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National Institutes of Health

Eunice Kennedy Shriver National Institute of Child Health and Human Development

2016 Annual Report of the Division of Intramural Research

Genetic and Environmental Determinants of Primate Biobehavioral Development

Owen Rennert
  • Stephen J. Suomi, PhD, Head, Comparative Behavior Genetics Section
  • Annika Paukner, PhD, Senior Visiting Fellow
  • Amanda M. Dettmer Erard, PhD, Postdoctoral Fellow
  • Angela M. Ruggiero, BS, BioScience Laboratory Technician
  • Kristen L. Byers, BS, Contract Employee
  • Michelle Miller, BS, Contract Employee
  • Ryan McNeil, BS, Postbaccalaureate Fellow
  • Ashley M. Murphy, BA, Postbaccalaureate Fellow
  • Lindsay P. Schwartz, BS, Postbaccalaureate Fellow
  • Emily Stonecker, BS, Postbaccalaureate Fellow
  • Lauren J. Wooddell, BS, Postbaccalaureate Fellow

We investigate primate behavioral and biological development through comparative longitudinal studies of rhesus monkeys (Macaca mulatta) and other primates. Our primary goals are to characterize different distinctive bio-behavioral phenotypes in our rhesus monkey colony, determine how genetic and environmental factors interact to shape the developmental trajectories of each phenotype, and assess the long-term behavioral, biological, epigenetic, and health 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 health and 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, a major focus of this project was detailed longitudinal studies of 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 their first 6–7 months of 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 the next six months (PR), or housed in individual cages containing an inanimate surrogate mother and given two hours of daily interaction with similarly reared peers (SPR). 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 7–8 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 more impulsive and aggressive, and exhibit much greater behavioral and biological disruption during and immediately following short-term social separation at six months of age than do MR monkeys. They also exhibit deficits in serotonin metabolism (as indexed by chronically low values of cerebrospinal fluid [CSF] 5-HIAA, the major serotonin metabolite), as do SPR monkeys. Additionally, they have significantly lower levels of 5-HTT (serotonin transporter) binding throughout many brain regions than do MR subjects. Many of these differences between MR and PR monkeys persist throughout the childhood years in the absence of experimental interventions. More recently, we published data extending these rearing condition differences to include patterns of brain lateralization, cortisol concentration in hair (a measure of chronic hypothalamic-pituitary-adrenal [HPA] activity), and measures of brain structure and function as assessed by structural MRI and positron emission tomography (PET), respectively. Additional differences in measures of social dominance status, maternal competence, telomere length, and physical health during childhood, adolescence, and adulthood were also documented. However, more recent studies indicated that many of these rearing condition differences in behavioral, biological, and health outcomes appear to be largely reversible following specific social interventions.

Another major focus of recent research for this project was to characterize interactions between differential early social rearing and polymorphisms in several candidate genes (G X E interactions), most notably the 5-HTTLPR polymorphic region of the 5-HTT gene. During the past two years, 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. In addition, we recently reported significant G x E interactions between early MR vs. PR rearing and polymorphisms for several other candidate genes including: DRD1, which encodes the dopamine receptor D1; NPY, which encodes neuropeptide Y; OPRM1, which encodes the mu opioid receptor 1; BDNF, which encodes brain-derived neurotrophic factor; NOS-1, which encodes nitric oxide synthase 1 neuronal; and a single-nucleotide polymorphism (SNP) in the glucocorticoid gene, with outcome measures including play behavior, social buffering, behavioral and HPA reaction to an unfamiliar conspecific, naloxone treatment, alcohol consumption, and plasma BDNF concentrations. In virtually every case a similar pattern was observed, i.e., the less efficient (from a transcriptional point of view) allele was associated with a negative outcome among PR–reared monkeys but a neutral or, in some cases, even an optimal outcome for MR–reared subjects carrying that same less efficient allele, suggesting an overall buffering effect of MR rearing for individuals carrying these so-called risk alleles.

Additionally, 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 (PFC) and in T cell lymphocytes. Our research involving mRNA expression, carried out in collaboration with Steven Cole and James Heckman, examined 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, and suppression of antiviral and antibacterial responses, a pattern curiously also seen in leukocyte expression in adult humans who perceive themselves as socially isolated. Since that initial study, we completed a prospective longitudinal study in which differentially reared subjects were sampled at 14 days, 30 days, 6–7 months, and every three 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 persist throughout development in the absence of any changes in the social environment but change dramatically whenever the social environment is altered during the juvenile years.

The other set of studies, carried out in collaboration with Moshe Szyf and his lab, involved genome-wide analyses of methylation patterns in differentially reared monkeys when they were adults. The initial study compared such patterns in PFC tissue and T cell lymphocytes obtained from 8-year-old monkeys differentially reared for the first 6–7 weeks of life and thereafter maintained under identical conditions until adulthood. The analyses revealed that 1) more than 4,400 genes were differentially methylated in both the PFC and lymphocytes; 2) although there was considerable tissue specificity, approximately 25% of the affected genes were identical in both PFC and lymphocytes; and 3) in both PFC and lymphocytes, methylated promoters tended to cluster both by chromosomal region and gene function. This past year, we completed a prospective longitudinal study of genome-wide methylation patterns in lymphocytes, collecting samples from exactly the same MR and SPR monkeys at exactly the same time points as in the aforementioned longitudinal study of mRNA expression. Preliminary findings suggest that, at least in lymphocytes, extensive effects of rearing conditions are present within the first month of life but can subsequently be, at least in part, significantly minimized and/or re-directed following a social environmental intervention utilizing “foster” grandparents.

In another collaboration with the Szyf lab, we examined the epigenetic consequences of high vs. low ranking in established social groups of adult female monkeys and in offspring whose relative social dominance status matched that of their mothers. It appeared that the cross-generational transmission of social status was mediated, at least in part, by the placenta, in that the genome-wide pattern of methylation in tissues collected from placentas immediately after birth differed dramatically between offspring of high- and low-ranking females; not only did the order of magnitude of these differences match that of the above-mentioned early social rearing condition differences, but many of the same genes were involved, suggesting the existence of a subset of “early adversity” genes, i.e., genes sensitive to a range of different early life adversities.

Mothers interact emotionally with their newborns through exaggerated facial expressions and mutual gaze, a capacity that has long been considered uniquely human. We previously began a research program on early face-to-face interactions in rhesus monkeys after we made the serendipitous discovery that very young rhesus monkey infants did, in fact, engage in extensive face-to-face interactions with their mothers, but only during the first month of life. This past year, we further characterized face-to-face interactions between mothers and their newborn infants in a naturalistic setting. We found large individual variability in rates of maternal/infant face-to-face interactions, in that mothers who had only one or two infants engaged in mutual gazing/lip-smacking in the first 30 days of life significantly more than mothers who had had three or more infants, whereas the more experienced mothers let their infants out of arms’ reach significantly more in the first 30 days of life than newer mothers. Overall, mothers tended to engage in more face-to-face interactions with their male infants.

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 the first postnatal day. We since investigated brain activity during periods of imitation using scalp electrodes to record EEG activity and found a distinctive EEG signature involving significant suppression of mu rhythm activity at low frequencies in frontal and parietal brain regions exclusively during periods of imitation. We reported that this pattern of EEG activity intensified through that first week and was significantly stronger in mother-reared than in nursery-reared neonates. The findings demonstrate similarities between infant human and infant monkey EEG during periods of imitation.

We also demonstrated, using eye-tracking technology, that week-old infants readily respond to a computer-generated dynamic monkey avatar, and that those infants who imitate tend to focus on different aspects of the avatar's face (eyes and mouth) compared with those that do not imitate (mouth only). We also compared neonatal imitation abilities in mother-reared and nursery-reared monkeys, focusing on day 3 performance only. We reported that, even though nursery-reared (NR) infants show an imitation effect when tested over the first week, they do not exhibit imitation specifically on day 3. In contrast, MR monkeys responded to facial gestures with more gestures themselves, consistent with our previous EEG findings that MR infants show larger mu suppression than NR infants when viewing facial gestures.

Given the potential impact of neonatal imitation on infants’ social, cognitive, and emotional development, we devised one intervention whereby NR infants either received additional facial gesturing from a human caretaker, received additional handling (but did not see facial gestures), or remained in standard nursery rearing. We found that only the group that had received facial gesturing showed improved performance on the standard neonatal imitation task on day 7 as well as greater sensitivity to facial identity of others in a standardized stranger task. Infants from the facial gesturing group also showed increased preference for a social video at day 30 and again at day 40, had better memory for social stimuli when tested at day 60, and had higher levels of social contact with peers from day 40 to day 60 than did infants in the handling and standard rearing groups.

A second intervention designed to increase infants’ social perception and social sensitivity looked at the effects of oxytocin on infants’ social interactions. NR infants were nebulized with either oxytocin or saline and then tested in an imitation recognition task. We reported increased time spent looking at faces following oxytocin, but not saline, treatment. Salivary assays confirmed increased levels of oxytocin, and infants also showed more affiliative gesturing towards 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 arranged features, suggesting a special sensitivity to faces and face-like stimuli. The preferences are particularly strong for faces of conspecifics, which suggests a genetic predisposition towards rhesus faces in particular. We also reported that neonatal imitators, but not non-imitators, exhibit particular sensitivities towards the eye region, which may indicate that neonatal imitation and differential social sensitivity are intricately linked.

A project begun last year involved the analysis of mothers’ milk in rhesus monkeys with respect to parity and early life history (i.e., rearing condition). In collaboration with Katie Hinde, we collected milk samples from mothers over the first 30 days of their infant's life and analyzed the samples for cortisol content and nutrient composition. Similar to Hinde's studies on human mothers' milk in older infants, we found that parity predicted milk yield volume (MYE) in the first month of life. Our findings also indicated that mothers with higher hair cortisol during pregnancy had a higher MYE in the first 30 days of life. Additionally, we found that cortisol levels in mothers’ milk predicted infant cognitive functioning and social behavior later in life. Infants who ingested milk with higher cortisol content were less impulsive in a cognitive task but also initiated social behaviors with peers less frequently.

We used hair cortisol as a measure of chronic HPA activity in three additional studies completed this past year. First, hair cortisol levels measured shortly after birth, which presumably reflect prenatal HPA activity from mid-gestation onward, predicted cognitive performance capabilities and infant temperament in the first postnatal months. Second, changes in hair cortisol concentrations during the juvenile years predicted differences in social dominance status among adult female monkeys.

A third project centered on the incidence of alopecia and related physiological processes. We had previously observed that many females undergo severe hair loss during pregnancy, only to regain full hair growth in the two months postpartum. In collaboration with Melinda Novak and Jerrold Meyer, we examined the role of chronic HPA axis activity, as assessed by hair cortisol concentrations in alopecia. Our early results indicate that overall concentrations change across pregnancy and that monkeys that exhibit the greatest amount of hair loss have higher hair cortisol concentrations than those that do not.

We continued our research program on personality and facial characteristics with our capuchin monkeys, focusing on five personality dimensions (assertiveness, openness, neuroticism, sociability, and attentiveness), and found that the monkeys’ facial width-to-height ratio, as well as their face width/lower face height, are positively and significantly associated with assertiveness. A lower face width/face height ratio was also associated with neuroticism. This past year, we also provided some of our capuchins with stone tools and observed for the first time in our colony spontaneous use of those tools to crack open walnuts. Nut-cracking has been observed in a few isolated wild populations of this species but is clearly far from universal. We plan to study its pattern of propagation in our captive colony, especially among juvenile and adolescent group members.


  1. Dettmer, AM, Rosenberg KL, Suomi SJ, Meyer JS, Novak MA. Associations between parity, hair hormone profiles during pregnancy and lactation, and infant development in rhesus monkeys (Macaca mulatta). PLoS One 2015;10:e0131692.
  2. Paukner A, Simpson EA, Ferrari PF, Mrozek T, Suomi SJ. Neonatal imitation predicts how infants engage with faces. Dev Sci 2015;17:833-840.
  3. Sclafani V, Paukner A, Suomi SJ, Ferrari PF. Imitation promotes affiliation in infant macaques at risk for impaired social behaviors. Dev Sci 2015;18:614-621.
  4. Vanderwert RE, Simpson EA, Paukner A, Suomi SJ, Fox NA, Ferrari PF. Early social experience affects neural activity to affiliative facial gestures in newborn nonhuman primates. Dev Neurosci 2015;37:243-252.
  5. Massert R, Nemoda Z, Sunderman MJ, Sutti S, Ruggiero AM, Dettmer AM, Suomi SJ, Szyf M. Early life adversity alters normal sex-dependent developmental dynamics of DNA methylation. Dev Psychopathol 2016;28(4pt2):1259-1272.


  • Enrico Alleva, MD, Istituto Superiore di Sanità, Rome, Italy
  • Christina Barr, PhD, DVM, Laboratory of Clinical Sciences, NIAAA, Bethesda, MD
  • Allyson J. Bennett, PhD, University of Wisconsin-Madison, Madison, WI
  • 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
  • Francesa Cirulli, PhD, Istituto Superiore di Sanità, Rome, Italy
  • Steven 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
  • Stafano Kaburu, PhD, University of California Davis, Davis, CA
  • Phyllis Lee, PhD, University of Stirling, Stirling, UK
  • K. Peter Lesch, MD, Universität Würzburg, Würzburg, Germany
  • Linda Mayes, MD, Yale University, New Haven, CT
  • Jerrold S. Meyer, PhD, University of Massachusetts, Amherst, MA
  • Eric Nelson, PhD, Section on Development and Affective Neuroscience, NIMH, Bethesda, MD
  • Melinda A. Novak, PhD, University of Massachusetts, Amherst, MA
  • Daniel A. Notterman, MD, PhD, Princeton University, Princeton, NJ
  • Andreas Reif, PhD, Universität Würzburg, Würzburg, Germany
  • David X. Reiss, MD, Yale University, New Haven, CT
  • Helena Rutherford, PhD, Yale University, New Haven, CT
  • Lisa M. Schneper, PhD, Princeton University, Princeton, NJ
  • Melanie L. Schwandt, PhD, Laboratory of Clinical and Translational Studies, NIAAA, Bethesda, MD
  • Valentina Sclafani, PhD, Reading University, Reading, UK
  • Alan Silberberg, PhD, American University, Washington, DC
  • Elizabeth A. Simpson, PhD, University of Miami, Miami, FL
  • 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 E. Vanderwert, PhD, Cardiff University, Cardiff, UK
  • Elisabetta Visalberghi, PhD, Istituto de Scienze e Technologie della Cognizione, CNR, Rome, Italy
  • Alexander Weiss, PhD, University of Edinburgh, Edinburgh, UK
  • Jane Widness, PhD, Yale University, New Haven, CT


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