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genetic and environmental determinants of primate

biobehavioral development

Stephen J. Suomi, PhD, Head, Section on Comparative Behavioral Genetics Kathlyn L. Robbins, PhD, Research Psychologist Sue B. Higley, BA, Technician Psychologist Courtney Shannon-Lindell, BA, Technician Psychologist Peggy O’Neill Wagner, MA, Senior Research Assistant Kimran Miller, PhD, Postdoctoral Fellow Matthew F.X. Novak, PhD, Postdoctoral Fellow Angela Ruggiero, BS, Postbaccalaureate Fellow Katlyn Kerekes, BS, Technical Training Fellow Halligan Lyons, BS, Technical Training Fellow Lisa Morin, BS, Technical Training Fellow Peter Roma, BS, Technical Training Fellow Erica Sheldon, BS, Technical Training Fellow Kenneth Vaughn, BS, Technical Training Fellow

Our research involves broad-based investigation of primate biobehavioral development through comparative longitudinal studies of rhesus monkeys and other nonhuman primate species. Our primary research goals are to characterize distinctive biobehavioral phenotypes in our rhesus monkey colony, to determine how genetic and environmental factors interact to shape the monkeys’ development, and to assess the long-term biobehavioral consequences for monkeys from different genetic backgrounds when they are reared in various physical and social environments. A second major program of research investigates how rhesus monkeys and other nonhuman 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 Higley S, Novak MF, Ruggiero, Shannon-Lindell, Sheldon, Suomi, Vaughn Over the past year, we developed a new experimental procedure to monitor rhesus monkey maternal and fetal heart rate and blood pressure from the second trimester of pregnancy to parturition; the procedure involves surgically implanting indwelling catheters in both mother and fetus and recording data online via a tethering device that does not impede the mother’s locomotor or exploratory activity. The initial pregnancy subjected to testing resulted in a successful birth and normal postnatal infant development. Preliminary analyses of the prenatal data revealed patterns of maternal and fetal heart rate and blood pressure changes that became increasingly synchronous with approaching parturition. We are currently following additional pregnancies. We also completed a study evaluating the relative heritability of various components of our standard neurobehavioral assessment battery for rhesus monkey infants throughout the first 30 days of life. The analyses revealed significant heritability for the Orientation, State Control, and Activity (but not Motor Maturity) clusters at 14 days of age. By 30 days, heritabilities had increased for the Orientation and Motor Maturity clusters, remained stable for the State Control cluster, and declined for the Activity cluster, suggesting marked changes in relative heritabilities during the infants’ first month of life. We also detected significant gender and early rearing condition components for three of the four clusters, and these components tended to increase in relative magnitude over the first month. A collaborative study with NIAAA and NIMH researchers employed PET imaging methodology to investigate possible differences in brain serotonin transporter receptor distribution and affinity in rhesus monkey juveniles that had been either reared by their biological mothers in small social groups or nursery-reared with same-age peers during the first seven months of life. Analyses of serotonin transporter ligand-binding potential and cerebral blood flow revealed significant deficits in raphe, thalamus, striatum, frontal, and parietal regions among peer-reared juveniles as compared with their mother-reared counterparts, thereby demonstrating long-term effects of variation in early rearing at the level of brain structure and function. Barr CS, Becker ML, Suomi SJ, Higley JD. Relationship among CSF monoamine metabolite levels, alcohol sensitivity, and alcohol-related aggression in rhesus macaques. Aggress Behav 2003;29:288-301. Polymorphisms in gene associated with serotonin metabolism Suomi; in collaboration with Champoux, Higley J, Lesch, Newman Several ongoing studies have focused on possible interactions between a polymorphism (due to length variation in the promoter region) in 5-HTT, a candidate gene for impaired serotonergic function, and differential early social experience. Over the past year, we published a report of a specific gene-environment interaction in rhesus monkey hypothalamic-pituitary-adrenal (HPA) axis responsiveness to short-term social separation at seven months of age: monkeys with the “short” (LS) allele exhibited excessive ACTH responsiveness relative to those with the “long” (LL) allele, but only if they had been nursery-peer–reared. In contrast, LS monkeys reared by their biological mother did not differ in ACTH responsiveness from mother-reared LL subjects, suggesting a “buffering” effect of maternal rearing. This gene-environment interaction was significantly greater in female than in male monkeys. We found a parallel pattern of gene-environment interaction involving a polymorphism in the MAO gene for levels of aggressive behavior exhibited by mother- and peer-reared rhesus monkey juveniles. We are now in the process of determining whether these and other specific polymorphisms are associated with specific gene-environment interactions with respect to a variety of behavioral and biological measures obtained throughout development in our rhesus monkey population. As a species, rhesus monkeys are notoriously aggressive compared with other macaques (indeed, compared with most other primates). We were able to genotype blood samples obtained from six other species of macaques (Barbary, crab-eating, pigtail, stumptail, Tibetan, and Tonkean) with respect to the 5-HTT gene and, unlike the case for rhesus monkeys, found no polymorphisms for the gene in any of these species. Moreover, we found an apparent inverse relationship between the relative length of the promoter region in the 5-HTT gene and the relative level of aggression reported from field observations of each species. For example, all the sampled Barbary macaques had an “extra long” (XL) allele (a form found in less than 2 percent of our rhesus monkeys genotyped to date); this species is notably unaggressive in both naturalistic and captive settings. Species generally considered less aggressive than rhesus macaques, all crab-eating, pigtail, stumptail, and Tonkean macaques sampled, had the LL allele. Finally, the Tibetan macaques had an “extra short” (XS) allele not seen in any of the other species; recent field data suggest that these monkeys may be even more aggressive than most rhesus monkeys. Subsequent comparisons of potential polymorphisms in three other “candidate” genes among the above macaque species revealed an intriguing pattern: as was the case with the 5-HTT gene, rhesus monkeys were the only species to exhibit polymorphisms in any of these genes. Rhesus monkeys also differ from the other macaque species in terms of their overall natural populations and the range of physical, social, and climatic environments in which they reside in nature, suggesting that their relative “success” as a species may be somehow related to their genetic variability, at least with respect to the genes of interest. Barr CS, Newman TK, Schwandt M, Shannon C, Dvoskin RL, Lindell SG, Taubman J, Thompson B, Champoux M, Lesch KP, Goldman D, Suomi SJ, Higley JD. Sexual dichotomy of an interaction between early experience and the serotonin transporter gene promoter variant in rhesus macaques. Proc Natl Acad Sci USA 2004;101:12358-12363. Newman TK, Syagallo YV, Barr CS, Wendland J, Champoux M, Graessie M, Suomi SJ, Higley JD, Lesch KP. MAOA gene promoter variation and rearing experience influences aggressive behavior in rhesus monkeys. Biol Psychiatry 2004, in press. Adaptation of laboratory-reared monkeys to field environments Kerekes, Miller, Morin, O’Neill Wagner, Roma, Shannon-Lindell, Suomi We assess adaptation by examining behavioral repertoires and monitoring a variety of physiological systems in monkeys throughout the lifespan, yielding broad-based indices of relative physical and psychological well-being. In similar fashion, we assess the responses of subjects to experimental manipulations of selected features of their respective environments. Whenever possible, we collect field data for appropriate comparisons. We also focus on investigating the cognitive, behavioral, and social processes involved in adaptation to new settings and circumstances. We began a pilot study to see if rhesus monkey neonates were capable of “imitating” specific facial expressions and hand movements directed toward them by a human “model” in their first days of life. Such early imitative capabilities have been reported for human neonates and are thought to be reflexively mediated by “mirror” neurons, a recently characterized class of visual-motor neurons found in Area F5 of the ventral premotor cortex. Preliminary findings indicated that some (but not all) rhesus monkey newborns were able to mimic specific facial expressions involving differential mouth and tongue movements, but not until their second or third day of life. Interestingly, the infants that demonstrated this imitative capacity spent significantly more time visually focusing on facial stimuli on Day 1 than those that did not exhibit any imitative behaviors on subsequent days. We are now testing additional infants and carrying out follow-up behavioral observations and biological sampling of the original infants to determine if individual differences in early imitative capabilities predict individual differences in biobehavioral functioning throughout subsequent development. We also completed most of the analyses of behavioral and biological data collected in a study in which some nursery-reared rhesus monkey infants (“masters”) were given operant control over access to highly desirable food treats, whereas other nursery-reared infants (“yoked controls”) received the same treats in the absence of any control. Analyses of behavioral and neuroendocrine data collected both in the infants’ home cages and in a novel environment indicated that the “master” subjects engaged in more exploratory and less anxious-like behavior and had lower levels of HPA activity than their yoked control counterparts. We are currently analyzing CSF monoamine metabolite concentrations obtained throughout the study. We completed data collection for a long-term prospective longitudinal study of maternal behavior across three successive generations of rhesus monkey females born and raised in our five-acre outdoor field enclosure. Analyses of the data should enable us to determine the degree to which specific patterns of maternal behavior exhibited toward successive offspring resemble those exhibited by the females’ mothers and grandmothers in both previous and (for those older females who continue to produce and rear offspring) concurrent years in each year’s birth cohort. Analyses of immunological data collected in another long-term prospective longitudinal study of free-ranging rhesus monkeys residing on the island of Cayo Santiago in Puerto Rico during the annual trapping of monkeys (for veterinary examinations) revealed a significant relationship between measures of immune system and HPA axis functioning and maternal dominance status in juvenile subjects. Monkeys whose mothers were low-ranking within their natal social groups exhibited higher cytotoxicity, greater numbers of C8 and C16 Raij targets, and higher concentrations of plasma cortisol than the offspring of more dominant mothers, demonstrating that differences in maternal rank have significant consequences not only for offspring social and emotional development but also for immune system and adrenocortical functioning. Another study investigated the relationship between social dominance ranking and food consumption as a function of food novelty and relative accessibility in a group of tufted capuchin monkeys. High-ranking group members consumed significantly more food that was easily accessible than portions hidden from view, whereas the reverse held for low-ranking subjects. Rates of aggressive threats by high-ranking monkeys toward lower-ranking monkeys were inversely related to the amount of food consumed by low-ranking group members. Thus, although tufted capuchin monkeys have been described as a relatively peaceable species (at least compared with rhesus monkeys) and readily share food in a variety of naturalistic and captive situations, dominance-related differences in food consumption appear to be mediated by differences in the relative occurrence and direction of threat behavior. Barr CS, Newman TK, Becker ML, Parker CC, Champoux M, Lesch KP, Suomi SJ, Goldman D, Higley JD. The utility of the non-human primate: model for studying gene by environment interactions in behavioral research. Genes Brain Behav 2003;2:336-340. Novak MF. Fetal-maternal interactions: psychobiological precursors to adaptive infant development. Curr Top Dev Biol 2004;59:37-60. Suomi SJ. Gene-environment interactions and the neurobiology of social conflict. Ann NY Acad Sci 2004;1008:132-139. Suomi SJ. How gene-environment interactions can influence emotional development in rhesus monkeys. In: Garcia-Cole C, Bearer EL, Lerner RM, eds. Nature and Nurture: the Complex Interplay of Genetic and Environmental Influences on Human Development. Mahwah, NJ: Lawrence Erlbaum Assoc., 2004;35-51. Suomi SJ. How gene-environment interactions shape biobehavioral development: lessons from studies with rhesus monkeys. Res Human Dev 2004;1:205-222. Tool use in rhesus monkeys Suomi; in collaboration with Novak MA, Westergaard We assessed tool-using capabilities in juvenile rhesus monkeys for tasks routinely solved by most capuchin monkeys. Subjects were required to use a rake to retrieve a reward located outside the cage or to use a PVC pipe to remove a reward from a tube. The sample of eight rhesus monkeys subjected to testing exhibited strong individual differences in capability. Two monkeys quickly solved the tool-using tasks, and three monkeys eventually solved them. Two monkeys showed partial understanding of the tasks but could not reliably obtain a reward, and the eighth rhesus subject failed both tasks. Successful tool users showed persistence in the tasks and varied their responses. Pivotal to their success was learning to push a tool away from them rather than pull it toward them. Unsuccessful monkeys became fixated on nonproductive strategies. Westergaard GC, Liv C, Rocca AM, Cleveland A, Suomi SJ. Tufted capuchins (Cebus apella) attribute value to food and tools during voluntary exchanges with humans. Anim Cogn 2004;7:19-24. COLLABORATORS Christina Barr, PhD, DVM, Laboratory of Clinical Sciences, NIAAA, Bethesda, MD Michelle Becker, PhD, Laboratory of Clinical Sciences, NIAAA, Bethesda, MD Allyson J. Bennett, PhD, Wake Forest University School of Medicine, Winston-Salem, NC Aron D. Brascomb, PhD, Columbia University, New York, NY Gayle D. Byrne, PhD, University of Maryland, College Park, MD Maribeth Champoux, PhD, Center for Scientific Review, DCPS, Bethesda, MD Carlo Contoreggi, MD, Brain Imaging Branch, NIDA, Baltimore, MD Barbara DeVinney, PhD, Office of Behavioral and Social Science Research, OD, Bethesda, MD Pier Ferrari, PhD, University of Parma, Italy Phillip W. Gold, MD, Clinical Neuroendocrinology Branch, NIMH, Bethesda, MD David A. Goldman, MD, Laboratory of Neurogenetics, NIAAA, Bethesda, MD J.D. Higley, PhD, Laboratory of Clinical Studies, NIAAA, Bethesda, MD Masanori Ichise, PhD, Molecular Imaging Branch, NIMH, Bethesda, MD Robert Innis, MD, Molecular Imaging Branch, NIMH, Bethesda, MD Mark L. Laudenslager, PhD, University of Colorado Health Sciences Center, Denver, CO K. Peter Lesch, MD, University of Würzburg, Germany Timothy K. Newman, PhD, Laboratory of Clinical Sciences, NIAAA, Bethesda, MD Melinda A. Novak, PhD, University of Massachusetts, Amherst, MA Eric Phoebus, PhD, University of Puerto Rico, Mayaguez, PR Becky Raboy, PhD, University of Maryland, College Park, MD Melanie L. Schwandt, PhD, Laboratory of Clinical Studies, NIAAA, Bethesda, MD Susan E. Shoaf, PhD, Laboratory of Clinical Studies, NIAAA, Bethesda, MD Angelika Timme, PhD, Freie Universität Berlin, Germany Elisabetta Visalberghi, PhD, Istituto de Scienze e Technologie della Cognizione, CNR, Rome, Italy Gregory C. Westergaard, PhD, Alpha Genesis, Inc., Yemassee, SC For further information, contact suomis@mail.nih.gov