi in males and fe- tem, resulting in higher anxiety in pups (Weaver et al., 2004).
males, and this difference persisted in adult life (Cater and In humans, a similar mechanism involving hypermethylation
Majdic, manuscript in preparation). Reduced hippocampi of the human orthologue site of GR promoter (GR 1F) was
could be explained by high levels of glucocorticoids caused discovered in postmortem hippocampus of suicide victims
by early life stress. Chronic exposure to high levels of glu- exposed to child abuse (McGowan et al., 2009). Mice, iso-
cocorticoids promotes faster aging of the hippocampus and lated from their mothers after birth, have persistently high
results in its atrophy, affecting memory and learning abil- expression of AVP in the paraventricular nucleus as well as
ities with increased vulnerability for Alzheimer's disease elevated blood corticosterone levels in adulthood. Altered ex-
(Kosik, 1992). Landfield et al., (1987) reported such effects pression of AVP, a hypothalamic peptide essential for regula-
of glucocorticoids in rats, while Lupien et al., (1998) stud- tion of the HPA response, correlates with the reduced levels
ied old people with chronically elevated cortisol and re- of DNA methylation in the AVP promotor region in the para-
ported similar results. The degree of hippocampal atrophy ventricular nucleus (Murgatroyd et al., 2009).
correlates with the degree of cortisol elevation over time. Epigenetic changes in the hippocampus of laboratory
Plastic changes in the hippocampus and hypothalamus are rodents and humans, caused by lack of maternal care in
thought to be caused mainly by the changes in neurotro- early life, are detected across large regions of the DNA
phins expression induced by early life stress, as these two (McGowan et al., 2009; Weaver et al., 2004). Changes are
brain regions are probably the sites of interaction between found not only in gene promoters but also in intragenic and
NGF and HPA axis (De Kloet, 1991; van Oers et al., 1998; intergenic regions that may be enhancer or repressor re-
Smith et al., 1997). gions, resulting in gene-­specific transcriptional adaptations.
Hypomethylation of DNA due to early maternal deprivation
has also been reported in other genes involved in the stress
6 | EF F E C TS AT T HE response, such as CRH, glucocorticoid receptor, SGK1, and
EP IG EN E T IC L E V E L FKBP5 genes (Chen et al., 2012; Klengel et al., 2013; Nuber
et al., 2005; Smart et al., 2015). SGK1 encodes a serine/
The molecular basis of the long-­life effects of early life ma- threonine-­protein kinase, which is under acute transcrip-
ternal deprivation is not yet clear, but epigenetic regulation tional control by glucocorticoids. SGK1 contributes to the
ČATER and MAJDIČ   
| 7

regulation of transport, hormone release, inflammation, the first generation of offspring from maternally separated
neuroexcitability, cell proliferation, and apoptosis (Lang & mothers and affect male and female offspring equally.
Shumilina, 2013; Lang et al., 2010). The FKGP5 protein Impaired emotional behavior and cognitive deficits in
acts as a co-­chaperone and modulates the GR activity in re- adult, neonatally stressed mice, are associated with increased
sponse to stressors and several other cellular processes in acetylation of histone H4K12 protein in the forebrain.
the brain and on the periphery. FKGP5 overexpression in However, in the absence of early maternal separation in sub-
the brain has also been associated with various behavioral sequent generations, epigenetic transmission fades. Different
pathologies (major depressive disorder, posttraumatic stress results from these studies suggest that transgenerational trans-
disorder, suicide attempts, aggression) in humans (Zannas mission of epigenetic modifications due to early life stress is
et al., 2015). Therefore, FKBP5 might also be an interesting species and strain specific and needs to be examined further.
therapeutic target. Some studies with macaques (Maestripieri, 2005) also show
Adverse circumstances in early life can cause genome-­ that maternal abuse of offspring, similar to child abuse in hu-
wide epigenetic marks. Some epigenetic changes are specific mans (Widom et al., 2015), can also be transmitted across
and occur only in a small number of cells in specific neural generations.
circuits, while others are observed in all tissues and cell types
(Provencal & Binder, 2015). This explains why stressful
events in the postnatal period not only have long-­term effects 7 | EFFECTS ON EM OTION ,
on brain function but also increase the risk for metabolic dis- COGNITION AND AGGRESSION
orders and affect the immune system. Provencal et al., (2012)
studied the impact of maternal rearing during the first year The separation of pups from their mothers has numerous
after birth on DNA methylation in rhesus macaques and re- consequences that become apparent during pups adolescence
ported alterations in both the prefrontal cortex and in T cells. and adulthood. These include disruption of some behavioral
In humans, changes in DNA methylation in peripheral blood patterns (social and emotional), impairment of cognition and
cells were observed after early childhood trauma (Suderman memory, development of anxiety-­and depression-­like behav-
et al., 2014; Weder et al., 2014). Differential levels of meth- iors, and increased succeptibility to drug abuse (Alyamani &
ylation have also been reported in promoter regions of loci Murgatroyd, 2018; Hofer, 1994). There is evidence that early
encoding microRNAs, suggesting that microRNAs also play life stress reduces neurosteroidogenesis and alters the activity
an important role in modulating the stress response (Issler of neuroactive steroids, which subsequently leads to altera-
et al., 2014; Suderman et al., 2014). tions in the HPA axis activity (Brunton, 2015). The long-­term
Among the known epigenetic modifications, DNA meth- dysregulatory effects are strongly dependent on the age of the
ylation is the best known permanent modification induced pups at which the maternal deprivation occurred, regardless
by early life exposure to stress. Effects on DNA methylation whether it was acute or chronic (Faturi et al., 2010; Girardi
are especially important because such epigenetic changes can et al., 2014; Levine et al., 1992).
sometimes be inherited into the next generations (Franklin Permanently altered anxiety-­like behavior in animal mod-
et al., 2010; McEwen, 2020; Meaney, 2001; Nishi, 2020). els and anxiety in humans are likely caused by altered levels
This was indeed shown for early life stress, although these of the CRH in the amygdala and altered glutamate neurotrans-
effects are not unequivocal. Mothers, who experienced mission in the hippocampus (Brunton, 2015). Increased inci-
stress and whose brains were remodeled, appear to trans- dence of anxiety and depression after early life stress might
mit epigenetic changes to their offspring. In mice, chronic be related to altered neuroactive steroids activity, as reduced
social stress in lactating mothers of F0 generation has been levels of allopregnanolone have also been found in people
shown to influence maternal caregiving behavior, basal cor- with anxiety disorders, major depressive disorder, post-­
tisol levels, and neuroendocrine gene expression in dams traumatic stress disorder and schizophrenia (Brunton, 2015).
of the next generations (Alyamani & Murgatroyd, 2018; Studies in animals confirmed the anxiolytic effects of neu-
Murgatroyd et al., 2016; Murgatroyd & Nephew, 2013). roactive steroids and their role in preventing anxiety-­like
Franklin et al., (2010) showed that the transmission of early behavior by suppressing of CRH expression, primarily in
life stress effects in C57Bl/6J mice occurs through males and the paraventricular nucleus of the hypothalamus (Crawley
affects the offspring in a sex-­dependent manner. Early life et al., 1986; Edinger & Frye, 2005; Holsboer, 2000; Morrow
stress induces alterations in DNA methylation in the germline et al., 2006; Patchev et al., 1994; Rodgers & Johnson, 1998;
of stressed males, affecting multiple genes. The epigenetic Vivian et al., 1997; Zimmerberg & Sageser, 2011).
alterations are present in subsequent generations in both the Long-­ term cognitive impairments such as decreased
male germline and in the brain. On the other hand, Schmauss learning abilities and reduced memory are also often linked to
et al., (2014) reported that behavioral and epigenetic pheno- the early life maternal deprivation stress. The hippocampus,
types in stress susceptible BALB/c mice are transmitted to which is important for memory consolidation and learning, is
8
|    ČATER and MAJDIČ

strongly affected by neonatal stress, which induces changes in maternal aggression was observed in animals and humans
the hippocampal structure and function. Neonatally stressed (Nephew, 2012; Veenema & Neumann, 2008). Maternal
rodents exhibit reduced neurogenesis (Korosi et al., 2012; deprivation decreases the expression of hypothalamic OXT
Mirescu et al., 2004; Oomen et al., 2010), reduced BDNF ex- in female mice, leading to increased aggressive behavior
pression (Roceri et al., 2002) and decreased long-­term poten- (Veenema et al., 2007). The precise underlying mechanisms
tiation (Brunson et al., 2005) in the hippocampus throughout of increased maternal aggression and decreased intermale
life. Neonatally stressed rats have altered mossy fiber den- aggression after early maternal deprivation are not yet un-
sity, reduced dendritic length, atrophy and decreased spine derstood. Intermale aggression and maternal aggression are
density, suggesting significantly altered synaptic plasticity functionally distinct behaviors, and different types of ag-
(Brunson et al., 2005; Huot et al., 2002; Ivy et al., 2010; gressive behaviors are regulated by different neurobiological
Oomen et al., 2011). Some of these effects are sex-­specific pathways. However, it is not yet known which genetic path-
and highly correlated with the timing of stress (Brunson ways are altered by early life maternal deprivation and how
et al., 2005; Oomen et al., 2009). They may be controlled they modulate changes in aggressive behaviors in both males
by sex steroids and neuroactive steroids (Brunton, 2015). and females.
Permanent alterations in CRH expression have been pro-
posed as one of the factors that mediate stress-­related cog-
nitive impairment. Several animal models of early life stress 8 | EFFECTS OF M ATERNAL
show that impaired levels of glucocorticoids and mineralo- DEPRIVATION ON DRUG ABUS E
corticoids in the hippocampus and an increase in the CRH
levels in hypothalamic paraventricular nucleus are associated Maternal separation in early life influences the risk of addic-
with changes in cognition (Brunton, 2015; Chen et al., 2012; tion in adulthood. Early life stress is an important risk factor
Gunn et al., 2013; de Kloet et al., 2008). for alcohol, morphine, methamphetamine, cocaine, and can-
Among many behavioral changes caused by lack of ma- nabinoid abuse in the adulthood (Delavari et al., 2016), likely
ternal affection and care in early life, aggressive behavior in through modulation of the mesolimbic dopaminergic reward
adulthood is often increased as a consequence of neonatal pathway.
stress. In mice, an increased maternal aggression towards Studies of interactions between stress and substance
intruders has been observed in adult dams that were mater- abuse suggest the involvement of neurotransmitter sys-
nally deprived in early life (Nephew, 2012). Interestingly, tems such as the opioid and dopamine systems (Ploj
somewhat counterintuitively, maternally separated rats, also et al., 2003). The mesolimbic dopaminergic pathway
showed increased maternal behavior (nest building, pup forms the reward pathway, and importance of dopamine
retrieval) (Bodensteiner, 2012). Possibly, this suggests a in regulating the reward pathway has long been recog-
compensatory mechanism in rats, whereby females lacking nized (Solinas et al., 2018). The ventral tegmental area
maternal care respond with increased maternal care towards is the main source of dopamine in the mesolimbic path-
their pups. On the other hand, adult male mice that were way, with primary connections to the nucleus accumbens
stressed in early life show less aggressive behavior than con- and prefrontal cortex. Dopaminergic innervation develops
trol males in resident-­intruder tests (Veenema et al., 2007). In postnatally and changes in this system occur up to PND 60
this study, stress-­induced changes in the AVP levels in males in rats (Suri et al., 2015). Maternal deprivation during the
and OXT levels in females were detected in the paraventricu- postnatal period can alter the morphology and signaling of
lar nucleus of the hypothalamus, suggesting their role in reg- the dopaminergic system. Long-­lasting changes in the con-
ulating the development of aggressive behavior. centration of dopamine receptors in the brain and increased
Both, AVP and OXT, are commonly associated with the uptake of ethanol, cocaine, and morphine in adolescent and
development of early life stress-­related depression, anxiety, adult male rats (Kosten et al., 2000; Moffett et al., 2007;
addictions, or aggressive behavior. Among other roles, AVP Ploj et al., 2003; Vazquez et al., 2005) have been observed
is known to be involved in the endocrine stress response as a consequence of continuous maternal separation during
through its actions in the pituitary gland, where it stimu- the first days after birth. In the adult rat hippocampus, the
lates the secretion of ACTH (Nephew, 2012; Veenema & density of the dopamine D1 receptors was altered as a con-
Neuman, 2008). Maternal deprivation in male mice increases sequence of early life stress, while the density of dopamine
AVP levels in the hypothalamus and results in decreased D2 receptors was altered in the ventral tegmental area and
aggression between males, suggesting that AVP inhibits ag- periaqueductal gray (Ploj et al., 2003). Maternal depri-
gressive behavior (Veenema et al., 2007). In addition, OXT vation causes hypoactivity of the enkephalinergic system
is known to be an important mediator of affiliative behaviors. and hypersensitivity to the reinforcing properties of mor-
The affiliative actions of OXT in mammals are strongly as- phine (Kalinichev et al., 2000; Vazquez et al., 2006), lead-
sociated with aggression, and inhibitory effect of OXT on ing to morphine dependence in adult rats. The proposed
ČATER and MAJDIČ   
| 9

mechanisms of action for early stress-­induced drug abuse to prevent the transgenerational transmission of epigenetic
in adulthood are neurochemical changes in the brain sero- changes that occur after early life stress in mice. They altered
tonin system (Feinn et al., 2005), changes in the HPA axis levels of H4K12 protein by treating adolescent pups with the-
(Huot et al., 2001) and changes in the endocannabinoid ophylline or fluoxetine after postnatal maternal separation.
system (de Almeida Magalhã et al., 2017; Llorente-­Berzal Reduced levels of H4K12 protein resulted in improvement
et al., 2013; Romano-­Lopez et al., 2012). in the pups' cognitive deficits but worsened emotional abnor-
The association between neonatal isolation from the malities. In contrast, the pups' emotional phenotype improved
mother and cocaine use in adulthood has been demon- when levels of H4K12 protein were increased, but no effects
strated in animals and humans. Increased cocaine abuse and on the cognitive deficits were observed. Treatments that pre-
greater sensitization to cocaine are associated with maternal vented the appearance of either emotional or cognitive defi-
deprivation in mice and rats (Kikusui et al., 2005; Kosten cits in the stressed mothers also prevented the establishment
et al., 2004; Martini & Valverde, 2012), and the endocan- of these deficits in their offspring. These results suggest that
nabinoid system is altered in adulthood by early life stress epigenetic transgenerational effects of early life stress could
(Llorente-­Berzal et al., 2013). Early life stress increases im- be prevented by effectively controlling the expression of spe-
pulsive behavior and depressive-­like behavior in maternally cific genes that are sensitive to epigenetic modifications in-
deprived rats, and these increase the risk for cannabinoid duced by early life stress.
abuse (Marco et al., 2009). Similarly, increased vulnerabil- Life-­long memory deficits have been shown to develop
ity to methamphetamine dependence has been observed in after maternal deprivation due to decreased expression of
maternally deprived rats (Lewis et al., 2013). Several stud- BDNF in the hippocampus. Environmental enrichment, ad-
ies in humans have confirmed the strong association be- ministered to rat pups in the post-­weaning period follow-
tween childhood abuse or neglect and substance abuse later ing maternal deprivation, increased hippocampal BDNF
in life (Dube et al., 2003; Koob & Volkow, 2010; Naqavi levels and protected against cognitive deficits (Menezes
et al., 2011; Sorensen et al., 2006), likely involving similar et al., 2020). In addition, an enriched environment has a ben-
alterations in the dopaminergic system as described in ani- eficial effect on alcohol intake and aggressive behaviors in
mal studies. rats, which often occur as a consequence of early life stress
(Odeon & Acosta, 2019). Environmental enrichment is also
effective in reversing the effects of early life stress in anxiety-­
9 | R E V E R S ING T H E E F F E C TS OF and depression-­like behaviors (Gonzales-­Pardo et al., 2019).
MATE R NA L DE P R IVAT IO N Interestingly, Papadakakis et al., (2019) reported that music
as a form of environmental enrichment also improved some
Numerous studies addressed the possibility of brain regener- behavioral impairments caused by early life stress. The ro-
ation after early life stress, caused by maternal deprivation, to dent studies correspond with the studies of early life parent–­
reverse effects of stress and prevent life-­long consequences. child separation, as an enhanced and stimulating environment
Different methods such as environmental enrichment or gene in adolescence helps to recalibrate cortisol reactivity during
expression regulation, and different neuronal pathways have puberty in human children (Gunnar et al., 2019; Zhang
been targeted in such studies. et al., 2021).
NPY deficiency seems to be one of the main effects of Depression-­like behavior as a consequence of early life
maternal deprivation, causing higher vulnerability to the stress has been reported to be successfully reduced by treat-
development of behavioral pathologies. Interestingly, NPY ment with progesterone. Administration of progesterone to
deficiency can be reversed by intranasal administration of neonatally stressed mouse pups had antidepressant-­like ef-
NPY (Serova et al., 2013, 2014), suggesting NPY replace- fects through attenuating the neuro-­immune response and
ment as a potential therapeutic approach to prevent or re- oxidative stress in the hippocampus (Nouri et al., 2020).
store stress-­related psychopathologies. Behavioral disorders Memantine, commonly used to treat symptoms of
associated with maternal deprivation in the postnatal period Alzheimer's disease, has been reported to have beneficial
may also occur as a consequence of epigenetic dysregulation. effects on regeneration of the stressed brain and as a preven-
Overexpression of FKBP5 due to promotor hypomethylation tive treatment for schizophrenia. Behavioral changes, volu-
has been targeted in the development of potential therapies. metric changes in the brain, and abnormalities in synaptic
Recently, several selective FKBP5 blockers were developed, connectivity induced by early maternal deprivation in rats,
showing promise for the treatment of stress-­related disorders. were successfully improved by s.c. administration of me-
Studies in mice have shown that such compounds can stimu- mantine to stressed neonates. Memantine seems to modulate
late neurite growth in primary hippocampal neuronal cultures the action of N-­methyl-­D-­aspartate receptors (NMDAR) and
and promote HPA axis homeostasis and stress-­coping behav- regulates dopaminergic transmission to the prefrontal cortex
iors (Gaali et al., 2015). Schmauss et al., (2014) studied how (Uribe et al., 2019).
10
|    ČATER and MAJDIČ

10 | CA N LACK OF PAT E R NA L et al., 2020). Furthermore, deficits in OXT expression and

CA R E A L S O CAU SE E A R LY L IF E poor communication between the prelimbic cortex and para-
ST R E S S ? ventricular nucleus have been found in both sexes of mandarin
voles exposed to paternal deprivation, consistent with stud-
In socially monogamous and biparental species, found in ies in humans and other animals (Bambico et al., 2015; He
primates (marmoset, tamarin, gibbon, siamang), rodents et al., 2017; Nephew, 2012; Rutter et al., 2001). Additionally,
(beaver, acouchi), carnivores (wolf, coyote, jackal), and ar- in humans, an association between father absence in the early
tiodactyls (dik-­dik) (Kleiman, 1977), fathers together with childhood and risk for alcoholism, aggressiveness, and delin-
mothers protect and care for the offspring. Paternal care quency has been reported (Baskerville, 2002; Boothroyd &
comprises all the behaviors of the father that benefit his Cross, 2017; Ojeda et al., 2020; Vaden-­Kiernan et al., 1995).
offspring (Fernandez-­Duque et al., 2009). However, pater- Similarly to maternal deprivation, several studies suggest that
nal deprivation in biparental species is much less studied. paternal deprivation effects can also be transmitted across
Behaviors such as the father transporting his infants and pro- generations in both animals and humans (Marler et al., 2003,
tecting them from predators have a direct impact on the infant 2005; Pembrey et al., 2014; Rodgers et al., 2013).
survival (Muller & Thompson, 2012). In mammals, paternal
care is observed in less than 10% of species, with the high-
est incidence of paternal care behavior found in the primates 11 | SUM M ARY AND
(Kleiman & Malcolm, 1981). Prolactin, AVP, and OXT have CONCLUSIONS
been hypothesized to stimulate paternal caregiving in ro-
dents, carnivores, and primates, whereas testosterone appears Exposure to stress in early life can have long-­term conse-
to have an opposite effect in mammals (Boner & Fernandez-­ quences for health in adulthood and plays an important role
Duque, 2017). However, further studies are needed to deter- as a trigger for breaking natural stress resilience, leading
mine the underlying mechanisms of how these hormones are to increased vulnerability to psychopathological disorders
involved in paternal care. and substance abuse. Postnatal maternal absence induces
Lack of paternal care increases the risk for emotional and persistent modifications of the HPA axis in offspring by af-
behavioral problems in adulthood. In rodents, most stud- fecting brain development and exerting a variety of lasting
ies about lack of paternal care and its effects on offspring effects, such as genetic reprogramming and brain remod-
development have been conducted in mandarin voles and eling, leading to changes in neuroendocrine signaling, neu-
California mice. The lack of paternal affection in early life ronal morphology, and plasticity. A hyperresponsive HPA
leads to altered play behavior, pair-­bonding, and social recog- axis amplifies the amygdala excitatory drive and impairs the
nition in mandarin voles (Cao et al., 2014; Kelly et al., 2020; regulatory negative feedback function of the hippocampus
Wang et al., 2012; Yu et al., 2012). Furthermore, increased and prefrontal cortex. The psychopathologies that develop
levels of anxiety and reduced levels of sociability have been as a consequence of early life stress depend on the develop-
found in mandarin voles lacking adequate neonatal paternal mental stage affected. Therefore, lack of maternal care has
care (He et al., 2019; Jia et al., 2009). In the brains of man- been a research model to study stress effects on brain de-
darin voles, sex-­specific changes in the presence of receptors velopment, occurrence of psychopathologies, problems with
for OXT, AVP, estrogens, and dopamine have been found as memory and learning and the development of aggressive and
a result of neonatal paternal deprivation (Yuan et al., 2020). addictive behaviors for several decades. It is most commonly
In biparental California mice, reduced aggression, increased studied in laboratory rodents, followed by primates, although
anxiety-­like behavior, and impaired adult learning and mem- there are now also numerous studies in humans with a history
ory are frequently observed as a consequence of reduced of child abuse.
paternal care in the neonatal period (Agarwal et al., 2020; Maternal absence is simulated in preclinical studies by
Frazier et al., 2006; Gleason & Marler, 2013; Marler using two approaches, maternal separation and maternal
et al., 2005). Sex-­dependent changes in the hippocampus due deprivation, although they are not equally potent in eliciting
to paternal deprivation in early life have also been reported. the stress response in pups. Lack of contacts with siblings
Female California mice exposed to paternal deprivation ex- in addition to maternal absence represents greater stress for
hibit reduced cell survival in the hippocampal dentate gyrus, pups, making the maternal deprivation approach more simi-
indicating increased hippocampal vulnerability and greater lar to simulating early life stress in the form of one-­time or
deficits in cognitive performance in females than males sustained moderate social stress in humans. The interchange-
(Glasper et al., 2018). Studies in degus demonstrated that able use of the two approaches in stress studies, as well as the
deprivation of paternal care alters neuronal connections in different time frames in which the manipulation occurs and
the limbic system and reduces the density of symmetric shaft whether it is applied acutely or chronically, leads to some-
synapses in the offspring (Ovtscharoff et al., 2006; de Schultz times conflicting results. This represents one of the main
ČATER and MAJDIČ   
| 11

drawbacks of maternal deprivation studies. It is known that ORCID

different brain regions develop at different time periods with Maša Čater https://orcid.org/0000-0002-2477-5279
the hippocampus developing early; therefore, the hippocam-
pus may be the most vulnerable to the effects of early stress. R E F E R E NC E S
Therefore, the age at which maternal deprivation occurs is Agarwal, P., Palin, N., Walker, S. L., & Glasper, E. R. (2020). Sex-­
one of the critical factors influencing stress-­related outcomes dependent effects of paternal deprivation and chronic variable stress
in adolescence and adulthood. In addition, epigenetic effects, on novel object recognition in adult California mice (Peromyscus
californicus). Hormones and Behavior, 117, 104610. https://doi.
which are interactions between genes and environment, influ-
org/10.1016/j.yhbeh.2019.104610
ence the outcome. Sex is another important factor, as differ-
Agis-­Balboa, R. C., Pinna, G., Pibiri, F., Kadriu, B., Costa, E., &
ent neurochemical and behavioral alterations were observed Guidotti, A. (2007). Down-­regulation of neurosteroid biosynthesis
in males and females. Therefore, greater uniformity in manip- in corticolimbic circuits mediates social isolation-­induced behav-
ulation protocols should be sought in future studies to achieve ior in mice. Proceeding of National Academy of Science USA, 104,
better comparability and reproducibility of studies. 18736–­18741.
As numerous studies have convincingly demonstrated in Aisa, B., Tordera, R., Lasheras, B., Del Rio, J., & Ramirez, M. J. (2008).
recent years, early life stress has important consequences Effects of maternal separation on hypothalamic-­pituitary-­adrenal re-
sponses, cognition and vulnerability to stress in adult female rats.
for the well-­being of adult animals and humans. Maternal
Neuroscience, 154, 1218–­1226.
deprivation or separation triggers long-­lasting changes in the
Akbarian, S., Sucher, N. J., Bradley, D., Tafazzoli, A., Trinh, D., &
brain. Although we have learned much about the effects of Hetrick, W. P. (1996). Selective alterations in gene expression for
maternal separation/deprivation in both animals and humans, NMDA receptor subunits in prefrontal cortex of schizophrenics.
we still do not understand all molecular and cellular mecha- Journal of Neuroscience, 16, 19–­30.
nisms that cause adverse effects in adult life. These studies Altemus, M., Sarvaiya, N., & Epperson, N. (2014). Sex differences
therefore need to continue in order to better understand the in anxiety and depression clinical perspectives. Frontiers in
underlying mechanisms, as understanding these mechanisms Neuroendocrinology, 35, 320–­330.
Alyamani, R. A. S., & Murgatroyd, C. (2018). Epigenetic programming
will hopefully lead to the development of novel interventions
by early-­life stress. Progress in Molecular Biology and Translational
to improve brain function in maternally deprived children and Science, 157, 133–­150.
to prevent the occurrence of psychopathologies and addictive Bambico, F. R., Lacoste, B., Hattan, P. R., & Gobbi, G. (2015). Father
behaviors. absence in the monogamous California mouse impairs social be-
havior and modifies dopamine and glutamate synapses in the me-
ACKNOWLEDGEMENTS dial prefrontal cortex. Cerebral Cortex, 25, 1163–­1175. https://doi.
This article is a result of a broad literature review accompa- org/10.1093/cerco​r/bht310
Barbosa Neto, J. B., Tiba, P. A., Faturi, C. B., de Castro-­Neto, E. F.,
nying a study cell transplantation as a model for brain injury
da Graca Naffah-­ Mazacoratti, M., de Jesus Mari, J., de Mello,
regeneration therapy (project C3330-­17-­529039), which was
M. F., & Suchecki, D. (2012). Stress during development alters
supported by Slovenian Ministry of Education, Science and anxiety-­like behavior and hippocampal neurotransmission in male
Sport and European Regional Development Fund. and female rats. Neuropharmacology, 62(1), 518–­526. https://doi.
org/10.1016/j.neuro​pharm.2011.09.011
CONFLICT OF INTERESTS Baskerville, S. (2002). The politics of fatherhood. PS: Political Science
The authors declare no conflict of interest regarding the pub- & Politics, 35, 695–­699.
lication of this paper. Benmhammed, H., El Hayek, S., Berkik, I., Elmostafi, H., Bousalham,
R., Mesfioui, A., Ouichou, A., & El Hessni, A. (2019). Animal
models of early-­life adversity. Methods in Molecular Biology, 2011,
AUTHOR CONTRIBUTIONS
143–­161.
MČ carried out literature search, conceived of the review, Bodensteiner, K. J., Ghiraldi, L. L., & Miner, S. S. (2012). Differential
wrote the initial draft, and made the figures. GM made the effects of short-­and long-­term early maternal separation on subse-
graphical abstract. MČ and GM critically reviewed and ed- quent maternal behavior in rats. The Journal of General Psychology,
ited the manuscript before approving the final version. 139(2), 78–­99. https://doi.org/10.1080/00221​309.2012.661377
Boldrini, M., Fulmore, C. A., Tartt, A. N., Simeon, L. R., Pavlova, I.,
PEER REVIEW Poposka, V., Rosoklija, G. B., Stankov, A., Arango, V., Dwork, A.
J., Hen, R., & Mann, J. J. (2018). Cell Stem Cell, 22(4), 589–­599.e5.
The peer review history for this article is available at https://
Bondi, C. O., Rodriguez, G., Gould, G. G., Frazer, A., & Morilak, D.
publo​ns.com/publo​n/10.1111/ejn.15238. A. (2008). Chronic unpredictable stress induces a cognitive deficit
and anxiety-­like behavior in rats that is prevented by chronic antide-
DATA AVAILABILIT Y STATEMENT pressant drug treatment. Neuropsychopharmacology, 33, 320–­331.
No primary data are presented in this review article. https://doi.org/10.1038/sj.npp.1301410
12
|    ČATER and MAJDIČ

Boner, R., & Fernandez-­Duque, E. (2017). Paternal care. In A. Fuentes de Kloet, E. R. (1991). Brain corticosteroid balance and homeostatic
(Eds), The international encyclopedia of primatology (pp. 90–­96). control. Frontiers in Neuroendocrinology, 12, 95–­164.
John Wiley & Sons. de Kloet, E. R., de Jong, I. E., & Oitzl, M. S. (2008). Neuropharmacology
Boothroyd, L. G., & Cross, C. P. (2017). Father absence and gendered of glucocorticoids: Focus on emotion, cognition and cocaine.
traits in sons and daughters. PLoS One, 12(7), e0179954. European Journal of Pharmacology, 585, 473–­482.
Bowlby, J. (1951). Maternal care and mental health. Bulleting of the de Schultz, T., Bock, J., & Braun, K. (2020). Paternal deprivation and
World Health Organization, 3(3), 355–­533. female biparental family rearing induce dendritic and synaptic
Braun, S. M. G., & Jessberger, S. (2014). Adult neurogenesis: changes in Octodon degus: I. Medial prefrontal cortex. Frontiers in
Mechanisms and functional significance. Development, 141(10), Synaptic. Neuroscience, 12, 38.
1983–­1986. https://doi.org/10.1242/dev.104596 Delavari, F., Sheibani, V., Esmaeili-­Mahani, S., & Nakhaee, N. (2016).
Brunson, K. L., Kramar, E., Lin, B., Chen, Y., Colgin, L. L., Yanagihara, Maternal separation and the risk of drug abuse in later life. Addiction
T. K., Lynch, G., & Baram, T. Z. (2005). Mechanisms of late-­onset and Health, 8(2), 107–­114.
cognitive decline after early-­life stress. Journal of Neuroscience, 25, Doreste-­Mendez, R., Rios-­Ruiz, E. J., Rivera-­Lopez, L. L., Gutierrez,
9328–­9338. A., & Torres-­Reveron, A. (2019). Effects of environmental enrich-
Brunton, P. (2015). Programming the brain and behavior by ment in aternally separated rats: Age and sex-­specific outcomes.
early life stress: A focus on neuroactive steroids. Journal of Frontiers in Behavioral Neuroscience, 13, 198.
Neuroendocrinology, 27(6), 468–­480. Dube, S., Felitti, V. J., Dong, M., Chapman, D. P., Giles, W. H., & Anda,
Buss, C., Lord, C., Wadiwalla, M., Hellhammer, D. H., Lupien, S. J., R. F. (2003). Childhood abuse, neglect, and household dysfunction
& Meaney, M. J. (2007). Maternal care modulates the relationship and the risk of illicit drug use: The adverse childhood experiences
between prenatal risk and hippocampal volume in women but not in study. Pediatrics, 111(3), 564–­572.
men. Journal of Neuroscience, 27, 2592–­2595. Dunn, E. C., Soare, T. W., Raffeld, M. R., Busso, D. S., Crawford, K.
Cao, Y., Wu, R., Tai, F., Zhang, X., Yu, P., & An, X. (2014). Neonatal M., & Davis, K. A. (2018). What life course theoretical models best
paternal deprivation impairs social recognition and alters levels of explain the relationship between exposure to childhood adversity
oxytocin and estrogen receptor alpha mRNA expression in the MeA and psychopathology symptoms: Recency, accumulation, or sensi-
and NAcc, and serum oxytocin in mandarin voles. Hormones and tive periods? Psychological Medicine, 26, 1–­11.
Behavior, 65, 57–­65. Edinger, K. L., & Frye, C. A. (2005). Testosterone's anti-­anxiety and
Chen, J., Evan, A. N., Liu, Y., Honda, M., Saavedra, J. M., & analgesic effects may be due in part to actions of its 5alpha-­reduced
Aguilera, G. (2012). Maternal deprivation in rats is associated with metabolites in the hippocampus. Psychoneuroendocrinology, 30,
corticotrophin-­releasing hormone (CRH) promoter hypomethyla- 418–­430.
tion and enhances CRH transcriptional responses to stress in adult- Eklund, M. B., & Arborelius, L. (2006). Twice daily long maternal
hood. Journal of Neuroendocrinology, 24, 1055–­1064. separations in Wistar rats decreases anxiety-­like behaviour in fe-
Chen, Y., & Baram, T. Z. (2016). Toward understanding how early-­ males but does not affect males. Behavior and Brain Research,
life stress reprograms cognitive and emotional brain networks. 172, 278–­285.
Neuropsychopharmacology, 41, 197–­206. https://doi.org/10.1038/ Ellenbriek, B. A., & Cools, A. R. (1998). The neurodevelopment hy-
npp.2015.181 pothesis of schizophrenia: Clinical evidence and animal models.
Cirulli, F., Alleva, E., Antonelli, A., & Aloe, L. (2000). NGF expres- Neuroscience Research Communications, 22, 127–­136.
sion in the developing rat brain: Effects of maternal separation. Fabianova, K., Zavodska, M., Raček, A., Angelidis, A., Martončikova,
Developmental Brain Research, 123, 129–­134. M., & Račekova, E. (2018). Analysis of Fos expression in the rat
Cirulli, F., Berry, A., & Alleva, E. (2003). Early disruption of the olfactory neurogenic region following single exposure to maternal
mother-­infant relationship: Effects on brain plasticity and impli- separation during different neonatal stages. General Physiology and
cations for psychopathology. Neuroscience and Biobehavioral Biophysics, 37(3), 275–­283.
Reviews, 27(1–­2), 73–­82. Farrell, M. R., Holland, F. H., Shansky, R. M., & Brenhouse, H. C.
Clayton, J. A., & Collins, F. S. (2014). Policy: NIH to balance sex in cell and (2016). Sex-­specific effects of early life stress on social interac-
animal studies. Nature, 509, 282–­283. https://doi.org/10.1038/509282a tion and prefrontal cortex dendritic morphology in young rats.
Cohen, H., Liu, T., Kozlovsky, N., Kaplan, Z., Zohar, J., & Mathe, A. Behavioural Brain Research, 310, 119–­125.
A. (2012). The neuropeptide Y (NPY)-­ergic system is associated Faturi, C. B., Tiba, P. A., Kawakami, S. E., Catallani, B., Kerstens,
with behavioral resilience to stress exposure in an animal model of M., & Suchecki, D. (2010). Disruptions of the mother-­ infant
post-­traumatic stress disorder. Neuropsychopharmacology, 37(2), relationship and stress-­ related behaviours: Altered corticos-
350–­363. https://doi.org/10.1038/npp.2011.230 terone secretion does not explain everything. Neuroscience &
Crawley, J. N., Glowa, J. R., Majewska, M. D., & Paul, S. M. (1986). Biobehavioral Reviews, 34(6), 821–­834. https://doi.org/10.1016/j.
Anxiolytic activity of an endogenous adrenal steroid. Brain neubi​orev.2009.09.002
Research, 398, 382–­385. Feinn, R., Nellissery, M., & Kranzler, H. R. (2005). Meta-­analysis of
Danzer, S. C. (2018). Adult neurogenesis in the human brain: Paradise the association of a functional serotonin transporter promoter poly-
lost? Epilepsy Currents, 18(5), 329–­331. morphism with alcohol dependence. American Journal of Medical
Davies, A. M. (1994). The role of neurotrophins in the developing ner- Genetics, 133B(1), 79–­84.
vous system. Journal of Neurobiology, 25, 1334–­1349. Fernandez-­Duque, E., Valeggia, C. R., & Mendoza, S. P. (2009). The
de Almeida Magalhã, T., Correia, D., de Carvalho, L. M., Damasceno, biology of paternal care in human and nonhuman primates. Annual
S., & Brunialti Godard, A. L. (2017). Maternal separation affects Review of Anthropology, 38, 115–­130.
expression of stress response genes and increases vulnerability to Franklin, T. B., Russig, H., Weiss, I. C., Graff, J., Linder, N., &
ethanol consumption. Brain and Behavior, 8(1), e00841. Michalon, A. (2010). Epigenetic transmission of the impact
ČATER and MAJDIČ   
| 13

of early stress across generations. Biological Psychiatry, 68, Gunnar, M. R., & Donzella, B. (2002). Social regulation of the cortisol
408–­415. levels in early human development. Psychoneuroendocrinology, 27,
Frazier, C. R., Trainor, B. C., Cravens, C. J., Whitney, T. K., & Marler, 199–­220.
C. A. (2006). Paternal behavior influences development of aggres- He, Z., Young, L., Ma, X.-­M., Guo, Q., Wang, L., Yang, Y., Luo, L.,
sion and vasopressin expression in male California mouse offspring. Yuan, W., Li, L., Zhang, J., Hou, W., Qiao, H., Jia, R., & Tai, F.
Hormones and Behavior, 50, 699–­707. (2019). Increased anxiety and decreased sociability induced by pa-
Frodl, T., Meisenzahl, E. M., Zetzsche, T., Born, C., Groll, C., & Jager, ternal deprivation Involve the PVN-­PrL OTergic pathway. eLife, 8,
M. (2002). Hippocampal changes in patients with a first episode of e44026.
major depression. American Journal of Psyciatry, 159, 1112–­1118. He, Z., Zhang, S., Yu, C., Li, Y., Jia, R., & Tai, F. (2017). Emotional
Gaali, S., Kirschner, A., Cuboni, S., Hartmann, J., Kozany, C., & attachment of pre-­weaning pups to mothers and fathers in mandarin
Balsevich, G. (2015). Selective inhibitors of the FK506-­binding pro- voles. Behavioural Processes, 135, 87–­94.
tein 51 by induced fit. Nature Chemical Biology, 11, 33–­37. Hedge, A., & Mitra, R. (2020). Environment and early life: Decisive
Gage, F. H. (2000). Mammalian neural stem cells. Science, 287, factors for stress-­resilience and vulnerability. International Review
1433–­1438. of Neurobiology, 150, 155–­185.
Gandelman, R. (1992). The psychobiology of behavioral development. Heilig, M. (2004). The NPY system in stress, anxiety and depression.
Oxford University Press. Neuropeptides, 38, 213–­224.
Gao, X. M., Sakai, K., Roberts, R. C., Conley, R. R., Dean, B., & Heim, C., Young, L. J., Newport, D. J., Mletzko, T., Miller, A. H., &
Tamminga, C. A. (2000). Ionotropic glutamate receptors and ex- Nemeroff, C. B. (2008). Lower CSF oxytocin concentrations in
pression of N-­methyl-­D-­aspartate receptor subunits in subregions of women with a history of childhood abuse. Molecular Psychiatry,
human hippocampus: Effects of schizophrenia. American Journal of 4, 954–­958.
Psychiatry, 157, 1141–­1149. Hofer, M. A. (1994). Hidden regulators in attachment, separation, and
Girardi, C. E., Zanta, N. C., & Suchecki, D. (2014). Neonatal stress-­ loss. Monographs of the Society for Research in Child Development,
induced affective changes in adolescent Wistar rats: Early signs of 59(2–­3), 192–­207.
schizophrenia-­like behavior. Frontiers in Behavioral Neuroscience, Holsboer, F. (2000). The corticosteroid receptor hypothesis of depres-
8, 319. sion. Neuropsychopharmacology, 23, 477–­501.
Glasper, E. R., Molly, M. H., & Hunter, T. J. (2018). Enduring effects of Hostinar, C. E., & Gunnar, M. R. (2013). The developmental effects
paternal deprivation in California mice (Peromyscus californicus): of early life stress: An overview of current theoretical frameworks.
Behavioral dysfunction and sex-­dependent alterations in hippocam- Current Directions in Psychological Science, 22, 400–­406.
pal new cell survival. Frontiers in Behavioral Neuroscience, 12, 20. Huot, R. L., Plotsky, P. M., Lenox, R. H., & McNamara, R. K. (2002).
https://doi.org/10.3389/fnbeh.2018.00020 Neonatal maternal separation reduces hippocampal mossy fiber
Gleason, E. D., & Marler, C. A. (2013). Non-­genomic transmission of density in adult Long Evans rats. Brain Research, 950, 52–­63.
paternal behavior between fathers and sons in the monogamous and Huot, R. L., Thrivikraman, K. V., Meaney, M. J., & Plotsky, P.
biparental California mouse. Proceedings of the Royal Society B: M. (2001). Development of adult ethanol preference and anx-
Biological Sciences, 280, 20130824. iety as a consequence of neonatal maternal separation in
Gobinath, A. R., Mahmoud, R., & Galea, L. A. M. (2015). Influence Long Evans rats and reversal with antidepressant treatment.
of sex and stress exposure across the lifespan on endophenotypes Psychopharmacology, Berlin, 158(4), 366–­ 373. https://doi.
of depression: Focus on behavior, glucocorticoids, and hippocam- org/10.1007/s0021​30100701
pus. Frontiers in Neuroscience, 8, 1–­18. https://doi.org/10.3389/ Issler, O., Haramati, S., Paul, E. D., Maeno, H., Navon, I., Zwang, R., Gil,
fnins.2014.00420 S., Mayberg, H. S., Dunlop, B. W., & Menke, A. (2014). MicroRNA
Goldfarb, W. (1943). Infant rearing and problem behavior. American 135 is essential for chronic stress resiliency, antidepressant efficacy,
Journal of Orthopsychiatry, 13, 249–­265. and intact serotonergic activity. Neuron, 83(2), 344–­360.
Gonzales-­Pardo, H., Arias, J. L., Vallejo, G., & Conejo, N. M. (2019). Ivy, A. S., Rex, C. S., Chen, Y., Dube, C., Maras, P. M., Grigoriadis,
Environmental enrichment effects after early stress on behavior and D. E., Gall, C. M., Lynch, G., & Baram, T. Z. (2010). Hippocampal
functional brain networks in adult rats. PLoS One, 14(12), e0226377. dysfunction and cognitive impairments provoked by chronic early-­
Goodwill, H. L., Manzano-­Nieves, G., Gallo, M., Lee, H.-­I., Oyerinde, life stress involve excessive activation of CRH receptors. Journal of
E., Serre, T., & Bath, K. G. (2019). Early life stress leads to sex Neuroscience, 30, 13005–­13015.
differences in development of depressive-­like outcomes in a mouse Jia, R., Tai, F., An, S., Zhang, X., & Broders, H. (2009). Effects of neo-
model. Neuropsychopharmacology, 44, 711–­720. natal paternal deprivation or early deprivation on anxiety and social
Gunn, B. G., Cunningham, L., Cooper, M. A., Corteen, N. L., Seifi, M., behaviors of the adults in mandarin voles. Behavioural Processes,
Swinny, J. D., Lambert, J. J., & Belelli, D. (2013). Dysfunctional 82, 271–­278.
astrocytic and synaptic regulation of hypothalamic glutamatergic Kalinichev, M., Easterling, K. W., & Holtzman, S. G. (2000). Periodic
transmission in a mouse model of early-­life adversity: Relevance postpartum separation from the offspring results in long-­lasting
to neurosteroids and programming of the stress response. Journal changes in anxiety-­related behaviors and sensitivity to morphine
of Neuroscience, 33, 19534–­19554. https://doi.org/10.1523/JNEUR​ in Long Evans mother rats. Psychopharmacology (Berl), 152(4),
OSCI.1337-­13.2013 431–­439.
Gunnar, M. R., DePasquale, C. E., Reid, B. M., Donzella, B., & Miller, Karsten, C. A., & Baram, T. Z. (2013). How does a neuron “know” to
B. S. (2019). Pubertal stress recalibration reverses the effects of modulate its epigenetic machinery in response to early-­life environ-
early life stress in postinstitutionalized children. Proceedings of ment/experience? Frontiers in Psychiatry, 4, 89.
National Academy of Science USA, 116(48), 23984–­23988. https:// Kelly, A. M., Ong, J. Y., Witmer, R. A., & Ophir, A. G. (2020).
doi.org/10.1073/pnas.19096​99116 Paternal deprivation impairs social behavior putatively via
14
|    ČATER and MAJDIČ

epigenetic modification to lateral septum vasopressin receptor. Lehmann, J., & Feldon, J. (2000). Long-­term biobehavioral effects of
Science Advances, 6(36), eabb9116. maternal separation in the rat: Consistent or confusing? Reviews in
Kember, R. L., Dempster, E., Lee, T. H. A., Schalkwyk, L. C., Mill, J., & the Neurosciences, 11, 383–­408.
Fernandes, C. (2012). Maternal separation is associated with strain-­ Lesse, A., Rether, K., Groger, N., Braun, K., & Bock, J. (2017). Chronic
specific responses to stress and epigenetic alterations to Nr3c1, Avp, postnatal stress induces depressive-­like behavior in male mice and
and Nr4a1 in mouse. Brain and Behavior, 2, 455–­467. programs second-­ hit stress-­induced gene expression patterns of
Kempermann, G., Gage, F. H., Aigner, L., Song, H., Curtis, M., Thuret, OxtR and AvpR1a in adulthood. Molecular Neurobiology, 54(6),
S., Kuhn, H. G., Jessberger, S., Frankland, P. W., Cameron, H. A., 4813–­4819. https://doi.org/10.1007/s1203​5-­016-­0043-­8
Gould, E., Hen, R., Abrous, D. N., Toni, N., Schinder, A. F., Zhao, Levine, S. (1994). The ontogeny of the hypothalamic-­pituitary-­adrenal
X., Lucassen, P. J., & Frisen, J. (2018). Human adult neurogenesis: axis: The influence of maternal factors. Annals of the New York
Evidence and remaining questions. Cell Stem Cell, 23(1), 25–­30. Academy of Sciences, 746, 275–­288.
Kikusui, T., Faccidomo, S., & Miczek, K. A. (2005). Repeated mater- Levine, S., Huchton, D. M., Wiener, S. G., & Rosenfeld, P.
nal separation: Differences in cocaine-­induced behavioral sensitiza- (1992). Time course of the effect of maternal deprivation
tion in adult male and female mice. Psychopharmacology, Berlin, on the hypothalamic-­ pituitary-­
adrenal axis in the infant rat.
178(2–­3), 202–­210. Developmental Psychobiology, 24(8), 547–­ 558. https://doi.
Kleiman, D. G. (1977). Monogamy in mammals. The Quarterly Review org/10.1002/dev.42024​0803
of Biology, 52, 39–­69. Lewis, C. R., Staudinger, K., Scheck, L., & Olive, M. F. (2013). The
Kleiman, D. G., & Malcolm, J. R. (1981). The evolution of male pa- effects of maternal separation on adult methamphetamine self-­
rental investment in mammals. In D. J. Gubernick, & P. H. Klopfer administration, extinction, reinstatement, and MeCP2 immunoreac-
(Eds.), Parental care in mammals (pp. 347–­387). Plenum Press. tivity in the nucleus accumbens. Frontiers in Psychiatry, 4, 55.
Klengel, T., Mehta, D., Anacker, C., Rex-­Haffner, M., Pruessner, J. C., Linnér, A., & Almgren, M. (2020). Epigenetic programming-­The im-
Pariante, C. M., Pace, T. W. W., Mercer, K. B., Mayberg, H. S., portant first 1000 days. Acta Paediatrica, 109(3), 443–­452.
Bradley, B., Nemerhoff, C. B., Holsboer, F., Heim, C. M., Ressler, Llorente-­
Berzal, A., Manzanedo, C., Daza-­ Losada, M., Valero, M.,
K. J., Rein, T., & Binder, E. B. (2013). Allele-­specific FKBP5 DNA Lopez-­Gallardo, M., & Aguilar, M. A. (2013). Sex-­dependent ef-
demethylation mediates gene-­childhood trauma interactions. Nature fects of early maternal deprivation on MDMA-­induced conditioned
Neuroscience, 16, 33–­41. place reference in adolescent rats: Possible neurochemical cor-
Koob, G. F., & Volkow, N. D. (2010). Neurocircuitry of addic- relates. Toxicology, 311(1–­2), 78–­86.
tion. Neuropsychopharmacology, 35(1), 217–­ 238. https://doi. Lukas, M., Bredewold, R., Neumann, I. D., & Veenema, A. H. (2010).
org/10.1038/npp.2009.110 Maternal separation interferes with developmental changes in
Korosi, A., Naninck, E. F., Oomen, C. A., Schouten, M., Krugers, H., brain vasopressin and oxytocin receptor binding in male rats.
Fitzsimons, C., & Lucassen, P. J. (2012). Early-­life stress mediated Neuropharmacology, 58(1), 78–­87. https://doi.org/10.1016/j.neuro​
modulation of adult neurogenesis and behavior. Behavior and Brain pharm.2009.06.020
Research, 227, 400–­409. https://doi.org/10.1016/j.bbr.2011.07.037 Lupien, S. J., de Leon, M., de Santi, S., Convit, A., Tarshish, C., Nair,
Kosik, K. S. (1992). Alzheimer's disease: A cell biological perspective. N. P., Thakur, M., McEwen, B. S., Hauger, R. L., & Meaney, M.
Science, 256, 780–­783. https://doi.org/10.1126/scien​ce.1589757 J. (1998). Cortisol levels during human aging predict hippocampal
Kosten, T. A., Miserendino, M. J., & Kehoe, P. (2000). Enhanced ac- atrophy and memory deficits. Nature Neuroscience, 1, 69–­73.
quisition of cocaine self-­administration in adult rats with neonatal Maccari, S., Krugers, H. J., Morley-­Fletcher, S., Szyf, M., & Brunton, P.
isolation stress experience. Brain Research, 875(1–­2), 44–­50. J. (2014). The consequences of early-­life adversity: Neurobiological,
Kosten, T. A., Sanchez, H., Zhang, X. Y., & Kehoe, P. (2004). Neonatal behavioural and epigenetic adaptations. Journal of Endocrinology,
isolation enhances acquisition of cocaine self-­administration and 26, 707–­723.
food responding in female rats. Behavior and Brain Research, Maestripieri, D. (2005). Earl experience affects the intergenerational trans-
151(1–­2), 137–­149. mission of infant abuse in rhesus monkeys. Proceedings of National
Kuhn, C. M., Pauk, J., & Schanberg, S. M. (1990). Endocrine responses Academy of Science of the United States of America, 102, 9726–­9729.
to mother-­ infant separation in developing rats. Developmental Marco, E. M., Adriani, W., Llorente, R., Laviola, G., & Viveros, M. P.
Psychobiology, 23, 395–­410. (2009). Detrimental psychophysiological effects of early maternal
Kundakovic, M., & Champagne, F. A. (2015). Early-­life experience, deprivation in adolescent and adult rodents: Altered responses to
epigenetics and the developing brain. Neuropsychopharmacology, cannabinoid exposure. Neuroscience and Biobehavioral Reviews,
40, 141–­153. 33(4), 498–­507. https://doi.org/10.1016/j.neubi​orev.2008.03.008
Kunzler, J., Braun, K., & Bock, J. (2015). Early life stress and sex-­ Marler, C. A., Bester-­Meredith, J. K., & Trainor, B. C. (2003). Paternal
specific sensitivity of the catecholaminergic systems in prefrontal behavior and aggression: Endocrine mechanisms and nongenomic
and limbic regions of Octodon degus. Brain Structure and Function, transmission of behavior. In P. J. B. Slater, J. S. Rosenblatt, C. T.
220, 861–­868. Snowdon, & T. J. Roper (Eds.), Advances in the study of behavior
Landfield, P., Waymire, J., & Lynch, G. (1987). Hippocampal aging and (pp. 263–­323). Academic Press.
adrenocorticoids: A quantitative correlation. Science, 202, 1098–­1102. Marler, C., Trainor, B. C., & Davis, E. (2005). Paternal behavior and
Lang, F., & Shumilina, E. (2013). Regulation of ion channels by the offspring aggression. Current Directions in Psychological Science,
serum-­and glucocorticoid-­inducible kinase SGK1. FASEB Journal, 14(3), 163–­166.
27(1), 3–­12. https://doi.org/10.1096/fj.12-­218230 Martini, M., & Valverde, O. (2012). A single episode of mater-
Lang, F., Strutz-­Seebohm, N., Seebohm, G., & Lang, U. E. (2010). nal deprivation impairs the motivation for cocaine in adolescent
Significance of SGK1 in the regulation of neuronal function. The mice. Psychopharmacology, Berlin, 219(1), 149–­158. https://doi.
Journal of Physiology, 588, 3349–­3354. org/10.1007/s0021​3-­011-­2385-­2
ČATER and MAJDIČ   
| 15

McAllister, A. K., Katz, L. C., & Lo, D. C. (1999). Neurotrophins and Murgatroyd, C., Patchev, A. V., Wu, Y., Micale, V., Bockmuhl, Y.,
synaptic plasticity. Annual Reviews in Neuroscience, 22, 295–­318. Fischer, D., Holsboer, F., Wotjak, C. T., Almeida, F. X., & Spengler,
McEwen, B. S. (2020). Hormones and behavior and the integration of D. (2009). Dynamic DNA methylation programs persistent adverse
brain-­body science. Hormones and Behavior, 119, 104619. effects of early-­life stress. Nature Neuroscience, 12(12), 1559–­1566.
McGowan, P. O., Sasaki, A., D'Alessio, A. C., Dymov, S., Labonte, B., Murthy, S., & Gould, E. (2018). Early life stress in rodents: Animal mod-
Szyf, M., Turecki, G., & Meanej, M. J. (2009). Epigenetic regulation els of illness or resilience? Frontiers in Behavioral Neuroscience,
of the glucocorticoid receptor in human brain associates with child- 12, 157.
hood abuse. Nature Neuroscience, 12, 342–­348. Naqavi, M. R., Mohammadi, M., Salari, V., & Nakhaee, N. (2011). The
Meaney, M. J. (2001). Maternal care, gene expression, and the transmis- relationship between childhood maltreatment and opiate depen-
sion of individual differences in stress reactivity across generations. dency in adolescence and middle age. Addiction and Health, 3(3–­4),
Annual Reviews in Neuroscience, 24, 1161–­1192. 92–­98.
Meaney, M. J., Mitchell, J. B., Aitken, D. H., Bhatnagar, S., Bodnoff, Nemeroff, C. B. (2016). Paradise Lost: The neurobiological and clinical
S. R., Iny, L. J., & Sarrieau, A. (1991). The effects of neonatal han- consequences of child abuse and neglect. Neuron, 89(5), 892–­909.
dling on the development of the adrenocortical response to stress: https://doi.org/10.1016/j.neuron.2016.01.019
Implications for neuropathology and cognitive deficits in later life. Nephew, B. C. (2012). Behavioral roles of oxytocin and vasopressin.
Psychoneuroendocrinology, 16, 85–­103. In T. Sumiyoshi (Ed.), Neuroendocirnology and behaviour. Intech
Menezes, J., Souto das Neves, B.-­H., Goncalves, R., Benetti, F., & Open. https://doi.org/10.5772/50422
Billig Mello-­ Carpes, P. (2020). Maternal deprivation impairs Nishi, M. (2020). Effects of early-­life stress on the brain and behaviors:
memory and cognitive flexibility, effect that is avoided by en- Implication of early maternal separation in rodents. International
vironmental enrichment. Behavioural Brain Research, 381c, Journal of Molecular Sciences, 21, 7212.
112468. Nouri, A., Hashemzadeh, F., Soltani, A., Saghaei, E., & Amini-­Khoei,
Millstein, R. A., & Holmes, A. (2007). Effects of repeated maternal H. (2020). Progesterone exerts antidepressant-­like effect in a mouse
separation on anxiety-­and depression-­related phenotypes in differ- model of maternal separation stress through mitigation of neuroin-
ent mouse strains. Neuroscience and Biobehavioral Reviews, 31(1), flammatory response and oxidative stress. Pharmaceutical Biology,
3–­17. 58(1), 64–­71.
Miragaia, A. S., Wertheimer, G. S., Consoli, A. C., Cabbia, R., Longo, Nuber, U. A., Kriaucionis, S., Roloff, T. C., Guy, J., Selfridge, J.,
B. M., Girardi, C. E. N., & Suchecki, D. (2018). Maternal depri- Steinhoff, C., Schulz, R., Lipkowitz, B., Ropers, H. H., Holmes, M.
vation increases anxiety-­and depressive-­like behaviors in an age-­ C., & Bird, A. (2005). Up-­regulation of glucocorticoid-­regulated
dependent fashion and reduces neuropeptide Y expression in the genes in a mouse model of Rett syndrome. Human Molecular
amygdala and hippocampus of male and female young adult rats. Genetics, 14(15), 2247–­2256.
Frontiers in Behavioral Neuroscience, 12, 159. Odeon, M. M., & Acosta, G. B. (2019). Repeated maternal separation:
Mirescu, C., Peters, J. D., & Gould, E. (2004). Early life experience Alcohol consumption, anxious behavior and corticosterone were
alters response of adult neurogenesis to stress. Nature Neuroscience, reversed by a non-­pharmacological treatment. Progress in Neuro-­
7, 841–­846. psychopharmacology and Biological Psychiatry, 95, 109726.
Miyazaki, T., Takase, K., Nakajima, W., Tada, H., Ohya, D., Sano, Ojeda, V. D., Magana, C., Burgos, J. L., & Vargas-­Ojeda, A. C. (2020).
A., Goto, T., Hirase, H., Malinow, R., & Takahashi, T. (2012). Deported men's and father's perspective: The impacts of family separa-
Disrupted cortical function underlies behavior dysfunction due tion on children and families in the U.S. Frontiers Psychiatry, 11, 148.
to social isolation. The Journal of Clinical Investigation, 122(7), Oomen, C. A., Girardi, C. E., Cahyadi, R., Verbeek, E. C., Krugers,
2690–­2701. H., Joels, M., & Lucassen, P. J. (2009). Opposite effects of early
Moffett, M. C., Vicentic, A., Kozel, M., Plotsky, P., Francis, D. D., & maternal deprivation on neurogenesis in male versus female rats.
Kuhar, M. J. (2007). Maternal separation alters drug intake patterns PLoS One, 4, e3675.
in adulthood in rats. Biochemical Pharmacology, 73(3), 321–­330. Oomen, C. A., Soeters, H., Audureau, N., Vermunt, L., van Hasselt, F.
https://doi.org/10.1016/j.bcp.2006.08.003 N., Mander, E. M., Joels, M., Krigers, H., & Lucassen, P. J. (2011).
Morrow, A. L., Porcu, P., Boyd, K. N., & Grant, K. A. (2006). Early maternal deprivation affects dentate gyrus structure and emo-
Hypothalamic-­ pituitary-­
adrenal axis modulation of GABAergic tional learning in adult female rats. Psychopharmacology (Berl),
neuroactive steroids influences ethanol sensitivity and drinking be- 214, 249–­260.
havior. Dialogues in Clonical Neuroscience, 8(4), 463–­477. Oomen, C. A., Soeters, H., Audureau, N., Vermunt, L., van Hasselt,
Muller, M. N., Thompson, E. M. et al (2012). Mating, parenting and F. N., Manders, E. M., Joels, M., Lucassen, P. J., & Krugers, H.
male reproductive strategies. In J. C. Mitani (Ed.), The evolution of (2010). Severe early life stress hampers spatial learning and neu-
primate societies (pp. 387–­411). University of Chicago Press. rogenesis, but improves hippocampal synaptic plasticity and emo-
Murgatroyd, C. A., Babb, J. A., Bradburn, S., Carini, L. M., Beamer, tional learning under high-­stress conditions in adulthood. Journal
G. L., & Nephew, B. C. (2016). Transgeneration social stress, im- of Neuroscience, 30, 6635–­ 6645. https://doi.org/10.1523/JNEUR​
mune factors, hormones and social behavior. Frontiers in Ecology OSCI.0247-­10.2010
and Evolution, 3, 149. Ovtscharoff, V., Helmeke, C., & Braun, K. (2006). Lack of paternal
Murgatroyd, C., & Bradburn, S. (2016). Epigenetics, the environment, care affects synaptic development in the anterior cingulate cortex.
and children's health. Across Lifespans (pp. 207–­229). Springer. Brain Research, 1116(1), 58–­ 63. https://doi.org/10.1016/j.brain​
Murgatroyd, C. A., & Nephew, B. C. (2013). Effects of early life res.2006.07.106
social stress on maternal behavior and neuroendocrinology. Papadakakis, A., Sidiropoulou, K., & Panagis, G. (2019). Music expo-
Psychoneuroendocrinology, 38, 219–­228. sure attenuates anxiety-­and depression-­like behaviors and increases
16
|    ČATER and MAJDIČ

hippocampal spine density in male rats. Behavioural Brain Research, Romano-­Lopez, A., Mednez-­Diaz, M., Ruiz-­Contreras, A. E., Carrisoza,
372, 112023. R., & Prospero-­Garcia, O. (2012). Maternal separation and procliv-
Paris, J. J., & Frye, C. A. (2011). Juvenile offspring of rats exposed to ity for ethanol intake: A potential role of the endocannabinoid sys-
restraint stress in late gestation have impaired cognitive performance tem in rats. Neuroscience, 223, 296–­304.
and dysregulated progestogen formation. Stress, 14, 23–­32. https:// Rosenfeld, P., Suchecki, D., & Levine, S. (1992). Multifactorial regu-
doi.org/10.3109/10253​890.2010.512375 lation of the hypothalamic-­pituitary-­adrenal axis during develop-
Patchev, V. K., Shoaib, M., Holsboer, F., & Almeida, O. F. ment. Neuroscience Biobehavior Reviews, 16, 553–­568. https://doi.
(1994). The neurosteroid tetrahydroprogesterone counteracts org/10.1016/S0149​-­7634(05)80196​-­4
corticotropin-­ releasing hormone-­ induced anxiety and alters the Rosenfeld, P., Wetmore, J. B., & Levine, S. (1992). Effects of repeated
release and gene expression of corticotropin-­ releasing hormone maternal separations on the adrenocortical response to stress of pre-
in the rat hypothalamus. Neuroscience, 62, 265–­271. https://doi. weanling rats. Physiology and Behavior, 52, 787–­791.
org/10.1016/0306-­4522(94)90330​-­1 Rutter, M. L., Kreppner, J. M., & O'Connor, T. G. (2001). Specifity and
Pembrey, M., Saffery, R., & Bygren, L. O. (2014). Human transgen- heterogeneity in children's responses to profound institutional pri-
erational responses to early-­life experience: Potential impact on vation. English and Romanian Adoptees (ERA) study team. British
development, health and biomedical research. Journal of Medical Journal of Psychiatry, 179, 97–­103.
Genetics, 51, 563–­572. Sapolsky, R. M., & Meaney, M. J. (1986). Maturation of the adrenocor-
Ploj, K., Roman, E., & Nylander, I. (2003). Long-­term effects of mater- tical stress response: Neuroendocrine control mechanisms and the
nal separation on ethanol intake and brain opioid and dopamine re- stress hyporesponsive period. Brain Research, 396, 64–­76. https://
ceptors in male Wistar rats. Neuroscience, 121(3), 787–­799. https:// doi.org/10.1016/0165-­0173(86)90010​-­X
doi.org/10.1016/S0306​-­4522(03)00499​-­8 Savignac, H. M., Dinan, T. G., & Cryan, J. F. (2011). Resistance to
Provencal, N., & Binder, E. B. (2015). The neurobiological effects of early-­life stress in mice: Effects of genetic background and stress
stress as contributors to psychiatric disorders: Focus on epigenetics. duration. Frontiers in Behavioral Neuroscience, 5, 13.
Current Opinion in Neurobiology, 30, 31–­37. Schmauss, C., Lee-­McDermott, Z., & Medina, L. R. (2014). Trans-­
Provencal, N., Suderman, M. J., Guillemin, C., Massart, R., Ruggiero, generational effects of early life stress: The role of maternal be-
A., Wang, D., Bennett, A. J., Pierre, P. J., Friedmanm, D. P., & havior. Scientific Reports, 4(1), 4873. https://doi.org/10.1038/srep0​
Cote, S. M. (2012). The signature of maternal rearing in the meth- 4873
ylome in rhesis macaque prefrontal cortex and T cells. Journal of Schmidt, M. V. (2019). Stress-­hyporesponsive period. In G. Fink (Ed),
Neuroscience, 32, 15626–­15642. Stress: Physiology, biochemistry, and pathology. Handbook of stress
Rajan, K. E., Soundarya, S., Karen, C., Shanmugapriya, V., & series (volume 3, pp. 49–­56). Academic Press, Elsevier.
Radhakrishnan, K. (2019). Presence of mother reduces early-­lie so- Seay, B., Hansen, E., & Harlow, H. F. (1962). Mother-­infant separa-
cial stress: Linking the alteration in hypothalamic-­pituitary-­adrenal tion in monkeys. Journal of Child Psychology and Psychiatry, 3,
axis and serotonergic system. Developmental Neuroscience, 41(3–­ 123–­132.
4), 212–­222. Serova, L. I., Laukova, M., Alaluf, L. G., Pucillo, L., & Sabban, E. L.
Reichmann, F., & Holzer, P. (2016). Neuropeptide Y: A stressful re- (2014). Intranasal neuropeptide Y reverses anxiety and depressive-­
view. Neuropeptides, 55, 99–­ 109. https://doi.org/10.1016/j.npep.​ like behavior impaired by single prolonged stress PTSD model.
2015.09.008 European Neuropsychopharmacology, 24(1), 142–­147.
Reshetnikov, V., Ryabushkina, Y., Kovner, A., Lepeshko, A., & Bodnar, Serova, L. I., Tillinger, A., Alaluf, L. G., Laukova, M., Keegan, K., &
N. (2020). Repeated and single maternal separation specifically alter Sabban, E. L. (2013). Single intranasal neuropeptide Y infusion at-
microglial morphology in the prefrontal cortex and neurogenesis in tenuates development of PTSD-­like symptoms to traumatic stress in
the hippocampus of 15-­day-­old male mice. NeuroReport, 31(18), rats. Neuroscience, 236, 298–­312.
1256–­1264. https://doi.org/10.1097/WNR.00000​00000​001544 Smart, C., Strathdee, G., Watson, S., Murgatroyd, C., & McAllister-­
Rice, C. J., Sandman, C. A., Lenjavi, M. R., & Baram, T. Z. (2008). A Williams, R. H. (2015). Early life trauma, depression and the gluco-
novel mouse model for acute and long-­lasting consequences of early corticoid receptor gene –­an epigenetic perspective. Psychological
life stress. Endocrinology, 149, 4892–­4900. Medicine, 45, 3393–­3410.
Riveros-­Barrera, I., & Dueñas, Z. (2016). Maternal separation during Smith, M. A., Kim, S. Y., van Oers, H. J., & Levine, S. (1997). Maternal
nursing alters basal neuroendocrine levels in juvenile and adult rats. deprivation and stress induce immediate early genes in the infant rat
Biomedica, 36(1), 67–­77. brain. Endocrinology, 138, 4622–­4628.
Roceri, M., Hendriks, W., Racagni, G., Ellenbroek, B. A., & Riva, M. Solinas, M., Belujon, P., Fernagut, P. O., Jaber, M., & Thiriet, N. (2018).
A. (2002). Early maternal deprivation reduces the expression of Dopamine and addiction: What have we learned from 40 years of re-
BDNF and NMDA receptor subunits in rat hippocampus. Molecular search. Journal of Neural Transmission (Vienna), 126(4), 481–­516.
Psychiatry, 7, 609–­616. Sorensen, H. J., Mortensen, E. L., Reinisch, J. M., & Mednick, S. A.
Rodgers, A. B., Morgan, C. P., Bronson, S. L., Revello, S., & Bale, T. (2006). Early weaning and hospitalization with alcohol-­ related
L. (2013). Paternal stress exposure alters sperm microRNA content diagnoses in adult life. American Journal of Psychiatry, 163(4),
and reprograms offspring HPA stress axis regulation. Journal of 704–­709.
Neuroscience, 33(21), 9003–­9012. https://doi.org/10.1523/JNEUR​ Sorrells, S. F., Paredes, M. F., Cebrian-­Silla, A., Sandoval, K., Qi,
OSCI.0914-­13.2013 D., Kelley, K. W., James, D., Mayer, S., Chang, J., Auguste, K. I.,
Rodgers, R. J., & Johnson, N. J. (1998). Behaviorally selective effects of Chang, E., Gutierrez Martin, A. J., Kriegstein, A. R., Mathern, G.
neuroactive steroids on plus-­maze anxiety in mice. Pharmacology W., Oldham, M. C., Huang, E. J., Garcia-­Verdugo, J. M., Yang, Z.,
Biochemistry and Behavior, 59, 221–­232. & Alvarez-­Buylla, A. (2018). Human hippocampal neurogenesis
ČATER and MAJDIČ   
| 17

drops sharply in children to undetectable levels in adults. Nature, morphine depencence and disturbs the enkephalinergic system in
555(7696), 377–­381. adulthood. Journal of Neuroscience, 25(18), 4453–­4462.
Spitz, R. A. (1945). Hospitalism: An inquiry into the genesis of psychi- Veenema, A. H., Blume, A., Niederle, D., Buwada, B., & Neumann,
atric conditions in early childhood. The Psychoanalytic Study if the I. D. (2006). Effects of early life stress on adult male aggression
Child, 1, 53–­74. and hypothalamic vasopressin and serotonin. European Journal of
Stankiewicz, A. M., Swiergiel, A. H., & Lisowski, P. (2013). Epigenetics Neuroscience, 24, 1711–­1720.
of stress adaptations in the brain. Brain Research Bulletin, 98, 76–­92. Veenema, A. H., Bredewold, R., & Neumann, I. (2007). Opposite ef-
Stanton, M. E., & Levine, S. (1988). Maternal modulation of infant glu- fects of maternal separation on intermale and maternal aggression
cocorticoid stress response: Role of age and maternal deprivation. in C57BL/6 mice: Link to hypothalamic vasopressin and oxytocin
Psychobiology, 16, 223–­228. immunoreactivity. Psychoneuroendocrinology, 32(5), 437–­450.
Suchecki, D. (2018). Maternal regulation of the infant's hypothalamic-­ Veenema, A. H., & Neumann, I. D. (2008). Central vasopressin and oxy-
pituitary-­adrenal axis stress response. Seymour 'Gig' Levine's leg- tocin release: Regulation of complex social behaviours. Progress in
acy to neuroendrocrinology. Journal of Neuroendocrinology, 30(7), Brain Research, 170, 261–­276.
e12610. Vivian, J. A., Barros, H. M., Manitiu, A., & Miczek, K. A. (1997).
Suderman, M., Borghol, N., Pappas, J. J., Pinto Pereira, S. M., Pembrey, Ultrasonic vocalizations in rat pups: Modulation at the gamma-­
M., Hertzman, C., Power, C., & Szyf, M. (2014). Childhood abuse aminobutyric acidA receptor complex and the neurosteroid recogni-
is associated with methylation of multiple loci in adult DNA. BMC tion site. Journal of Pharmacology and Experimental Therapeutics,
Medical Genomics, 7, 13. 282, 318–­325.
Suri, D., Teixeira, C. M., Cagliostro, M. K., Mahadevia, D., & Walker, C.-­D., Perrin, M., Vale, W., & Rivier, C. (1986). Ontogeny of
Ansorge, M. S. (2015). Monoamine-­ sensitive developmen- the stress response in the rat: Role of the pituitary and the hypothal-
tal periods impacting adult emotional and cognitive behaviors. amus. Endocrinology, 118, 1445–­1451.
Neuropsychopharmacology, 40, 88–­112. Wang, J., Tai, F., Yan, X., & Yu, P. (2012). Paternal deprivation alters
Takahashi, M., Shirakawa, O., Toyooka, K., Kitamura, N., Hashimoto, play-­fighting, serum corticosterone and the expression of hypotha-
T., & Maeda, K. (2000). Abnormal expression of brain-­derived lamic vasopressin and oxytocin in juvenile male mandarin voles.
neurotrophic factor and its receptor in the corticolimbic system of Journal of comparative physiology. A Neuroethology, Sensory,
schizophrenic patients. Molecular Psychiatry, 5, 293–­300. Neural, and Behavioral Physiology, 198, 787–­796.
Tata, D. A. (2012). Maternal separation as a model of early stress: Weaver, I. C. G., Cervoni, N., Champagne, F. A., D'Alessio, A.,
Effects on aspects of emotional behavior and neuroendocrine func- Sharma, S., Seckl, J. R., Dymov, S., Szyf, M., & Meaner, M. J.
tion. Hellenic Hournal of Psychology, 9, 84–­101. (2004). Epigenetic programming by maternal behavior. Nature
Thorsell, A., & Mathe, A. A. (2017). Neuropeptide Y in alcohol ad- Neuroscience, 7, 847–­854.
diction and affective disorders. Frontiers in Endocrinology, 8, 178. Weder, N., Zhang, H., Jensen, K., Yang, B. Z., Simen, A., Jackowski, A.,
Uribe, E., Fernandez, L., Pacheco, D., Fernandez, L., Nayadoleni, N., Lipschitz, D., Douglas-­Palumberi, H., Ge, M., & Perepletchikova, F.
& Eblen-­Zajjur, A. (2019). Administration of memantine reverses (2014). Child abuse, depression, and methylation in genes involved
behavioral, histological, and electrophysiological abnormalities with stress, neural plasticity, and brain circuitry. Journal of the
in rats subjected to early maternal deprivation. Journal of Neural American Academy of Child and Psychiatry, 53, 417–­424.
Transmission (Vienna), 126(6), 759–­770. https://doi.org/10.1007/ Wei, L., David, A., Duman, R. S., Anisman, H., & Kaffman, A. (2010).
s0070​2-­019-­02007​-­x Early life stress increases anxiety-­like behavior in Balb c mice de-
Vaden-­Kiernan, N., Ialongo, N. S., Pearson, J., & Kellam, S. (1995). spite a compensatory increase in levels of postnatal maternal care.
Household family structure and children's aggressive behavior: A Hormones and Behavior, 57, 396–­404.
longitudinal study of urban elementary school children. Journal of Widom, C. S., Czaja, S. J., & Dumont, K. A. (2015). Intergenerational
Abnormal Child Psychology, 23, 553–­568. https://doi.org/10.1007/ transmission of child abuse and neglect: Real or detection bias?
BF014​47661 Science, 347, 1480–­1485.
van Bodegom, M., Homberg, J. R., & Heckens, M. J. A. G. (2017). Yu, P., An, S., Tai, F., Zhang, X., He, F., & Wang, J. (2012). The effects
Modulation of the hypothalamic-­pituitary-­adrenal axis by early life of neonatal paternal deprivation on pair bonding, NAcc dopamine
stress exposure. Frontiers in Cellular Neuroscience, 11, 87. receptor mRNA expression and serum corticosterone in mandarin
van Oers, H. J., de Kloet, E. R., Whelan, T., & Levine, S. (1998). voles. Hormones and Behavior, 61, 669–­677.
Maternal deprivation effect on the infant's neural stress markers is Yuan, W., Li, L., Hou, W., He, Z., Wang, L., Zhang, J., Yang, Y.,
reversed by tactile stimulation and feeding but not by suppressing Cai, W., Guo, Q., Zhang, X., Jia, R., Lian, Z., & Tai, F. (2020).
corticosterone. Journal of Neuroscience, 18(23), 10171–­10179. Preweaning paternal deprivation impacts parental responses to pups
https://doi.org/10.1523/JNEUR​OSCI.18-­23-­10171.1998 and alters the serum oxytocin and corticosterone levels and oxytocin
Vazquez, D. M., van Oers, H., Levine, S., & Akil, H. (1996). Regulation receptor, vasopressin 1A receptor, estrogen receptor, dopamine type
of glucocorticoid and mineralocorticoid receptor mRNAs in the I receptor, dopamine type II receptor levels in relevant brain regions
hippocampus of the maternally deprived infant rat. Brain Research, in adult mandarin voles. Neuroendocrinology, 110(3–­4), 292–­306.
731, 79–­90. Zannas, A. S., Weichmann, T., Gassen, N. C., & Binder, E. B. (2015).
Vazquez, V., Giros, B., & Dauge, V. (2006). Maternal deprivation spe- Gene-­stress-­epigenetic regulation of FKBP5: Clinical and transla-
cifically enhances vulnerability to opiate dependence. Behavioral tional implications. Neuropsychopharmacology, 41, 261–­274.
Pharmacology, 17(8), 715–­724. https://doi.org/10.1097/FBP.0b013​ Zannas, A. S., & West, A. E. (2014). Epigenetics and the regulation
e3280​116e6f of stress vulnerability and resilience. Neuroscience, 264, 157–­170.
Vazquez, V., Penit-­Soria, J., Durand, C., Besson, M. J., Giros, B., & Zhang, D.-­D., Fang, J., Zhang, L., Yuan, J.-­Y., Wan, Y.-­H., Su, P.-­Y.,
Dauge, V. (2005). Maternal deprivation increases vulnerability to Tao, F.-­B., & Sun, Y. (2021). Pubertal recalibration of cortisol
18
|    ČATER and MAJDIČ

reactivity following early life parent-­child separation. Journal of

Affective Disorders, 278, 320–­326. How to cite this article: Čater M, Majdič G. How
Zhang, L.-­X., Levine, S., Dent, G., Zhan, Y., Xing, G.-­Q., Okimoto, D., early maternal deprivation changes the brain and
Gordin, M. C., Post, R. M., & Smith, M. A. (2002). Maternal depri- behavior?. Eur J Neurosci. 2021;00:1–­18. https://doi.
vation increases cell death in the infant rat brain. Developmental org/10.1111/ejn.15238
Brain Research, 133, 1–­11.
Zimmerberg, B., & Sageser, K. A. (2011). Comparison of two rodent
models of maternal separation on juvenile social behavior. Frontiers
in Psychiatry, 2, 39.