4.1.3: Early Childhood Experience

Early childhood experience

The development of an individual is an active process of adaptation that occurs within a social and economic context. For example, the closeness or degree of positive attachment of the parent (typically mother)–infant bond and parental investment (including nutrient supply provided by the parent) that define early childhood experience also program the development of individual differences in stress responses in the brain, which then affect memory, attention, and emotion. In terms of evolution, this process provides the offspring with the ability to physiologically adjust gene expression profiles contributing to the organization and function of neural circuits and molecular pathways that support (1) biological defensive systems for survival (e.g., stress resilience), (2) reproductive success to promote establishment and persistence in the present environment, and (3) adequate parenting in the next generation (Bradshaw, 1965).

Parental investment and programming of stress responses in the offspring

The most comprehensive study to date of variations in parental investment and epigenetic inheritance in mammals is that of the maternally transmitted responses to stress in rats. In rat pups, maternal nurturing (licking and grooming) during the first week of life is associated with long-term programming of individual differences in stress responsiveness, emotionality, cognitive performance, and reproductive behavior (Caldji et al., 1998; Francis, Diorio, Liu, & Meaney, 1999; Liu et al., 1997; Myers, Brunelli, Shair, Squire, & Hofer, 1989; Stern, 1997). In adulthood, the offspring of mothers that exhibit increased levels of pup licking and grooming over the first week of life show increased expression of the glucocorticoid receptor in the hippocampus (a brain structure associated with stress responsivity as well as learning and memory) and a lower hormonal response to stress compared with adult animals reared by low licking and grooming mothers (Francis et al., 1999; Liu et al., 1997). Moreover, rat pups that received low levels of maternal licking and grooming during the first week of life showed decreased histone acetylation and increased DNA methylation of a neuron-specific promoter of the glucocorticoid receptor gene (Weaver et al., 2004). The expression of this gene is then reduced, the number of glucocorticoid receptors in the brain is decreased, and the animals show a higher hormonal response to stress throughout their life. The effects of maternal care on stress hormone responses and behaviour in the offspring can be eliminated in adulthood by pharmacological treatment (HDAC inhibitor trichostatin A, TSA) or dietary amino acid supplementation (methyl donor L-methionine), treatments that influence histone acetylation, DNA methylation, and expression of the glucocorticoid receptor gene (Weaver et al., 2004; Weaver et al., 2005). This series of experiments shows that histone acetylation and DNA methylation of the glucocorticoid receptor gene promoter is a necessary link in the process leading to the long-term physiological and behavioral sequelae of poor maternal care. This points to a possible molecular target for treatments that may reverse or ameliorate the traces of childhood maltreatment.

Parental care during one’s childhood has important and consequential effects on the development of an individual, effects that persist even into adulthood. [Image: The White Ribbon Alliance, https://goo.gl/KgY6N5, CC BY-NC-SA 2.0, https://goo.gl/Toc0ZF]

Several studies have attempted to determine to what extent the findings from model animals are transferable to humans. Examination of post-mortem brain tissue from healthy human subjects found that the human equivalent of the glucocorticoid receptor gene promoter (NR3C1 exon 1F promoter) is also unique to the individual (Turner, Pelascini, Macedo, & Muller, 2008). A similar study examining newborns showed that methylation of the glucocorticoid receptor gene promoter maybe an early epigenetic marker of maternal mood and risk of increased hormonal responses to stress in infants 3 months of age (Oberlander et al., 2008). Although further studies are required to examine the functional consequence of this DNA methylation, these findings are consistent with our studies in the neonate and adult offspring of low licking and grooming mothers that show increased DNA methylation of the promoter of the glucocorticoid receptor gene, decreased glucocorticoid receptor gene expression, and increased hormonal responses to stress (Weaver et al., 2004). Examination of brain tissue from suicide victims found that the human glucocorticoid receptor gene promoter is also more methylated in the brains of individuals who had experienced maltreatment during childhood (McGowan et al., 2009). These finding suggests that DNA methylation mediates the effects of early environment in both rodents and humans and points to the possibility of new therapeutic approaches stemming from translational epigenetic research. Indeed, similar processes at comparable epigenetic labile regions could explain why the adult offspring of high and low licking/grooming mothers exhibit widespread differences in hippocampal gene expression and cognitive function (Weaver, Meaney, & Szyf, 2006).

However, this type of research is limited by the inaccessibility of human brain samples. The translational potential of this finding would be greatly enhanced if the relevant epigenetic modification can be measured in an accessible tissue. Examination of blood samples from adult patients with bipolar disorder, who also retrospectively reported on their experiences of childhood abuse and neglect, found that the degree of DNA methylation of the human glucocorticoid receptor gene promoter was strongly positively related to the reported experience of childhood maltreatment decades earlier. For a relationship between a molecular measure and reported historical exposure, the effects size is extraordinarily large. This opens a range of new possibilities: given the large effect size and consistency of this association, measurement of the GR promoter methylation may effectively become a blood test measuring the physiological traces left on the genome by early experiences. Although this blood test cannot replace current methods of diagnosis, this unique and addition information adds to our knowledge of how disease may arise and be manifested throughout life. Near-future research will examine whether this measure adds value over and above simple reporting of early adversities when it comes to predicting important outcomes, such as response to treatment or suicide.

---

Epigenetics in Psychology by Ian Weaver is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Permissions beyond the scope of this license may be available in our Licensing Agreement.