Genetic and Environmental Determinants of Primate Biobehavioral Development

Stephen J. Suomi, PhD, Head, Comparative Behavior Genetics Section
Matthew F.X. Novak, PhD, Senior Postdoctoral Researcher
Kathlyn L. Robbins, PhD, Research Psychologist
Craig Abbott, PhD, Statistician
Peggy O’Neill Wagner, MA, Senior Research Assistant
Angela Ruggiero, BS, BioScience Laboratory Technician
Consuel S. Ionica, PhD, Visiting Fellow
Annika Paukner, PhD, Visiting Fellow
Amanda Dettmer, MS, Predoctoral Fellow
Khalisa Herman, MS, Predoctoral Fellow
Marja Knappe, MS, Visiting Predoctoral Fellow
Lisa Darcey, BS, Postbaccalaureate Fellow
Daniel Hipp, BS, Technician-in-Training
Elizabeth Kerschner, BS, Technician-in-Training
Elizabeth Mallott, BS, Technician-in-Training

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 different 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.

Developmental continuity of individual differences in rhesus monkey biobehavioral development

Darcey, Hipp, Knappe, Ruggiero, Suomi; in collaboration with Adler, Alleva, Barr, Bennett, Chefer, Cirulli, Cole, Epel, Goldman, Heckman, Heilig, Herman, Higley, Lesch, Meaney, Nelson, Schwandt, Shoaf, Spinelli, Stein, Szyf, Winslow

This past year, we characterized, by assaying plasma BDNF and NGF, developmental changes in peripheral measures of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in rhesus monkeys with different early social rearing backgrounds reared either by their biological mother (MR) or in the neonatal nursery with subsequent continuous access to peers (PR). We replicated our previous findings that BDNF levels decrease dramatically over the first two months and then more gradually over the rest of the animals’ first year, except for PR females, whose levels remain high throughout their first two months. In contrast, NGF levels remain relatively stable for the first two months and then increase sharply from two months to one year of age, achieving adult levels at that point, except for PR males whose increases in NGF levels occur much earlier. Among PR (but not MR) infants, plasma NGF and cortisol levels are significantly correlated. In addition, within each rearing group, individual differences in both plasma BDNF and NGF values remain largely stable throughout development, suggesting possible genetic influences. One potential candidate gene is the BDNF gene, for which functional polymorphisms have been characterized in both humans and rodents. We identified a functionally similar BDNF polymorphism in our rhesus monkey colony and are determining whether allelic differences in the rhesus monkey BDNF gene are associated with individual differences in plasma BDNF values and other measures of biobehavioral functioning throughout development.

We carried out two brain neuroimaging studies on 2-year-old MR and PR rhesus monkey juveniles. Structural MRI revealed that PR juveniles had a significantly greater volume of cerebellar vermis, medial prefrontal cortex, and dorsal anterior cingulated cortex than MR juveniles. In addition, PR females had significantly lower hippocampal volume than PR males and both MR males and females. PET neuroimaging of the same monkeys revealed both gender and rearing-condition effects; females had significantly lower 5-HT_1A receptor densities throughout the brain than males, and both female and male PR juveniles had significantly lower 5-HT_1A receptor densities than their MR counterparts. We found significantly greater 5-HT_1A binding potential (BP) in the prefrontal cortex of female PR monkeys had than of MR females, whereas PR males had significantly lower BP than MR males in the medial cingulated cortex. We demonstrated that differences in early rearing history resulted in differences in laterality; as adolescents, MR monkeys had a greater right-handed behavioral bias than did PR monkeys. Finally, throughout their first year of life PR monkeys had chronically higher levels of cortisol than MR monkeys.

We continued data collection and analysis on two other projects that compared MR and PR rhesus monkeys on additional measures of biological functioning. In collaboration with colleagues from McGill University, we are assessing methylation patterns in glucocorticoid receptor genes in hippocampus and prefrontal cortex obtained from young adult MR and PR subjects as well as in buccal samples and lymphocytes obtained longitudinally from MR and PR monkeys throughout development. In collaboration with colleagues from the University of California Los Angeles and University of Chicago, we are performing whole-genome scanning of lymphocyte samples obtained longitudinally from MR and PR subjects from infancy onward in order to identify possible rearing-condition differences in patterns of gene expression in the initial week of life and how those patterns might change differentially throughout development.

We are also characterizing interactions between differential early social rearing and polymorphisms in several candidate genes (G x E interactions), most notably the serotonin transporter gene (5-HTT) and 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 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 allele. In addition, in collaboration with colleagues from NIAAA, we identified additional functional polymorphisms in the corticotrophin-releasing factor (CRH)_2A gene and mu opioid receptor gene and characterized G x E interactions with respect to (1) behavioral responses to social separation by juvenile rhesus monkeys and (2) several measures of alcohol preference and consumption among young adult monkeys.

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 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. Psychoneuroendocrinol 2008; [E-pub ahead of print].
Spinelli S, Schwandt ML, Lindell SG, Newman TK, Heilig M, Higley DH, Suomi SJ, Goldman D, Barr CS. Association between the rh-5httLPR polymorphism and behavior in rhesus macaques during social separation stress. Develop Psychopath 2007;19:977-987.
Stevens H, Leckman J, Coplan JD, Suomi SJ. Risk, resilience, and recovery: early manipulation of macaque social experience results in persistent behavioral and neurophysiological sequelae. J Amer Acad Child Adolesc Psychiat, in press.
Suomi SJ. Gene-environment interactions and inter-individual differences in rhesus monkey behavioral and biological development. In: Fogel A, King BJ, Shanker SG, eds. Human Development in the 21st Century: Visionary Policy Ideas from Systems Scientists. Cambridge University Press, 2008:47-54.

Adaptation of laboratory-reared monkeys to field environments

Abbott, Dettmer, Ionica, Kershner, Mallott, Novak MFX, Paukner, Robbins, O’Neill Wagner, Suomi; in collaboration with Byrne, Ferrari, Fox, Huntsberry, Murray, Novak MA, Silberberg, Thierry, Timme, Visalberghi

We assess adaptation by examining behavioral repertoires and monitoring a variety of physiological systems in monkeys throughout the lifespan, developing broad-based indices of relative physical and psychological well-being. We also assess the responses of subjects to experimental manipulations of their environments. Whenever possible, we collect field data for appropriate comparisons. In addition, we investigate the cognitive, behavioral, and social processes involved in adaptation to new settings and circumstances.

We expanded our study of rhesus monkey infants’ capacity to imitate facial expressions directed toward them by a human model throughout their initial week of life. Such early imitative capabilities have been reported for human neonates and are thought to be mediated reflexively by mirror neurons. We found that approximately 60 percent of tested NR newborns were able to mimic facial expressions involving differential mouth and tongue movements, whereas over 90 percent of MR neonates were successful imitators. Follow-up behavioral observations revealed that, compared with infants who failed to imitate during their first week of life, NR infants who exhibited imitative behavior during their first week subsequently exhibited significantly greater sensory-motor coordination throughout their first month and higher levels of social play during peer interaction sessions from four months onward. Moreover, when NR monkeys were subsequently moved permanently into large groups of same-age peers, those individuals who had failed to imitate during their initial days of life developed much higher rates of self-directed and autistic-like repetitive stereotypic behavior than NR monkeys who demonstrated imitative capabilities as neonates.

In collaboration with colleagues from the University of Maryland, we monitored EEG activity in the monkey neonates in their first postnatal week during imitative test sessions and during appropriate non-imitative control periods. Preliminary analyses revealed, concomitant with imitative behavior, patterns of slow-wave EEG alpha that are not seen in infants who fail to imitate in the same setting.

We intensified 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 mother-infant dyads engaged in frequent and intensive face-to-face interactions throughout the infants’ first three weeks of life, after which those behaviors largely disappear. We demonstrated that rhesus infants can differentiate pictures of monkey faces from non-social stimuli from day 1 onward and that, by day 10, they show a significant preference for pictures of adult female monkey faces over those of adult males, without any postnatal exposure to adults of either gender.

Another collaboration involves colleagues from the University of California San Francisco (UCSF) who had previously demonstrated differences in telomere length in adult humans as a function of differences in social status and cumulative social stress. Telomere length is thought to be a marker of relative cellular age. The UCSF researchers hypothesized that differences in telomere length may have their origin in differential experiences with social stress during the childhood years, a period when telomeres shorten rapidly. Accordingly we have been providing our UCSF colleagues with DNA extracted from rhesus monkeys living outdoors in a physically and socially naturalistic setting. Initial analyses revealed both age and status differences in telomere length; younger monkeys had longer telomeres than older ones, and members of high-ranking families had longer telomeres than members of low-ranking families. In collaboration with colleagues from the University of Massachusetts, we assayed cortisol concentrations in hair samples as a potential index of chronic stress. We found significant differences in age, gender, and social status. 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 a captive colony of Tonkean macaques living in an outdoor enclosure similar to that in which the rhesus monkeys were living. The Tonkean macaques exhibited the same pattern of age, gender, and status differences, but their overall cortisol levels were significantly higher than those of their rhesus counterparts.

We completed several studies with our colony of tufted capuchin monkeys. One study demonstrated that capuchin monkeys are capable of recognizing when a human observer is imitating them and revealed that such imitation influences their behavioral preferences. Another study, in contrast, found that capuchin monkeys fail to exhibit the same pattern of memory awareness previously demonstrated in rhesus monkeys, apes, and humans. We found that (1) the animals consistently used visual but not auditory information when locating hidden food items; (2) when faced with choices offering differential potential reward, capuchin monkeys did not demonstrate loss aversion but instead chose on the basis of alternatives in delay of reinforcement; and (3) fur-rubbing behavior, previously thought to have largely medicinal functions, instead serves social purposes, especially with respect to affiliative and aggressive activities.

Basile BM, Hampton RR, Suomi SJ, Murray EA. An assessment of memory awareness in tufted capuchin monkeys (Cebus apella). Animal Cognit 2008; [E-pub ahead of print].
Dettmer AM, Novak MA, Meyer JS, Suomi SJ. Surrogate mobility and orientation affect the early neurobehavioral development of infant rhesus macaques. Develop Psychobiol 2008;50:418-422.
Ferrari PF, Paukner A, Ruggiero AM, Darcey L, Unbehagen S, Suomi SJ. Interindividual differences in neonatal imitation and the development of action chains in rhesus macaques. Child Develop, in press.
Paukner A, Suomi SJ. The effects of fur rubbing on the social behavior of tufted capuchin monkeys. Am J Primatol 2008;70:1-6.
Silberberg A, Roma PG, Huntsberry ME, Warren-Boulton FR, Sakagami T, Ruggiero AM, Suomi SJ. On loss aversion in capuchin monkeys. J Exp Anal Behav 2008;89:145-155.

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
Francesca 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, Neuroimaging 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

For further information, contact suomis@mail.nih.gov.