Abstract The early-life social environment can induce stable changes that influence neurodevelopment and mental health. Research focused on early-life adversity revealed that early-life experiences ...have a persistent impact on gene expression and behavior through epigenetic mechanisms. The hypothalamus-pituitary-adrenal axis is sensitive to changes in the early-life environment that associate with DNA methylation of a neuron-specific exon 17 promoter of the glucocorticoid receptor (GR) ( Nr3c1 ). Since initial findings were published in 2004, numerous reports have investigated GR gene methylation in relationship to early-life experience, parental stress, and psychopathology. We conducted a systematic review of this growing literature, which identified 40 articles (13 animal and 27 human studies) published since 2004. The majority of these examined the GR exon variant 1F in humans or the GR17 in rats, and 89% of human studies and 70% of animal studies of early-life adversity reported increased methylation at this exon variant. All the studies investigating exon 1F /17 methylation in conditions of parental stress (one animal study and seven human studies) also reported increased methylation. Studies examining psychosocial stress and psychopathology had less consistent results, with 67% of animal studies reporting increased exon 17 methylation and 17% of human studies reporting increased exon 1F methylation. We found great consistency among studies investigating early-life adversity and the effect of parental stress, even if the precise phenotype and measures of social environment adversity varied among studies. These results are encouraging and warrant further investigation to better understand correlates and characteristics of these associations.
The importance of maternal depression for child outcomes is well established, and impairments in psychosocial function and parenting are as severe in women with high subsyndromal levels of depressive ...symptoms as they are in women with clinical depression. The author conducted a systematic review that explored the association between maternal depressive symptoms and child neurodevelopmental outcomes, including in neuroimaging studies. The results strongly suggest that the influences of maternal depressive symptoms operate across a continuum to influence child outcomes, implying that maternal depression may appropriately be considered an issue of population health. This conclusion is strengthened by recent findings that reveal distinct influences of positive maternal mental health on parenting and child outcomes. AJP AT 175: Remembering Our Past As We Envision Our Future April 1851: Fleetwood Churchill, "On the Mental Disorders of Pregnancy and Childbed" "Women affected with any degree of mental derangement during pregnancy are more disposed than others to puerperal mania. But the serious character of these attacks is even deepened by the fact, abundantly established, that the evil is not limited to the mother. Not only may organic diseases of the body be transmitted to the infant, but a predisposition to insanity, thus multiplying the distress in a most alarming ratio." (Am J Psychiatry 1851; 7:297-317 ).
Variations in phenotype reflect the influence of environmental conditions during development on cellular functions, including that of the genome. The recent integration of epigenetics into ...developmental psychobiology illustrates the processes by which environmental conditions in early life structurally alter DNA, providing a physical basis for the influence of the perinatal environmental signals on phenotype over the life of the individual. This review focuses on the enduring effects of naturally occurring variations in maternal care on gene expression and phenotype to provide an example of environmentally driven plasticity at the level of the DNA, revealing the interdependence of gene and environmental in the regulation of phenotype. (Contains 6 figures.)
The quality of fetal growth and development predicts the risk for a range of noncommunicable, chronic illnesses. These observations form the basis of the "developmental origins of health and disease" ...hypothesis, which suggests that the intrauterine signals that compromise fetal growth also act to "program" tissue differentiation in a manner that predisposes to later illness. Fetal growth also predicts the risk for later psychopathology. These findings parallel studies showing that antenatal maternal emotional well-being likewise predicts the risk for later psychopathology. Taken together, these findings form the basis for integrative models of fetal neurodevelopment, which propose that antenatal maternal adversity operates through the biological pathways associated with fetal growth to program neurodevelopment. The authors review the literature and find little support for such integrated models. Maternal anxiety, depression, and stress all influence neurodevelopment but show modest, weak, or no associations with known stress mediators (e.g., glucocorticoids) or with fetal growth. Rather, compromised fetal development appears to establish a "meta-plastic" state that increases sensitivity to postnatal influences. There also remain serious concerns that observational studies associating either fetal growth or maternal mental health with neurodevelopmental outcomes fail to account for underlying genetic factors. Finally, while the observed relation between fetal growth and adult health has garnered considerable attention, the clinical relevance of these associations remains to be determined. There are both considerable promise and important challenges for future studies of the fetal origins of mental health.
Human brain development occurs within a socioeconomic context and childhood socioeconomic status (SES) influences neural development--particularly of the systems that subserve language and executive ...function. Research in humans and in animal models has implicated prenatal factors, parent-child interactions and cognitive stimulation in the home environment in the effects of SES on neural development. These findings provide a unique opportunity for understanding how environmental factors can lead to individual differences in brain development, and for improving the programmes and policies that are designed to alleviate SES-related disparities in mental health and academic achievement.
Maternal care is associated with long-term effects on behavior and epigenetic programming of the NR3C1 (GLUCOCORTICOID RECEPTOR) gene in the hippocampus of both rats and humans. In the rat, these ...effects are reversed by cross-fostering, demonstrating that they are defined by epigenetic rather than genetic processes. However, epigenetic changes at a single gene promoter are unlikely to account for the range of outcomes and the persistent change in expression of hundreds of additional genes in adult rats in response to differences in maternal care.
We examine here using high-density oligonucleotide array the state of DNA methylation, histone acetylation and gene expression in a 7 million base pair region of chromosome 18 containing the NR3C1 gene in the hippocampus of adult rats. Natural variations in maternal care are associated with coordinate epigenetic changes spanning over a hundred kilobase pairs. The adult offspring of high compared to low maternal care mothers show epigenetic changes in promoters, exons, and gene ends associated with higher transcriptional activity across many genes within the locus examined. Other genes in this region remain unchanged, indicating a clustered yet specific and patterned response. Interestingly, the chromosomal region containing the protocadherin-α, -β, and -γ (Pcdh) gene families implicated in synaptogenesis show the highest differential response to maternal care.
The results suggest for the first time that the epigenetic response to maternal care is coordinated in clusters across broad genomic areas. The data indicate that the epigenetic response to maternal care involves not only single candidate gene promoters but includes transcriptional and intragenic sequences, as well as those residing distantly from transcription start sites. These epigenetic and transcriptional profiles constitute the first tiling microarray data set exploring the relationship between epigenetic modifications and RNA expression in both protein coding and non-coding regions across a chromosomal locus in the mammalian brain.
There are numerous examples in psychology and other disciplines of the enduring effects of early experience on neural function. In this article, we review the emerging evidence for epigenetics as a ...candidate mechanism for these effects. Epigenetics refers to functionally relevant modifications to the genome that do not involve a change in nucleotide sequence. Such modifications include chemical marks that regulate the transcription of the genome. There is now evidence that environmental events can directly modify the epigenetic state of the genome. Thus studies with rodent models suggest that during both early development and in adult life, environmental signals can activate intracellular pathways that directly remodel the "epigenome," leading to changes in gene expression and neural function. These studies define a biological basis for the interplay between environmental signals and the genome in the regulation of individual differences in behavior, cognition, and physiology.
The developing brain in utero and during the first years of life is highly vulnerable to environmental influences. Experiences occurring during this period permanently modify brain structure and ...function through epigenetic modifications (alterations of the DNA structure and chromatin function) and consequently affect the susceptibility to mental disorders. In this review, we describe evidence linking adverse environmental variation during early life (from the fetal period to childhood) and long‐term changes in brain volume, microstructure, and connectivity, especially in amygdala and hippocampal regions. We also describe genetic variations that moderate the impact of adverse environmental conditions on child neurodevelopment, such as polymorphisms in brain‐derived neurotrophic factor and catechol‐O‐methyltransferase genes, as well as genetic pathways related to glutamate and monoaminergic signaling. Lastly, we have depicted positive early life experiences that could benefit childhood neurodevelopment and reverse some detrimental effects of adversity in the offspring.
What this paper adds
Prenatal, peripartum, and postnatal adversities influence child behavior and neurodevelopment.
Exposure to environmental enrichment and positive influences may revert these effects.
Putative mechanisms involve alterations in neurotrophic factors and neurotransmitter systems.
New tools/big data improved the understanding on how early adversity alters neurodevelopment.
This permits better translation/application of the findings from animal models to humans.
Resumen
Influencias ambientales tempranas en el desarrollo de la estructura y función del cerebro de los niños
El cerebro en desarrollo en el útero y durante los primeros años de vida es altamente vulnerable a las influencias ambientales. Las experiencias que se producen durante este período modifican permanentemente la estructura y función del cerebro a través de modificaciones epigenéticas (alteraciones de la estructura del ADN y la función de la cromatina) y, por consiguiente, afectan la susceptibilidad a los trastornos mentales. En esta revisión, describimos la evidencia que vincula la variación ambiental adversa durante la vida temprana (desde el período fetal hasta la infancia) y los cambios a largo plazo en el volumen cerebral, la microestructura y la conectividad, especialmente en las regiones de la amígdala y el hipocampo. También describimos variaciones genéticas que moderan el impacto de las condiciones ambientales adversas en el desarrollo neurológico infantil, como los polimorfismos en los genes del factor neurotrófico derivado del cerebro y de la catecol‐O‐metiltransferasa, así como las vías genéticas relacionadas con el glutamato y la señalización monoaminérgica. Por último, hemos descrito experiencias positivas de la vida temprana que podrían beneficiar el desarrollo neurológico infantil y revertir algunos efectos perjudiciales de la adversidad en la descendencia.
Influências ambientais precoces no desenvolvimento da estrutura e função cerebral em crianças
O cérebro em desenvolvimento no útero e durante os primeiros anos devida é altamente vulnerável a influências ambientais. Experiências que ocorrem durante este período modificam permanentemente a estrutura e função cerebrais por meio de modificações epigenéticas (alterações da estrutura do DNA e função da cromatina). Consequentemente, afetam a suscetibilidade a desordens mentais. Nesta revisão, nós descrevemos a evidência relacionando variação ambiental adversa durante o início da vida (do período fetal à infância) e mudanças de longo prazo no volume, microestrutura e conectividade cerebral, especialmente nas regiões da amídala e hipocampo. Também descrevemos variações genéticas que moderam o impacto de condições ambientais adversas no neurodesenvolvimento infantil, tais como polimorfismos em fatores neurotróficos derivados do cérebro, e genes catechol‐O‐metiltransferases, assim como vias genéticas ligadas à sinalização por glutamato e momonoaminérgica. Por fim, descrevemos experiências precoces positivas que podem beneficiar o neurodesenvolvimento infantil e reverter alguns efeitos detrimentais da adversidade na prole.
What this paper adds
Prenatal, peripartum, and postnatal adversities influence child behavior and neurodevelopment.
Exposure to environmental enrichment and positive influences may revert these effects.
Putative mechanisms involve alterations in neurotrophic factors and neurotransmitter systems.
New tools/big data improved the understanding on how early adversity alters neurodevelopment.
This permits better translation/application of the findings from animal models to humans.
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•Treatment resistant depression (TRD) is a major public health concern.•Yet little is known about how TRD differs from treatment-responsive depression.•A multi-scale, systems biology approach is ...needed to better understand & treat TRD.•This involves a coordinated study of depressed humans and improved animal models.•And integrated use of genetic, epigenetic, cellular, and circuit analyses.•The goal is a precision medicine approach to depression including TRD.
An estimated 50% of depressed patients are inadequately treated by available interventions. Even with an eventual recovery, many patients require a trial and error approach, as there are no reliable guidelines to match patients to optimal treatments and many patients develop treatment resistance over time. This situation derives from the heterogeneity of depression and the lack of biomarkers for stratification by distinct depression subtypes. There is thus a dire need for novel therapies. To address these known challenges, we propose a multi-scale framework for fundamental research on depression, aimed at identifying the brain circuits that are dysfunctional in several animal models of depression as well the changes in gene expression that are associated with these models. When combined with human genetic and imaging studies, our preclinical studies are starting to identify candidate circuits and molecules that are altered both in models of disease and in patient populations. Targeting these circuits and mechanisms can lead to novel generations of antidepressants tailored to specific patient populations with distinctive types of molecular and circuit dysfunction.
Naturally occurring variations in maternal care alter the expression of genes that regulate behavioral and endocrine responses to stress, as well as hippocampal synaptic development. These effects ...form the basis for the development of stable, individual differences in stress reactivity and certain forms of cognition. Maternal care also influences the maternal behavior of female offspring, an effect that appears to be related to oxytocin receptor gene expression, and which forms the basis for the intergenerational transmission of individual differences in stress reactivity. Patterns of maternal care that increase stress reactivity in offspring are enhanced by stressors imposed on the mother. These findings provide evidence for the importance of parental care as a mediator of the effects of environmental adversity on neural development.
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