Introduction

Childhood adversity affects upto 40% of children raised in the West.1 Psychiatric conditions such as anxiety and depressive disorders, schizophrenia and autism spectrum disorders have each been associated with stress in childhood.2, 3, 4, 5, 6 The neurobiological and psychosocial implications of early adversity have also been associated with the development of other disorders in which stress plays a role, such as cardiovascular disease, type 2 diabetes mellitus and obesity.7, 8, 9

Psychiatric disorders are projected to become the second leading cause of morbidity in 2020.10 As individuals exposed to stress in childhood display an enhanced susceptibility to these conditions, modulation of the neurobiological sequelae that result from early adversity may represent a novel target for the reduction or even prevention of chronic stress-related disorders, potentially alleviating their significant burden on the health-care system.

Animal models enable characterisation of the spectra of neurobiological alterations induced by early stress, determination of which is not possible through human studies. A number of animal models of early adversity exist. Although differing in specifics, each centres on the importance of the mother for normal development, and as such involve manipulation of this relationship.11 Animal models enable delineation of the mechanism by which a given intervention exerts its effect on a specific neurobiological change that is often not possible in clinical intervention studies.

To date, there has been no comprehensive review detailing the mechanisms and effects of interventions on the deleterious alterations in neurobiology induced by childhood stress. The objective of this review is therefore to present the current evidence in order to critically evaluate whether behavioural interventions, environmental enrichment (EE) and pharmacological interventions have properties that modulate the neurobiological alterations that result from early adversity. This review focuses on describing interventions and the mechanisms underlying their ability to modulate early stress-induced neurobiological changes using animal models. From a translational perspective, the results of this review may stimulate research in humans that were exposed to early life stress and adversity.

Methods

The PubMed, Medline and PsychInfo databases were searched to identify literature to conduct this review. In brief, the search was performed to identify works demonstrating modulation of changes in neurobiology induced by early stress in animal models. The search terms (‘stress, psychological’ [MeSH] or ‘maternal deprivation’ [MeSH] or ‘maternal separation’) and (‘therapeutics’ [MeSH] or ‘drug therapy’ [MeSH] or ‘modulation’ or ‘intervention’) and (‘models, animal’ [MeSH]) were used, and limits were set to articles published between 1980 and 2013 and in the English language. Reference lists were cross-referenced to locate additional works. In total, 242 full-text articles were identified after assessment of abstracts pertaining to these criteria. To determine inclusion of full-text articles within this review, animal models of early stress were restricted to those involving manipulation of the mother–pup relationship, including maternal separation, maternal deprivation, variations in maternal care and exposure to an abusive mother during childhood. Animal models examining the ability of intervention to modulate changes induced by neonatal immune challenge with lipopolysaccharide (LPS) were excluded, as were interventions that occurred exclusively before early stress exposure. Finally, 86 full-text articles were excluded on the basis of these criteria and 158 articles were included in the final analysis.

Animal models of early life stress

A number of animal models of early life stress exist. Those commonly utilised include those that involve manipulation of the mother–pup relationship such as maternal separation and maternal deprivation. Paradigms differ in specifics, however generally maternal separation refers to separation of pups (either individually or as a group) from the dam for 2–6 h daily from post-natal day (PND) 14 or 21, although paradigms exist that involve separation for differing lengths of time. Maternal deprivation represents a more severe form of early life stress, and involves separating pups from the dam for a single 24-h period during early post-natal life, usually on PNDs 3 or 9. Exposure to an abusive mother during the post-natal period represents another animal model of early life stress.12 While not early life stress per se, models that examine the impact of variations in maternal care enable characterisation of the influence low versus high levels of care exert on offspring.13 Bedding deprivation is another form of early stress, in which reduced volumes of bedding are provided to the stressed group. Stress occurs as a result of abnormal fragmented interactions with the dam due to limited bedding material.14 Disrupted long-term potentiation and decreased numbers of dendritic spines in the hippocampus,15 considered correlates for learning and memory16 and synaptic plasticity respectively,17 have been reported in models utilising bedding deprivation. Neuroendocrine alterations have also been demonstrated following bedding deprivation, with reports of elevated basal plasma corticosterone levels and reduced corticotropin-releasing hormone (CRH) mRNA expression in the hypothalamus in adulthood.14 Research is yet to assess the effect that interventions exert on changes induced by bedding deprivation; hence, such studies will not be addressed in this review.

The influence of interventions on changes in neurobiology caused by early life stress is complicated by the use of a variety of different control groups. In brief, control groups include those that are either stressed without an intervention or non-stressed with and without an intervention. Consideration of the control groups helps determine the influence a given intervention exerts under different treatment conditions.

Factors influencing the effect of early life stress

The long term influence early stress exerts on neurobiology and the longevity of these changes are dependent on a number of factors. (1) The nature of early stress: as discussed previously, there are a number of animal models that involve manipulation of the mother–pup relationship (that will be discussed in depth in this review). (2) The developmental period in which stress occurs: the brain displays enhanced plasticity during times of rapid brain development, making it more vulnerable to perturbations in the environment during this time. Stress exposure during the early post-natal period, later childhood and early adolescence exerts a disproportionately large effect on the developing brain.18 (3) The duration of stress exposure and (4) the age of assessment. (5) Finally, maternal separation studies indicate that rats and mice respond differently to stress early in life; species and strains must be taken into consideration when interpreting study findings. Enhanced basal neuroendocrine reactivity has been reported in rats following maternal separation19,20 while unaltered neuroendocrine activity has been widely reported in mouse models.21,22 Similarly, rats display enhanced anxiety23,24 and depression-like19,25 behaviours after early stress. Mixed reports exist in mice, once again with unchanged behaviour in mouse models,22,26, 27, 28, 29 although findings are varied. As each of these factors ultimately influences the long-term sequelae of early adversity, it is likely that they also influence the way in which interventions alter changes in neurobiology.

Early life stress induces changes in neurobiology

Although predominantly controlled by genetic factors, the nature of the early environment influences development.30 The immature nervous, endocrine and immune systems share an intertwined ontogenesis,31 with stimulation of one during early life may ultimately impact the development of the others.32 Depending on the quality of the environment early in life, maturation is programmed along a specific axis. Stress exposure in childhood may therefore set the stage for a stress-susceptible phenotype, enhancing the predisposition to psychiatric disorder development in adulthood.

Findings from animal models of childhood adversity indicate that early stress influences behaviour, with reports of enhanced anxiety23,24,33 and depression-like19,25,34, 35, 36, 37 behaviour and impaired spatial learning and memory23,38, 39, 40 after early stress. At present, the specific neurobiological changes underlying these behavioural changes remain to be fully characterised. Animal studies indicate that early stress exerts wide-ranging effects within the brain at a cellular level, with altered neuroendocrine activity, immune function and neurotransmission reported after early adversity. Changes often occur within specific brain regions. Studies to date have predominantly focused on the influence it exerts over the hippocampus and prefrontal cortex, although some works examine changes in the amygdala secondary to early adversity. Similarly interventional studies tend to investigate the ability of interventions to modulate changes in the hippocampus and prefrontal cortex caused by early stress; such modulatory influences will be examined in detail throughout this review.

Although inconsistencies exist across the literature, evidence suggests that early stress enhances basal hypothalamo–pituitary–adrenal (HPA) axis activity;19,23 both augmented41,42 and attenuated43 neuroendocrine responses to later stress have been shown in animal models. Impaired cell-mediated immune function has been demonstrated in both non-human primate44, 45, 46 and rodent47, 48, 49, 50 models of early stress, alongside elevated basal pro-inflammatory activity.51 Reports from animal studies remain divided as to whether subsequent inflammatory responses are enhanced52, 53, 54 or reduced51,54,55 following early stress.

Neurotransmitter systems appear vulnerable to adversity early in life. Reduced serotonin receptor expression has been demonstrated in the prefrontal cortex,56,57 hippocampus56,57 and raphe nucleus22,58 following early stress in animal models, indicating that adversity impairs serotonergic signalling. Reports also indicate that early stress influences dopaminergic signalling; decreased activity of the mesolimbic dopaminergic system has been demonstrated following separation, once again in line with depression-like behaviour.58 Alterations in social,59 anxiety57 and depression-like58,60 behaviours have each been associated with altered monoaminergic neurotransmission in several works. Similarly decreased expression of parvalbumin, a GABAergic marker, has been reported in the prefrontal cortex following maternal separation, with reductions correlated with the expression of depression-like behaviour.60

Behavioural interventions modulate early stress-induced changes in neurobiology

Offspring of low-care dams display lower levels of oestrogen receptor α (ERα) expression in the medial preoptic area (MPOA) compared with those raised by high-care dams.61 In the hippocampus, reduced glucocorticoid receptor (GR) expression and enhanced anxiety61 and depression-like62 behaviours have similarly been reported in offspring of low- versus high-care dams, suggesting early stress exerts its influence across a number of different brain regions. Cross-fostering (CF) of Long Evans hooded rats from low- to high-care dams within 12 h of birth has been shown to increase ERα expression in the MPOA of offspring on PND 90,63 indicating that enhanced levels of maternal care can influence ERα expression. Maternal behaviour is facilitated by the expression of the oxytocin receptor (OXTR) in the MPOA,64, 65, 66 whose expression is ERα-dependent.13 In animal models, oxytocin has been shown to have a role in modulation of the neuroendocrine stress axis,67, 68, 69, 70 the expression of anxiety-like behaviour71 and pain perception.72,73 Alterations in OXTR expression secondary to variations in maternal care may therefore influence the stress axis, behaviour and pain perception.

Sprague Dawley rats exposed to stroking on PND 10 exhibit enhanced oxytocin concentrations in the hypothalamus compared with non-stroked controls,74 prompting investigation into the ability of simulated maternal grooming (SMG) to modulate behavioural changes induced by maternal separation. SMG, the application of short, heavy strokes on the head and back for 3 s immediately following maternal separation for the first month of life reversed separation-induced anxiety behaviours in Lewis rats in adulthood.75 Serum corticosterone concentrations were unaltered by maternal separation,75 preventing characterisation of the influence SMG exerted on the neuroendocrine stress response, however indicating that SMG did not exert its beneficial effect by modulating neuroendocrine activity. Attenuation of separation-induced hyperalgesia has also been reported following SMG from PNDs 1 to 27, as indicated by increased hot-plate latencies in SMG-treated Wistar rats compared with control.76 Similarities exist between the influence SMG exerted over the stress axis and pain perception and the role of oxytocin within the brain. As such, it may be that SMG exerted its modulatory effect via influencing central oxytocinergic signalling, although oxytocin concentrations were not quantified in this study.76

Mixed housing (MH) involves communal housing of separated and non-separated animals in the same cage from the time of weaning, and has been shown to attenuate enhanced anxiety behaviours following maternal separation in male Sprague Dawley rats.77 Following administration of chronic homotypic stress, MH also reversed the increased CRH mRNA expression and immunoreactivity in the hypothalamus induced by early stress at 8–9 weeks of age.77 Similar reversal of stress-induced changes in hypothalamic oxytocin mRNA expression was also noted in separated rats housed in mixed conditions.77 Together these findings suggest that MH may exert its modulatory effect on behaviour by reducing CRH and enhancing oxytocin expression within the hypothalamus, thereby decreasing the magnitude of the HPA response to subsequent stress.

Whilst SMG and MH differ in specifics, each centres on enhancing the level of care provided during childhood. The similarities between the modulatory effects of these interventions with the roles of oxytocin within the central nervous system, including in the expression of maternal behaviour, suggest that these interventions may act via enhancing oxytocin signalling within the brain. Additional studies are required to quantify central oxytocin and OXTR expression levels in response to such interventions to ascertain whether these behavioural interventions influence oxytocin expression in animal models of early stress(Table 1).

Table 1 Behavioural interventions modulate early stress-induced changes

Exercise modulates early stress-induced changes

Evidence is beginning to emerge indicating that exercise may have an important role in the prevention and treatment of psychiatric disorders78 and may attenuate age-related cognitive decline.79 This is of interest given the association between early life stress and the development of disorders such as depression later in life. Enhanced neuroplasticity has been shown in response to exercise, with changes often dependent on the type of exercise performed. Aerobic and resistance training have recently been reported to increase neuroplasticity to a greater extent compared with other subtypes of exercise.80 Results from a meta-analysis indicate that exercise can improve cognitive performance in older adults (0.5 s.d. on average), irrespective of the nature of cognitive task, type of exercise or participant characteristics.79 Taken together, findings suggest that enhanced neuroplasticity may be associated with functional improvement.

Exercise from PNDs 25 to 68 attenuated the increased immobility times in the forced swim test (FST) displayed by maternally separated Sprague Dawley rats compared with control from PND 26,81 suggesting reduced depression-like behaviour following intervention. The modulatory influence of exercise also appears to extend to other behaviours influenced by early stress in animal models. Maternally separated Sprague Dawley rats exercised from PNDs 21 to 30 exhibited improved long-term memory capability and spatial learning, as indicated by improved performance in the step-down latency and radial arm maze tasks compared with their non-exercised counterparts.82 Reports indicate that early stress can suppress the serotonin system83,84 and the role serotonin has in modulation of neural stabilisation and behavioural impairment.85 While not a modulatory effect per se, exercise also enhanced serotonin synthesis and tryptophan expression in the hippocampus and dorsal raphe nuclei in both separated and non-separated Sprague Dawley rats82 alongside behavioural changes. Taken together, modulation of both serotonin expression and behaviour by exercise suggests that the positive influence exercise exerts may be partially attributable to its ability to alter the serotonergic system and the role it has in neural connectivity and behaviour.

Additional insight into the mechanisms by which exercise exerts its beneficial effect over early stress-induced changes in neurobiology comes from research examining modulation of cellular changes following maternal separation. Sprague Dawley rats exercised over a 6-week period in adulthood (from PNDs 40 to 82) following maternal separation from PNDs 2 to 14 exhibited reversal of changes in 16 of 23 proteins induced by maternal separation, including those involved in neuronal structure, signalling, neurotransmission and anti-oxidative stress.86 Exercise was also reported to reduce the susceptibility of neurons to cell death previously increased by separation.86 Treadmill exercise has also been shown to enhance synaptophysin and CamKII protein expression in the ventral hippocampus of both separated and non-separated Sprague Dawley rats on PND 65.87 No differences in protein expression were noted in the dorsal hippocampus or prefrontal cortex in exercised versus non-exercised (both stressed and non-stressed),87 indicating that the effect of exercise may in fact be brain-region-specific.

Evidently, exercise modulates a number of cellular changes (such as changes in proteins involved in neuronal structure, neurotransmission, and oxidative stress and cell death) that result from early stress, indicating that it likely exerts its beneficial influence on behaviour (including depression-like behaviour, spatial learning and memory, and long-term memory capability) via a number of intertwined mechanisms. Considered together with its ability to modulate behavioural changes induced by early stress, it may be that exercise modulates the negative influence early stress exerts on behaviour and the later predisposition to disease by attenuating the impact childhood stress exerts on the developing brain at a structural level, potentially within the hippocampus, given that a number of behaviours modulated by exercise are known to be hippocampal-dependent.

Early stress-induced changes can be modulated by environmental enrichment

Improved dendritic arborisation, neurogenesis, synaptogenesis and long-term potentiation have been reported following EE in animal models.88,89 EE has recently been hypothesised to prevent some of the deleterious effects of stress exposure.90, 91, 92 However, only one study has addressed the ability of EE to modulate neurobiological changes induced by maternal separation to date. EE involved housing Wistar rats in groups of 7–10 in cages containing toys, wooden blocks, climbing platforms and running wheels.93 Maternally separated rats raised under conditions of EE displayed reversal of separation-induced decreases in grooming behaviour in the open field test, and attenuation of separation-induced impairments in the step-down test.93 Findings from the step-down test indicate that early stress induced a deficit in memory acquisition, consolidation or retrieval, and that this was reversed by EE. At this stage it is unknown as to exactly how EE alters behavioural changes that result from early stress, however it is known to enhance neuroplasticity on a structural level.93 Findings from animal studies indicate that EE results in functional enhancement of neurophysiology and memory, while increasing dendritic arborisation, neurogenesis, synaptogenesis and long-term potentiation.88,89 As such, EE may modulate memory deficits induced by maternal separation by ‘reprogramming’ some of these same circuits in response to the enriched environment, thereby attenuating the influence early separation exerts on memory. It would be of interest for further studies to assess the ability of EE to modulate other behaviours known to be adversely effected by early stress such as anxiety and depression-like behaviours (Table 2).

Table 2 Environmental enrichment modulates early stress-induced changes

Pharmacological interventions can modulate the neurobiological sequelae of early stress

The endocannabinoid system has an imperative role in key neurodevelopmental processes such as cell proliferation, migration and differentiation, axonal elongation and synaptogenesis.96, 97, 98, 99 It is also considered to function as a crucial regulator of the neuroendocrine stress response.100 Recent evidence also suggests that the endocannabinoid system serves as a homeostatic neuroprotective mechanism, counteracting diverse neural insults.49 For example, administration of WIN-55, a cannabinoid agonist, has been shown to reduce neuronal loss in neonatal rats following severe asphyxia.101 Similarly, modulation of the endocannabinoid system has been shown to decrease behavioural impulsivity following maternal deprivation in adolescent rats.102

Two endocannabinoid system enhancers, arachidonoyl serotonin (AA-5HT) and OMDM-2 have been shown to modulate cellular changes within the CA1 and CA3 of the hippocampus following maternal deprivation,103 an area proposed to have a key role in mediating the behavioural effects of endocannabinoids.104 Administration of AA-5HT and OMDM-2 from PNDs 7 to 12 reduced deprivation-induced increases in glial fibrillary acidic protein (GFAP) expressed by astrocytes in Wistar rats on PND 13 compared with control.103 Attenuation of elevations in plasma corticosterone concentrations secondary to deprivation were also reported in treated male Wistar rats versus control,103 suggesting that raised corticosterone may have influenced cellular changes in the hippocampus of the male rat, and that both AA-5HT and OMDM-2 acted to reduce these changes. Similar findings have been reported in the cerebellum of maternally deprived Wistar rats, with female Wistar rats treated with AA-5HT or OMDM-2 displaying reduced numbers of GFAP-positive cells compared with their non-treated counterparts.105 The influence of early stress on FJC-positive cells, indicative of degenerating neuron numbers, in the cerebellum was also attenuated in male rats given AA5-HT or OMDM-2, while expression was unchanged in females.105 When considered together, it appears that the endocannabinoid system enhancers AA-5HT and OMDM-2 reduce the influence maternal deprivation exerts on cellular changes within the brain in a sex-dependent manner in both the hippocampus and cerebellum, possibly via altering neuroendocrine function.

To date, only one study has addressed the ability of endocannabinoid system modulators to alter behavioural changes induced by early stress. URB597 is a selective inhibitor of the enzyme fatty acid amide hydrolase, which is responsible for the breakdown of the endocannabinoid anandamide.102 Administration of URB597 from PNDs 31 to 43 results in attenuation of increases in behavioural impulsivity displayed by maternally deprived Wistar rats,102 suggesting that enhancing endocannabinoid signalling can exert beneficial effects on behaviour.

Anti-inflammatories modulate early stress-induced changes

Dysfunction or loss of γ-aminobutyric acid-ergic (GABA) cells that express parvalbumin, a calcium-binding protein, have been implicated in the aetiopathogenesis of a variety of psychiatric conditions.106, 107, 108 Reduced parvalbumin expression has been reported in Sprague Dawley rats maternally separated from PNDs 2 to 20.109 Administration of the cyclo-oxygenase 2 (COX-2) inhibitor (NS398), a key mediator of both oxidative stress and excitotoxicity, attenuated decreases in parvalbumin expression in the prefrontal cortex of separated rats compared with vehicle-treated rats upon assessment in adolescence.110 Moreover, improved working memory previously impaired by maternal separation was also reported in rats treated with NS398, as indicated by reduced errors in the win-shift maze task.110 NS398 is reported to have neuroprotective effects, and to exert a modulatory influence over excitotoxicity and neuroinflammatory insults111, 112, 113 potentially by reducing the conversion of arachadonic acid to prostaglandin, thereby reducing the multifaceted downstream effects of prostaglandins (such as induction of inflammatory mediators causing neuronal damage,114 aggravation of excitotoxic neurodegeneration115 or induction of apoptosis via stimulation of astrocytes to release glutamate116). As a possible mechanism of action, it can be speculated that the effects of NS398 on parvalbumin expression may therefore have been via attenuation of inflammatory changes induced by early stress, although inflammatory markers were not quantified directly in this study. In support of these suggestions is the observation that separation-induced decreases in parvalbumin expression are attenuated by the intracerebroventricular administration of the anti-inflammatory interleukin (IL) 10.117 Moreover, a linear relationship between IL6 and parvalbumin expression in the prefrontal cortex was reported in separated rats treated with IL10,117 suggesting that the enhanced pro-inflammatory activity that persists after early stress leads to decreased parvalbumin expression in the prefrontal cortex, potentially altering the predisposition to psychiatric disease.

Modulation of early stress-induced changes through antidepressant administration

Animal models illustrate that monoaminergic neurons such as those containing serotonin and noradrenaline are susceptible to perturbations in the early environment.118 Both serotonergic and noreadrenergic neurons are known to have critical roles in stress-related behaviours and disorders;109,119,120 the development of psychiatric disorders such as anxiety and depressive disorders has been linked to changes in the density of these neurons.121, 122, 123, 124

Tricyclic antidepressants

Initial studies focusing on the ability of monoaminergic-modulating drugs to alter neurobiological changes induced by early adversity centred on the use of tricyclic antidepressants (TCAs). Complete reversal of maternal separation-induced anxiety behaviours was reported in Lewis rats treated with imipramine from adolescence into adulthood.75 The authors also demonstrated attenuation of changes in experimental autoimmune encephalomyelitis clinical scores following imipramine administration.75 Similar reductions in hyperalgesia induced by maternal separation were noted in a subsequent study by this group, as indicated by improved hot-plate latencies in imipramine versus vehicle-treated rats in adulthood.76

Desipramine also appears to exert a beneficial influence over behavioural changes induced by early stress. Reduced immobility times in the FST have been shown in maternally separated Sprague Dawley rats treated with desipramine compared with vehicle-treated rats from PND 21,81 suggesting reduced depression-like behaviours in those given desipramine. Anxiety-like behaviour was unaltered by desipramine,81 suggesting that its modulatory effect may be behaviour-dependent. Although speculative, it may be that desipramine exerts a greater influence over the hippocampus than over the amygdala, thereby altering depression but not anxiety-like behaviours that result from early stress. It would be of use to investigate this further in future models. Transmission of depression-like behaviour from maternally separated male C57BL/6 mice to their female offspring has recently been demonstrated. Adult male C57BL/6 mice maternally separated (and that displayed enhanced depression-like behaviours) as pups were bred with control females. Offspring were treated with desipramine in childhood. Compared with those treated with the vehicle, female offspring treated with desipramine displayed attenuation of depression-like behaviours in the FST.125 In contrast, desipramine administration to female offspring in adulthood did not influence depression-like behaviour,125 indicating that transgenerational transmission of depression-like behaviours are only amenable to intervention during the early post-natal period. When considered together, these studies indicate that enhanced depression-like behaviour following maternal separation, and even transgenerational transmission of these behaviours, are amenable to intervention with desipramine.

Selective serotonin reuptake inhibitors

In addition to work focusing on the modulatory effect TCAs exert on alterations induced by early adversity, a number of studies have centred on the ability of selective serotonin reuptake inhibitors (SSRIs) to alter changes that result from early stress. Maternally separated Sprague Dawley rats treated with fluoxetine in adolescence were reported to exhibit attenuation of decreases in step-down latency and increases in radial arm maze completion time compared with those treated with the vehicle.82 From a molecular perspective, this study showed that fluoxetine reduced the influence separation exerted on neuronal apoptosis in the hippocampus, while enhancing hippocampal cell proliferation on PND 35.82 As such, it is likely that fluoxetine enhanced long-term memory capability and spatial learning via increasing cell proliferation in the hippocampal dentate gyrus. Additionally, although not a modulatory effect, fluoxetine increased serotonin synthesis and tryptophan expression in the dorsal raphe nuclei in both separated and non-separated Sprague Dawley rats on PND 35.82 Others have reported similar modulation of the serotonergic system by fluoxetine following early stress. Female Sprague Dawley rats treated with fluoxetine from PND 35 displayed attenuation of maternal separation-induced reductions in serotonin expression in the raphe nucleus compared with control.126 Fluoxetine has also been shown to reverse separation-induced changes in metabotropic glutamate receptor 4 (mGluR4) expression in the hippocampus of Sprague Dawley rats in a study comparing the efficacy of fluoxetine with electroconvulsive therapy and ketamine. Interestingly, neither electroconvulsive therapy nor ketamine administration altered changes in mGluR4 expression in these maternally separated rats.127 As such, it may be hypothesised that fluoxetine exerts at least part of its therapeutic benefit by targeting group III mGlu receptors, thereby attenuating the reduction in mGluR4 receptors caused by early stress and preventing the decrease in negative feedback, which can ultimately lead to excessive glutamate release and hyper-excitability.

Escitalopram also appears to modulate cellular alterations induced by early stress. Decreased concentrations of the neurometabolites N-acetylaspartate, choline and myoinositol, indicative of reduced neural density and functional integrity, were noted in the hippocampus of Sprague Dawley rats following maternal separation.128 These separation-induced changes in neurometabolite concentrations were attenuated significantly in escitalopram versus vehicle-treated rats in adulthood;128 separated escitalopram-treated rats displayed higher concentrations of these neurometabolites compared with separated rats that received vehicle. Consistent with this, others have reported that escitalopram reduced depression-like behaviour that occurred after maternal separation in Wistar rats.129 The mechanisms underlying the antidepressant effect of escitalopram are thought to be the result of either stimulation of neuronal remodelling in the hippocampus,130 or via modulation of the HPA axis.131 Furthermore, in the same experiment, improved hippocampal-dependent memory in the probe trial of the Morris Water maze was demonstrated in escitalopram-treated rats, which is in line with the beneficial effects escitalopram exerts on separation-induced depression-like behaviours.129

Considered together, works examining the modulatory influence of TCAs and SSRIs indicate that modulation of monoaminergic signalling acts to attenuate or reverse alterations in behaviour induced by early stress, in addition to a number of cellular changes. The specific mechanisms underlying the way in which antidepressants achieve these effects remain to be fully characterised. It may be hypothesised that TCAs and SSRIs attenuate deficits in monoaminergic signalling caused by early stress, thereby partially restoring their function and the role they have in the regulation of stress-related behaviours. Modulation of the HPA axis131 and neuronal remodelling130 may also contribute to their effect on depression-like behaviours. Changes in memory capability following antidepressant administration may be the result of enhanced cell proliferation in the hippocampus.82 Clearly, the mechanisms underpinning these actions need to be further characterised in future models to ascertain at what level these drugs exert their influence (Table 3).

Table 3 Antidepressants modulate early stress-induced changes

Epigenetic-modifying drugs modulate early stress-induced changes

The first studies assessing whether epigenetic changes induced by variations in the early environment were amenable to intervention centred on the use of methionine, a drug that enhances the methylation status of candidate genes. Generally, the methylation status of a candidate gene is inversely correlated with the level of gene expression; low levels of gene methylation have generally been associated with increased gene expression to date.136,137

Intracerebroventricular methionine administration from PNDs 97 to 103 in the offspring of high-care Long-Evans hooded dams has been shown to increase the methylation status of the nerve growth factor-inducible protein A (NGFI-A) consensus sequence of the exon 17 GR promoter to the level of offspring of low-care dams.138 These results indicate that the influence of early environment on the epigenome are amenable to intervention in adulthood. A concomitant decrease in histone 3 lysine 9 (H3K9) in association with the exon 17 GR promoter and decreased GR mRNA and protein expression in the hippocampus of high-care offspring was also demonstrated, once again to the level of low-care offspring.138 Such findings suggest that the changes in the epigenome modified by methionine administration were functionally relevant. Specifically, methionine administration in high-care offspring was shown to enhance anxiety61 and depression-like62 behaviour to the level of low-care offspring. Such results illustrate that epigenetic alterations are associated with behavioural changes, potentially via their influence on the HPA axis and stress responsivity, and that it is possible to modulate changes in behaviour through the administration of epigenetic-modifying drugs such as methionine in adulthood. Although these results are of little translational benefit as they worsen behavioural changes induced by early stress, the findings demonstrate the susceptibility of the epigenome to pharmacologic manipulation in adulthood.

Initial studies on methionine lead to investigation into the ability of the DNA methylation inhibitor zebularine to modulate changes in brain-derived neurotrophic factor (BDNF) expression induced by early stress.12 Long Evans hooded rats exposed to abusive Long Evans mothers in childhood and treated with zebularine in adulthood (PNDs 83–89) displayed attenuation of stress-induced decreases in BDNF mRNA expression in the prefrontal cortex in adulthood compared with those that recieved vehicle.12 These findings are of interest as they illustrate that differences in DNA methylation, specifically gene hypermethylation, induced by early stress can be reversed in adulthood.

Post-translational histone modifications represent another epigenetic mechanism that appears to be modulated by the early environment, and level of care received by offspring. The level of histone acetylation correlates positively with the level of gene expression.139 Reduced histone acetylation therefore tends to result in decreased expression of a certain gene. Trichostatin A (TSA), a histone deacetylase inhibitor, reduces the rate of deacetylation of candidate genes, enhancing the level of histone acetylation and therefore gene expression. It has been shown that low levels of maternal care reduce histone acetylation in rat offspring, and result in decreased gene transcription and protein expression.138 In addition, TSA administration (from PNDs 90 to 97) in low-care offspring has been shown to enhance GR mRNA expression in the hippocampus to the level of high-care Long Evans hooded offspring.138 The authors extrapolated their findings in further work (utilising the same experimental design) demonstrating that TSA administration reduced anxiety-like behaviours of low-care offspring to the level of high-care offspring.62 Together, the results of this collection of works suggests that the adverse behavioural consequences associated with low levels of maternal care in early life are amenable to intervention in adulthood through histone deacetylase inhibitor administration.

Another histone deacetylase inhibitor, valproic acid, has been reported to attenuate decreases in acoustic startle in maternally separated female Sprague Dawley rats when administered during childhood.140 Interestingly however, valproic acid only modulated behaviour when administered in the early post-natal period (PNDs 2–9); administration from PNDs 28 to 36 did not influence behaviour,140 indicating that the ability of valproic acid to modulate changes in histone modifications may be time-dependent. It is hypothesised that such time-dependent effects of valproic acid occur as decreased frontal cortical H3K9 monomethylation (due to maternal separation) is the cause of reduced acoustic startle responses, because it results in decreased expression of key genes involved in fear conditioning. As such, administration of valproic acid early in life reverses decreases in H3K9 monomethylation that occur due to separation, thereby preventing reduced expression of those genes involved in fear conditioning, thereby increasing acoustic startle responses compared with separated rats treated with vehicle.

Taken together, results from studies examining the modulatory influence of epigenetic-modifying drugs illustrate that changes in both DNA methylation and histone acetylation of candidate genes that occur in response to early environmental adversities are amenable to intervention. Of particular interest, administration of drugs in adulthood still appears to result in modulation of changes in the epigenome induced by early life stress. As such, earlier intervention with epigenetic-modifying drugs may be able to prevent the negative influence early stress exerts on the epigenome and protein expression of key candidate genes, including those involved in stress system regulation, and the influence such epigenetic changes exert on behaviour and disease susceptibility (Table 4).

Table 4 Epigenetic-modifying drugs modulate early stress-induced changes

Discussion

It is widely accepted that individuals exposed to adversity in childhood tend to be relatively resistant to pharmacotherapy in clinical practice.142, 143, 144 Current interventions that aim to reduce the negative influence early stress exerts on later disease susceptibility are minimal at best. Findings from this review, although from animal studies only, suggest that some targeted interventions, particularly during early life, have the ability to attenuate or even reverse changes in neurobiology and behaviour that occur after adversity in childhood.

Findings from animal studies indicate that behavioural interventions such as SMG and MH, exercise and pharmacotherapies such as epigenetic-modifying drugs are likely to be most efficacious in reducing the negative consequences of childhood adversity. Each of these interventions modulates specific early stress-induced changes in neurobiology on both cellular and behavioural levels. Modulation of the latter is likely to be of most importance from a clinical and translational perspective.

The relevance of interventions such as SMG and MH, which potentially act though enhancing oxytocin signalling within the brain, is supported by reports of altered oxytocin levels following early stress. Exposure to adversity of early stress has been shown to alter OXTR expression and immunoreactivity in animal models of early stress,33,145,146 and also in children147 and adult humans.148,149 From a translational standpoint, this is of interest, as while it may be possible to implement behavioural interventions in children exposed to early adversity, behavioural therapies are less likely to be as well tolerated in adolescents and adults. As such, oxytocin administration may represent a novel way to enhance oxytocin signalling in these individuals, thereby attenuating the influence childhood stress exerts on neurobiology across the lifespan, and the predisposition to later disease. Additional research is required in animal models to ascertain the mechanisms underlying the influence of SMG and MH, and to quantify their effects on the oxytocin system. It may then be possible to begin trialling these behavioural therapies in humans, to ascertain whether administration in childhood can reverse the sequelae of early stress, preventing the development of psychiatric disorders, and if intervention later in life can influence the extent of treatment resistance commonly seen in those with a history of childhood adversity and established psychiatric conditions.

From a translational perspective, the minimal side effect profile of exercise makes it a promising therapeutic option for both the prevention and treatment of psychiatric conditions. It can be adjusted on a patient-by-patient basis according to comorbidities and functional status.150, 151, 152 Clinical models point towards improved relapse prevention in patients treated with exercise compared with those treated with some pharmacotherapies,153 and synergism between some drug therapies and exercise exists.154 Findings from animal models also indicate that exercise can attenuate some of the negative neurobiological changes that result from early adversity. Exercise may be of benefit in the clinical setting, potentially acting as a preventative measure reducing the sequelae of childhood adversity and decreasing the predisposition to psychiatric disease. In those with current psychiatric conditions and a history of childhood adversity, the antidepressant- and neuroplasticity-enhancing effects of exercise may enable it to attenuate the extent to which early adversity influences neurobiology, thereby potentially reducing treatment resistance. Further work is required to delineate how to translate exercise therapy into human studies and then clinical practice. The influence the type, duration and frequency of exercise exerts on its modulatory ability requires investigation to ensure its benefits are obtained. The age at which exercise therapy should be introduced in order for it to act as a preventative measure following childhood adversity must also be established.

The ability of epigenetic-modifying drugs, such as DNA methylation inhibitors and histone deacetylase inhibitors, makes them a promising option to alter neurobiological changes induced by early stress across the lifespan. Additionally, their effects are more wide-ranging than those of other pharmacotherapies, in that they influence not only epigenetic changes induced by early stress but also the resultant alterations in neuroendocrine axis regulation and behaviour. Additionally, they appear to be able to effectively modulate early stress-induced changes in adulthood, often to a greater degree than other pharmacotherapies such as antidepressants, which can be less effective later in life. Given the positive findings from animal models of early stress, clinical studies are required to ascertain the efficacy and safety of epigenetic-modifying drugs in humans. It may be that if administered in childhood, DNA methylation inhibitors are able to reverse the hypersensitive, exaggerated stress response that frequently persists following childhood adversity, and the way in which it enhances the predisposition to psychiatric disorders development. As animal studies suggest that epigenetic changes can be modified in adulthood, intervention with these drugs later in life may act to attenuate the extent to which childhood stress influences neurobiology and the predisposition to disease.

Conclusion

Findings from this review suggest that the neurobiological sequelae of early stress can be attenuated or even reversed in animal models. Considerable effort is required before both behavioural and pharmacological therapies aimed at reducing the vulnerability to psychiatric disorders in those exposed to stress in childhood can be implemented in clinical practice. However, there are substantial gains to be had should the neurobiological sequelae of early adversity be amenable to intervention in humans. It may be possible to reduce or even eliminate characteristics of the vulnerable phenotype, thereby decreasing the incidence of psychiatric disorders in individuals with a history of childhood adversity.