Conserved epigenetic sensitivity to early life experience in the rat and human hippocampus

Sackler Program for Epigenetics and Developmental Psychobiology at McGill University and Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada H3G 1Y6.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 10/2012; 109(Supplement 2):17266-17272. DOI: 10.1073/pnas.1121260109


Early life experience 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. However, it is unlikely that such effects completely capture the evolutionarily
conserved epigenetic mechanisms of early adaptation to environment. Here we present DNA methylation profiles spanning 6.5
million base pairs centered at the NR3C1 gene in the hippocampus of humans who experienced abuse as children and nonabused controls. We compare these profiles to
corresponding DNA methylation profiles in rats that received differential levels of maternal care. The profiles of both species
reveal hundreds of DNA methylation differences associated with early life experience distributed across the entire region
in nonrandom patterns. For instance, methylation differences tend to cluster by genomic location, forming clusters covering
as many as 1 million bases. Even more surprisingly, these differences seem to specifically target regulatory regions such
as gene promoters, particularly those of the protocadherin α, β, and γ gene families. Beyond these high-level similarities,
more detailed analyses reveal methylation differences likely stemming from the significant biological and environmental differences
between species. These results provide support for an analogous cross-species epigenetic regulatory response at the level
of the genomic region to early life experience.


Available from: Matthew Suderman
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    • "The increased DNA methylation was related to decreased rates of GR expression. Other groups have extended this work by demonstrating a relationship between ELS and methylation status of the Nr3c1 gene, with both increased and decreased methylation states for different GR transcripts (Perroud et al., 2011; Labonté et al., 2012; Suderman et al., 2012; Tyrka et al., 2012; Steiger et al., 2013). "
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    ABSTRACT: Early life stress interacts with adult stress to differentially modulate neural systems and vulnerability to various psychiatric illnesses. However, the effects of early life stress and adult stress on addictive behaviors have not been sufficiently investigated. We examined the effects of early life stress in the form of prolonged maternal separation, followed in early adulthood by either 10 days of chronic variable stress or no stress, on methamphetamine self-administration, extinction, and cue-induced reinstatement. We observed that chronic variable stress in adulthood reduced methamphetamine self-administration in rats with a history of early life stress. These findings add to an emerging body of literature suggesting interactions between early life and early adulthood stressors on adult behavioral phenotypes.
    Behavioural pharmacology 07/2015; DOI:10.1097/FBP.0000000000000166 · 2.15 Impact Factor
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    • "For instance, adults with a history of childhood abuse and neglect display lower total GR gene expression in the hippocampus than those without a history of childhood adversity (McGowan et al., 2009), and gene expression is in turn mediated by epigenetic processes including DNA methylation. Low LG in rats and early life abuse and neglect in humans are correlated with increased DNA methylation within the GR promoter and lower expression of the gene in the hippocampus (McGowan et al., 2011; Suderman et al., 2012; Weaver et al., 2004; Weaver et al., 2005; Weaver et al., 2007). "
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    ABSTRACT: Rat dams show natural variations in maternal care, licking and grooming (LG), that are associated with distinct behavioral and neural phenotypes in offspring. However, there has been limited research on the effects of differences in LG received by female pups and of variations in maternal care within the litter. Here, we investigated LG received by measuring active maternal care after pup retrieval of female offspring. We then examined locomotor activity, open field exploration, and restraint stress reactivity in adult female offspring. We also investigated the expression of mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) and DNA methylation of the GR17 promoter in the hippocampus. High compared with low LG siblings and female offspring from high compared with low LG dams showed increased locomotor activity. High compared with low LG siblings also showed reduced anxiety behavior regardless of the overall level of LG received in the litter. Unexpectedly, both the lowest licked offspring from low LG litters and the highest licked offspring from high LG litters showed suppressed corticosterone (CORT) responses to stress. However, high LG offspring within litters also showed increased expression of the GR gene, which was negatively correlated with the CORT response to restraint. DNA methylation at 2 CpG sites within GR17 promoter was significantly higher in high LG offspring. These differences in the response to maternal care both within- and between-litters were distinct in part from previous reports of between litter effects, potentially a result of the sex studied or the methods used to observe maternal care. (PsycINFO Database Record (c) 2014 APA, all rights reserved).
    Behavioral Neuroscience 09/2014; 128(6). DOI:10.1037/bne0000014 · 2.73 Impact Factor
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    • "In recent years, DNA methylation of HPA-axis genes, among others the promotor regions of the GR (80, 116), the vasopressin (VP) gene (117), and 11βHSD (118) was observed. In particular, the epigenetic change in GR was found associated with a behavioral response pattern and HPA-axis setpoint in later life, and therefore is considered to represent some sort of “molecular memory” for salient events (68). "
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    ABSTRACT: Prematurely born infants may be at risk, because of inadequate maturation of tissues. If there are signs of preterm birth, it has become common practice therefore to treat either antenatally the mother or postnatally the infant with glucocorticoids to accelerate tissue development, particularly of the lung. However, this life-saving early glucocorticoid treatment was found to increase the risk of adverse outcome in later life. In one animal study, the authors reported a 25% shorter lifespan of rats treated as newborns with the synthetic glucocorticoid dexamethasone, but so far this finding has not been replicated. After a brief clinical introduction, we discuss studies in rodents designed to examine how perinatal glucocorticoid action affects the developing brain. It appears that the perinatal action of the glucocorticoid depends on the context and the timing as well as the type of administered steroid. The type of steroid is important because the endogenous glucocorticoids cortisol and corticosterone bind to two distinct receptor populations, i.e., mineralocorticoid and glucocorticoid receptors (GR), while synthetic glucocorticoids predominantly bind to the GR. In addition, if given antenatally hydrocortisone is inactivated in the placenta by 11β-HSD type 2, and dexamethasone is not. With respect to timing, the outcome of glucocorticoid effects is different in early vs. late phases of brain development. The context refers to the environmental input that can affect the susceptibility to glucocorticoid action in the newborn rodent brain; early handling of pups and maternal care obliterate effects of post-natal dexamethasone treatment. Context also refers to coping with environmental conditions in later life, for which the individual may have been programed epigenetically by early-life experience. This knowledge of determinants affecting the outcome of perinatal glucocorticoid exposure may have clinical implications for the treatment of prematurely born infants.
    Frontiers in Endocrinology 07/2014; 5:100. DOI:10.3389/fendo.2014.00100
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