Here we report that increased pup licking and grooming (LG) and arched-back nursing (ABN) by rat mothers altered the offspring epigenome at a glucocorticoid receptor (GR) gene promoter in the hippocampus. Offspring of mothers that showed high levels of LG and ABN were found to have differences in DNA methylation, as compared to offspring of 'low-LG-ABN' mothers. These differences emerged over the first week of life, were reversed with cross-fostering, persisted into adulthood and were associated with altered histone acetylation and transcription factor (NGFI-A) binding to the GR promoter. Central infusion of a histone deacetylase inhibitor removed the group differences in histone acetylation, DNA methylation, NGFI-A binding, GR expression and hypothalamic-pituitary-adrenal (HPA) responses to stress, suggesting a causal relation among epigenomic state, GR expression and the maternal effect on stress responses in the offspring. Thus we show that an epigenomic state of a gene can be established through behavioral programming, and it is potentially reversible.

/pdf/epigenetic-programming-by-maternal-behavior-nhsklwyk7o.pdf

Epigenetic programming by maternal behavior.

How we raise young children is one of today's most highly personalized and sharply politicized issues, in part because each of us can claim some level of "expertise." The debate has intensified as discoveries about our development-in the womb and in the first months and years-have reached the popular media. How can we use our burgeoning knowledge to assure the well-being of all young children, for their own sake as well as for the sake of our nation? Drawing from new findings, this book presents important conclusions about nature-versus-nurture, the impact of being born into a working family, the effect of politics on programs for children, the costs and benefits of intervention, and other issues. The committee issues a series of challenges to decision makers regarding the quality of child care, issues of racial and ethnic diversity, the integration of children's cognitive and emotional development, and more. Authoritative yet accessible, From Neurons to Neighborhoods presents the evidence about "brain wiring" and how kids learn to speak, think, and regulate their behavior. It examines the effect of the climate-family, child care, community-within which the child grows.

/pdf/from-neurons-to-neighborhoods-the-science-of-early-childhood-3bfl5g72ow.pdf

From Neurons to Neighborhoods: The Science of Early Childhood Development

Chronic exposure to stress hormones, whether it occurs during the prenatal period, infancy, childhood, adolescence, adulthood or aging, has an impact on brain structures involved in cognition and mental health. However, the specific effects on the brain, behaviour and cognition emerge as a function of the timing and the duration of the exposure, and some also depend on the interaction between gene effects and previous exposure to environmental adversity. Advances in animal and human studies have made it possible to synthesize these findings, and in this Review a model is developed to explain why different disorders emerge in individuals exposed to stress at different times in their lives.

Effects of stress throughout the lifespan on the brain, behaviour and cognition

▪ Abstract Socioeconomic status (SES) is one of the most widely studied constructs in the social sciences. Several ways of measuring SES have been proposed, but most include some quantification of family income, parental education, and occupational status. Research shows that SES is associated with a wide array of health, cognitive, and socioemotional outcomes in children, with effects beginning prior to birth and continuing into adulthood. A variety of mechanisms linking SES to child well-being have been proposed, with most involving differences in access to material and social resources or reactions to stress-inducing conditions by both the children themselves and their parents. For children, SES impacts well-being at multiple levels, including both family and neighborhood. Its effects are moderated by children's own characteristics, family characteristics, and external support systems.

Socioeconomic status and child development.

In response to stress, the brain activates several neuropeptide-secreting systems. This eventually leads to the release of adrenal corticosteroid hormones, which subsequently feed back on the brain and bind to two types of nuclear receptor that act as transcriptional regulators. By targeting many genes, corticosteroids function in a binary fashion, and serve as a master switch in the control of neuronal and network responses that underlie behavioural adaptation. In genetically predisposed individuals, an imbalance in this binary control mechanism can introduce a bias towards stress-related brain disease after adverse experiences. New candidate susceptibility genes that serve as markers for the prediction of vulnerable phenotypes are now being identified.

Stress and the brain: from adaptation to disease

Variations in maternal care affect the development of individual differences in neuroendocrine responses to stress in rats. As adults, the offspring of mothers that exhibited more licking and grooming of pups during the first 10 days of life showed reduced plasma adrenocorticotropic hormone and corticosterone responses to acute stress, increased hippocampal glucocorticoid receptor messenger RNA expression, enhanced glucocorticoid feedback sensitivity, and decreased levels of hypothalamic corticotropin-releasing hormone messenger RNA. Each measure was significantly correlated with the frequency of maternal licking and grooming (all r 9s > −0.6). These findings suggest that maternal behavior serves to “program” hypothalamic-pituitary-adrenal responses to stress in the offspring.

http://science.sciencemag.org/content/sci/277/5332/1659.full.pdf

Maternal Care, Hippocampal Glucocorticoid Receptors, and Hypothalamic-Pituitary-Adrenal Responses to Stress

In the rat, variations in maternal care appear to influence the development of behavioral and endocrine responses to stress in the offspring. The results of cross-fostering studies reported here provide evidence for (i) a causal relationship between maternal behavior and stress reactivity in the offspring and (ii) the transmission of such individual differences in maternal behavior from one generation of females to the next. Moreover, an environmental manipulation imposed during early development that alters maternal behavior can then affect the pattern of transmission in subsequent generations. Taken together, these findings indicate that variations in maternal care can serve as the basis for a nongenomic behavioral transmission of individual differences in stress reactivity across generations.

https://science.sciencemag.org/content/sci/286/5442/1155.full.pdf

Nongenomic Transmission Across Generations of Maternal Behavior and Stress Responses in the Rat

We report that variations in maternal care in the rat promote hippocampal synaptogenesis and spatial learning and memory through systems known to mediate experience-dependent neural development. Thus, the offspring of mothers that show high levels of pup licking and grooming and arched-back nursing showed increased expression of NMDA receptor subunit and brain-derived neurotrophic factor (BDNF) mRNA, increased cholinergic innervation of the hippocampus and enhanced spatial learning and memory. A cross-fostering study provided evidence for a direct relationship between maternal behavior and hippocampal development, although not all neonates were equally sensitive to variations in maternal care.

Maternal care, hippocampal synaptogenesis and cognitive development in rats.

The quality of family life influences the development of individual differences in vulnerability to illness throughout later life. As adults, victims of childhood physical or sexual abuse are at considerably greater risk for mental illness, as well as for diabetes and heart disease (e.g., Refs. 1–3). Children need not be beaten to be compromised. Persistent emotional neglect or conditions of harsh, inconsistent discipline serve to increase the risk of depression and anxiety disorders to a level comparable to that observed in cases of abuse. 4 Indeed, for certain outcomes, the consequences of persistent neglect exceed those of abuse. 5,6 More subtle relationships exist. Low scores on parental bonding scales, reflecting cold, distant parent–child relationships, significantly increase the risk of depression and anxiety in later life (e.g., Refs. 7,8). And the risk is not unique to mental health. Russak and Schwartz 9 found that by midlife those individuals who, as undergraduate students, rated their relationship with parents as cold and detached, had a fourfold greater risk of chronic illness, including depression and alcoholism as well as heart disease and diabetes. Parental factors also serve to mediate the effects of environmental adversity on development. For example, the effects of poverty on emotional and cognitive development are mediated by parental factors, to the extent that if such factors are controlled, there is no discernible effect of poverty on child development. 10,11 Moreover, treatment outcomes associated with early intervention programs are routinely correlated with changes in parental behavior: In cases where parental behavior proves resistant to change, treatment outcomes are seriously limited. These findings suggest that variations in parental care mediate, in part at least, the effects of environmental adversity on child development. One of the more common findings here is that maternal depression associated with environmental conditions not only compromises parent–child interactions, but also limits the efficacy of early intervention programs.

Maternal Care, Gene Expression, and the Development of Individual Differences in Stress Reactivity

The sections in this article are:


1
Hypothalamic-Pituitary-Adrenal Stress Response

2
Environmental Regulation of Hypothalamic-Pituitary-Adrenal Development
2.1
Effects of Handling (or Infantile Stimulation)

2.2
Effects of Prolonged Periods of Maternal Separation

2.3
Effects of Neonatal Endotoxin Exposure




3
Summary of Early Environmental Effects
3.1
Effects of Handling on Chronic Responses to Stress

3.2
Acute Stress Responses in Handled and Nonhandled Rats: Revisited




4
Summary

5
Biological Significance

6
Early Environmental Effects: The Levine Maternal Mediation Hypothesis
6.1
Stability of Individual Differences in Maternal Behavior

6.2
Transmission of Individual Differences in Maternal Care to Offspring

6.3
Mode of Transmission: Genomic or Nongenomic?




7
Conclusions

Dong Liu

Papers

Maternal Care, Hippocampal Glucocorticoid Receptors, and Hypothalamic-Pituitary-Adrenal Responses to Stress

Nongenomic Transmission Across Generations of Maternal Behavior and Stress Responses in the Rat

Maternal care, hippocampal synaptogenesis and cognitive development in rats.

Maternal Care, Gene Expression, and the Development of Individual Differences in Stress Reactivity

Development of Individual Differences in Behavioral and Endocrine Responses to Stress: Role of the Postnatal Environment