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Genetic and Environmental Determinants of Primate Biobehavioral Development
- Stephen J. Suomi, PhD, Head, Comparative Behavior Genetics Section
- Craig Abbott, PhD, Statistician
- Kathlyn L. Robbins, PhD, Research Psychologist
- Annika Paukner, PhD, Senior Visiting Fellow
- Amanda M. Dettmer Erard, PhD, Postdoctoral Fellow
- Angela M. Ruggiero, BS, BioScience Laboratory Technician
- Kristen L. Byers, BS, Postbaccalaureate Fellow
- Grace K. Maloney, BS, Postbaccalaureate Fellow
- Neal M. Marquez, BS, Postbaccalaureate Fellow
- Ashley M. Murphy, BA, Postbaccalaureate Fellow
- Amanda J. Riddle, BS, Postbaccalaureate Fellow
- Lindsay P. Schwartz, BS, Postbaccalaureate Fellow
We investigate primate behavioral and biological development through comparative longitudinal studies of rhesus monkeys and other primates. Our primary goals are to characterize different distinctive bio-behavioral phenotypes in our rhesus monkey colony, to determine how genetic and environmental factors interact to shape the developmental trajectories of each phenotype, and to assess the long-term behavioral, biological, and epigenetic consequences for monkeys from various genetic backgrounds when they are reared in different physical and social environments. Another major program investigates how rhesus monkeys and other nonhuman primate species, born and raised under different laboratory conditions, adapt to placement in environments that contain specific physical and social features of their species’ natural habitat. Adaptation is assessed by examining behavioral repertories and by monitoring a variety of physiological systems in the subjects, yielding broad-based indices of relative physical and psychological well-being. The responses of subjects to experimental manipulation of selected features of their respective environments are also assessed in similar fashion. Whenever possible, we collect field data for appropriate comparisons. A major current focus is to investigate face-to-face interactions between mothers and infants during their initial days and weeks of life and to characterize the imitative capabilities of newborn infants and patterns of brain activity associated with imitative behavior. A second major focus is the study of cognitive and social behavioral development in capuchin monkeys (Cebus apella).
As in previous years, we conduct detailed longitudinal studies on the behavioral and biological consequences of differential early social rearing, most notably comparing rhesus monkey infants reared by their biological mothers, in pens containing adult males and other mothers with same-age infants for the first 6–7 months of their life (MR), with monkeys separated from their mothers at birth, hand-reared in the lab's neonatal nursery for their first month and then raised in small groups of same-age peers for their next 6 months (PR). In a third standard rearing environment, surrogate-peer rearing (SPR), infants are separated from their mothers and nursery-reared just as PR infants, but then at one month are housed in individual cages containing an inanimate surrogate "mother" and additionally are placed in a play cage with three other like-reared peers for two hours each weekday for the next 6 months. At 7–8 months of age, MR, PR, and SPR infants are all moved into one large pen, where they live together until puberty. Thus, the differential social rearing occurs only for the first 6–7 months; thereafter MR, PR, and SPR share the same physical and social environment. We previously demonstrated that PR monkeys cling more, play less, tend to be markedly more impulsive and aggressive, and exhibit much greater behavioral and biological disruption during and immediately following short-term social separation at 6 months of age than do MR monkeys, and they also exhibit deficits in serotonin metabolism (as indexed by chronically low values of CSF 5-HIAA, the main metabolite of serotonin, which reflects serotonin levels), as do SPR monkeys, and they have significantly lower levels of 5-HTT (serotonin transporter) binding throughout many brain regions than do MR subjects. Many of the differences between MR and PR monkeys persist throughout the childhood years in the absence of experimental interventions. More recently, we published data extending our studies on rearing condition differences to include patterns of brain lateralization, cortisol concentration in hair (a measure of chronic hypothalamic-pituitary axis [HPA] activity), and measures of brain structure and function as assessed by structural magnetic resonance imaging and positron emission tomography, respectively. Additional differences in measures of social dominance status, maternal competence, and physical health during adulthood were also documented. Somewhat surprisingly, however, MR and PR juveniles did not exhibit differential behavioral responses to chronic treatment with the serotonin reuptake inhibitor fluoxetine, and as adolescents their pattern of serotonin transporter distribution throughout their brains did not differ as a function of differential rearing but did reflect highly significant fluoxetine treatment effects.
Another major focus of recent research was to characterize interactions between differential early social rearing and polymorphisms in several candidate genes (G X E interactions), most notable the 5HTTLPR (serotonin transporter–linked polymorphic region) of the serotonin transporter gene (SLC6A4). During the past year, we expanded the range of outcomes for which G x E interactions involving the 5-HTTLPR polymorphism and early rearing condition differences appear, including social play and behavioral reactions to a variety of social stressors, and in epigenetic regulation of brain activity. We also recently reported significant G x E interactions between early MR vs. PR rearing and polymorphisms for several other candidate genes, including those encoding the dopamine transporter (DAT1), the dopamine receptor (DRD1), neuropeptide Y (NPY), the mu opioid receptor (OPRMI), brain-derived neurotrophic factor (BDNF), nitric oxide synthase (NOS1), and a single nucleotide polymorphism (SNP) in the glucocorticoid receptor gene (NR3C1). Outcome measures included play behavior, social buffering, behavioral and HPA reaction to an unfamiliar conspecific, naloxone treatment, alcohol consumption, and plasma BDNF concentrations. In virtually every case, we observed a similar pattern: the less efficiently transcribed allele was associated with a negative outcome among PR monkeys but a neutral or, in some cases, even an optimal outcome among MR subjects carrying the same less efficient allele, suggesting an overall buffering effect of maternal rearing for individuals carrying such so-called "risk" alleles.
We recently published the results of two sets of studies investigating the effects of differences in early social rearing (MR vs. SPR) on genome-wide patterns of mRNA expression in leukocytes and on methylation patterns in the prefrontal cortex and in T cell lymphocytes. In collaboration with Steven Cole and James Heckman, we examined mRNA expression patterns in differentially reared 4-month-old infants. In all, 521 different genes were significantly more expressed in MR infants than in SPR infants, whereas the reverse was the case for another 717 genes. In general, SPR–reared infants showed enhanced expression of genes involved in inflammation, T lymphocyte activation, and cell proliferation but suppression of antiviral and antibacterial responses, a pattern curiously also seen in leukocyte expression among adult humans who perceive themselves as being socially isolated. Since that initial study, we completed a prospective longitudinal study in which differentially reared monkeys were sampled at 14 days, 30 days, 6–7 months, and every 4 months thereafter until they reached puberty. Data analyzed to date revealed that the above rearing-condition differences in genome-wide patterns of mRNA expression in leukocytes are pervasive and persistent throughout development.
In collaboration with Moshe Szyf and his lab, we conducted genome-wide analyses of methylation patterns in differentially reared monkeys when they were adults. The initial study compared such patterns in prefrontal cortex (PFC) tissue and T cell lymphocytes obtained from 8-year-old monkeys differentially reared for their initial 6–7 weeks of life and thereafter maintained under identical conditions until adulthood. The analyses revealed (i) that more than 4,400 genes were differentially methylated in both PFC and lymphocytes; (ii) that, although there was considerable tissue specificity, approximately 25% of the affected genes were identical in both PFC and lymphocytes; and (iii) that, in both PFC and lymphocytes, methylated promoters tended to cluster both by chromosomal region and gene function. This past year, we finished the data collection for a prospective longitudinal study of genome-wide methylation patterns in lymphocytes, collecting samples from the same MR and SPR monkeys at the same time points as in the afore-mentioned longitudinal study of mRNA expression. Preliminary findings indicate that, at least for lymphocytes, extensive rearing-condition differences are present within the first month of life but at least in part can be significantly minimized and/or redirected subsequently following a social intervention.
Human mothers interact emotionally with their newborns through exaggerated facial expressions and mutual gaze, a capacity that has long been considered uniquely human. We previously initiated a research program on early face-to-face interactions in rhesus monkeys after we had serendipitously discovered that very young rhesus monkey infants engage in extensive face-to-face interactions with their mothers, but only during their first month or so of life. This past year, we further characterized face-to-face interactions between mothers and their newborn infants in a naturalistic setting. We found, similar to our previous results from mother-infant pairs housed in social pens, large individual dyad variability in the rates of mother-infant face-to-face interactions. Further analyses revealed that first-time mothers engaged in mutual gazing/lipsmacking with their infant during its first 30 days of life significantly more than mothers who had at least two previous infants. Conversely, the more experienced mothers let their infants out of their arms significantly more in the first 30 days of life than first-time mothers.
We also discovered that, during their first week, some (but not all) infants could accurately match certain facial gestures produced by a human experimenter, even after a delay. For those infants who could imitate in this fashion, the capability was evident on their first postnatal day, although their imitative behavior largely disappeared after the first week.
We have since been investigating brain activity during periods of imitation vs. exposure to a dynamic but nonsocial stimulus (a rotating disk) and during non-stimulus baseline periods, using scalp electrodes to record EEG activity. We found a distinctive EEG signature involving significant suppression of mu rhythm activity at low frequencies in frontal and parietal brain regions during periods of imitation but not during baseline and control periods and not in monkeys who failed to imitate. The pattern of EEG activity intensified through that first week and was significantly stronger in mother-reared than in nursery-reared neonates. We also documented the emergence of EEG rhythms in one-week-old infant rhesus macaques under both light and dark conditions. Our data show that the 57 Hz frequency band responds reliably to changes in illumination. We also found EEG in higher frequencies (1220 Hz) that significantly increase between dark and light conditions similar to the increase in the beta band of humans during cognitive tasks. The findings demonstrate similarities between infant human and infant monkey EEG.
Using eye-tracking technology, we also demonstrated that week-old rhesus macaque infants readily respond to a computer-generated dynamic monkey avatar and that those infants who imitate tend to focus more on different aspects of the avatar's face (eyes and mouth) than those that do not imitate (mouth only). We also compared neonatal imitation capabilities in mother-reared (MR) and nursery reared (NR) infants, focusing on Day 3 performance only. We reported that even though NR infants showed an imitation effect when tested over the first week, they did not exhibit imitation specifically on Day 3. In contrast, MR infants responded to facial gestures with more gestures themselves, consistent with our previous EEG findings that MR infants show greater mu suppression than NR infants when viewing facial gestures.
Given the potential impact of imitation on infants' cognitive, social, and emotional development, we devised an intervention for NR infants whereby the infants either received additional facial gesturing from a human caregiver, received additional handling without seeing any additional facial gesturing, or remained in standard nursery rearing. We found that only the group that had received additional facial gesturing showed improved performance on the standard neonatal facial imitation task on Day 7 and showed greater sensitivity to facial identity of others in a standardized stranger task. Infants from the facial gesturing group also appeared to be less inhibited in their latency to touch a toy in a novel object task and had better memory for social stimuli than infants in the other two groups. A second attempt to increase infants' social perception and social sensitivity looked at the effects of oxytocin on infants' social interaction. NR infants were nebulized with oxytocin or saline and then were tested on an imitation recognition task. We reported that salivary assays confirmed increased levels of oxytocin, and infants showed significantly increased affiliative gesturing toward a human experimenter following oxytocin administration.
We further explored infants' facial processing strategies by presenting them with various faces and facial configurations on a remote eye tracker. Rhesus macaque infants generally prefer faces with normally arranged features over faces with linearly arranges features, suggesting a special sensitivity to faces and face-like stimuli. The preferences are particularly strong for rhesus rather than human faces, suggesting a genetic predisposition to rhesus faces in particular. We also reported that specific sensitivities toward the eye region are exhibited by neonatal imitators but not by non-imitators, which may indicate that neonatal imitation and differential social sensitivity are intricately linked.
A new project begun this year involved the analysis of rhesus monkey mothers’ milk with respect to parity, early social history (i.e., MR vs. PR), and infant sex. In collaboration with Katie Hinde, we began collecting milk samples from monkey mothers within the first 30 days postpartum, and we are currently analyzing the samples for cortisol content and nutrient composition. Hinde found that human mothers at 3–4 months postpartum produce milk of differing quality and quantity based on the sex of their baby. The amount of cortisol in the milk is also predictive of infant temperament at this age. We are now in the unique position to study similar relationships in neonatal monkey milk. Consistent with Hinde’s findings, maternal parity predicts milk yield volume (MYV) in the first postpartum month. Preliminary findings also suggest that mothers with higher hair cortisol concentrations during pregnancy have a higher MYV in the first postpartum month. We are currently examining the extent to which differences in cortisol and nutrient content in mothers’ milk during the infant neonatal period are predictive of differences in long-term HPA axis activity (in both mothers and infants) and in infant social behavior, cognitive development, and temperament in subsequent months.
Another recent focus of our work was on the incidence of alopecia and related physiological processes. We had previously observed that many rhesus monkey females undergo severe hair loss during pregnancy, only to regain full hair growth within two months postpartum. In collaboration with Melinda Novak and Jerrold Meyer, we examined the role of chronic HPA axis activity, as assessed via hair cortisol concentrations, and extent of alopecia. Our initial findings indicated that, overall, hair cortisol concentrations change throughout pregnancy and that monkeys that exhibit hair loss have higher hair cortisol levels than those who do not.
We continued our research program on personality and facial characteristics with our Cebus monkeys, focusing on five personality dimensions (Assertiveness, Openness, Neuroticism, Sociability, and Attentiveness, also known as "the Big 5"), and reported that Cebus monkeys' facial width-to-height ratio, as well as their facial width are positively and significantly associated with Assertiveness. A lower face width/face height ratio was associated with Neuroticism.
- Dettmer AM, Novak MA, Meyer JS, Suomi SJ. Population-dependent hair cortisol concentrations in rhesus monkeys (Macaca mulatta). Psychoneuroendocrinology 2014;42:59-67.
- Massart R, Suderman M, Provincal N, Yi C, Bennett AJ, Suomi SJ, Szyf M. Hydroxymethylation and DNA methylation profiles in the prefrontal cortex of the nonhuman primate rhesus macaque and the impact of maternal deprivation on hydroxymethylation. Neuroscience 2014;268:139-148.
- Paukner A, Simpson EA, Ferrari, PF, Mrozek T, Suomi SJ. Neonatal imitation predicts how infants engage with faces. Dev Sci 2014;E-pub ahead of print.
- Shrestha S, Nelson EE, Liow J, Yoo C, Henter I, Noble P, Kruger J, Zhang B, Suomi SJ, Morse C, Svenningsson P, Winslow J, Liebenluft E, Pine D, Innis R. Fluoxetine administered to juvenile monkeys: effects on the serotonin transporter and behavior. Am J Psychiatry 2014;171:323-331.
- Simpson EA, Sclafani V, Paukner A, Hamel AF, Novak MA, Meyer JS, Suomi SJ, Ferrari PF. Inhaled oxytocin increases positive social behaviors in newborn macaques. Proc Natl Acad Sci USA 2014;111:6922-6927.
- Enrico Alleva, MD, Istituto Superiore di Sanità, Rome, Italy
- Christina Barr, PhD, DVM, Laboratory of Clinical Sciences, NIAAA, Bethesda, MD
- Allyson J. Bennett, PhD, Wake Forest University School of Medicine, Winston-Salem, NC
- Igor Brachi, PhD, Istituto Superiore di Sanità, Rome, Italy
- Sarah Brosnan, PhD, Georgia State University, Atlanta, GA
- Hannah Buchanan-Smith, PhD, University of Stirling, Stirling, UK
- Svetlana Chefer, PhD, Neuroimaging Research Branch, NIDA, Bethesda, MD
- Francesa Cirulli, PhD, Istituto Superiore di Sanità, Rome, Italy
- Steve W. Cole, PhD, University of California Los Angeles, Los Angeles, CA
- Jennifer Essler, MS, Bucknell University, Lewisburg, PA
- Pier F. Ferrari, PhD, Università di Parma, Parma, Italy
- Nathan A. Fox, PhD, University of Maryland, College Park, MD
- David Goldman, MD, Laboratory of Neurogenetics, NIAAA, Bethesda, MD
- James J. Heckman, PhD, University of Chicago, Chicago, IL
- Markus Heilig, MD, Laboratory of Clinical Studies, NIAAA, Bethesda, MD
- J.D. Higley, PhD, Brigham Young University, Provo, UT
- Katie Hinde, PhD, Harvard University, Cambridge, MA
- Phyllis Lee, PhD, University of Stirling, Stirling, UK
- K. Peter Lesch, MD, Universität Würzburg, Würzburg, Germany
- Francis J. McMahon, MD, Human Genetics Branch, NIMH, Bethesda, MD
- Jerrold S. Meyer, PhD, University of Massachusetts, Amherst, MA
- Eric Nelson, PhD, IRP Neurobiology Primate Core, NIMH, Bethesda, MD
- Melinda A. Novak, PhD, University of Massachusetts, Amherst, MA
- Andreas Reif, PhD, Universität Würzburg, Würzburg, Germany
- Melanie L. Schwandt, PhD, Laboratory of Clinical and Translational Studies, NIAAA, Bethesda, MD
- Valentina Sclafani, PhD, Università di Parma, Parma, Italy
- Susan E. Shoaf, PhD, Laboratory of Clinical Studies, NIAAA, Bethesda, MD
- Alan Silberberg, PhD, American University, Washington, DC
- Elizabeth Simpson, PhD, Università di Parma, Parma, Italy
- Simona Spinelli, PhD, Laboratory of Clinical Studies, NIAAA, Bethesda, MD
- Elliot Stein, PhD, Neuroimaging Research Branch, NIDA, Bethesda, MD
- Moshe Szyf, PhD, McGill University, Montreal, Canada
- Bernard Thierry, PhD, Centre d'Écologie, Physiologie et Éthologie, CNRS, Strasbourg, France
- Angelika Timme, PhD, Freie Universität Berlin, Berlin, Germany
- Ross Vanderwert, PhD, Harvard University, Cambridge, MA
- Elisabetta Visalberghi, PhD, Istituto de Scienze e Technologie della Cognizione, CNR, Rome, Italy
- Alexander Weiss, PhD, University of Edinburgh, Edinburgh, United Kingdom
- Jane Widness, PhD, Yale University, New Haven, CT
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