See this link: http://learn.genetics.utah.edu/content/epigenetics/rats/

Alan refers to the work of the group of Michael Meaney and Moshe Szyf in McGill (Canada). The quick reply to your question is that yes there is a lot of literature on early life adversity and anxiety and stress response in later life, and yes maternal care is important, as is the social environment, and offspring can adopt the maternal phenotype.

However, I think that the underlying mechanisms are not as clear-cut as in the suggested web page.

Back in 2004 the McGill group published a paper (first author: IGC Weaver) that suggested that the stress behaviour of rats was transmitted epigenetically through the glucocorticoid receptor promoter. This study has not yet been reproduced despite several attempts that I know of. Several other studies have been published looking at this promoter in slightly different paradigms (Herbeck et al, and Daniels et al), and neither saw similar methylation levels in the corresponding sites, nor any effect of the paradigm on methylation.

We published in 2005 the structure of the human GR promoter and its close homology to the rat. After this, again the Meaney group published an important study on the human 1F promoter, and found a link between suicide, prior childhood abuse, and methylation of the GR promoter, although not in a corresponding region (McGowan et al 2009).

There are quite a few differences that are now becoming clear between the rat and the human, and I would even suggest that even the rat is not as clear cut as proposed. The regulation of the promoter 1F / 1-7 hinges on a transcription factor called Ngfi-a, and it was in the binding site for this factor that Weaver at al first saw the methylation back in 2004. We have just published a study where we upregulated endogenous Ngfi-a expression, and there was no effect on the associated GR transcript levels, suggesting the regulation is more complicated than previously thought. Similarly, Weaver et al observed methylation levels of 0 or 100% in the Ngfi-a binding site, levels that have never been re-observed.

Similarly, it is doubtful that methylation at one single CpG dinucleotide is as important as reported by Weaver et al, we have reported a clear correlation in expression between the sum of methylation throughout promoter 1-7 rather than any single CpG (Witzmann et al 2012). We have similar preliminary data from the human, although IIRC Tyrka et al and de Rooji et al have observations that correlate with single CpG methylation levels.

So, as a word of warning, read all the papers from the subject, and make your own mind up!

Jon

Thank you Jon. I'm already prepare my thesis, and I'll investigate the topic that I´ve questioned. I want to inquire the effect of the maternal care mediated by the enviromental conditions, so I want to know the opinion and works of other researchers. I appreciate a lot your answer, it was very clarifier. I will take it account.

I think Jon's answer was very thoughtful, and there are other groups looking at maternal separation paradigms. As he said, read beyond just one group's studies.

The most general answer to this question seems to be yes, but there are many studies that present quite some variability in the expected outcomes, probably resulting from usage of different models of early life stress and other very sensitive experimental conditions. If it helps, we have published recently a review on this topic that highlights the most common observations and future perspectives, including epigenetic changes:

Early-life stress mediated modulation of adult neurogenesis and behavior.

Korosi A, Naninck EF, Oomen CA, Schouten M, Krugers H, Fitzsimons C, Lucassen PJ.

Behav Brain Res. 2012 Feb 14;227(2):400-9.

There is a lot of research conducted on this subject but one I like is the one published Emory University: Department of Psychiatry

www.psychiatry.emory.edu/PROGRAMS/GADrug/Feature%20Articles/...

"Prenatal stress and perinatal outcomes—Maternal stress and anxiety during pregnancy has been associated with:

-shorter gestation & higher incidence of preterm birth

--smaller birth weight and length

-increased risk of miscarriage"

One of the first things one would have to discriminate is whether one is concerned about the effects of stressing the mother has on the offspring (prenatal stress) or whether one is concerned about the direct effects of stress has on the offspring itself (early life stress or early postnatal stress). This may sound as a trivial difference but it makes a lot of difference on the (re) programming of the offspring HPA axis

Thank you @Carlos Fitzsimons, your comments and article are very interesting; I already have the review. But, considering the nonexistence of manipulated stress over the mothers, but the natural behavior of care over the offspring; could be that performance in high/low maternal care is related to natural previous stress conditions? The literature tells that, naturally, exist a group of mother placed in the higher performance place in a distribution curve, and others in the opposite. So, is possible that this tendency in the high/low performance in maternal care is related to the conditions in the early life of the mothers? And, in the case of offspring, the effect of the maternal care could be modified by their environmental an social conditions of housing?

Hello Mijail,

I think you have gotten some excellent feedback above. I would like to add just a couple of comments. First, maternal care in laboratory rats is quite sensitive to environmental conditions. It is quite easy to manipulate....stress rat mothers and you typically decrease maternal care (as measured by Meaney etc) which then influences the development of offspring. Providing a more 'enriched' environment for rat mothers tends to increase maternal care. There is a very high correlation, in female rats, between maternal care received and how these rats then perform as mothers later in life. With respect to altering offspring phenotypes later in life (I think you are primarily interested in stress-sensitive measures and behaviors) this is possible using different environmental interventions (the most common one is environmental enrichment). I will attach two papers below which are relevant to your questions.

I would caution you that these findings are reported almost exclusively in laboratory rodents and that, without doubt, the full answer is much more complicated than the simple way findings are reported in published papers. In the review paper I will attach there is a discussion about the adaptive significance in maternal behaviors that may also help!

Here is the review paper....

Article Adaptive significance of natural variations in maternal care...

This paper is relevant to the use of environmental enrichment to modify effects of early maternal effects.

Article Environmental Enrichment Reverses the Effects of Maternal Se...

@ Darlene: Right, this effect of environmental enrichment is nearly the same what I have found (in prep.) in the semi-precocial rodent Octodon degus.

Andreas, this is good to know...thanks!

In addition to the animal work there is a human literature reviewed by Monk and colleagues. See:

Monk C, Fitelson EM, Werner E.

Pediatr Res. 2011 May;69(5 Pt 2):3R-10R. doi: 10.1203/PDR.0b013e3182131a2e.

PMID: 21289532

When considering maternal anxiety prenatally and postnatally as it might affect the infant and young child's social-emotional development, it is important also to consider the effects of anxiety on maternal regulatory functions (behaviorally and physiologically) in the context of attachment. There are several studies of importance in the human literature looking at anxiety related to violent trauma and related PTSD and effects on maternal functioning in terms of anxiety/withdrawal and short and long-term effects on child development.

Dutra L, Bureau JF, Holmes B, Lyubchik A, Lyons-Ruth K. (2009) Quality of early care and childhood trauma: a prospective study of developmental pathways to dissociation.J Nerv Ment Dis. 197(6):383-90.

Lyons-Ruth K, Bureau JF, Holmes B, Easterbrooks A, Brooks NH. (2012)

Borderline symptoms and suicidality/self-injury in late adolescence: Prospectively observed relationship correlates in infancy and childhood.Psychiatry Res. 2012 Oct 31 (epub)

Schechter DS, Willheim E, McCaw J, Turner JB, Myers MM, Zeanah CH (2011). The relationship of violent fathers, posttraumatically stressed mothers and symptomatic children in a preschool-age inner-city pediatrics clinic sample.J Interpers Violence. 26(18):3699-719.

Schechter DS, Coates SW, Kaminer T, Coots T, Zeanah CH Jr, Davies M, Schonfeld IS, Marshall RD, Liebowitz MR, Trabka KA, McCaw JE, Myers MM (2008). Distorted maternal mental representations and atypical behavior in a clinical sample of violence-exposed mothers and their toddlers. J Trauma Dissociation.9(2):123-47.

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