Monday, November 9, 2009

Epigenetics of stress

Last week in journal club I presented "Prenatal exposure to maternal depression, neonatal methylation of human glucocorticoid receptor gene (NR3C1) and infant cortisol stress responses," by Oberlander et al., published in Epigenetics in 2008. This paper tries to get at one small part of the mechanism for how the in utero experience can affect a fetus, possibly even affecting the baby's personality.

Oberlander's study builds on earlier work done in rats. Researchers found that the offspring of particular rat dams were less fearful than average. Specifically, these rat moms were spending extra time licking and grooming their babies, and performing "arched-back nursing." They were dubbed "LG-ABN" dams (licking grooming, arched-back nursing.) Their babies acted less fearful in stressful situations, and had a blunted stress response on the HPA axis.

The HPA axis... This is in large part what I'm studying for my Masters project, so it's hard to limit myself to a short explanation of what it is. In short, one way in which one's brain (or part of it: the hypothalamus, the H in HPA) responds to stress is to send a message to the pituitary (P), which in turns sends a message to the adrenals (A). The adrenals release cortisol, which is known as the stress hormone. Cortisol is what researchers look for in your blood if they want to quantify how stressed you are. Stress out two animals, check their cortisol levels, conclude that the one with higher levels reacted more strongly to the stimulus — that's the formula for any number of experiments, including this one. (It is, as always with physiology, more complicated than that, but the idea that there's a correlation between increased cortisol levels and increased stress is a good start.)

So these babies of LG-ABN moms had a smaller cortisol spike in response to stress. Further work elucidated part of why that happened: the receptors to which cortisol binds in the brain send a message back to the top of the HPA to tell it to stop releasing cortisol ("that's enough, there's plenty out here!") in a negative feedback loop. These receptors (glucocorticoid receptors, abbreviated "GR") were in excessive supply in the brains of these less fearful rats, so the negative feedback loop worked well, and the rats' brains responded to rising cortisol levels by releasing less cortisol — with the result that the spike of cortisol was smaller in response to a stressful stimulus.

Meanwhile, the researchers also found that this trait of decreased fearfulness was not genetic in the normal sense. If they fostered baby rats from non-LG-ABN dams on LG-ABN dams, these babies who were not genetically related to the LG-ABN mom grew up to be less fearful, presumably simply by being raised by her. And they passed the trait on to their offspring! It turned out that the trait was being passed along epigenetically. We all learned in elementary school about genetic traits — getting brown eyes because you got brown eye genes from mom and dad. And we all know that genes are coded on DNA. Epigenetic changes involve not different genes, but changes to the higher-level structure of the DNA. Instead of involving changing the building blocks of the DNA (the genes), epigenetics involve changing the shape of the building, or sometimes tacking something new on to the outside of it.

In this case, it turned out that in order for GR to be produced (remember that receptor for cortisol, necessary for negative feedback?), the machinery for reading genes had to have free access to the GR gene itself. However, an area of that gene had become methylated — in other words, another object was sitting on it, blocking access. The machinery for reading genes couldn't read that gene as well, so fewer GRs were made. Fewer GRs meant less negative feedback and a more easily stressed baby rat.

That's all background. Oberlander, who wrote the paper I presented, wondered whether the same mechanism applied to humans. He knew that human mothers who are depressed during pregnancy often give birth to babies with more reactive HPA axes. Could that be because those babies had fewer GRs, as a result of methylation of the GR gene? He also wondered about the effects of SRI medication, such as Prozac, on this system.

82 pregnant women were enrolled in this study. 33 were taking SRI medication. All were tested using a scale for depression, which resulted in a numeric score; higher scores implied greater depression. Blood was drawn from the moms in their second and third trimesters, and when they gave birth. Blood was taken from the babies' umbilical cords at birth. Then the babies were tested at three months of age for their response to a mild stressor.

The researchers found that the babies of depressed moms did tend to have increased methylation of the GR gene, exactly in the spot that they expected. That increased methylation correlated with an increased cortisol spike when the babies were mildly stressed. SRI exposure in utero didn't have any effect on the size of the spike, although babies whose moms were medicated did tend to have lower cortisol levels in general.

This paper spoke to me on two levels. I enjoy reading about mechanisms; I like imagining how all these little machines in our bodies interact to form our personality and affect how we experience the world. I also liked the study's methods, because I'm interested in finding ways of learning about living individuals. I want to study dogs, so I want to find ways of looking into their brains figuratively, not literally. Examining changes in DNA extracted from a blood draw is cool — it's something I could potentially do to someone's pet, perhaps as part of a study aimed at understanding why some dogs are more easily stressed to the point of biting than are others.

I think that the people who attended journal club found the paper interesting. Two professors who were in attendance work in this area of genetics and behavior, and had useful input for me. One pointed out that the list of variables that the paper's authors checked for in the pregnant women was very small. (It consisted of things like age, whether this was a first pregnancy, whether the pregnancy ended in C-section, whether the woman smoked or drank.) She listed some other things she would have checked for, such as body weight (fat can apparently produce cortisol). She also noted that the baby's blood sample came from umbilical cord blood, which is actually a mix of infant and maternal blood. Also, different parenting strategies weren't taken into account — did depressed mothers treat their babies differently in some way? She concluded that we'd all like to be able to see useful DNA changes just by taking blood samples (which is precisely one of the things that drew me to this paper), but it's actually very hard to do so, so this paper's results should be taken very cautiously.

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