Stressed mice moms, less licking & grooming, DNA methylation, & sad mouse dads: An epigenetic model of intergenerational transmission of psychopathology

The recent special issue of Biological Psychiatry on Stress, Neuroplasticity and Posttraumatic Stress Disorder (September 1, 2010) includes an intriguing piece on the transmission of the impact of stressed child-rearing among mice across generations: “Epigenetic transmission of the impact of early stress across generations.” This article was announced by the publisher’s regular newsletter as having implications for intergenerational trauma, and so I figured I better take a look.

Before going into the article itself, a couple of terms. First, epigenetics. Genetics is the study of how traits are passed on from one generation to the next via genes (in DNA) and epi is a prefix indicating essentially “related to but not of” (from the Greek preposition meaning on, around, above, nearby, outer, etc.), so epigenetics concerns those phenomena that result in traits being passed from one generation to the next that are not directly due to genetic material alone. In other words, those things that affect the phenotype without affecting the genotype (for those of you in High School biology). Epigenetics has been a hot field in mental health research for a few years now, particularly among those who want to explain how childhood adversity might influence the ability to tolerate stress later in life.

Second term, DNA methylation (I’ll admit I had to look this one up). Methylation is the addition of a methyl group — a group of chemical characterized by CH3 (for those of you in High School Chemistry) — to DNA. The addition of a methyl group to DNA is critical to development, and the amount and location influences how a gene will be expressed. Importantly, (1) methylation happens because of phenomena external to the gene — i.e., it is epigenetic — and (2) it can be passed on to later generations.

Okay, the article. A group of researchers in Switzerland set up an animal model of transgenerational transmission of the impact of early life stress using mice. (Animal models are useful to mental health research because they allow researchers to manipulate aspects of research design.) How did the Swiss operationalize early life stress in this model?

Dams and litters were subjected to unpredictable maternal separation combined with unpredictable maternal stress (MSUS). (p. 408)

Essentially, they stressed out the new mice mothers (“dams”) and took them away from their mice children (“litters”) at irregular intervals (“MSUS”) throughout the first two weeks following birth. They also left a separate group of dams and litters alone. They observed these two groups of mice, and found what others have found, that among the “treated group” (i.e., the ones with unpredictably separated and stressed mothers) there were fewer of the behaviors associated with healthy mouse development — arched-back nursing, regular licking and grooming, and time hanging out on the nest — when the moms were in contact with their litters. In addition, when the little mice grew up, males in the treated group spent more time floating passively in a “forced swim” test (dropping mice in water and seeing how fast they swim, essentially), spent more time immobile in a “tail suspension” test (holding mice by their tails), and ate less sugar (a “sucrose consumption test”) than mice in the nontreated group. These traits were seen as “depressive-like” behavior. Notably, females were not different from all the mice who were raised without the unpredictable and stressed mothering.

Once the two groups of litters were old enough to breed, the researchers bred the males of the stressed group with a new set of female mice (who grew up normally) quickly separated them from their litters and female partners so as not to influence the behavior of their children once born, did not stress the mothers, and then observed the behaviors of their offspring — i.e., the second generation. Then they did the same thing with the next — the third — generation as well. With some slight variability, results from the first generation were replicated in both second and third generations, suggesting that not only is there an effect of early life maternal child-rearing practices that persists across (mice) generations, but also that this effect is independent of how subsequent mothers rear their litters, and thus it must be carried by the father.

So how is this done? What is the mechanism of transmission? Combining their findings and the knowledge about epigenetics, our Swiss friends thought that maternal separation combined with unpredictable maternal stress might be altering gene expression through DNA methylation in sperm cells. So:

To determine whether DNA methylation was altered by early stress in the male germline, we examined its level in the promoter of the several candidate genes in sperm from F1 MSUS males. (p. 412)

The “several candidate genes” here were genes that are associated with the regulation of depressive-like behavior. What did they find?

Methylation of the CpG island surrounding the transcription initiation site of MeCP2 and CB1 genes was increased in F1 MSUS sperm. In contrast, for the CRFR2 gene, methylation in a stretch of the CpG island located 5′ of the transcription initiation site was decreased. Methylation was not changed in target regions of the 5-HT1A or MAOA gene. (p. 413)

What did they find? Essentially, DNA methylation was different for some of the genes in the group that had been subjected to maternal separation combined with unpredictable maternal stress than in the group that had been allowed to lead a normal mouse childhood.

So early maternal separation and distress can have effects at the epigenetic level that are carried through paternal lines to subsequent offspring. This is important news for developmental psychologists studying depression and other disorders, and should not be underestimated. That someone has figured out how care-taking behavior affects gene expression and can be carried across generations to me is simply phenomenal. But what does it all mean for trauma studies? I mentioned above this article was advertised as important for trauma studies, but the term trauma never comes up once in the manuscript — rather, the authors focus on “depression-like” behavior. This may be relevant to trauma studies — most people who develop PTSD also develop depressive disorders as well — but the research doesn’t show that somehow PTSD is passed along intergenerationally.

There is another, more subtle critique to be made here as well. The title of the article mentions “early stress” and the authors consistently refer to “chronic and unpredictable stress in early postnatal life” (p. 413) and the like. But I think it’s a mistake to apply these findings to childhood adversity in general, or even neonatal adversity in general. Their model of early stress was particular to one key developmentally crucial relationship: that of an offspring to it’s mother. Although there is good reason to believe that several types of early life adversity can affect one’s proclivity towards depression and other disorders, it does not follow that among these several types that there is one pathway for all, and certainly not that all are best seen as versions of being unpredictably separated from a stressed mother.