Article summary with Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function by Anacker a.o. - 2014

Purpose: We review studies with (non)human species that examine the hypothesis that epigenetic mechanisms, particularly those affecting the expression of genes implicated in stress responses, mediate the association between early childhood adversity and later risk of depression.

The quality of family life influences the development of individual differences in vulnerability for affective illnesses. Victims of childhood abuse or parental neglect are at a greater risk for affective disorders (association found between adverse childhood experiences and the risk for depression). Mediators in this relationship: personality (neuroticism), low self-esteem, conduct disorder, increased risk of adverse life events, low social support, difficulties in interpersonal relationships. Other variables compromising cognitive and emotional development and increasing risk of depression/anxiety disorders to a level comparable to that for abuse: familial dysfunction/conflict, persistent neglect, cold, distant parent-child relationships, harsh and inconsistent discipline. But family life can also be a source of resilience against chronic stress: warm, nurturing families promote resistance to stress and diminish vulnerability to stress-induced illness. The epidemiology of affective disorders reflects the influence of family life on neural development and mental health.

This review gathers evidence linking variations in parental care to the epigenetic mechanisms regulating a specific phenotype, stress reactivity, that influences vulnerability for many forms of psychopathology.

Parental influences on stress reactivity 

The relationship between the quality of early social environment and health in adulthood seems to be partly mediated by individual differences in neural systems underlying the expression of behavioural and endocrine responses to stress. Physical and sexual abuse in early life increases endocring and autonomic responses to stress in adulthood. The influence of familial depressive illness is mediated by increased stress reactivity, enhancing the response of the individual to mild/regular stressors. Individuals with early adverse experience appear to be sensitized to the depressive effects of acute stress in adulthood.

Hypothalamic-pituitary-adrenal axis function and Major Depressive Disorder

Hypothalamic-pituitary-adrenal (HPA) axis activity is governed by the secretion of corticotropin-releasing factor (CRF) and vasopressin (AVP) form the paraventricular nucleus of the hypothalamus, in turn activating secretion of the adrenocorticotrophic hormone (ACTH) from pituitary corticotropes, which tne stimulates the synthesis and secretion of glucocorticoids (cortisol in humans and other primates, and corticosterone in rodents) from the adrenal cortex. Cortisol/corticosterone bind to and activate glucocorticoid (GR) and mineralocorticoid (MR) receptors in multiple target issues including brain regions that influence hypothalamic synthesis of CRF and vasopressin, regulating HPA activity. Activation of GR in particular leads to negative feedback inhibition of hypothalamic CRF and AVP from the hypothalamus and directly on secretion of ACTH from pituitary corticotropes.

Humans have a daily pattern of HPA activity: cortisol levels rise later in the night, further rise 30 minutes after waking up, followed by a gradual decline over the day.

A depression shows elevated basal levels of ACTH and cortisol. Difference in basal levels of cortisol shown to be greatest during the afternoon when cortisol should be falling. The increase in these levels is marked in melancholic and psychotic depression, but not in atypical depression. Since elevated cortisol acts to inhibit subsequent HPA activity, it’s suggested that the glucocorticoid negative feedback is impaired in depressed patients. Successful antidepressant treatment is associated with resolution of the impairment in the negative feedback on the HPA axis by glucocorticoids. Normalization of glucocorticoid function by antidepressants is a significant predictor of long-term clinical outcome.

Enhanced HPA activation is also apparent at the level of the brain: higher levels of CRF/CRF-expressing neurons in postmortem samples from depressed compared to nondepressed individuals. CRF1 receptors are reduced in postmortem brains from suicide victims, many who showed a history of depression.

While increased HPA activity among depressed patients isn’t universal, it’s of clinical significance.

Developmental adversity in HPA function

Childhood maltreatment is associated with increased HPA response to stress. Childhood abuse was the strongest predictor of increased HPA activity (i.e. ACTH responsiveness), followed by abusive events, adulthood traumas, and depression. 

CRF concentrations correlate with the severity/duration of physical and sexual abuse. High CRF may arise due to GR down-regulation and impaired negative feedback inhibition. 

Childhood adversity influences HPA responses to stress. It also moderates the relation between stressful life events in adulthood and depression, with increased risk for depression or anxiety in response to moderately stressful circumstances among individuals with a history of childhood adversity.

Developmental adversity and epigenetic regulation of HPA function

This study explores potential mechanisms for parental effects examining the influence of variations in maternal care in rats on the development of individual differences in behavioural and endocrine responses to stress.

Lactating female Long-Evans rats show considerable variation in the frequency of pop licking/grooming (LG). Individual differences in frequency of pup LG among adult female rats are reliable across litters, and so a stable feature of the maternal phenotype. It’s found that variations in pup LG over the first week of life affect the development of behavioural and HPA responses to stress in adulthood.

There are differences in HPA responses to acute stress apparent in circulating levels of ACTh and adrenal corticosterone. As adults, the offspring of high-LG mothers show more modest plasma ACTH and corticosterone responses to acute stress compared to low-LG offspring. Offspring of high-LG mothers show increased hippocampal GR mRNA and protein expression, enhanced glucocorticoid negative feedback sensitivity and decreased hypothalamic CRF mRNA levels.

Effects of maternal care on gene expression and stress responses are reversed with cross-fostering: stress responses of animals born from low-LG mothers and reared by high-LG mothers are comparable to normal offspring of high LG mothers, and vice versa. Studies show that animals brushed for 15min/day increased hippocampal GR expression - revealing a direct relation between maternal care and phenotypic development of offspring. 

Tactile stimulation from maternal licking appears to be the critical environmental signal for the regulation of hippocampal GR expression in newborns. Maternal effects on hippocampal GR expression are mediated by increases in hippocampal serotonin (5-HT) turnover and expression of the nerve-growth factor-inducible factor-A (NGFI-A) transcription factor. Maternal licking increases hippocampal expression of the transcription factor (NGFI-A).

The 5’ non-coding variable exon 1 region of the hippocampal GR gene contains multiple alternate promoter sequences including a neuron-specific, exon 1 sequence. Increased pup LG enhances hippocampal expression of GR mRNA splice variants containing exon 1 sequence, which contains an NGFI-A response element. Pup LG increases hippocampal NGFI-A expression and binding to the exon 1 promoter. 

There is a similar effect on hippocampal Gad1, an NGFI-A regulated gene that encodes for glutamic acid decarboxylase, the rate-limiting enzyme for GABA synthesis. The association of NGFI-A with the Gad1 promoter is increased in the offspring of high compared with low LG mothers, but only following a nursing bout. This finding suggests that maternal care regulates the expression of a range of NGFI-A-sensitive genes. 

Mechanism by which hippocampal GR expression remains elevated following weaning and separation from the mother: one possibility is that the increased NGFI-A-exon1 interaction occurring within hippocampal neurons in the pups of high LG mothers might result in an epigenetic modification of the exon1 sequence that alters NGFI-A binding and maintains the maternal effect into adulthood. The initial studies were focused on potential influences on DNA methylation. 

Preliminary studies revealed greater methylation across the entire exon1 GR promoter sequence in the hippocampus of adult offspring of low LG mothers. These findings suggested a parental effect on DNA methylation patterns in the offspring. The effect of maternal care involves significant alterations in the methylation status of the NGFI-A site.

These reusults suggest a direct relation between maternal care, histone acetylation, DNA methylation of the GR-1 promoter, GR expression and HPA responses to stress. 

Variations in parent-offspring interactions epigenetically program hippocampal GR expression and thus the nature of the HPA response to stress. However, subsequent studies reveal effects of early experience on multiple components of the HPA axis, and in each case there is evidence for stable epigenetic programming. 

Environmental conditions that increase frequency of pup LG in the rat are associated with decreased paraventricular CRF expression. This maternally regulated decrease in CRF expression is accompanied by an increase in hippocampal GR expression. However, the difference in CRF expression develops independent of GR regulation, since CRF expression occurs earlier in development than does the difference in hippocampal GR expression. This is not surprising since hippocampal-mediated negative feedback emerges only about the time of puberty in the rat. 

Maternal regulation of HPA function extends to the level of the pituitary. Maternal separation of neonatal mice produces an enduring hypomethylation of the Pomc gene, which encodes for the ACTH pro-hormone, proopiomelanocortin, increased Pomc mRNA expression and increased basal and CRF-induces levels of ACTH. 

The quality of postnatal maternal care epigenetically programs gene expression at multiple levels of the HPA axis to regulate both basal and stress-induced activity. 

Epigenetic regulation of glucocorticoid receptor expression in humans 

They found decreased hippocampal GR expression in samples from suicide completers with histories of childhood maltreatment compared with controls (sudden, involuntary fatalities).

The exon1 sequence shows increased DNA methylation and decreased NGFI-A binding in samples from suicide victims with a history of maltreatment. This finding bears considerable similarity to the maternal effect in the rat and are suggestive of early-environment regulation of the neural epigenome in humans. 

Forebrain GR activation inhibits HPA activity through tonic negative-feedback inhibition. Thus, selective knockdown of GR expression in the corticolimbic system in rodents is associated with increased HPA activity under basal as well as stressful conditions. Conversely, GR overexpression is associated with a dampened HPA response to acute stress. These findings are consistent with a working hypothesis linking early social environment to epigenetic modifications of the GR gene and expression, and HPA function. 

Childhood maltreatment associates with an increased level of exon 1F methylation. Furthermore, the methylation status of the promoter was closely correlated with both the frequency and severity of maltreatment. 

Summary 

Epigenetic modifications of genes implicated in HPA function are a mediating process that links the quality of childhood experience to the risk for major depression. But there are caveats that limit the degree to which this hypothesis might be applied across the population: altered HPA activity is apparent only in a subset of MDD patients and it is not clear that this subset is defined by developmental history. It is clear that genotype moderates the impact of adverse childhood experiences and resulting epigenetic modifications. 

The majority of variably-methylated regions were best explained by a gene x environment interaction. Unfortunately, with few exceptions, preclinical studies haven’t established models of gene x environment interactions. Likewise, preclinical studies have yet to widely capitalize on the finding that adverse childhood experience alters the response to antidepressant medications. This study provides a basis for studies of the mechanism by which developmental history might contribute to treatment resistance in MDD. One question of interest for the development of effective patient stratification is whether epigenetic marks associated with childhood adversity might identify individuals that are resistant to medications. 

A challenge for future research is integrating our knowledge of the importance of childhood experience into treatment models.