Announcer: From the Eunice Kennedy Shriver National Institute of Child Health and Human Development, part of the National Institutes of Health, welcome to another installment of NICHD Research Perspectives. Your host is the Director of the NICHD, Dr. Alan Guttmacher.
Dr. Alan Guttmacher: Hello, I’m Alan Guttmacher. Thanks for joining us for another in our monthly series of podcasts from the Eunice Kennedy Shriver National Institute of Child Health and Human Development at the National Institutes of Health.
Our guests today are Dr. Stephen Suomi and research fellows Dr. Amanda Dettmer-Erard and Dr. Annika Paukner. We are talking with them today about their work in NICHD’s Laboratory of Comparative Ethology. Much of their research takes place at the NIH Animal Center located on a 509-acre expanse of farmland in rural Montgomery County, about 30 miles from the main NIH campus in Bethesda, Maryland. The Center houses sheep, pigs, and other species, which serve as animal models for numerous research studies seeking information to improve human health.
Ethology is the study of human and animal behaviors. Ethologists tend to study animals in their natural settings. An important component of the lab is an open-air enclosure that houses a free-ranging troop of rhesus macaques. The enclosure encompasses 5 acres and includes a pond.
Rhesus monkeys share about 95 percent of human DNA. They also resemble humans in their ability to thrive in most climates, their tendency to live in social groups, and their mother-infant interactions. The developmental life cycle of rhesus monkeys is four times faster than that of human beings, making them a unique and effective model for studying development across the life span.
A point of pride for NIH is the high level of care that all the animals in this facility receive. Our veterinarian, Dr. Ruth Woodward, and the animal care staff adhere to rigid standards for housing, handling, diet, and sanitation. All of the animals receive regular veterinary care, and staff members care for them 365 days a year. The veterinary staff works hard to keep the animals healthy—helping ensure that our scientists get sound results from their studies. The staff also provides what’s referred to as “environmental enrichment.” Animals under managed care need stimuli that mimic interactions in their natural environments, to keep them healthy and prevent them from getting bored. This is especially true with monkeys. So, for example, facility staff might hide sunflower seeds in the animals’ bedding, which results in their actively searching for food—simulating their activity in the wild.
The Laboratory of Comparative Ethology focuses on the role of genetic and environmental factors in shaping individual psychological development in the rhesus monkeys as well as in a few other nonhuman primate species at the facility. Applying what we learn from animal behavior to human health is always a little tricky, of course. Animals, after all, aren’t people, and we can’t necessarily generalize what they do to how people conduct themselves. But animals can provide important clues that open up new areas of study and, in the case of the Laboratory of Comparative Ethology, important new insights into human development.
One such area is interaction between a gene for serotonin metabolism, behavior, and the early life environment. Serotonin is a neurotransmitter, a compound brain cells use to communicate. It appears to be involved in regulating mood, appetite, and sleep as well as learning and memory. Serotonin is also a target of a class of medications used to treat depression in humans.
Our first guest is Dr. Stephen Suomi, the lab’s chief. Steve, can you tell us a little about your findings regarding serotonin metabolism as well as studies by other groups involving serotonin metabolism in human beings?
Dr. Stephen Suomi: Sure, my pleasure. By way of background, a major emphasis in our work out at Poolesville, the animal center, is a study of individual differences in personality or temperament in our monkeys and the biological substrates that underlie these individual differences and in particular how genetic and environmental factors interact to shape individual personality and behavioral development.
We have been especially interested in two subgroups of monkeys, one subgroup-- maybe 20 percent of the populations-- seem to be unusually fearful or anxious in new situations. This is about the same percentage of fearful monkeys that you will find in wild populations. There’s another 5 to 10 percent of the population who seem to be unusually impulsive and aggressive. We know that there are biological substrates that go along with these characteristics when we study monkeys in naturalistic habitats; so for example, the fearful monkeys tend to show excessive hypothalamic-pituitary-adrenal axis activity that we see in terms of the stress, high levels of the stress hormone cortisol, whereas aggressive-impulsive monkeys tend to have low levels of serotonin metabolism.
We’ve been able, with the help of colleagues in other parts of the NIH, to characterize these monkeys genetically with respect to a number of genes; the one that has gotten the most attention is a gene called the serotonin transporter gene. Rhesus monkeys and humans have the same gene, and in both rhesus monkeys and humans there are two different forms of this gene. There is what is called the long allele and the short allele. And psychiatrists have tried to associate individuals carrying the short allele with certain types of aggression and depression. We find that when our monkeys grow up with very good early social experiences, they don’t develop these patterns of behavior even if they carry the short allele. But if they have adverse early experiences, we find that those monkeys tend to get excessively aggressive and also paradoxically prone to depression as well.
There are human studies—pioneering human studies—that have reported the same thing. Caspi and Moffitt in their research group studying a human population in Dunedin, New Zealand, reported essentially the same finding—that individuals who carry the short version of this gene had higher levels of depression in their mid-twenties, but only if they also either had high levels of concurrent stress or had a history of child maltreatment. Absent any of those environmental situations, carrying the short version of the gene conferred no greater risk for developing depression than carrying the long version of this gene. And we’ve seen a similar pattern now with several other candidate genes, maybe up to 9 or 10 now.
And it’s an interesting situation in that when you have polymorphisms, you can characterize one of the alleles as more efficient in terms of transcribing less, transcribing RNA from DNA, and the other more efficient in the case of serotonin transporter gene, the short allele is the less efficient gene. And what found now repeatedly, for eight or nine different type of genes, is that if you have the less efficient version of the gene and it goes-- it’s in a person or in a monkey-- that’s had somewhat adversely early experiences, you’ll get deficits in behavior and biology, but if you take that very same less efficient allele and pair it with a monkey who has very supportive early social experiences, that individual will come out as good or better than normal than individuals who carry the more efficient version of this gene.
So whereas until recently psychiatrists have characterized these genes or these alleles as being risk alleles, to us they seem to be more like sensitivity alleles in that they seem for whatever reason to have individuals who carry these so called sensitivity alleles to be more sensitive to whatever is out there in their environment. If it’s an adverse environment, they’re going to pick up the worst of it; if it’s a supportive environment, they’re going to pick out the best of it. And this means that these so-called risk alleles do not always have bad outcomes and that there are ways of protecting or supporting individuals who carry them.
And one major focus of our upcoming work is what we call intervention studies, or resilience studies, to see if it’s possible to take individuals who are genetically and environmentally at risk and get them back on normal developmental trajectories.
Dr. Guttmacher: Thanks. Those studies demonstrate an interesting relationship between genetic factors and environmental factors. It also demonstrates I guess an interesting relationship as we have said between studying animals and studying humans. Your own work in monkeys—and then the really parallel and tied-in work of Caspi and Moffitt in humans—really does demonstrate, I think, the benefit of studying behaviors in certain animals and then being able to apply that to the human condition. I know you’ve also been involved in other studies that show how early life environment can influence how genes are expressed. And I believe those studies have demonstrated a lasting effect from early life influences. Can you tell us more about that work?
Dr. Suomi: Yes, we’ve been able to study monkeys who grow up under different circumstances, different early social experiences is the primary thing that we, where we looked at differences, and we found that differences in early experience, early social experience, especially with attachment figures like mothers, can have their effects not only at the level of behavioral output and emotional regulation, but also at the level of neuroendocrine function, at the level of neurotransmitter metabolism, at the level of brain structure and function, that we can tell by doing neuroimaging studies of differentially reared monkeys, and most recently in terms of patterns of gene expression.
And we recently published a paper that suggests that a full 20 percent of the rhesus monkey genome, which is about the same size in number of genes as the human genome, approximately 20 percent of that genome, is differentially expressed as a function of what goes on during that first 6 months of life in the monkeys, which would be roughly equivalent to the first 2 years of life in humans. So this means that these early experiences can have lasting effects.
What we are now interested in doing, as I mentioned before, is to see how reversible these patterns are. Are there interventions that we can do either early in life or later in life—around puberty, for example, or in adulthood—that can reverse the effects of these early experiences? And if these reversals are possible, at what level do they occur? Are we just reversing behavior? Are we normalizing neuroendocrine function? Are we changing the way the brain is wired and how it functions? And are we turning some of those genes that were turned off by early experience, are we able to turn them back on? And this is the work that I’m very excited about. It’s going to keep us pretty busy for the next few years.
Dr. Guttmacher: It certainly will and it’s fascinating work and it certainly ties in with a lot of work now, which is emphasizing in humans the importance of what some people refer to as the first thousand days, that is, the period of pregnancy and the first 2 years of life is really important in terms of both health and human development, behavioral development, etc. really being, and having, long-lasting, if not lifelong, influence, so it’s certainly an area that will keep you busy and a lot of folks busy in trying to figure out in coming years.
Dr. Suomi: And if I can just add, we are now in collaboration with not only our superb veterinarian but also some individuals working in other institutions who have made, put a premium on the importance of early experience, most notably the Nobel prize-winning economist James Heckman. And we are working with Heckman and with Ruth to see if some of these early experience effects also apply to health outcomes beyond anything psychological or beyond the traditional biological sorts of measures. So quality of life, and health outcomes throughout development are now a new focus of interest in our efforts.
Dr. Guttmacher: It’s also, I must say, a wonderful example of folks in our intramural programs such as your laboratory working with folks who are part of the NIH and NICHD’s extramural community of researchers. NICHD has long been a financial supporter of Dr. Heckman and his work for which he has won the Nobel Prize, and the idea of our intramural scientists working so closely with our extramural scientists is certainly a wonderful use of NIH resources to further our understanding of humanity and do some interesting things, I think.
Dr. Suomi: The work is not only interesting, but at least for me, it’s a lot of fun.
Dr. Guttmacher: Thanks, Dr. Suomi. That’s a good note, I think, to turn to our next guest who’s Dr. Amanda Dettmer-Erard, a postdoctoral fellow who recently joined the lab. She’s involved with several studies to assess long-term, or chronic, stress by measuring the level of the hormone cortisol in hair. Research has suggested that cortisol concentrations found in the hair may be a measure of an individual’s response to stress. Amanda, can you please tell us what you’ve learned so far and how hair cortisol concentrations might be used to study the stress response system?
Dr. Amanda Dettmer-Erard: Absolutely. As we know, cortisol is considered the stress hormone, and we’ve known for a long time that elevated levels of cortisol are detrimental to psychological and physical outcomes for the individual. But typically methods for assessing cortisol have relied on samples of blood or urine. These are very valuable for assessing an individual’s immediate response to a stressor; however, they only provide a snapshot into an individual’s physiology, meaning that they really only reflect what happened inside the individual within about the last 15 minutes. So they are very valuable for measuring an immediate response to stress, but one limitation is that in order to get longitudinal data, you’re required to get repeated samples, which especially in the case of laboratory housed animals, can be a problem.
Another issue is that these types of samples of blood and saliva and other short-term measures are really vulnerable to numerous confounds. One of these is the time of day that they’re measured, also environmental confounds, even something as simple as how recently an animal or person has had a meal. So about 6 years ago, collaborators of ours at University of Massachusetts—Drs. Melinda Novak and Jerry Meyer, and in particular, their graduate student Dr. Matt Davenport—developed an assay to measure cortisol in hair. And they developed and validated this in rhesus monkeys and showed that hair cortisol was really a way to measure the body’s kind of overall aggregate stress response over a period of many months versus minutes and in addition to measuring kind of chronic stress levels, it’s very minimally invasive and is not really subject to the confounds that I mentioned earlier.
And so since this assay has been developed, it’s really taken off in the literature in both animals and humans. And it’s been shown in humans and animals, notably monkeys, to be a predictor or biomarker of numerous health outcomes. And so in our laboratory at the LCE, we’ve mostly focused on how hair cortisol is a biomarker in infant monkeys for future development. And so one thing that we found is in our nursery-reared monkeys, where we were able to do very intensive cognitive testing is that earlier infant levels of hair cortisol predicted cognitive development. So high levels of hair cortisol meant that the individual monkeys showed poor performance on cognitive tasks. But more interesting to us and in relation to what Steve was talking about as far as developmental outcome in regards to early life experiences, we found that hair cortisol measured in infancy, before infants underwent a major life stressor, predicted the level of anxious behavior they had in response to that stressor. And this was particularly true for those infant monkeys who were at risk and those who underwent suboptimal early life experiences.
Dr. Guttmacher: That’s fascinating and again ties in with a lot of work that we’re seeing-- certainly humans as well showing that stress is such an important factor in terms of health and may indeed be one of the root causes of the health disparities that we see in various populations. So that’s fascinating work. I know you’re also managing the large rhesus enclosure at the NIH Animal Center. Can you tell us more about your work there?
Dr. Dettmer-Erard: Sure. As you mentioned earlier on, one of the highlights of the animal Center is our outdoor 5-acre field enclosure and this is about as close to paradise as monkeys can get if they are not going to be in the wild, I think. It’s a 5-acre field enclosure, and we currently have 80 monkeys, which includes infants from this year, about 15 to 20 infants, and they live in semi-free ranging habitat—“semi-free ranging” meaning they are enclosed, but it’s 5 acres so they have a lot of space. There’s a pond in the middle with an island in the middle of pond. Just this weekend, I was in getting data, and there was a pool party going on. The monkeys were swimming, jumping around, back and forth, to and from the island, and so it’s really a great opportunity because we can take and what we hope to do in the next few years is look at what are we observing in the laboratory setting, so monkeys who are reared in different conditions in the nursery or monkeys, some of which are able to show this neonatal imitative response, which Annika will speak to in a moment, and then we can go down the hill and study it in our naturalistic population and see do these phenomena also occur in a quite naturalistic population of monkeys.