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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
Judy Songrady, BS, Technician-in-Training
Matthew Novak, PhD, Senior Postdoctoral Researcher
Peggy O’Neill Wagner, MA, Senior Research Assistant
Annika Paukner, PhD, Visiting Fellow
Kathlyn L. Robbins, PhD, Research Psychologist
Angela Ruggiero, BS, BioScience Laboratory Technician
Seth Bower, BS, Postbaccalaureate Fellow
Michelle Miller, BS, Contract Employee

Our research involves broad-based investigations of primate biological and behavioral development through comparative longitudinal studies of rhesus monkeys and other primates. Our primary goals are to characterize distinctive biobehavioral 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 and biological consequences for monkeys from various genetic backgrounds when they are reared in different physical and social environments. A second major program of research investigates how rhesus monkeys and other non-human primate species born and raised under different laboratory conditions adapt to placement into environments that model specific features of their natural habitat.

As in previous years, a major focus of this project has been detailed longitudinal study 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 laboratory’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 1 month are housed in individual cages containing an inanimate surrogate mother and additionally are placed in a play cage with 3 other like-reared peers for 2 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 all 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 do MR monkeys, exhibit deficits in serotonin metabolism (as indexed by chronically low values of CSF 5-HIAA), as do SPR monkeys, and have significantly lower levels of 5-HTT binding throughout many brain regions than do MR subjects. Many of these differences between MR and PR monkeys persist throughout the childhood years. Research in collaboration with colleagues from NIAAA has demonstrated that both PR and SPR monkeys also consume significantly more alcohol when placed in a happy-hour situation as adolescents and young adults. This past year, we published data extending these rearing condition differences to include developmental changes in plasma concentrations of BDNF and NGF (Cirulli et al.), behavioral lateralization, acoustic startle response patterns following fluoxetine treatment, and structural differences in various brain regions. Finally, we found that PR monkeys had chronically higher levels of cortisol—measured in hair samples—than did MR and SPR monkeys throughout their first year of life, whereas during the second year SPR monkeys had higher levels than the other two rearing groups.

During the past year, we completed data collection and preliminary analyses for two projects comparing the results of genome-wide scans of blood and tissue samples collected from differentially reared monkeys. First, in collaboration with colleagues from McGill and Wake Forest Universities, we assessed methylation patterns in lymphocyte T cells and prefrontal cortex (pfc) obtained from 8 year-old adult MR and SPR subjects who had been living in the same or comparable physical and social environments since 7 months of age. Over 4,000 genes, i.e., almost 1/5 of the entire genome, showed significant differences in methylation as a function of early experience in both T cells and pfc, with approximately half of the affected genes significantly more methylated in MR-derived samples and the remaining half significantly more methylated in SPR-derived samples. Additionally, there was considerable overlap among the specific genes in T cells and pfc that were differentially methylated: about 30% of the genes showed the same pattern of significant rearing condition differences in both T cells and pfc, whereas approximately 25% of the genes showed exactly the opposite pattern in T cells vs. pfc. Furthermore, there were a substantial number of genes in specific known pathways (e.g., various interleukin, monoamine transporter, and corticotropin-releasing hormone pathways) that were differentially methylated as a function of differential early experience again in both T cells and pfc.

The second project utilizing genome-wide scans of samples obtained from differentially reared monkeys—a collaboration with colleagues from UCLA and the University of Chicago—involved microarray scanning of leukocyte samples obtained from MR, PR, and SPR infants at 7 months of age to determine possible differences in gene expression. As in the aforementioned case of differential methylation patterns, we found significant differences in gene expression as a function of differential early experience throughout the entire genome. Relative to those of MR infants, genes upregulated in leukocytes from PR infants included the pro-inflammatory cytokine IL8, a diverse array of transcription factors, regulators of cell proliferation, and multiple T cell–associated transcripts. Genes notably suppressed in leukocytes from PR infants included those involved in Type 1 Interferon–mediated antiviral responses, several immunoglobulin-encoding genes involved in B cell antibody production, several hematopoietic growth regulators, monocyte-associated gene products, and a variety of memory T cell–related markers. Analyses of gene expression patterns in SPR infants yielded results qualitatively similar to those of PR monkeys, but the differences in MR subjects were generally quantitatively less pronounced than those of PR subjects, albeit with a number of exceptions. Taken together, these two sets of genome-wide analyses demonstrate that the consequences of differential early experience for monkeys clearly extend to the level of gene methylation patterns and actual expression.

Another major focus of recent research for this project has involved characterizing interactions between differential early social rearing and polymorphisms in several candidate genes (G x E interactions), most notably the 5-HTT-LPR gene and the MAO-A gene, for a variety of measures of behavioral and biological functioning throughout development in MR and PR rhesus monkeys. This past year we identified significant G x E interactions involving the 5-HTT-LPR polymorphism among MR infants whose mothers differed significantly in their care-giving patterns. Infants whose mothers exhibited low levels of ventral contact and grooming vocalized and explored less and were more passive in an open field test but only if they carried the "short" 5-HTT-LPR allele. In addition, in collaboration with colleagues from NIAAA and the University of Würzburg, we identified additional functional polymorphisms in the corticotropin-releasing hormone gene (CRH 2A), the mu opioid receptor gene (OPRM1) (Barr et al.), the NPY gene, the DRD1 5UTR gene, the BDNF gene, and the NOS-1 gene. We were also able to characterized specific G x E interactions with respect to behavioral responses to social separation by juvenile rhesus monkeys for the 5-HTT-LPR and NPY polymorphisms, as well as in several measures of alcohol preference and consumption among young adult monkeys for the CRH, NPY, and DRD1 5UTR polymorphisms (Barr et al.).

This past year, we expanded our investigation of the capacity of rhesus monkey neonates to imitate specific facial expressions directed toward them by a human model throughout their first week of life. Such early imitative capabilities have been reported for human neonates, and they are thought to be initially reflexively mediated by mirror neurons. We found that approximately 60% of nursery-reared newborns tested were able to mimic specific facial expressions involving different facial expressions such as lip-smacking and tongue protrusion but that their imitative capacity largely disappeared by 10 days of age. Follow-up behavioral observations throughout the first month of life revealed that infants who had exhibited imitative behavior during their first week subsequently displayed significantly more developed skills in goal-directed movements (e.g., reaching for and grasping objects) and finer hand motor control than non-imitators, possibly reflecting differential maturation of motor chains in the parietal and motor cortices, which partially overlap with the mirror neuron system. In collaboration with colleagues from the University of Maryland, we also monitored EEG activity in the neonates throughout their imitative test sessions, as well as during appropriate non-imitative control periods, during their first postnatal week. Preliminary analyses revealed specific patterns of slow-wave EEG alpha desynchronization concomitant with imitative behavior, but not under other conditions and not in infants who failed to imitate in the same setting, again consistent with an interpretation of mirror neuron involvement in these phenomena.

This past year, we also expanded our study of rhesus monkey mother-infant interactions during the initial postnatal days. In marked contrast to previous reports concerning the normative development of attachment relationships in this species, we found that rhesus monkey mother-infant dyads engage in frequent and intensive face-to-face interactions throughout their first 3 weeks of life, after which those patterns largely disappear. Interestingly, the developmental timing of this disappearance largely coincides with the period when infants begin to voluntarily break physical contact with their mother, as they start exploring their external physical and social environment (Ferrari et al.). We also demonstrated that rhesus monkey infants can differentiate pictures of monkey faces from nonsocial stimuli from Day 1 onward and that by Day 10, in the absence of any postnatal exposure to adults of either gender, they show a significant preference for pictures of adult female monkey faces over those of adult males.

In collaboration with colleagues from the University of Massachusetts, Amherst, we collected multiple samples of hair from various groups of rhesus monkeys in order to assay for cortisol concentrations as a potential index of chronic stress, and we found significant age, gender, and social status differences: younger, female, and low-ranking monkeys had higher hair cortisol concentrations than older, male, and high-ranking individuals. We also compared these values with hair cortisol samples obtained from captive colonies of Tonkean macaques (Macaca tokeana) and Barbary macaques (M. silvana), respectively, each maintained in a similar outdoor enclosures. The Tonkean macaques exhibited the same pattern of age, gender, and status differences that characterized the rhesus groups, but overall their cortisol levels were significantly higher than those of their rhesus counterparts; in contrast, the hair cortisol concentrations for the Barbary macaques were consistently lower than those of their rhesus counterparts, possibly reflecting differences in the overall social dominance structure and relative levels of aggression among these three different macaque species. Another study demonstrated that differences in hair cortisol concentrations among rhesus monkey infants reliably predicted differences in performance on a variety of measures of cognitive development: infants with higher cortisol levels took longer to reach criterion on Piagetian object permanence tasks (Dettmer et al.).

Finally, this past year we published several studies utilizing our colony of tufted capuchin monkeys (Cebus apella). A landmark study demonstrated that capuchin monkeys are capable of recognizing when they are being imitated by a human observer and that such imitation leads them to prefer observers who imitate them to those who do not (Paukner et al.). Another study found that, in contrast, capuchin monkeys fail to exhibit the same pattern of memory awareness previously demonstrated in rhesus monkeys, apes, and humans. A third study investigated the use of a variety of sensory information by capuchin monkeys when locating hidden food items and found that the animals consistently utilize visual but not auditory information in such endeavors. Another study characterized face-to-face and other intimate social interactions exhibited by infant and juvenile capuchin monkeys; we found that most of these activities were directed not toward their mother but instead involved other members of their social group, in marked contrast to the intense face-to-face interactions between rhesus infants and their mothers. On the other hand, capuchin monkey juveniles exhibit significant gender differences in the form and amount of social play with peers that were completely consistent with those previously reported for other primate species, including humans.

Publications

Barr CS, Schwandt ML, Lindell SG, Higley JD, Maestripieri D, Goldman D, Suomi SJ, Heilig M. Variation at the mu-opioid receptor gene (OPRM1) influences attachment behavior in infant primates. Proc Natl Acad Sci USA 2008 105:5277-5281.
Cirulli F, Francia N, Brachi I, Antonucci M, Aloe L, Suomi SJ, Alleva E. Changes in plasma levels of BDNF and NGF reveal a gender-selective vulnerability to early adversity in rhesus macaques. Psychoneuroendocrinology 2009 34:172-180.
Dettmer AM, Novak MFSX, Novak MA, Meyer JS, Suomi SJ. Hair cortisol poredicts object permanence performance in infant rhesus macaques (Macaca mulatta). Dev Psychobiol 2009 [Epub ahead of print].
Ferrari PF, Paukner A, Ionica CS, Suomi SJ. Reciprocaol face-to-face communication between rhesus monkey mothers and their newborn infants. Curr Biol 2009 19:1762-1772.
Paukner A, Suomi SJ, Visalberghi E, Ferrari PF. Capuchin monkeys display affiliation toward humans who imitate them. Science 2009 325:880-883.

Collaborators

Nancy Adler, PhD, University of California San Francisco, San Francisco, CA
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
Gayle D. Byrne, PhD, University of Maryland, College Park, MD
Svetlana Chefer, PhD, Neuroimaging Research Branch, NIDA, Bethesda, MD
Francesa Cirulli, PhD, Istituto Superiore di Sanità, Rome, Italy
Steve W. Cole, PhD, Molecular Biology Institute, University of California Los Angeles, Los Angeles, CA
Elissa Epel, PhD, University of California San Francisco, San Francisco, CA
Pier F. Ferrari, PhD, Università di Parma, Parma, Italy
Nathan A. Fox, PhD, University of Maryland, College Park, MD
David A. 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
Mary E. Huntsberry, MS, American University, Washington, DC
K. Peter Lesch, MD, Universität Würzburg, Würzburg, Germany
Michael J. Meaney, PhD, Université McGill, Montréal, Canada
Elisabeth A. Murray, PhD, Laboratory of Neuropsychology, NIMH, Bethesda, MD
Eric Nelson, PhD, IRP Neurobiology Primate Core, NIMH, Bethesda, MD
Melinda A. Novak, PhD, University of Massachusetts, Amherst, MA
Melanie L. Schwandt, PhD, Laboratory of Clinical and Translational Studies, NIAAA, Bethesda, MD

Susan E. Shoaf, PhD, Laboratory of Clinical Studies, NIAAA, Bethesda, MD

Alan Silberberg, PhD, American University, Washington, DC

Simona Spinelli, PhD, Laboratory of Clinical Studies, NIAAA, Bethesda, MD

Elliot Stein, PhD, vNeuroimaging Research Branch, NIDA, Bethesda, MD
Moshe Szyf, PhD, Université McGill, Montréal, Canada
Bernard Thierry, PhD, Centre d’Écologie, Physiologie et Éthologie, CNRS, Strasbourg, France
Angelika Timme, PhD, Freie Universität Berlin, Berlin, Germany
Elisabetta Visalberghi, PhD, Istituto de Scienze e Technologie della Cognizione, CNR, Rome, Italy
James T. Winslow, PhD, IRP Neurobiology Primate Core, NIMH, Bethesda, MD

Contact

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

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