Maternal care as a model for experience-dependent chromatin plasticity?

doi:10.1016/j.tins.2005.07.006

Trends in Neurosciences

Volume 28, Issue 9, September 2005, Pages 456-463

https://doi.org/10.1016/j.tins.2005.07.006 Get rights and content

It is widely acknowledged that the nature of the maternal care a child receives can have long-term repercussions, and that children raised in deprived environments can have severe cognitive and behavioural difficulties that last into adulthood. The mechanisms underlying these effects are not understood, but recent data from rodents provide insight into a potential molecular mechanism. Like humans, rodent maternal behaviour towards offspring can effect long-term changes in responses of the offspring to stress throughout the rest of their lives. Remarkably, these changes reflect permanently altered gene expression, so-called ‘environmental programming’, and its downstream effects on the hypothalamic–pituitary–adrenal axis. This review discusses the nature of this environmental programming – the mechanism by which it occurs in rats, its long-term implications, and opportunities for its reversal in rodents and ultimately in humans.

Introduction

The quality of early family life influences health throughout life [1]. In part, such influences appear to be mediated by effects of parent–offspring interactions on the development of neural systems, including those that mediate responses to stress 2, 3, 4, 5, 6. There is evidence in humans that parental care can affect endocrine and autonomic responses to stress that endure into adulthood. Dramatic examples derive from studies on the effects of sexual and/or physical abuse on stress responses [7]. These findings represent environmental programming – instances where exposure to an environmental event in development stably alters phenotype in adulthood. A model for such programming effects lies in older studies on handling of newborn rats. Such handling decreases the magnitude of hypothalamic–pituitary–adrenal (HPA; Figure 1) responses to stress in adulthood 8, 9, 10. Interestingly, these effects are mediated by changes in maternal care. Handling increases pup licking and grooming (LG) by the rat mother 11, 12, 13. Predictably, adult offspring of mothers that naturally (i.e. in the absence of any experimental manipulation) show increased levels of pup LG over the first week postpartum (high-LG mothers) show reduced plasma adrenocorticotropin hormone (ACTH) and corticosterone responses to acute stress compared with adult offspring of low-LG mothers 12, 14. These effects are, in part, mediated by the influence of maternal care on gene expression. The offspring of high-LG mothers show significantly increased hippocampal glucocorticoid receptor (GR) mRNA and protein expression, enhanced glucocorticoid negative feedback sensitivity and decreased hypothalamic corticotrophin release factor (CRF) mRNA levels (Figure 1). Cross-fostering the biological offspring of high-LG and low-LG mothers reverses the phenotype, suggesting a direct relationship between variations in maternal care and development of HPA responses to stress [15]. Finally, reversing the effect on hippocampal GR levels eliminates the influence of early experience on HPA responses to stress [16].

Section snippets

Molecular mechanisms for maternal effects on HPA responses to stress

Results of in vitro and in vivo studies 10, 17, 18, 19, 20, 21 suggest that maternal effects on hippocampal GR expression are mediated by increases in 5-hydroxytryptamine (serotonin or 5-HT) turnover and in hippocampal expression of the transcription factor nerve-growth-factor-inducible factor A (NGFI-A, also known as zif-268, krox-24, egr-1 and zenk; Figure 2). In vitro, 5-HT increases expression of both GR and NGFI-A in cultured rat hippocampal neurons, and the effect of 5-HT is blocked by

The epigenome: chromatin structure and DNA methylation

Most DNA is tightly packaged into nucleosomes and wrapped around a core of histone proteins [27]. The histone–DNA configuration is maintained by electrostatic bonds between positively-charged histones and negatively-charged DNA, and regulates gene expression [28]. This ‘closed’ chromatin structure commonly precludes transcription-factor binding to DNA and underscores the importance of enzymes that modify histone–DNA interactions. One class of such proteins, which includes many known

Epigenetic programming of HPA stress responses

We initially found evidence that methylation across the GR exon 1₇ promoter sequence in the hippocampus was greater in adult offspring of low-LG mothers than in those of high-LG mothers [14]. These findings suggested maternal effects on DNA methylation patterns in offspring. We then examined the methylation status of individual CpGs in the exon 1₇ sequence using sodium bisulfite mapping [53], focusing on the NGFI-A consensus sequence (Figure 3). The results reveal significant differences in

Reversal of maternal effects on GR expression and HPA stress responses

HDAC inhibitors can trigger active, replication-independent DNA demethylation 49, 50. We tested [14] whether this approach could reverse the epigenetic state of GR in the adult offspring of low-LG mothers. Central infusion of adult rats with the HDAC-inhibitor trichostatin A (TSA) [55] significantly increased H3 acetylation, cytosine demethylation and NGFI-A binding at the exon 1₇ site in the offspring of low-LG mothers, to levels comparable with those observed in the offspring of high-LG

How does maternal care alter cytosine methylation?

Developmental studies provide clear evidence for an active process of ‘demethylation’ driven by maternal care. High-LG and low-LG mothers differ in the frequency of pup LG only during the first postnatal week 12, 13, 48, 58. This period corresponds to appearance of the difference in DNA methylation of the NGFI-A-response element of the GR exon 1₇ promoter. On embryonic-day 20 (24–28 h before birth), the entire exon 1₇ region is completely unmethylated. On P1, both the 5′ and 3′ CpGs of the

Conclusions: experience-dependent chromatin plasticity?

A defining question for scientists interested in development concerns the mechanism by which environmental effects, including social interactions such as parenting, in early development are ‘biologically embedded’ and thus sustained into adulthood. The challenge is to define the exact nature of the gene–environment interactions that mediate such environmental programming. The differential epigenetic status of the GR exon 1₇ promoter in the offspring of high-LG mothers is a possible mechanism

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Therefore, from the existing literature it is evident that there is a plausible bidirectional influence that exists between maternal psychological status and its influence on epigenome or vise versa. The reviewed literature together highlight the influence of maternal behavior on the offspring and its translational impact on altered neurobehavioural outcomes during adult life (Meaney and Szyf, 2005; Beery and Francis, 2011; Curley and Champagne, 2016). Many studies have emerged highlighting the influence of maternal diet on the health status of the offspring during adult life.
Widespread persistence of endocrine-disrupting chemicals (EDCs) in the environment has mandated the need to study their potential effects on an individual's long-term health after both acute and chronic exposure periods. In this review article a particular focus is given on in utero exposure to EDCs in rodent models which resulted in altered epigenetic programming and transgenerational effects in the offspring causing disrupted reproductive and metabolic phenotypes. The literature to date establishes the impact of transgenerational effects of EDCs potentially associated with epigenetic mediated mechanisms. Therefore, this review aims to provide a comprehensive overview of epigenetic programming and it’s regulation in mammals, primarily focusing on the epigenetic plasticity and susceptibility to exogenous hormone active chemicals during the early developmental period. Further, we have also in depth discussed the epigenetic alterations associated with the exposure to selected EDCs such as Bisphenol A (BPA), di-2-ethylhexyl phthalate (DEHP) and vinclozlin upon in utero exposure especially in rodent models.
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In terms of serotonergic signaling, although there is a well-known link between 5-HT and HPA axis activity, the findings seem to be less consistent. In many instances, elevated levels of 5-HT signaling have been associated with stress and CA, whereas reduced 5-HT has been linked to reduced GR in animals receiving low LG (Meaney and Szyf, 2005), and it is reduced GR that is associated with CA. Other pathways that have been found to be affected by CA are also implicated in HPA axis regulation, including glutamatergic signaling (Evanson and Herman, 2015), adrenergic signaling (Bugajski et al., 1995), and opioidergic signaling (Fountas et al., 2018).
Childhood abuse (CA) is a prevalent global health concern, increasing the risk of negative mental health outcomes later in life. In the literature, CA is commonly defined as physical, sexual, and emotional abuse, as well as neglect. Several mental disorders have been associated with CA, including depression, bipolar disorder, schizophrenia, and post-traumatic stress disorder, along with an increased risk of suicide. It is thought that traumatic life events occurring during childhood and adolescence may have a significant impact on essential brain functions, which may persist throughout adulthood. The interaction between the brain and the external environment can be mediated by epigenetic alterations in gene expression, and there is a growing body of evidence to show that such changes occur as a function of CA. Disruptions in the HPA axis, myelination, plasticity, and signaling have been identified in individuals with a history of CA. Understanding the molecular impact of CA on the brain is essential for the development of treatment and prevention measures. In this review, we will summarize studies that highlight the molecular changes associated with CA in the human brain, along with supporting evidence from peripheral studies and animal models. We will also discuss some of the limitations surrounding the study of CA and propose extracellular vesicles as a promising future approach in the field.
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Trends in Neurosciences

Maternal care as a model for experience-dependent chromatin plasticity?

Introduction

Section snippets

Molecular mechanisms for maternal effects on HPA responses to stress

The epigenome: chromatin structure and DNA methylation

Epigenetic programming of HPA stress responses

Reversal of maternal effects on GR expression and HPA stress responses

How does maternal care alter cytosine methylation?

Conclusions: experience-dependent chromatin plasticity?

Clin. Psychol. Rev.

Mol. Cell. Endocrinol.

Neuroscience

Cell

Biochim. Biophys. Acta

Cell

Cell

Cancer Cell

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Biochem. Pharmacol.

Trends Pharmacol. Sci.

J. Biol. Chem.

Physiol. Behav.

Trends Ecol. Evol.

Risky families: family social environments and the mental and physical health of offspring

Psychol. Bull.

Nonhuman primate model of alcohol abuse: effects of early experience, personality and stress on alcohol consumption

Proc. Natl. Acad. Sci. U. S. A.

The role of early adverse experience and adulthood stress in the prediction of neuroendocrine stress reactivity in women: a multiple regression analysis

Depress. Anxiety

Early experience is associated with the development of categorical representations for facial expressions of emotion

Proc. Natl. Acad. Sci. U. S. A.

Dopamine release in response to a psychological stress in humans and its relationship to early life maternal care: a positron emission tomography study using [11C]raclopride

J. Neurosci.

Pituitary–adrenal and autonomic responses to stress in women after sexual and physical abuse in childhood

J. Am. Med. Soc.

Plasma-free corticosteroid response to electric shock in rats stimulated in infancy

Science

Critical periods, stimulus input, and emotional reactivity: a theory of infantile stimulation

Psychol. Rev.

The development of individual differences in behavioral and endocrine responses to stress

Annu. Rev. Neurosci.

Long term changes in nest condition and pup grouping following handling of rat litters

Dev. Psychobiol.

Maternal care, hippocampal glucocorticoid receptor gene expression and hypothalamic–pituitary–adrenal responses to stress

Science

Maternal care during infancy regulates the development of neural systems mediating the expression of behavioral fearfulness in adulthood in the rat

Proc. Natl. Acad. Sci. U. S. A.

Epigenetic programming through maternal behavior

Nat. Neurosci.

Nongenomic transmission across generations in maternal behavior and stress responses in the rat

Science

Neonatal handling alters adrenocortical negative feedback sensitivity and hippocampal type II glucocorticoid receptor binding in the rat

Neuroendocrinology

Serotonin regulates type II, corticosteroid receptor binding in cultured hippocampal cells

J. Neurosci.

Dopamine release in response to a psychological stress in humans and its relationship to early life maternal care: a positron emission tomography study using [¹¹C]raclopride