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Genetic and Environmental Determinants of Primate Biobehavioral Development

Stephen J. Suomi, PhD
  • 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
  • Michelle Miller, BS, Contract Employee
  • Grace K. Maloney, BS, Postbaccalaureate Fellow
  • Neal Marquez, BS, Postbaccalaurate Fellow
  • Amanda J. Riddle, 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 into environments that contain specific physical and social features of the species’ natural habitat. Adaptation is assessed by examining behavioral repertories and by monitoring a variety of physiological systems in these 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.

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 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 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 like 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 daily for the next are 6 months. At 7 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 much more aggressive and exhibit much greater behavioral and biological disruption during and immediately following short-term social separation at 6 months of age than MR monkeys. PR monkeys also exhibit deficits in serotonin metabolism (as indexed by chronically low values of CSF 5-HIAA), as do SPR monkeys, and demonstrate significantly lower levels of 5-HTT binding throughout many brain regions than do MR subjects. Many of the differences between MR and PR monkeys persist throughout the childhood years. In collaboration with colleagues from NIAAA, we demonstrated that, compared with MR monkeys, both PR and SPR monkeys consume significantly more alcohol when placed in a happy hour situation as adolescents and young adults. This past year, 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.

Another major focus of our recent research involved characterizing 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. In addition, we 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 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−reared monkeys but a neutral or, in some cases, even an optimal outcome among MR−reared subjects carrying the same less efficient allele, suggesting an overall buffering effect of MR rearing for individuals carrying such so-called "risk" alleles.

This past year, we reported 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 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 and in T lymphocyte activation and cell proliferation but suppression of antiviral and antibacterial responses. Since that initial study, we have embarked on a prospective longitudinal study in which differentially reared subjects are being sampled at 14 days, 30 days, 6–7 months, and every 4 months thereafter until they reach puberty.

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. We have since initiated 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.

Human mothers interact emotionally with their newborns through exaggerated facial expressions and mutual gaze, a capacity that has long been considered uniquely human. A few years ago, we started 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. More detailed subsequent observations revealed that, during this time, mother-infant dyads communicated via complex forms of emotional exchange, including exaggerated lip-smacking and sustained mutual gaze. 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 of up to 24 hours, which indicated a sophisticated capacity to control and flexibly engage in affective communication. For those infants who could imitate in this fashion, this capability was evident on their first postnatal day, although their imitative behavior largely disappeared after the first week. Interestingly, we found major rearing-condition differences in imitative abilities: whereas approximately 55% of nursery-reared infants could imitate, over 90% of mother-reared infants were successful imitators. Follow-up studies, comparing infants who displayed imitative capabilities during their first week with those who did not, revealed that imitators performed better on tests of sensory-motor capabilities throughout their first month, played twice as much as non-imitators from 4 to 6 months of age, and, whereas a sizeable number of non-imitators developed idiosyncratic, autistic-like stereotypic behaviors during their second year, none of the monkeys who had displayed imitative behavior their first week exhibited any such stereotypes.

Individual difference in delayed imitation suggest that differentially matured cortical mechanisms may be involved, allowing some newborns macaques to actively participate in communicative exchanges from birth. Thus, rhesus monkey infants are endowed with basic social competencies of inter-subjective communication, which indicate cognitive and emotional commonality between humans and macaques and which may have evolved to nurture an affective mother-infant relationship in primates.

We also investigated 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. This past year, we reported that these experiments revealed 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. This 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. More recently, using eye-tracking technology, we demonstrated that week-old 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).

This past year, we published two studies on our colony of tufted capuchin monkeys (Cebus apella). The first study focused on fur-rubbing behavior. The behavior is widely believed to have a social bonding function in capuchin monkeys. Yet, a recent study of tufted capuchins revealed increased levels of aggression and reduced levels of affiliation after fur-rubbing bouts. The observed reduction in group cohesion may be attributable to increased intra-group competition for fur-rub material rather than to a direct effect of fur rubbing itself. To test this hypothesis, we separated individual monkeys from their social group and provided them with fur-rub material or control material, thereby avoiding intra-group competition. After engagement with materials, we released subjects back into their social group and observed their subsequent interaction with group members. We found that subjects were more likely to encounter aggression and less likely to receive affiliation from others in the fur-rub condition than in the control condition. The results support the idea that fur rubbing has social after-effects for capuchin monkeys.

The second study focused on the relationships among cognitive performance, emotional state, and stress hormone levels. Abnormal stereotypic behavior is widespread among captive non-human primates and is generally associated with jeopardized well-being. However, attributing the same significance to every repetitive, unvarying, and apparently functionless behavior may be misleading, as some behaviors may be better indicators of stress than others. Previous studies demonstrated that the affective state of the individual can be inferred from its bias in appraising neutral stimuli in its environment. Therefore, in order to assess the emotional state of stereotyping individuals, we tested 16 captive tufted capuchins on a judgment bias paradigm and measured their fecal corticoid levels in order to assess the intensity of the emotional state. Capuchins with higher levels of stereotypic head twirls exhibited a negative bias while judging ambiguous stimuli and had higher levels of fecal corticoids than subjects with lower levels of head twirls. Levels of stereotypic pacing, however, were not correlated with the monkeys' emotional state. The study is the first to reveal a positive correlation between levels of stereotypic behavior and a pessimistic-like judgment bias in a non-human primate by employing a recently developed cognitive approach. Combining cognitive tests that evaluate the animals affective valence (positive or negative) with hormonal measurements that provide information on the strength of the emotional state is conducive to a better understanding of the animals' affective state and therefore to their well-being.

Publications

  1. Cole SW, Conti G, Arevalo, JM, Ruggiero AM, Heckman JJ, Suomi SJ. Transcriptional modulation of the developing immune system by early life social adversity. Proc Natl Acad Sci USA 2012;109:20578-20583.
  2. Paukner A, Bower SB, Simpson EA, Suomi SJ. Sensitivity to first-order relations of facial elements in rhesus macaques. Infant Child Dev 2013;22:320-330.
  3. 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 2013;in press.
  4. Spinelli S, Chefer S, Carson RE, Jagoda E, Lang L, Heilig M, Barr CS, Suomi SJ, Higley JD. Females are more sensitive to early life stress alterations in the serotonergic system during development. Biol Psychiat 2013;in press.
  5. Vanderwert RE, Ferrari PF, Paukner A, Bower SB, Fox NA, Suomi SJ. Spectral characteristics of the newborn rhesus macaque EEG reflect functional cortical activity. Physiol Behav 2012;107:787-791.

Collaborators

  • 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
  • Frans de Waal, PhD, Emory University, Atlanta, GA
  • Elissa Epel, PhD, University of California San Francisco, San Francisco, 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
  • James T. Winslow, PhD, IRP Neurobiology Primate Core, NIMH, Bethesda, MD
  • Alexander Weiss, PhD, University of Edinburgh, Edinburgh, UK
  • Jane Widness, PhD, Yale University, New Haven, CT

Contact

For more information, email suomis@mail.nih.gov.

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