Trends in Neurosciences
Maternal care as a model for experience-dependent chromatin plasticity?
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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2022, Current Opinion in Behavioral SciencesIn utero exposure to endocrine-disrupting chemicals, maternal factors and alterations in the epigenetic landscape underlying later-life health effects
2022, Environmental Toxicology and PharmacologyCitation Excerpt :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.
Molecular impacts of childhood abuse on the human brain
2021, Neurobiology of StressCitation Excerpt :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).