Epigenetic mechanisms mediating the long-term effects of maternal care on development

doi:10.1016/j.neubiorev.2007.10.009

Neuroscience & Biobehavioral Reviews

Volume 33, Issue 4, April 2009, Pages 593-600

https://doi.org/10.1016/j.neubiorev.2007.10.009 Get rights and content

Abstract

The long-term consequences of early environmental experiences for development have been explored extensively in animal models to better understand the mechanisms mediating risk of psychopathology in individuals exposed to childhood adversity. One common feature of these models is disruption of the mother–infant relationship which is associated with impairments in stress responsivity and maternal behavior in adult offspring. These behavioral and physiological characteristics are associated with stable changes in gene expression which emerge in infancy and are sustained into adulthood. Recent evidence suggests that these long-term effects may be mediated by epigenetic modification to the promoter regions of steroid receptor genes. In particular, DNA methylation may be critical to maternal effects on gene expression and thus generate phenotypic differentiation of offspring and, through effects on maternal behavior of offspring, mediate the transmission of these effects across generations. In this review we explore evidence for the influence of mother–infant interactions on the epigenome and consider evidence for and the implications of such epigenetic effects for human mental health.

Section snippets

Deprivation, separation and variation: studying maternal influence on offspring development

The profound effect of maternal deprivation on infant development that has been implied by longitudinal studies of orphans reared in institutional settings (Kaler and Freeman, 1994, Gunnar et al., 2001, Chugani et al., 2001, Roy et al., 2004) has been investigated experimentally in both primates and rodents. Harlow's artificial rearing paradigm in which infant rhesus macaques were socially isolated for periods of 3–12 months (Harlow and Suomi, 1971, Harlow and Suomi, 1974) illustrated that

Maternal influence on the epigenome

Converging evidence from primate and rodent studies support the hypothesis that maternal environment has a profound influence on offspring phenotype and that this influence is mediated by changes in gene expression. Consequently, understanding the mechanisms governing these effects requires an investigation of the molecular mechanisms which regulate gene transcription and thus exploration of the epigenetics of gene expression. The molecular mechanisms involved in the epigenetics of the genome

Pharmacological manipulations of the epigenome

The mediating role of epigenetic modifications in sustaining the differences in gene expression and behavior of High and Low LG offspring is supported by findings that these phenotypes can be altered through pharmacological manipulation of DNA methylation. ICV influsion of trichostatin-A (TSA), a histone deacetylase inhibitor that promotes demethylation, has been demonstrated to reverse the effects of low levels of maternal LG when administered to adult offspring (Weaver et al., 2006, Weaver et

Signalling pathways from maternal care to DNA methylation

In the maternal rat, licking/grooming may serve as a critical source of tactile stimulation for the developing pup. The question is how this physical stimulation leads to epigenetic changes to specific genes within hippocampal and medial preoptic area cells that have been observed in offspring of High compared to Low LG dams. Pups provided with tactile stimulation in the form of stroking with a paintbrush or maternal LG both exhibit increases in hippocampal GR expression (Jutapakdeegul et al.,

Implications of the study of epigenetics for psychiatry

Epigenetic modification in response to early environmental conditions provides an elegant mechanism to explain the effects of childhood adversity on increasing risk of psychopathology in adulthood. However, studying the role of epigenetic modifications in mediating these effects in humans is limited by several methodological constraints. Nevertheless, recent studies in humans suggest that similar epigenetic processes to those observed experimentally in the rat may play a significant role in

Concluding remarks

The long-term neurobiological consequences of early experiences have been explored extensively in animal models and suggest that epigenetic mechanisms may play a critical role in shaping stable individual differences in gene expression, physiology and behavior. In particular, these studies suggest that maternal care can have profound effects on offspring phenotype that is associated with molecular changes in the structure of DNA with consequences for the activity level of genes that are

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Glucocorticoid receptor expression in blood, but not across brain regions, reveals long-term effects of early life adversity in zebra finches
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Citation Excerpt :
Using a scarcity-adversity model of low nesting material, they found that, specifically in this adverse early environment, females received more maltreatment from the dams than males. This is an important consideration, since differences in maternal care are known to have a long-term impact on epigenetic regulation (Champagne and Curley, 2009; Riyahi et al., 2019; Weaver et al., 2004) but it is often difficult to tease apart whether epigenetic and behavioural sex differences observed after postnatal stress are a direct result of the exposure to the stressor or if they, in part, can stem from environmental factors related to differential treatment from the dams. Maternal or paternal ELS can additionally lead to the inheritance of behavioural phenotypes related to susceptibility and resilience to stress in the offspring (Coley et al., 2019; Franklin et al., 2010; Gapp et al., 2014, 2016; Rodgers et al., 2013; Roth et al., 2009; Weiss et al., 2011).
Exposures to stress at all stages of development can lead to long-term behavioural effects, in part through changes in the epigenome. This review describes rodent research suggesting that stress in prenatal, postnatal, adolescent and adult stages leads to long-term changes in epigenetic regulation in the brain which have causal impacts on rodent behaviour. We focus on stress-induced epigenetic changes that have been linked to behavioural deficits including poor learning and memory, and increased anxiety-like and depressive-like behaviours. Interestingly, aspects of these stress-induced behavioural changes can be transmitted to offspring across several generations, a phenomenon that has been proposed to result via epigenetic mechanisms in the germline. Here, we also discuss evidence for the differential impact of stress on the epigenome in males and females, conscious of the fact that the majority of published studies have only investigated males. This has led to a limited picture of the epigenetic impact of stress, highlighting the need for future studies to investigate females as well as males.

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ReviewEpigenetic mechanisms mediating the long-term effects of maternal care on development

Abstract

Section snippets

Deprivation, separation and variation: studying maternal influence on offspring development

Maternal influence on the epigenome

Pharmacological manipulations of the epigenome

Signalling pathways from maternal care to DNA methylation

Implications of the study of epigenetics for psychiatry

Concluding remarks

Am. J. Hum. Genet.

Biol. Psychiatry

Neuropsychopharmacology

Biol. Psychiatry

Curr. Opin. Neurobiol.

Physiol. Behav.

Neuroimage

Biol. Psychiatry

Psychiatry Res.

Pharmacol. Biochem. Behav.

Horm. Behav.

Biol. Psychiatry

Behav. Biol.

Neurosci. Lett.

Neuron

Brain Res. Dev. Brain Res.

Pharmacol. Biochem. Behav.

Neurobiol. Aging

Behav. Brain Res.

Horm. Behav.

Neurosci. Biobehav. Rev.

Behav. Brain Res.

Child Abuse Negl.

Neuroscience

Horm. Behav.

Brain Res. Mol. Brain Res.

Neurosci. Biobehav. Rev.

Physiol. Behav.

Brain Res.

Hypomethylation of MB-COMT promoter is a major risk factor for schizophrenia and bipolar disorder

Hum. Mol. Genet.

Hypermethylation of the reelin (RELN) promoter in the brain of schizophrenic patients: a preliminary report

Am. J. Med. Genet. B: Neuropsychiatr. Genet.

The enduring effects of abuse and related adverse experiences in childhood: a convergence of evidence from neurobiology and epidemiology

Eur. Arch. Psychiatry Clin. Neurosci.

Attachment in monkey infants raised in variable- and low-demand environments

Child Dev.

The development of affiliative and agonistic social patterns in differentially reared monkeys

Child Dev.

Epigenetic transgenerational actions of endocrine disruptors and male fertility

Science

Effects of social deprivation on maternal behavior of rhesus monkeys

J. Comp. Physiol. Psychol.

Childhood maltreatment as a risk factor for adult cardiovascular disease and depression

J. Clin. Psychiatry

Intergenerational transmission of maternal rejection rates among free-ranging rheus monkeys on Cayo Santiago

Anim. Behav.

Effect of resource availability on biparental care, and offspring neural and behavioral development in the California mouse (Peromyscus californicus)

Eur. J. Neurosci.

Maternal care influences neuronal survival in the hippocampus of the rat

Eur. J. Neurosci.

Variations in nucleus accumbens dopamine associated with individual differences in maternal behavior in the rat

J. Neurosci.

Naturally occurring variations in maternal behavior in the rat are associated with differences in estrogen-inducible central oxytocin receptors

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

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

Natural variations in maternal care are associated with estrogen receptor alpha expression and estrogen sensitivity in the medial preoptic area

Endocrinology

On the epigenetic regulation of the human reelin promoter

Nucleic Acids Res.

Epigenetic mechanisms and gene networks in the nervous system

J. Neurosci.

Synchronized maternal-infant elevations of primate CSF CRF concentrations in response to variable foraging demand

CNS Spectr.

Cerebrospinal fluid concentrations of somatostatin and biogenic amines in grown primates reared by mothers exposed to manipulated foraging conditions

Arch. Gen. Psychiatry

The quantification of COMT mRNA in post mortem cerebellum tissue: diagnosis, genotype, methylation and expression

BMC Med. Genet.

Maternal genistein alters coat color and protects Avy mouse offspring from obesity by modifying the fetal epigenome

Environ. Health Perspect.

Review
Epigenetic mechanisms mediating the long-term effects of maternal care on development