Saturday, May 7, 2011

What We Do Can Change the Brain - Trauma, Genes, and Epigenetics

Back in 2003, Avshalom Caspi published a paper in Science that rocked everyone's world (at least in psychiatry): Influence of Life Stress on Depression: Moderation by a Polymorphism in the 5-HTT Gene.

I know that doesn't sound all that exciting, but everyone who is anyone will pull a graph from this 4-page seminal Caspi work and ooh and aww over it. In fact, as of this week, the article has been cited by 2022 other articles. This paper links nature and nurture and depression in one elegant demonstration - so without further ado…

Caspi used subjects from a lifelong observational study, the white New Zealanders known as the Dunedin Multidisciplinary Health and Development Study. This cohort of 1037 children was studied at ages 3,5,7,9,11,13,15, 18, and 21, and 96% of the subjects could still be found at the age of 26. This careful observation meant that Caspi could not only rely on the lifelong memories of the subjects about history of trauma and medical/depressive issues (which can be to some extent unreliable), but also what was studied at all the data points in the subject's lives.

847 members of the cohort were divided into three groups based on 5-HTTLPR genotype - l/l, s/s, and s/l. No need to scratch your head - let me explain!

Basically, we are talking serotonin here. Serotonin is an important neurotransmitter in regulating our emotional state. Like any neurotransmitter, serotonin is made by one neuron, which then spits it out into the synapse in between neurons. Then the serotonin floats over to the second neuron and activates the receptors over there. On the first neuron, there is a serotonin reuptake transporter that sucks serotonin back into the first neuron to be recycled and used again. See the picture below:

Image Credit

So peer at that reuptake transporter (yellow) and have a look. All of us have genes that code for the making of that transporter. And this gene happens to have a special promoter (called the 5HTTLPR) that directs how much serotonin reuptake transporter we make. People (and rhesus monkeys, as it happens) that have two LONG (l/l) copies of the promoter have higher levels of serotonin in the spinal fluid. People (and monkeys) with two SHORT (s/s) copies of the promoter have lower levels of serotonin in the spinal fluid. People with a short and a long (s/l) are, predictably, intermediate. Got it? Serotonin-speaking, s/s is the short end of the stick, s/l is in the middle, and l/l is protective.

Back to New Zealand, where it was found that 17% of the young adults in the Dunedin cohort were s/s, 51% were s/l, and 31% were l/l. Caspi and his crew collected information about previous depressive episodes, suicide attempts, previous traumatic events (employment, financial, housing, health, and relationship stressors), and current psychological state. It turns out that when you look at current or previous depression or suicide attempts, the link between the type of promoter you have and those findings are non-significant. Uh oh. That sounds like a big bust! The type of serotonin transporter gene promoter you have doesn't seem to matter…

Then Caspi's team ran the numbers backwards and forwards, plugged in number of stressful life events and generated this remarkable finding:


As you can see, if you've had no stressful life events, your likelihood of having a depressive episode is around 10%. If you have the protective l/l version of the promoter, even if you have 4+ major stressful events, your chance of having a depressive episode only climbs a little. But if you have the s/s "short end of the stick" promoter, add stress and your risk of developing depression climbs very quickly. When you plug in severe childhood maltreatment as a variable, the s/s folks have a 63% chance of having a major depressive episode by age 26. The l/l severely maltreated children had a 30% risk of having a major depressive episode by age 26. The s/s folks with 4 or more stressful life events accounted for only 10% of the cohort, but 23% of the cases of diagnosed depression in the cohort.

So what we have found here is that this particular genetic lottery can tell us to some extent which of us are more resilient to stress, and which of us are less so, at least with respect to depressive episodes and suicide attempts (plotting suicide attempts against number of stressful life events generates a similar graph). These percentages (roughly 20% s/s, 50% s/l, and 30% l/l) are pretty much the same as those in Europe and America. The yearly incidence of Major Depressive Disorder is right around 20% too, by the way.

We've learned also that trauma changes our brain. Years later, if we have endured trauma, we are more vulnerable to having a major depressive episode and to make suicide attempts, modulated in part by how many serotonin reuptake transporters we have.

How does trauma change the brain? Our genes are pretty much set in stone from the moment 23 chromosomes from Mama meet 23 from Dada (except for random mutations). However, gene expression can change throughout life (and over generations). How does that happen? Well, that's (in part) what we mean by the word epigenetics.

A lot of our DNA spends its life wrapped up like candy. Proteins called histones wrap around the DNA and prevent it from being transcribed into RNA (RNA is the stuff that is eventually translated into proteins). Histone wrapping is entirely necessary - after all, all of our cells (except sperm and eggs) have the same DNA, and yet it is patently obvious that a skin cell is quite different from an eyeball cell which is different than a neuron. So in some cells, certain DNA is expressed, but not in other cells.

Histones that are highly methylated hang on tight to the DNA and keep it from being transcribed. Once you demethylate the histones, the DNA is set free to be expressed. A practical example - certain species of rodents called voles have species that have very attentive mothers, and less attentive mothers. The baby voles raised by the less attentive mothers seem to be more vulnerable to stress later in life. But put a less attentive species vole with a high attentive species mother, and the baby vole grows up resilient to stress. Decreased methylation of the attentive (oxytocin) gene results in a genetically inattentive vole becoming more like an attentive vole.

Y'all remember Lamarck, right? He's the guy who postulated that giraffe's necks got all long because they stretched them to reach the high leaves, and the stretchiness-length was passed on to baby giraffes. Well, it turns out that in some respect, Lamarck had it right - what we do, what we eat, what we experience, how we cope - all of these things can affect the expression of our DNA. So Lamarck gets the last laugh - to some extent. You want to change those brown eyes blue - don't wait for Lamarck - get some contacts. And don't expect the kids to inherit the faux color.

And so at last we come around to Evolutionary Psychiatry. Our gene expression has been modulated by selection pressure for thousands and thousands of human generations. Live and eat and sleep more like a hunter-gatherer, and it seems to me you are more likely to deactivate the histones for the genes for survival, strength, resilience, and happiness. When you are the most resilient you can be, presumably you raise little resilient humans to take your place.

And some things we cannot change. If I'm a l/l, theoretically I can deal with more stress than an s/s without being depressed - but of course, many of the s/s cohort had no depressive episodes, despite having 4 or more stressful life events. But why has s/s been maintained in the population despite serving up a higher risk of suicide and depression in combination with stress? Well, the most likely explanation is that the short allele of the serotonin reuptake transporter promoter gives us some sort of resistance to disease (1). But who knows. In the mean time, I'll try to limit my stress and eat more like a hunter-gatherer.

23 comments:

  1. I was hoping you would get into more details! (do you plan to, in a future post?)

    I found this paper rather interesting:
    "Impact of diet on adult hippocampal neurogenesis."
    http://www.ncbi.nlm.nih.gov/pubmed/19685256


    And I also think this paper could be quite interesting, but alas, my university isn't subscribed to Psychoneuroendocrinology..
    "The double edged sword of neural plasticity: increasing serotonin levels leads to both greater vulnerability to depression and improved capacity to recover."
    http://www.ncbi.nlm.nih.gov/pubmed/20875703

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  2. OK, I'm totally juvenile, but am I the only one who snickered at that autoreceptor?

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  3. Awesome, Dr. Deans. You can see from that graph that if you looked at population that was homogeneous for very low stress you'd see not only no significance, but no difference at all, and if you looked at a population homogeneous for high-stress, you'd conclude that the allele variation was determinative and explained a much larger amount of variation than it really does, when all possible contexts are allowed for. One could imagine there are many other interacting factors, including nutritional ones, that haven't been identified. And in some cases, a population might be fairly homogeneous for those nutritional (or other) factors. So I think to quantify the proportion of effect explained by an allele is a very inexact science, subject to potentially extraordinary revision, and shouldn't be given a lot of weight (I don't mean the qualitative finding that the allele plays a role; just the quantitative finding of how important the role is relative to other factors). Great example of nature/nurture interaction!

    Chris

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  4. "A practical example - certain species of rodents called voles have species that have very attentive mothers, and less attentive mothers. The baby voles raised by the less attentive mothers seem to be more vulnerable to stress later in life. But put a less attentive species vole with a high attentive species mother, and the baby vole grows up resilient to stress. Decreased methylation of the attentive (oxytocin) gene results in a genetically inattentive vole becoming more like an attentive vole."

    I don't know much about epigenetics. But is this an example of it? How do we know that these closely related vole species aren't simply responding in a similar way to a more attentive mother? Essentially being more "well-adjusted" with a more nurturing mom regardless of species?

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  5. "But why has s/s been maintained in the population despite serving up a higher risk of suicide and depression in combination with stress?"

    Because even if you get that depression and commit that suicide, it doesn't usually happen before you reach reproductive age?

    That's what weeds someone out of the gene pool, after all. They have to die before they reach reproductive age. Once you've hit reproductive age and had the baby, your genes have been passed on and it doesn't matter how much their expression makes your life suck otherwise.

    My simple answer to anyone who goes "of what possible use is this genetic trait?" is pretty much that: "It hasn't killed you young enough."

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  6. Rudolph - thanks for the links! More details are good but I thought this one was heavy enough on its own...

    Thanks Chris!

    Prague - some of that info is from a lecture, the voles definitely experienced demethlyation of the histones on the oxytocin gene and I seem to recall they had higher licking behavior with their young, making the change epigenetic.

    Dana - this cohort was measured at 26, still well in reproductive age, and there were certainly previous suicide attempts in the cohort. Also, being a depressed (or suicided) parent would seemingly be disadvantageous for the offspring for many years - thus it seems there must be another plus to the s allele for it to remain so prevalent.

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  7. I was thinking, perhaps s/s people are not less stress resiliant, perhaps they merely express the effects of stress differently than a l/l. I would assume a low serotonin person would be more impulsive, more likely to express emotion, more likely to engage in attentional seeking behaviors like suicide attempts or behave aggressively. It might not necessarily be that s/s people are "more depressed", but perhaps they are more likely to take up psychiatric resources and be labeled depressed due to dramatic behavior like suicide attempts or going to an ER complaining of suicidal thinking.

    Speaking personally I have had some brutal lows, and I never spoke about them, never postured suicide, never cut my wrists, never called a suicide hotline crying. I had these thoughts in my head, and I have wished to die, thought of jumping off a bridge many times, of gassing myself in a car, of shooting myself in the head, and I have cried alone, and I have dropped out of life a few times from depression... but the only time I saw a psychiatrist was at 23 and that was because I thought I was becoming schizophrenic like my grandparents (this lead to me being diagnosed bipolar).

    But then I know other people with depression who tell everyone they know that they are depressed, and have no inhibitions what so ever. They take every opportunity to burden others with their internal struggles.

    The difference, as far as I can see, is that by personality I am extremely inhibited and reserved and this carries over to my depressions as well. A less reserved, more impulsive person would have reacted very differently perhaps to the same internal states and mood episodes. I try to carry on at all costs and maintain a stable life and my personality is hyper inhibited and lacking in aggression or expression.


    The problem, as I see it, is that l/l types might not have less depression, but because they are naturally serotonin replete, they are less likely to behave in hysterical ways, aggressive or impulsive ways, and so they fall under the psychiatric radar.

    My psych file was clean until 25, but I have been crazy since late childhood.

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  8. Good post.

    Too bad there is a bad effect reported for caffeine in the article posted by Rudolf
    "Impact of diet on adult hippocampal neurogenesis."
    http://www.ncbi.nlm.nih.gov/pubmed/19685256

    Please allow "name" option for coments. Thanks

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  9. Emily, thanks, it makes more sense to me that the results were chemically measured. BTW, I really liked your concise description of the mechanism of epigenetics and gene expression.

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  10. An interesting fact about serotonin is that the bulk of it in the human body is produced in the gut, not the brain. So, I have a “gut feeling” that the intestinal microbiome may play a very large role in one’s emotional state. See “The Second Brain” by Michael Gershon, M.D. for details.

    On the subject of our ancestry and its relation to our current emotional state, I have written a few books touching on the subject, including “The Wellness Project,” and “Nature’s Detox Plan.” They are devoted to nature-based primary illness prevention, including an early Paleo eating plan that is quite unique, as well as physical and emotional detox protocols.

    Regarding emotional detoxification, there is a fascinating and very controversial body of work in the field of psychotherapy known as Family Constellations, pioneered by Bert Hellinger. It is based in part on the concept of certain orders of love that have been found to exist in healthy family systems. For info in this area, see “The Healing of Individuals, Families & Nations” by John Payne, and “The Healing Power of the Past” by Bertold Ulsamer.

    In a nutshell, the hypothesis is that many of us carry the consciousness of our ancestors, and it can act out in a variety of positive and negative behaviors. In some cases we carry on the unresolved burdens of one of our ancestors, and in essence relive their lives to our detriment.
    In constellation work, you interact with your ancestry in a form of roleplaying, and significant healing can take place in as little as 45 minutes.

    There have been some anecdotal reports, supported by test data, of patients who have heavy metal toxicity and are not responsive to detox agents until they have undergone “emotional detoxification.” The release of emotional toxins apparently leads the way to the release of physical toxins in some people.

    Anne Schutzenberger further discusses this phenomena in her incredible book "The Ancestor Syndrome." Example: generation after generation, the same event may befall members of a family on a time schedule that is predictable.

    Roy Mankovitz, Director
    http://www.MontecitoWellness.com
    A research organization

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  11. Fascinating, how do I go about finding out which type of promoters I have?

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  12. Dr. Deans, thanks for another fascinating post.

    The basic of guideline of limiting stress and eating more like a hunter-gatherer is great. Simple, succinct. I like that.

    It's been interesting doing reading about the hunter-gatherer diets in my own heritage.

    Am enjoying this series and looking forward to the next posts.

    Thank you very much.

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  13. many of the answers are buried in the sleep literature. This is an area I will explore in my writings. Its where metabolism, sleep, and neurochemistry all collide. Timing is critical. And epigenetic modification appears to be very very important.

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  14. Doc K - yes, all the same areas of the brain, all the same neurotransmitters. Be sure to let us know when you start up your blog.

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  15. Of course, as soon as you said that Rhesus Monkeys have the same polymorphisms I started wondering about the poor sad monkeys... It would be interesting if those that were least depressed despite the high O6 diet had the l/l phenotype. I keep wondering how higher O6:O3 ratios in membranes affect membrane fluidity and therefore transmembrane receptor activation and signal transduction... Fun to think about!

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  16. And, of course, as soon as I posted my last comment I remembered that the sad monkeys were cynomolgus monkeys! Whoops!

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  17. Here is Peter Kramer´s post on the sudiesthet found no evidence that the serotonin transporter genotype alone or in interaction with stressful life events is associated with an elevated risk of depression.

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  18. Interesting study, but I wish some of these studies could be performed on a good sized sampling of hunter-gathers. I always wonder how relevant psychiatry is on humans that don't eat modern foods.

    Emily, do you know of any such studies? Is there a chance that maybe paleo diet followers might at some point be researched?

    I must be one of the s/s people and I've had several severe traumas in my early life. I was suicidal and depressed most of my life. (I didn't ever try to commit suicide before reproductive age, Dana. Brilliant point!)

    A while after changing my lifestyle and diet to some version of a hunter-gatherer's diet, all of that just disappeared. I became one of the happiest most resilient people I know. And it's been this way for many years. Thinking of the way I used to be is like thinking of a fictional character. The painful experiences don't even hurt. It's that removed from reality.

    So what is all this science then, I ask?

    http://theprimalparent.com

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  19. Gibberish name: this link should be of interest to you about a larger meta-analysis in the Archives that found issues with the JAMA meta-analysis and confirmed the Caspi work: http://pn.psychiatryonline.org/content/46/3/17.1.full

    Peggy: i don't think it has been done. It would be interesting.

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  20. Sorry, I repeat because the link was missing, I have problems to post using the identification. If you can, please allow using name/url. Thanks.

    Here is Peter Kramer´s post on the sudiesthet found no evidence that the serotonin transporter genotype alone or in interaction with stressful life events is associated with an elevated risk of depression.
    http://www.psychologytoday.com/blog/in-practice/200910/due-comeback

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  21. I second that! If possible, please use name/url. I attempted to post my comment three times and had to restart my browser to finally get that comment to post!

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  22. I know it is easier to comment without moderation or without an account - but I find people are more polite this way and less likely to post an anonymous hit and run… so comments will remain the same! Thanks for understanding.

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  23. In the study Rudolf linked there is a reference to High-fat diet impairs hippocampal neurogenesis in male rats.
    http://www.ncbi.nlm.nih.gov/pubmed/17116226

    Anyone know what type of fat was used? Is this a warning for paleo diets?

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