Some people who experience severe stress, such as prolonged economic hardship or sexual or physical abuse, develop devastating psychological or other health problems.
Others are more flexible. For example, if one identical twin shows signs of stress-related depression, the other will also be depressed only in about 40% of cases. I believe epigenetic mechanisms help to explain why1,2. These are experience-dependent molecular changes in DNA or proteins that change how genes behave without changing the information contained in them.
Recent studies suggest that epigenetic mechanisms shape short-term (lasting hours) and long-term (lasting months, years or even a lifetime) responses to stress. Some studies also indicate that epigenetic changes may affect the next generation.
A serious effort to both map and reinforce associations between behavioral responses and epigenetic changes – although costly and challenging – will almost certainly mark the possibilities for treatments that either reverse the effects of stress or reduce a person’s ability to cope. Increases capacity.
When a person is stressed, gene expression may be up- or down-regulated in certain parts of the brain. This can happen through chemical modifications to DNA, regulatory proteins or histones (proteins that package and order DNA) in the nucleus of brain cells. Many stress-induced changes are adaptive, but some appear to be harmful.
In my laboratory, we have stressed them by repeatedly exposing rats to more aggressive rats (see ‘A switch to resilience’). After ten days of this treatment, stressed rats begin to avoid other rats, show less interest in things that normally excite them (such as sweets and sex), become less adventurous and even obese. (they enjoy eating less but eat more)
Many of these symptoms can persist for months and are treatable with standard antidepressant medications. We have also found that cocaine-given mice a week before invasive mouse exposure have more extensive epigenetic modifications, inducing more stress-related symptoms.
Of the hundreds of rats studied in my lab, about a third become less adventurous when stressed but have no other symptoms. Given the differences in gene expression and structural organization of the DNA between these ‘resilient’ mice and the more sensitive mice, we have linked specific behavioral responses to specific molecular changes – all regions of the brain important in reward recognition 3,4 , 5,6.
These changes include differences in DNA methylation, patterns of attachment of acetyl or methyl groups to histones, and the activity of various transcription factors. They last for days or, in some cases, several weeks.
We can make susceptible mice resilient by blocking or inducing epigenetic modifications in certain genes, or by changing the expression patterns of those genes to mimic epigenetic tweaks. Similarly, epigenetic modifications and gene expression can be altered in resilient mice to make them more sensitive.
Other groups have found similar epigenetic changes that last throughout life. For example, rat pups that are rarely nursed and groomed by their mothers are more vulnerable to stress later in life, compared to pups with more diligent care.
They are less courageous than better cared for offspring and fight less in unpleasant situations (such as being placed in a beaker of water). In addition, females are less nurturing towards their offspring. Epigenetic modifications occur in several genes in the hippocampus in response to how young mice are groomed, and these changes persist into adulthood.
These findings are likely to hold in humans. For example, researchers have found that genes identified in rat-grooming studies were more methylated in the hippocampi of suicide victims who had experienced trauma as children than in those who died of suicide or natural causes and whose Childhood was normal.
Similarly, our findings in rats let cocaine mirror epidemiological studies from the past few decades that have linked drug abuse, obesity and conditions such as multiple sclerosis, diabetes and heart disease to increased stress susceptibility in humans.
More controversial is whether animals inherit epigenetic vulnerability to stress. According to this notion, epigenetic modifications in sperm or eggs drive abnormal patterns of gene expression in the next generation.
Several groups have reported that male rats exposed to stress – removed from their mothers as pups or exposed to more aggressive rats as adults, for example – produce offspring that Are more sensitive to stress.