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Epigenetic alterations following early postnatal stress: a review on novel aetiological mechanisms of common psychiatric disorders

Clinical Epigenetics volume 7, Article number: 122 (2015) Cite this article

Abstract

Stressor exposure during early life has the potential to increase an individual’s susceptibility to a number of neuropsychiatric conditions such as mood and anxiety disorders and schizophrenia in adulthood. This occurs in part due to the dysfunctional stress axis that persists following early adversity impairing stress responsivity across life. The mechanisms underlying the prolonged nature of this vulnerability remain to be established. Alterations in the epigenetic signature of genes involved in stress responsivity may represent one of the neurobiological mechanisms. The overall aim of this review is to provide current evidence demonstrating changes in the epigenetic signature of candidate gene(s) in response to early environmental adversity. More specifically, this review analyses the epigenetic signatures of postnatal adversity such as childhood abuse or maltreatment and later-life psychopathology in human and animal models of early life stress. The results of this review shows that focus to date has been on genes involved in the regulation of hypothalamic-pituitary-adrenal (HPA) axis and its correlation to subsequent neurobiology, for example, the role of glucocorticoid receptor gene. However, epigenetic changes in other candidate genes such as brain-derived neurotrophic factor (BDNF) and serotonin transporter are also implicated in early life stress (ELS) and susceptibility to adult psychiatric disorders. DNA methylation is the predominantly studied epigenetic mark followed by histone modifications specifically acetylation and methylation. Further, these epigenetic changes are cell/tissue-specific in regulating expression of genes, providing potential biomarkers for understanding the trajectory of early stress-induced susceptibility to adult psychiatric disorders.

Background

Early life stress (ELS) encompasses childhood abuse, neglect, poverty and parental illness, alongside a multitude of other stressors. Some forms of ELS affect 30–40 % of the Western population and have been implicated in approximately half of all childhood and a third of adulthood psychiatric disorders [1, 2]. Exposure to ELS results in enhanced susceptibility to neuropsychiatric disorders such as major depressive disorder, generalised anxiety disorder, schizophrenia and autism spectrum disorders [1, 3, 4]. Chronic health conditions such as obesity, type two diabetes mellitus, respiratory disorders and cardiovascular diseases are also increased in individuals with a history of ELS [5, 6].

The impact of early adversity on the susceptibility to psychiatric disorders in later life is influenced by a number of factors. Environmental factors include nature of stressors [7], time of exposure in development [8, 9] and severity and cumulative exposure effects [10–12]. Biological factors include gender, age of assessment [13] and predisposing genetic polymorphisms in genes associated with mood regulation, stress response and inflammatory processes. These include genes such as serotonin transporter (5-HTT), brain-derived neurotrophic factor (BDNF) and FK506 binding protein (FKBP5) [14–16]. A dysfunctional hypothalamic-pituitary-adrenal (HPA) stress axis and impaired immune responses such as increased cytokines have also been implicated in the increased vulnerability to ELS [17, 18]. In spite of the increasing knowledge, the molecular mechanisms underlying ELS-mediated long-term vulnerability to later-life stressors are unclear.

Gene-environment interactions, such as those occurring when exposed to ELS, often encompass epigenetic changes. Epigenetics processes occur at the level above the genome, which includes DNA methylation, posttranslational histone modifications and gene regulation by micro-RNA (miRNA). Collectively, these epigenetic changes can stably mark the genome in response to environment, potentially altering gene expression across lifespan [19, 20] and across generations [21]. As such, epigenetic alterations may represent one of the key mechanisms underlying the long-lasting nature of ELS-induced changes in neurobiology, behaviour and disease susceptibility [22, 23].

We first present a brief overview of the stress response pathways followed by a detailed review of evidence demonstrating epigenetic alterations following ELS in animal models and humans. Changes in the epigenetic signature of candidate genes and alterations in genome-wide methylation will be reported. Finally, we aim to understand how these changes mediate long-term effects such as their role in risk to developing psychiatric disorders in adulthood.

The central role of hypothalamus-pituitary-adrenal system

Adversities during early postnatal life are able to shape the experience-dependent maturation of stress-regulating pathways, such as the HPA system. This can lead to persistent alterations in stress responsivity during adulthood—a phenomenon often referred to as “early-life programming”. Tight regulation of the HPA axis is therefore core to the long-term control of systems governing stress responsivity. The HPA axis involves the release, following a stressor, of the neuropeptide corticotrophin-releasing hormone (CRH) and arginine vasopressin (AVP) from the paraventricular nucleus (PVN) of the hypothalamus. These bind to their specific receptors (the CRHR1 and V1b receptors) in the anterior pituitary that stimulate the release of adrenocorticotrophic hormone (ACTH) which stimulates the adrenal cortex to release glucocorticoid (GC) hormones, cortisol in human and corticosterone in rodents. These GCs in turn mobilise glucose from energy stores and increase cardiovascular tone, among further widespread effects. Feedback loops, primarily mediated through glucocorticoid receptors (GRs) in the PVN and pituitary, regulate responsiveness of the HPA axis ensuring a return to a homeostatic balance when it is no longer challenged (Fig. 1).

Fig. 1
figure1

The hypothalamic-pituitary-adrenal (HPA) axis and its response to stress stimuli: the signalling events (green, solid lines) in the HPA axis in response to stress stimuli and how glucocorticoids (GCs) produced by the adrenal gland can have a negative feedback role in maintaining GC levels in the blood. The negative feedback in the hypothalamus and pituitary (red, dotted lines) are both mostly regulated by glucocorticoid receptors (GRs), and dysfunctional negative feedback system is often seen associated with chronic exposure to stress stimuli

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A loss of this negative feedback control, particularly following periods of chronic stress, may influence the development of affective disorders. Indeed, dysregulated HPA activity is one of the most commonly observed neuroendocrine symptoms in major depressive disorder (for review see [24]). Childhood stress has also been shown to be a strong predictor of impaired inhibitory feedback regulation of the HPA axis with evidence linking to a role of CRH and/or AVP systems. For example, postmortem brain tissue of depressed individuals revealed elevated CRH and AVP in the hypothalamus [25, 26]. Studies in rodent models further support the concept that exposure to a chronic stressor can lead to long-term changes in HPA regulation and behaviour stemming from changes in neuropeptide regulation (for review see [27]).

The role of candidate genes outside of the HPA axis

Candidate genes such as the serotonin transporter SLC6A4 and BDNF have been highly implicated in stress response and in increased risk for psychiatric disorders [28–32]. BDNF is the most prevalent growth factor in the central nervous system (CNS) and important in neuronal development and plasticity [33]. Serotonin transporter is involved in the reuptake of serotonin from the brain synapses regulating serotonin signalling and is the target for many antidepressants [34]. SLC6A4 or 5-HTT carries a genetic polymorphism in the promoter region resulting in a short “s” and a long “l” allele version of the promoter [35]. The “s” allele is associated with poor transcriptional efficiency of SLC6A4 compared to “l” allele [35]. The BDNF gene carries a Val66Met polymorphism which impacts an activity-dependent expression of BDNF and the intracellular trafficking [36]. In combination with exposure to ELS events, both SLC6A4 and BDNF polymorphisms have been attributed to increased risk for depression in later life [28, 30, 37]. Further, steroid hormone estrogen and its receptors have been shown to influence brain function and psychiatric disorders (for review see [38]). Animal models analysing maternal care in rats identified estrogen receptor α expression was altered with the type of maternal care, and this was passed across generations [39]. A detailed analysis of the role of these and other candidate genes implicated in ELS and later-life psychopathology is reviewed in the following sections.

ELS-induced epigenetic modifications in animal models

A variety of animal models are currently being used to model ELS paralleling childhood adversity in humans (Table 1). Each paradigm facilitates investigation into ELS-induced alterations in the developing animal and centres on the importance of mother for normal nervous, immune and endocrine system development [40–42]. A majority of the literature on animal models discussed in this review will therefore be on variations in maternal care.

Table 1 Commonly used models of early adversity in animal studies
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ELS-induced epigenetic changes in HPA axis genes

Given the central role of the HPA axis in stress responsivity and adaptation to ELS, the genes involved in regulating this system have been of focus in ELS-induced epigenetic studies (see Table 2 for summary of studies).

Table 2 Early stress-induced epigenetic changes in stress-regulatory genes in animal studies
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Glucocorticoid receptor gene

Pioneering studies on epigenetic alterations in GR promoter in response to variations in maternal care were first shown by Weaver and colleagues [20]. They reported increased methylation of the 5′ exon17 GR promoter and decreased H3K9 acetylation both associated with reduction in GR messenger RNA (mRNA) expression in the hippocampus of pups raised by low licking grooming arched-back nursing (LG-ABN) dams [20]. Extended studies showed that increased 5′ cytosine phosphate guanine (CpG) site methylation in the low LG-ABN pups reduced binding of transcription factor nerve growth factor inducible protein A (NGFI-A) to GR exon 17 promoter and reduced recruitment of CREB binding protein (CBP), subsequently reducing the levels of GR mRNA in hippocampus [20, 43]. These changes were observed both at postnatal day (PND) 6 (early) and PND90 (adulthood) suggesting the long-lasting nature of the epigenetic mark. In contrast, Daniels and colleagues reported no differences in the methylation status of exon 17 GR promoter in maternally separated (MS) compared to control rats on PND21 [44]. The conflicting results could be due to differences in the early stress model (maternal care vs MS) and strain (Long-Evans vs Sprague Dawley) which may exert different effects on the epigenetic signature of the glucocorticoid receptor. Other studies also report epigenetic alterations in the GR promoter using different ELS models of rat/mouse strains [45, 46] (Table 2).

Crh

Chen and colleagues reported hypomethylation of the Crh promoter in the PVN of maternally deprived (MD) Sprague Dawley rats on PND61 [47]. This was associated with increased phosphoCREB binding to the Crh cAMP response element (CRE), critical in the regulation of transcription of Crh. Similarly, Wang and colleagues reported increased H3 acetylation and hypomethylation of the Crh promoter region in the hippocampal cornu ammonis 1 (CA1) region of rats with postnatal MS [48]. Franklin and colleagues reported hypomethylation of the CRH receptor 2 (Crhr2) in maternally separated male C57/BL6 mice at 3–8 months of age and demonstrated a transgenerational effect [21]. The hypomethylation was associated with decreased Crhr2 gene expression which in this case was assessed in vitro using zebularine, a DNA methylation inhibitor [21]. This is in contrast to conventional understanding that DNA methylation is repressive [49, 50]; however, results correlate with the expected ELS-induced changes in HPA axis regulation and decreased Crhr2 expression.

Avp

Murgatroyd and colleagues reported hypomethylation of the AVP enhancer sequence in the parvocellular neurons of the PVN [23]. Hypomethylation of the AVP enhancer was associated with increased Avp expression following ELS (maternal separation) from 6 weeks of age and was still evident at 1 year suggesting the long-lasting nature of this epigenetic mark. Mechanistic analysis using mouse hypothalamic-like cells revealed that the hypomethylated CpG sites bound MeCP2 during postnatal life that in turn recruited DNA methyl transferase (DNMTs) and histone deacetylase (HDACs) to regulate expression of Avp [23] and that MeCP2 occupancy further depended on polycomb binding earlier in hypothalamic development [51]. Contrasting results were reported in a more recent study showing hypermethylation of the Avp enhancer CpG site in the hippocampus of maternally deprived C57BL/6 and DBA/2 males [45]. This could be due to the type of tissue analysed and the fact that the CpG sites analysed by these two studies did not overlap.

ELS-induced epigenetic changes in genes outside of the HPA axis

Brain-derived neurotrophic factor

ELS has been shown to decrease Bdnf expression whilst enhancing anxiety and depression-like behaviours [41, 52]. Roth and colleagues exposed Long-Evans rat pups to an abusive mother during the first week of life [53]. They reported hypermethylation of the Bdnf exons IV and IX in the prefrontal cortex on PND8 with associated reduction of Bdnf mRNA which persisted into adulthood. Bai and colleagues reported significantly decreased Bdnf mRNA and protein and increased miR-16 expression in the hippocampus of MD rats compared to those exposed to chronic unpredictable stress in adulthood (CUPS) and control rats [54] (see Table 3). The results suggested significant association of depression induced by MD to Bdnf and miR-16 levels but not the late-life stressors such as the CUPS thus emphasising the role of ELS-induced epigenetic alterations.

Table 3 Early stress-induced epigenetic modifications in other candidate genes
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Serotonin transporter (5-HTT or Slc6a4) gene

Reduction in 5-HTT expression has been observed in response to ELS in non-human primate and rodent models [55, 56]. Kinnaly and colleagues investigated the role of ELS-induced epigenetic modifications in the 5-HTT gene using non-human primate models [57, 58] (see Table 3). These studies assessed the relationship between 5-HTT expression and 5-HTT gene methylation following ELS in infant rhesus macaques [57] and adolescent bonnet macaques [58]. No significant effect of rearing was observed on the 5-HTT methylation status in either study. However, carriers of the short allele of the 5-HTT polymorphism had higher mean 5-HTT CpG methylation, and this was significantly associated to the levels of peripheral 5-HTT expression in the infant rhesus macaques [57]. In adolescent and adult Bonnet macaques, genome-wide methylation levels were associated with 5-HTT expression in those exposed to early stress as infants compared to controls [58]. The above studies suggest that 5-HTT gene methylation is not susceptible to variations in maternal care; however, polymorphisms in the 5-HTT gene and methylation at other cis or Trans regulating sites as may be conferring increased stress reactivity.

Estrogen receptor-α gene

Increased expression of estrogen receptor-α (ERα) in response to variations in maternal care was first reported by Champagne and colleagues using the LG-ABN rat model [39]. The study reported elevated ERα mRNA expression in the medial preoptic area of high LG-ABN dams compared to low LG-ABN, and this effect was transmitted to the female offspring of the high LG-ABN dams [39, 59]. Champagne and colleagues then demonstrated decreased ERα1b promoter methylation in high vs low LG-ABN offspring on PND6 [59] (Table 3). It was characterised that this hypomethylation of the promoter region enhanced binding of the STAT5 transcription factor to the ERα1b promoter and a corresponding increase in ERα mRNA expression in response to increased maternal care.

Glutamate decarboxylase-1 and Reelin genes

Glutamate decarboxylase 1 (GAD1) is a key enzyme in the synthesis of gamma amino-butyric acid (GABA), and Reelin (Reln) is important in migration of new neurons in the central nervous system (CNS). Postmortem studies of schizophrenic patient brains have shown decreased forebrain expression of GAD1 [60, 61] and increased methylation of the GAD1 promoter [62, 63] and decreased RELN expression [64, 65]. Zhang and colleagues assessed the methylation status of the Gad1 promoter in the offspring of the high vs low LG-ABN dams [66] (See Table 3). Hypomethylation, increased histone H3K9 acetylation and increased NGFI-A association with the Gad1 promoter were observed in those raised by high LG-ABN dams leading to increased Gad1 mRNA expression [66]. Qin and colleagues reported hypermethylation of the Reln gene and subsequent down-regulation of Reln mRNA in the hippocampus of Wistar rats exposed to MS from PND2–15 compared to controls [67].

Early stress-induced epigenetic modifications in humans

Epigenetic alterations in candidate genes

In human studies, most focus to date has been on the role of GR due to its negative feedback control in stress responsivity and serotonin transporter (5-HTT) due to its polymorphisms and role in mediating ELS and later-life stress effects on adult depression status [14, 68] (see Table 4 for summary of studies).

Table 4 Early stress-induced epigenetic modifications of candidate genes in humans
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GR gene

McGowan and colleagues were the first to demonstrate hypermethylation of the GR promoter exon 1F and decreased GR mRNA in the hippocampus of adults who were exposed to childhood abuse [19]. When compared to suicide victims or controls with no childhood abuse the GR promoter of suicide victims with a history of childhood abuse showed a significant increase (p < 0.05; d = 1.07) in methylation. This study was thus able to translate the results previously described in LG-ABN rat model [43]. McGowan and colleagues extended research by analysing a wider locus containing the GR gene on chromosome 5 and reported differential methylation in promoters of the protocadherin (PCDH) gene family which are implicated in synaptic plasticity [69]. Whilst McGowan and colleagues analysed the epigenetic changes in hippocampal GR gene, other human studies have reported similar hypermethylation GR gene promoter in peripheral blood leukocytes of adults exposed to early childhood stress [70, 71]. Murgatroyd and colleagues have recently demonstrated maternal stroking to modify CpG methylation within this GR region further translating the rat LG results [72]. These studies have shown that hypermethylation of specific CpG sites were associated to type of early stress or the severity of early maltreatment (see Table 4).

5-HTT gene

Philibert and colleagues were the first to report hypermethylation of the 5-HTT promoter and subsequent reduction in 5-HTT mRNA; however, this study did not assess the role of early maltreatment [73]. Further work from Beach and colleagues reported association of increased methylation of the 5-HTT promoter to childhood abuse. In their 2010 study, Beach and colleagues report significant association of overall methylation of the 5-HTT promoter region (CpGs analysed = 71, CpGs used in analyses = 26) to childhood abuse (p < 0.0004, d = 0.73) [74]. In particular, increased methylation of the sites CpG1 and CpG3 in the 5-HTT promoter was significantly associated in abused females. In their 2011 study, the same group showed significant association of childhood abuse to 5-HTT promoter methylation, 5-HTT mRNA levels and a correlation to 5-HTT genotype and adult anti-social personality disorder [75]. The study reported that 9 % of the variation in the personality disorder was attributed to increased 5-HTT promoter methylation observed only in those that were sexually abused (see Table 4 for details). Kang and colleagues also reported similar hypermethylation of the 5-HTT promoter (total of seven CpG sites) in abused compared to non-abused people with current MDD [76]. The average methylation percentage of the seven CpG sites for any adversity was significantly higher in those who were abused in childhood (p < 0.001, d = 1.1).

Genome-wide methylation

A number of studies have assessed the effect of early stress on genome-wide methylation patterns (See Table 5 for summary of studies). Naumova and colleagues demonstrated hypermethylation of 28 genes involved in brain development and function including those regulating the arginine vasopressin 1A receptor (AVPR1A), GABA A receptor (GABRA5), glutamate receptor (GRM5), among others, in 7- to 10-year-old children following institutionalisation [77]. Hypermethylation of candidate genes has also been shown in adulthood, with Labonte and colleagues reporting hypermethylation of 248 gene promoters and associated decreases in mRNA expression of these promoters in the hippocampi of adult men who completed suicide [78]. Genes responsible for cellular and neuronal plasticity were the most differentially methylated, including the alsin (ALS2) gene promoter. Many other studies have also shown significant global methylation differences between those exposed to early adversity [79–81]. These studies suggest that alterations in the early environment have the ability to cause changes in the methylation status of numerous genes across the genome, including those involved in control of nervous and immune system development and function.

Table 5 Effects of early stress on genome-wide methylation in humans
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Discussion

As evidenced in the studies reviewed above, changes in DNA methylation in response to the early environment remain the best characterised to date. This could be due to DNA methylation being a robust epigenetic mark and available to study across lifespan and generations [21, 82]. More recent studies however have also analysed the role of microRNAs [54], histone modifications [83] and DNA hydroxymethylation [84] in mediating early stress effects.

Results from the animal models reviewed suggest that ELS exerts significant methylation changes in the stress-regulatory genes. Enhanced Crh and Avp expression in the hypothalamus may lead to a hypersensitive HPA axis [23, 47], whilst reduced Crhr2 and GR expression (in the hypothalamus and hippocampus respectively) may affect negative feedback of the HPA response to stress [20, 21]. Epigenetic signatures in the GR gene promoter in humans exposed to a variety of early adversity translate the results observed in animal models and confirm the central role of GR methylation in the dysfunctional negative feedback of HPA axis [19, 70, 71]. Analysis of a broader GR locus (~7 Mpb centred with Nr3c1) in both rats and humans exposed to early adversity revealed conserved methylated sequences in the GR locus including the GR promoter methylations thus emphasising an evolutionary role of the GR locus in stress responsivity [46, 69] (See Tables 2 and 4 for details).

Studies of animal models have centred on other candidate genes implicated in the pathogenesis of neuropsychiatric disorders. Altered 5-HTT expression early in life may moderate the impact of early environment on emotion development [28] as also shown by pharmacological blocking studies [85, 29]. The findings on 5-HTT promoter methylation therefore support the role of reduced 5-HTT activity in the onset of adult depression-like behaviours [57, 58]. Reduced BDNF expression has been implicated in anxiety and depression-like behaviours [41, 52]; therefore, hypermethylation of the Bdnf gene alongside reduced Bdnf mRNA expression in the prefrontal cortex (PFC) of rats exposed to abuse (67) suggests early stress may play a role in the development of anxiety and depression disorders. In humans exposed to early adversity, 5-HTT hypermethylation has been associated to adult depression status depending on the polymorphic status of the 5-HTT gene, emphasising the role of genetic polymorphisms on epigenetic effects [14, 76]. Interestingly, studies to date have only analysed the effect of prenatal stress on the methylation status of the BDNF gene in humans [86, 87] and not variations in postnatal stress. BDNF is known to regulate neuronal development, serotonergic functions and signalling [88]. For example, BDNF promotes the development and function of serotonergic neurons where high affinity receptors for BDNF, Trkb, are also found [89]. Therefore, ELS-induced reduced BDNF could also potentially lead to decreased function of the serotonergic system thus leading to mood and affective behavioural dysfunctions as reported in the above studies. In addition, BDNF has been shown to be regulated by estrogen via ERα within the hippocampus of rat brains [90]. In this context, the increased ERα expression in the brains of the high LG-ABN rats [59] suggests that estrogen is important in regulating normal brain development and possibly involves maturation of neural systems via BDNF regulation. The down-regulation of Reelin post ELS [67] may negatively impact hippocampal function, potentially altering stress axis regulation and predisposing to anxiety and depression across the lifespan. A neurodevelopmental origin for schizophrenia is shown from the study suggesting increased methylation and reduced Gad1 expression in rats [66] which fits with the observations in postmortem brains of schizophrenic patients [62, 63].

One of the major questions in psychiatric epigenetics is whether epigenetic changes observed in the periphery reflect the changes in the brain. For example, hypermethylation of GR gene promoter and subsequent increase in GR mRNA was reported in both peripheral leukocytes [70, 71] and in the neurons of the hippocampus [19]. Analysis of methylome of cells in the PFC and T cells in mother vs surrogate-reared rhesus macaques revealed similarities in the methylation of cells in PFC and T cells, specifically the GR receptor promoter region alongside genes in the immune response, transcription and response to stimulus [91]. These findings suggest that peripheral GR methylation or cell specific (example T cells) methylation changes could be a potential biomarker for assessing early stress-induced HPA dysfunction. Genome-wide methylation studies show that childhood maltreatment leaves a systemic, genome-wide mark by altering the methylation status of key genes in regulatory pathways such as intra and extra cellular signalling [77, 79, 80, 92, 93]. Although most work to date has focused on the stress response, it may be interesting to consider whether prolonged immune dysfunction that often persists after early stress is secondary to epigenetic changes in immunoregulatory genes as reported by Smith and colleagues in PTSD [81] or if it results indirectly from epigenetic changes in stress-regulatory genes.

Conclusions

Research to date highlights the remarkable susceptibility of the genome, and particularly of genes involved in stress and emotion regulation, to environmental alterations early in the lifespan. Many of these changes persisted into adulthood, and epigenetic mechanisms have been shown to contribute to the long-lasting nature of ELS and its contribution to an individual’s disease risk and susceptibility to neuropsychiatric conditions across the lifespan.

Abbreviations

5-HTT:

5-hyrodxytryptamine transporter (serotonin transporter)

ACTH:

adrenocorticotrophic hormone

AVP:

arginine vasopressin

BDNF:

brain-derived neurotrophic factor

CA1:

cornu ammonis 1

CpG:

cytosine phosphate guanine

CRH:

corticotrophin-releasing hormone

DNMT:

DNA methyl transferase

ELS:

early life stress

GAD1:

glutamate decarboxylase 1

GR:

glucocorticoid receptor

HDAC:

histone deacetylase

HPA:

hypothalamic-pituitary-adrenal axis

MD:

maternal deprivation

MS:

maternal separation

PCDH:

protocadherin

PFC:

prefrontal cortex

PND:

postnatal day

PVN:

para ventricular nucleus

References

  1. 1.

    Green JG, McLaughlin KA, Berglund PA, Gruber MJ, Sampson NA, Zaslavsky AM, et al. Childhood adversities and adult psychiatric disorders in the national comorbidity survey replication I: associations with first onset of DSM-IV disorders. Arch Gen Psychiatry. 2010;67(2):113–23.

    PubMed Central  Article  PubMed  Google Scholar 

  2. 2.

    Kessler RC, McLaughlin KA, Green JG, Gruber MJ, Sampson NA, Zaslavsky AM, et al. Childhood adversities and adult psychopathology in the WHO World Mental Health Surveys. Br J Psychiatry. 2010;197(5):378–85.

    PubMed Central  Article  PubMed  Google Scholar 

  3. 3.

    Bernet CZ, Stein MB. Relationship of childhood maltreatment to the onset and course of major depression in adulthood. Depress Anxiety. 1999;9(4):169–74.

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Varese F, Smeets F, Drukker M, Lieverse R, Lataster T, Viechtbauer W, et al. Childhood adversities increase the risk of psychosis: a meta-analysis of patient-control, prospective- and cross-sectional cohort studies. Schizophr Bull. 2012;38(4):661–71.

    PubMed Central  Article  PubMed  Google Scholar 

  5. 5.

    Scott KM, Von Korff M, Angermeyer MC, Benjet C, Bruffaerts R, de Girolamo G, et al. Association of childhood adversities and early-onset mental disorders with adult-onset chronic physical conditions. Arch Gen Psychiatry. 2011;68(8):838–44.

    PubMed Central  Article  PubMed  Google Scholar 

  6. 6.

    Scott KM, Von Korff M, Alonso J, Angermeyer MC, Benjet C, Bruffaerts R, et al. Childhood adversity, early-onset depressive/anxiety disorders, and adult-onset asthma. Psychosom Med. 2008;70(9):1035–43.

    Article  PubMed  Google Scholar 

  7. 7.

    Gershon A, Sudheimer K, Tirouvanziam R, Williams LM, O’Hara R. The long-term impact of early adversity on late-life psychiatric disorders. Curr Psychiatry Rep. 2013;15(4):013–0352.

    Article  Google Scholar 

  8. 8.

    Kaplow JB, Widom CS. Age of onset of child maltreatment predicts long-term mental health outcomes. J Abnorm Psychol. 2007;116(1):176–87.

    Article  PubMed  Google Scholar 

  9. 9.

    Schoedl AF, Costa MC, Mari JJ, Mello MF, Tyrka AR, Carpenter LL, et al. The clinical correlates of reported childhood sexual abuse: an association between age at trauma onset and severity of depression and PTSD in adults. J Child Sex Abus. 2010;19(2):156–70.

    PubMed Central  Article  PubMed  Google Scholar 

  10. 10.

    Evans GW, Schamberg MA. Childhood poverty, chronic stress, and adult working memory. Proc Natl Acad Sci. 2009;30:2009.

    Google Scholar 

  11. 11.

    Felitti VJ, Anda RF, Nordenberg D, Williamson DF, Spitz AM, Edwards V, et al. Relationship of childhood abuse and household dysfunction to many of the leading causes of death in adults. The Adverse Childhood Experiences (ACE) Study. Am J Prev Med. 1998;14(4):245–58.

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Wise LA, Zierler S, Krieger N, Harlow BL. Adult onset of major depressive disorder in relation to early life violent victimisation: a case-control study. Lancet. 2001;358(9285):881–7.

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Gershon A, Minor K, Hayward C. Gender, victimization, and psychiatric outcomes. Psychol Med. 2008;38(10):1377–91.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  14. 14.

    Caspi A, Sugden K, Moffitt TE, Taylor A, Craig IW, Harrington H, et al. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science. 2003;301(5631):386–9.

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Buchmann AF, Hellweg R, Rietschel M, Treutlein J, Witt SH, Zimmermann US, et al. BDNF Val 66 Met and 5-HTTLPR genotype moderate the impact of early psychosocial adversity on plasma brain-derived neurotrophic factor and depressive symptoms: a prospective study. Eur Neuropsychopharmacol. 2013;23(8):902–9.

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Binder EB, Bradley RG, Liu W, Epstein MP, Deveau TC, Mercer KB, et al. Association of FKBP5 polymorphisms and childhood abuse with risk of posttraumatic stress disorder symptoms in adults. JAMA. 2008;299(11):1291–305.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  17. 17.

    Heim C, Newport DJ, Mletzko T, Miller AH, Nemeroff CB. The link between childhood trauma and depression: insights from HPA axis studies in humans. Psychoneuroendocrinology. 2008;33(6):693–710.

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Danese A, Pariante CM, Caspi A, Taylor A, Poulton R. Childhood maltreatment predicts adult inflammation in a life-course study. Proc Natl Acad Sci U S A. 2007;104(4):1319–24.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  19. 19.

    McGowan P, Sasaki A, D’Alessio AC, Dymov S, Labonte B, Szyf M, et al. Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse. Nat Neurosci. 2009;12(3):342–8.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  20. 20.

    Weaver IC, Cervoni N, Champagne FA, D’Alessio AC, Sharma S, Seckl JR, et al. Epigenetic programming by maternal behavior. Nat Neurosci. 2004;7(8):847–54.

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Franklin TB, Russig H, Weiss IC, Graff J, Linder N, Michalon A, et al. Epigenetic transmission of the impact of early stress across generations. Biol Psychiatry. 2010;68(5):408–15.

    Article  PubMed  Google Scholar 

  22. 22.

    McGowan PO, Szyf M. The epigenetics of social adversity in early life: implications for mental health outcomes. Neurobiol Dis. 2010;39(1):66–72.

    Article  PubMed  Google Scholar 

  23. 23.

    Murgatroyd C, Patchev A, Wu Y, Micale V, Bockmuhl Y, Fischer D, et al. Dynamic DNA methylation programs persistent adverse effects of early-life stress. Nat Neurosci. 2009;12(12):1559–66. doi:10.038/nn.2436. Epub 009 Nov 8.

  24. 24.

    Holsboer F. The corticosteroid receptor hypothesis of depression. Neuropsychopharmacology. 2000;23(5):477–501.

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Meynen G, Unmehopa UA, van Heerikhuize JJ, Hofman MA, Swaab DF, Hoogendijk WJ. Increased arginine vasopressin mRNA expression in the human hypothalamus in depression: A preliminary report. Biol Psychiatry. 2006;60(8):892–5.

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Raadsheer FC, Hoogendijk WJ, Stam FC, Tilders FJ, Swaab DF. Increased numbers of corticotropin-releasing hormone expressing neurons in the hypothalamic paraventricular nucleus of depressed patients. Neuroendocrinology. 1994;60(4):436–44.

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    Murgatroyd C, Spengler D. Epigenetics of early child development. Front Psychiatry. 2011;2:16.

    PubMed Central  Article  PubMed  Google Scholar 

  28. 28.

    Bennett AJ, Lesch KP, Heils A, Long JC, Lorenz JG, Shoaf SE, et al. Early experience and serotonin transporter gene variation interact to influence primate CNS function. Mol Psychiatry. 2002;7(1):118–22.

    CAS  Article  PubMed  Google Scholar 

  29. 29.

    Ansorge MS, Zhou M, Lira A, Hen R, Gingrich JA. Early-life blockade of the 5-HT transporter alters emotional behavior in adult mice. Science. 2004;306(5697):879–81.

    CAS  Article  PubMed  Google Scholar 

  30. 30.

    Gatt JM, Nemeroff CB, Dobson-Stone C, Paul RH, Bryant RA, Schofield PR, et al. Interactions between BDNF Val66Met polymorphism and early life stress predict brain and arousal pathways to syndromal depression and anxiety. Mol Psychiatry. 2009;14(7):681–95.

    CAS  Article  PubMed  Google Scholar 

  31. 31.

    Cirulli F, Francia N, Berry A, Aloe L, Alleva E, Suomi SJ. Early life stress as a risk factor for mental health: role of neurotrophins from rodents to non-human primates. Neurosci Biobehav Rev. 2009;33(4):573–85.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  32. 32.

    Karege F, Perret G, Bondolfi G, Schwald M, Bertschy G, Aubry JM. Decreased serum brain-derived neurotrophic factor levels in major depressed patients. Psychiatry Res. 2002;109(2):143–8.

    CAS  Article  PubMed  Google Scholar 

  33. 33.

    Black IB. Trophic regulation of synaptic plasticity. J Neurobiol. 1999;41(1):108–18.

    CAS  Article  PubMed  Google Scholar 

  34. 34.

    White KJ, Walline CC, Barker EL. Serotonin transporters: implications for antidepressant drug development. AAPS J. 2005;7(2):E421–33.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  35. 35.

    Lesch KP, Bengel D, Heils A, Sabol SZ, Greenberg BD, Petri S, et al. Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science. 1996;274(5292):1527–31.

    CAS  Article  PubMed  Google Scholar 

  36. 36.

    Egan MF, Kojima M, Callicott JH, Goldberg TE, Kolachana BS, Bertolino A, et al. The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell. 2003;112(2):257–69.

    CAS  Article  PubMed  Google Scholar 

  37. 37.

    van der Doelen RH, Calabrese F, Guidotti G, Geenen B, Riva MA, Kozicz T, et al. Early life stress and serotonin transporter gene variation interact to affect the transcription of the glucocorticoid and mineralocorticoid receptors, and the co-chaperone FKBP5, in the adult rat brain. Front Behav Neurosci. 2014;8:355.

    PubMed Central  PubMed  Google Scholar 

  38. 38.

    Osterlund MK, Hurd YL. Estrogen receptors in the human forebrain and the relation to neuropsychiatric disorders. Prog Neurobiol. 2001;64(3):251–67.

    CAS  Article  PubMed  Google Scholar 

  39. 39.

    Champagne FA, Weaver IC, Diorio J, Sharma S, Meaney MJ. Natural variations in maternal care are associated with estrogen receptor alpha expression and estrogen sensitivity in the medial preoptic area. Endocrinology. 2003;144(11):4720–4. Epub 2003 Jul 24.

    CAS  Article  PubMed  Google Scholar 

  40. 40.

    Pinheiro M, Ferraz-de-Paula V, Ribeiro A, Sakai M, Bernardi M, Palermo-Neto J. Long-term maternal separation differentially alters serum corticosterone levels and blood neutrophil activity in A/J and C57BL/6 mouse offspring. Neuroimmunomodulation. 2011;18(3):184–90. Epub 2011 Feb 9.

    CAS  Article  PubMed  Google Scholar 

  41. 41.

    Roceri M, Hendriks W, Racagni G, Ellenbroek BA, Riva MA. Early maternal deprivation reduces the expression of BDNF and NMDA receptor subunits in rat hippocampus. Mol Psychiatry. 2002;7(6):609–16.

    CAS  Article  PubMed  Google Scholar 

  42. 42.

    George ED, Bordner KA, Elwafi HM, Simen AA. Maternal separation with early weaning: a novel mouse model of early life neglect. BMC Neurosci. 2010;11:123.

    PubMed Central  Article  PubMed  Google Scholar 

  43. 43.

    Weaver ICG, D’Alessio AC, Brown SE, Hellstrom IC, Dymov S, Sharma S, et al. The transcription factor nerve growth factor-inducible protein a mediates epigenetic programming: altering epigenetic marks by immediate-early genes. J Neurosci. 2007;27(7):1756–68.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  44. 44.

    Daniels WMU, Fairbairn L, Tilburg G, McEvoy C, Zigmond M, Russell V, et al. Maternal separation alters nerve growth factor and corticosterone levels but not the DNA methylation status of the exon 1(7) glucocorticoid receptor promoter region. Metab Brain Dis. 2009;24(4):615–27.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  45. 45.

    Kember RL, Dempster EL, Lee TH, Schalkwyk LC, Mill J, Fernandes C. Maternal separation is associated with strain-specific responses to stress and epigenetic alterations to Nr3c1, Avp, and Nr4a1 in mouse. Brain Behav. 2012;2(4):455–67.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  46. 46.

    McGowan P, Suderman M, Sasaki A, Huang T, Hallett M, Meaney MJ, et al. Broad epigenetic signature of maternal care in the brain of adult rats. PLoS One. 2011;6(2):e14739.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  47. 47.

    Chen J, Evans A, Liu Y, Honda M, Saavedra J, Aguilera G. Maternal deprivation in rats is associated with corticotrophin-releasing hormone (CRH) promoter hypomethylation and enhances CRH transcriptional responses to stress in adulthood. J Neuroendocrinol. 2012;24(7):1055–64.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  48. 48.

    Wang A, Nie W, Li H, Hou Y, Yu Z, Fan Q, et al. Epigenetic upregulation of corticotrophin-releasing hormone mediates postnatal maternal separation-induced memory deficiency. PLoS One. 2014;9(4):e94394.

    PubMed Central  Article  PubMed  Google Scholar 

  49. 49.

    Rishi V, Bhattacharya P, Chatterjee R, Rozenberg J, Zhao J, Glass K, et al. CpG methylation of half-CRE sequences creates C/EBPalpha binding sites that activate some tissue-specific genes. Proc Natl Acad Sci U S A. 2010;107(47):20311–6.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  50. 50.

    Zhang X, Odom DT, Koo SH, Conkright MD, Canettieri G, Best J, et al. Genome-wide analysis of cAMP-response element binding protein occupancy, phosphorylation, and target gene activation in human tissues. Proc Natl Acad Sci U S A. 2005;102(12):4459–64.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  51. 51.

    Murgatroyd C, Spengler D. Polycomb binding precedes early-life stress responsive DNA methylation at the Avp enhancer. PLoS One. 2014;9(3):e90277.

    PubMed Central  Article  PubMed  Google Scholar 

  52. 52.

    Roceri M, Cirulli F, Pressina C, Peretto P, Racagni G, Riva MA. Postnatal repeated maternal deprivation produces age-dependent changes of brain-derived neurotrophic factor expression in selected rat brain regions. Biol Psychiatry. 2004;55(7):708–14.

    CAS  Article  PubMed  Google Scholar 

  53. 53.

    Roth TL, Lubin FD, Funk A, Sweatt JD. Lasting epigenetic influence of early-life adversity on the BDNF gene. Biol Psychiatry. 2009;65(9):760–9. doi:10.1016/j.biopsych.2008.11.028. Epub 9 Jan 15.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  54. 54.

    Bai M, Zhu X, Zhang Y, Zhang S, Zhang L, Xue L, et al. Abnormal hippocampal BDNF and miR-16 expression is associated with depression-like behaviors induced by stress during early life. PLoS One. 2012;7(10):e46921.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  55. 55.

    Kinnally EL, Tarara E, Mason W, Mendoza S, Abel K, Lyons L, et al. Serotonin transporter expression is predicted by early life stress and is associated with disinhibited behavior in infant rhesus macaques. Genes Brain Behav. 2010;9(1):45–52.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  56. 56.

    Lee J-H, Kim B-T, Kim HJ, Kim JG, Ryu V, Kang D-W, et al. Depressive behaviors and decreased expression of serotonin reuptake transporter in rats that experienced neonatal maternal separation. Neurosci Res. 2007;58(1):32–9.

    CAS  Article  PubMed  Google Scholar 

  57. 57.

    Kinnally EL, Capitanio JP, Leibel R, Deng L, LeDuc C, Haghighi F, et al. Epigenetic regulation of serotonin transporter expression and behavior in infant rhesus macaques. Genes Brain Behav. 2010;9(6):575–82.

    PubMed Central  CAS  PubMed  Google Scholar 

  58. 58.

    Kinnally EL, Feinberg C, Kim D, Ferguson K, Leibel R, Coplan JD, et al. DNA methylation as a risk factor in the effects of early life stress. Brain Behav Immun. 2011;25(8):1548–53.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  59. 59.

    Champagne FA, Weaver ICG, Diorio J, Dymov S, Szyf M, Meaney MJ. Maternal care associated with methylation of the estrogen receptor-alpha1b promoter and estrogen receptor-alpha expression in the medial preoptic area of female offspring. Endocrinology. 2006;147(6):2909.

    CAS  Article  PubMed  Google Scholar 

  60. 60.

    Volk DW, Austin MC, Pierri JN, Sampson AR, Lewis DA. Decreased glutamic acid decarboxylase 67 messenger RNA expression in a subset of prefrontal cortical gamma-aminobutyric acid neurons in subjects with schizophrenia. Arch Gen Psychiatry. 2000;57(3):237–45.

    CAS  Article  PubMed  Google Scholar 

  61. 61.

    Heckers S, Stone D, Walsh J, Shick J, Koul P, Benes FM. Differential hippocampal expression of glutamic acid decarboxylase 65 and 67 messenger RNA in bipolar disorder and schizophrenia. Arch Gen Psychiatry. 2002;59(6):521–9.

    CAS  Article  PubMed  Google Scholar 

  62. 62.

    Kundakovic M, Chen Y, Costa E, Grayson D. DNA methyltransferase inhibitors coordinately induce expression of the human reelin and glutamic acid decarboxylase 67 genes. Mol Pharmacol. 2007;71(3):644–53.

    CAS  Article  PubMed  Google Scholar 

  63. 63.

    Costa E, Dong E, Grayson DR, Ruzicka WB, Simonini MV, Veldic M, et al. Epigenetic targets in GABAergic neurons to treat schizophrenia. Adv Pharmacol. 2006;54:95–117.

    CAS  Article  PubMed  Google Scholar 

  64. 64.

    Fatemi SH, Earle JA, McMenomy T. Reduction in Reelin immunoreactivity in hippocampus of subjects with schizophrenia, bipolar disorder and major depression. Mol Psychiatry. 2000;5(6):654–63.

    CAS  Article  PubMed  Google Scholar 

  65. 65.

    Guidotti A, Sharma R, Uzunov D, Costa E, Auta J, Davis JM, et al. Decrease in Reelin and glutamic acid decarboxylase67 (GAD67) expression in schizophrenia and bipolar disorder: a postmortem brain study. Arch Gen Psychiatry. 2000;57(11):1061–9.

    CAS  Article  PubMed  Google Scholar 

  66. 66.

    Zhang T-Y, Hellstrom IC, Bagot R, Wen X, Diorio J, Meaney MJ. Maternal care and DNA methylation of a glutamic acid decarboxylase 1 promoter in rat hippocampus. J Neurosci. 2010;30(39):13130–7. doi:10.1523/JNEUROSCI.1039-10.2010.

    CAS  Article  PubMed  Google Scholar 

  67. 67.

    Qin L, Tu W, Sun X, Zhang J, Chen Y, Zhao H. Retardation of neurobehavioral development and reelin down-regulation regulated by further DNA methylation in the hippocampus of the rat pups are associated with maternal deprivation. Behav Brain Res. 2011;217(1):142–7.

    CAS  Article  PubMed  Google Scholar 

  68. 68.

    Aas M, Djurovic S, Athanasiu L, Steen NE, Agartz I, Lorentzen S, et al. Serotonin transporter gene polymorphism, childhood trauma, and cognition in patients with psychotic disorders. Schizophr Bull. 2012;38(1):15–22.

    PubMed Central  Article  PubMed  Google Scholar 

  69. 69.

    Suderman M, McGowan PO, Sasaki A, Huang TC, Hallett MT, Meaney MJ, et al. Conserved epigenetic sensitivity to early life experience in the rat and human hippocampus. Proc Natl Acad Sci U S A. 2012;109 Suppl 2:17266–72.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  70. 70.

    Perroud N, Paoloni-Giacobino A, Prada P, Olie E, Salzmann A, Nicastro R, et al. Increased methylation of glucocorticoid receptor gene (NR3C1) in adults with a history of childhood maltreatment: a link with the severity and type of trauma. Transl Psychiatry. 2011;1:e59.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  71. 71.

    Tyrka AR, Price LH, Marsit C, Walters OC, Carpenter LL. Childhood adversity and epigenetic modulation of the leukocyte glucocorticoid receptor: preliminary findings in healthy adults. PLoS One. 2012;7(1):e30148.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  72. 72.

    Murgatroyd C, Quinn J, Sharp H, Pickles A, Hill J. Effects of prenatal and postnatal depression, and maternal stroking, at the glucocorticoid receptor gene. Transl Psychiatry. 2015. In press.

  73. 73.

    Philibert RA, Sandhu H, Hollenbeck N, Gunter T, Adams W, Madan A. The relationship of 5HTT (SLC6A4) methylation and genotype on mRNA expression and liability to major depression and alcohol dependence in subjects from the Iowa Adoption Studies. Am J Med Genet B Neuropsychiatr Genet. 2008;147B(5):543–9.

    CAS  Article  PubMed  Google Scholar 

  74. 74.

    Beach SR, Brody GH, Todorov AA, Gunter TD, Philibert RA. Methylation at SLC6A4 is linked to family history of child abuse: an examination of the Iowa adoptee sample. Am J Med Genet B Neuropsychiatr Genet. 2010;153B(2):710–3.

    PubMed Central  CAS  PubMed  Google Scholar 

  75. 75.

    Beach SR, Brody GH, Todorov AA, Gunter TD, Philibert RA. Methylation at 5HTT mediates the impact of child sex abuse on women’s antisocial behavior: an examination of the Iowa adoptee sample. Psychosom Med. 2011;73(1):83–7.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  76. 76.

    Kang HJ, Kim JM, Stewart R, Kim SY, Bae KY, Kim SW, et al. Association of SLC6A4 methylation with early adversity, characteristics and outcomes in depression. Prog Neuropsychopharmacol Biol Psychiatry. 2013;44:23–8.

    CAS  Article  PubMed  Google Scholar 

  77. 77.

    Naumova OY, Lee M, Koposov R, Szyf M, Dozier M, Grigorenko EL. Differential patterns of whole-genome DNA methylation in institutionalized children and children raised by their biological parents. Dev Psychopathol. 2012;24(1):143–55.

    PubMed Central  Article  PubMed  Google Scholar 

  78. 78.

    Labonte B, Yerko V, Gross J, Mechawar N, Meaney MJ, Szyf M, et al. Differential glucocorticoid receptor exon 1(B), 1(C), and 1(H) expression and methylation in suicide completers with a history of childhood abuse. Biol Psychiatry. 2012;72(1):41–8.

    CAS  Article  PubMed  Google Scholar 

  79. 79.

    Borghol N, Suderman M, McArdle W, Racine A, Hallett M, Pembrey M, et al. Associations with early-life socio-economic position in adult DNA methylation. Int J Epidemiol. 2012;41(1):62–74.

    PubMed Central  Article  PubMed  Google Scholar 

  80. 80.

    Mehta D, Klengel T, Conneely KN, Smith AK, Altmann A, Pace TW, et al. Childhood maltreatment is associated with distinct genomic and epigenetic profiles in posttraumatic stress disorder. Proc Natl Acad Sci U S A. 2013;110(20):8302–7.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  81. 81.

    Smith AK, Conneely KN, Kilaru V, Mercer KB, Weiss TE, Bradley B, et al. Differential immune system DNA methylation and cytokine regulation in post-traumatic stress disorder. Am J Med Genet B Neuropsychiatr Genet. 2011;156B(6):700–8.

    PubMed Central  Article  PubMed  Google Scholar 

  82. 82.

    Champagne FA, Meaney MJ. Transgenerational effects of social environment on variations in maternal care and behavioral response to novelty. Behav Neurosci. 2007;121(6):1353–63.

    Article  PubMed  Google Scholar 

  83. 83.

    Levine A, Worrell TR, Zimnisky R, Schmauss C. Early life stress triggers sustained changes in histone deacetylase expression and histone H4 modifications that alter responsiveness to adolescent antidepressant treatment. Neurobiol Dis. 2012;45(1):488–98.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  84. 84.

    Massart R, Suderman M, Provencal N, Yi C, Bennett AJ, Suomi S, et al. Hydroxymethylation and DNA methylation profiles in the prefrontal cortex of the non-human primate rhesus macaque and the impact of maternal deprivation on hydroxymethylation. Neuroscience. 2014;268:139–48.

    CAS  Article  PubMed  Google Scholar 

  85. 85.

    Maciag D, Simpson KL, Coppinger D, Lu Y, Wang Y, Lin RCS, et al. Neonatal antidepressant exposure has lasting effects on behavior and serotonin circuitry. Neuropsychopharmacology. 2006;31(1):47–57.

    PubMed Central  CAS  PubMed  Google Scholar 

  86. 86.

    Ikegame T, Bundo M, Murata Y, Kasai K, Kato T, Iwamoto K. DNA methylation of the BDNF gene and its relevance to psychiatric disorders. J Hum Genet. 2013;58(7):434–8.

    CAS  Article  PubMed  Google Scholar 

  87. 87.

    Kundakovic M, Gudsnuk K, Herbstman JB, Tang D, Perera FP, Champagne FA. DNA methylation of BDNF as a biomarker of early-life adversity. Proc Natl Acad Sci U S A. 2014;112(22):6807–13. doi:10.1073/pnas.1408355111.

    PubMed Central  Article  PubMed  Google Scholar 

  88. 88.

    Martinowich K, Lu B. Interaction between BDNF and serotonin: role in mood disorders. Neuropsychopharmacology. 2008;33(1):73–83.

    CAS  Article  PubMed  Google Scholar 

  89. 89.

    Madhav TR, Pei Q, Zetterstrom TS. Serotonergic cells of the rat raphe nuclei express mRNA of tyrosine kinase B (trkB), the high-affinity receptor for brain derived neurotrophic factor (BDNF). Brain Res Mol Brain Res. 2001;93(1):56–63.

    CAS  Article  PubMed  Google Scholar 

  90. 90.

    Solum DT, Handa RJ. Estrogen regulates the development of brain-derived neurotrophic factor mRNA and protein in the rat hippocampus. J Neurosci. 2002;22(7):2650–9.

    CAS  PubMed  Google Scholar 

  91. 91.

    Provencal N, Suderman MJ, Guillemin C, Massart R, Ruggiero A, Wang D, et al. The signature of maternal rearing in the methylome in rhesus macaque prefrontal cortex and T cells. J Neurosci. 2012;32(44):15626–42.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  92. 92.

    Khulan B, Manning JR, Dunbar DR, Seckl JR, Raikkonen K, Eriksson JG, et al. Epigenomic profiling of men exposed to early-life stress reveals DNA methylation differences in association with current mental state. Transl Psychiatry. 2014;4:e448.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  93. 93.

    Labonte B, Suderman M, Maussion G, Navaro L, Yerko V, Mahar I, et al. Genome-wide epigenetic regulation by early-life trauma. Arch Gen Psychiatry. 2012;69(7):722–31.

    CAS  Article  PubMed  Google Scholar 

  94. 94.

    Levine S. Infantile experience and resistance to physiological stress. Science. 1957;126(3270):405.

    CAS  Article  PubMed  Google Scholar 

  95. 95.

    Laban O, Markovic B, Dimitruevic M, Jankovic B. Maternal deprivation and early weaning modulate experimental allergic encephalomyelitis in the rat. Brain Behav Immun. 1995;9(1):9–19.

    CAS  Article  PubMed  Google Scholar 

  96. 96.

    Plotsky P, Meaney M. Early, postnatal experience alters hypothalamic corticotropin-releasing factor (CRF) mRNA, median eminence CRF content and stress-induced release in adult rats. Brain Res Mol Brain Res. 1993;18(3):195–200.

    CAS  Article  PubMed  Google Scholar 

  97. 97.

    Liu D, Diorio J, Tannenbaum B, Caldji C, Francis D, Freedman A, et al. Maternal care, hippocampal glucocorticoid receptors, and hypothalamic-pituitary-adrenal responses to stress. Science. 1997;277(5332):1659.

    CAS  Article  PubMed  Google Scholar 

  98. 98.

    McGowan PO, Sasaki A, Huang TC, Unterberger A, Suderman M, Ernst C, et al. Promoter-wide hypermethylation of the ribosomal RNA gene promoter in the suicide brain. PLoS One. 2008;3(5):e2085.

    PubMed Central  Article  PubMed  Google Scholar 

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Acknowledgements

The presented work is partly supported by the National Health and Medical Research Council Australia (APP1003788 to BTB). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

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Affiliations

  1. Discipline of Psychiatry, School of Medicine, University of Adelaide, Adelaide, SA, 5005, Australia

    Magdalene C. Jawahar, Emma L. Harrison & Bernhard T. Baune

  2. School of HealthCare Science, Manchester Metropolitan University, Manchester, UK

    Chris Murgatroyd

  3. School of Medicine and Dentistry, James Cook University, Townsville City, Australia

    Emma L. Harrison

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  1. Magdalene C. Jawahar
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  3. Emma L. Harrison
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Correspondence to Bernhard T. Baune.

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The authors declare that they have no competing interests.

Authors’ contributions

All authors meet the 3 authorship criteria of the International Committee of Medical Journal Editors. MCJ contributed to design, acquisition of data, analysis and interpretation of results along with drafting and revising the article. CM contributed to the design, interpretation of the data and revising for critically important intellectual content. ELH contributed to design, acquisition of data, analysis and interpretation and drafting the article. BTB contributed to conception and design, interpretation of the results and critically reviewing for intellectual content. All authors gave approval of the final version to be submitted.

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Jawahar, M.C., Murgatroyd, C., Harrison, E.L. et al. Epigenetic alterations following early postnatal stress: a review on novel aetiological mechanisms of common psychiatric disorders. Clin Epigenet 7, 122 (2015). https://doi.org/10.1186/s13148-015-0156-3

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Keywords

  • Early life stress
  • Maternal separation
  • Epigenetics
  • DNA methylation
  • Stress-responsive genes
  • Histone acetylation
  • Psychopathology

Clinical Epigenetics

ISSN: 1868-7083

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