Can traumatic events during early childhood permanently affect the way the brain responds to stress at a molecular level? Moshe Szyf, a McGill University epigeneticist, and Michael Meaney, a McGill University neurologist previously found evidence for long-lasting molecular changes in stress-response brain regions of rats exposed to poor parental care. Now, in a follow-up study, they show that similar changes may occur in human suicide victims who suffered childhood abuse.
Dr. Szyf and Dr. Meaney focus on epigenetic changes, or changes “on top of the genome.” While childhood experience cannot change the actual DNA basepairs that form the genetic code, experience may permanently mark certain regions of the genome in ways that change gene expression and have long-lasting consequences on behavior. These marks include methylation of DNA basepairs and acetylation of histones, the proteins that DNA is wrapped around inside the nucleus. We are only now beginning to understand how experience can change these epigentic tags, and in turn how these epigentic tags can feedback and affect our behavior.
In 2004, Dr. Szyf and Dr. Meaney published a paper on epigenetic changes caused by maternal behavior in rats. Rats whose mothers did less licking and grooming and arched-back nursing had exaggerated behavioral and hypothalamic-pituitary-adrenal responses to stressful stimuli compared with rats whose mothers groomed them more. These rats also had altered epigentic tags — increased DNA methylation and reduced histone acetylation — in the promoter of an important stress response gene, the glucocorticoid receptor gene in the hippocampus, and reduced expression of this gene. In order to show that the maternal behavior caused the epigenetic changes, some rats whose birth mothers did not groom were fostered by mothers with high grooming behaviors, and vice versa. These adopted rats showed methylation patterns similar to the mothers that reared them, instead of their biological mothers. Interestingly, the effects of neglectful maternal behavior on methylation in the promotor, altered hippocampal glucocorticoid receptor expression, and the hypothalamic-pituitary-adrenal response to stress were reversed when the adult offspring were given a histone deacetylase inhibitor, which globally removes many epigentic tags.
Does childhood abuse and neglect produce similar epigenetic tags on this stress response gene in humans? In another study, Dr. Meaney’s group compared expression of the neuron-specific glucocorticoid receptor gene in the hippocampus of 12 suicide victims with a history of childhood abuse (including severe neglect) to those of 12 suicide victims who had no history of abuse and those of 12 controls. Again, they found increased methylation of a glucocorticoid receptor promotor, and less glucocorticoid receptor gene expression. This finding, that childhood abuse and neglect is associated with methylation of a glucocorticoid receptor promotor in the hippocampus mirrors the result in their 2004 paper that found the same epigenetic change in rats who were neglected by their mothers.
Dr. Szyf and Dr. Meaney also looked more broadly for epigentic tags associated with abuse. In a recent paper, they compared the brains of 13 people who had suffered early childhood abuse (sexual contact, severe physical abuse and/or severe neglect) and committed suicide and 11 people who had no history of abuse and had died suddenly in accidents. The hippocampus in the brains of suicide victims had higher methylation levels in DNA regions controlling the expression of ribosomal RNA (rRNA), a general purpose gene, broadly important for protein syntehsis in a given cell. The epigentic tags resulted in reduced rRNA expression in the hippocampus. Whether or not the person had had a psychiatric illness or a substance abuse problem did not account for any difference in methylation level. The methylation differences were specific to the hippocampus, which is commonly associated with psychopathology, and did not exist in the cerebellum, which is not associated with pathology (using samples from 8 brains, 4 from each of the conditions). Thus the authors provide two examples of long-lasting molecular “scars” in humans that may affect gene expression and behavior.
This research is very interesting but not without caveats. The authors acknowledge that they have not been able to account for other environmental factors besides childhood abuse and neglect that might cause these epigenetic changes. Future studies would require much larger sample sizes to address other possible causative environmental variables. Also, the authers show “scars” on two genes, one important for stress-response and one for protein synthesis, but there are twenty-thousand genes in the human genome. With new technologies to look at epigentic tags on a genome-wide level (the epigenome), future studies can look at all genes in an unbiased manner for a more complete picture of epigentic “scars” that are enriched in people who suffered from childhood abuse and neglect. Finally, we should be careful not to conflate suicidality with abuse; this research does not directly address suicide risk from abuse.
Possible legal and policy implications of this area of research remain far in the future, but could include identifying earlier critical periods for childhood intervention programs, better understanding abuse as a mitigating factor if the person is later convicted of a crime related to an abnormal stress response, or calculating damages in a civil lawsuit against the abusive caregiver. The most significant implication is better understanding epigenetic pathology caused by childhood abuse and neglect, which may be an important part of a multi-faceted approach towards treating survivors of abuse who continue to suffer from its lasting effects.
– Kelly Lowenberg (Hat tip to Alex Pollen)