Stephen J. Suomi, PhD, Head, Section on Comparative Behavior Genetics
Kathlyn L. Robbins, PhD, Research Psychologist
Sue B. Higley, BA, Technician Psychologist
Peggy O'Neill Wagner, MA, Senior Research Assistant
Corrine M. Lutz, PhD, Postdoctoral Fellow
Matthew F.X. Novak, PhD, Postdoctoral Fellow
Consuel S. Ionica, PhD, Visiting Fellow
Annika Paukner, PhD, Visiting Fellow
Khalisa Herman, MS, Predoctoral Fellow
Lisa Darcey, BS, Postbaccalaureate Fellow
Carolyn Kenney, BS, Postbaccalaureate Fellow
Angela Ruggiero, BS, Postbaccalaureate Fellow
Katalin Kerekes, BS, Technician-in-Training
Michelle L. Miller, BS, Technician-in-Training
Lisa Morin, BS, Technician-in-Training
Margaret K. Unkefer, BS, Technician-in-Training
Sarah J. Ubehagen, BS, Technician-in-Training

Our research involves broad-based investigation of primate biobehavioral development through comparative longitudinal studies of rhesus monkeys and other primate species. Our primary goals are to characterize different distinctive biobehavioral phenotypes in our rhesus monkey colony, to determine how genetic and environmental factors interact to shape the monkeys' development, and to assess 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 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

Darcey, Herman, Higley, Lutz, Paukner, Ruggiero, Suomi, Ubehagen; in collaboration with Barr, Goldman, Heilig, Higley, Ichise, Innis, Lesch, Newman, Schwandt, Timme, Wendland

This past year we continued our collaborative project with investigators from the Istituto di Sanità Superiore to characterize developmental changes in nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) in rhesus monkeys with different early social rearing backgrounds. The initial study examined NGF and BDNF levels in both plasma and cerebrospinal fluid (CSF) in monkeys reared from birth either by their biological mother (MR) or in the neonatal nursery with continuous access to peers (PR). The infants were sampled at one month and again at one year of age and their values compared with those from a separate adult sample. Plasma NGF levels increased sharply from one month to one year for both MR and PR subjects, essentially achieving adult levels at that point. There was also a significant age-by-rearing condition interaction: compared with PR infants, MR infants had marginally higher NGF values at one month but significantly lower levels at one year. We observed the opposite developmental pattern for plasma BDNF: MR subjects had much higher one-month levels than PR infants, and values for both rearing groups dropped to adult levels by one year of age. CSF assays for NGF and BDNF revealed the same general pattern of developmental change and interaction with rearing condition as was found for the plasma samples. A second study examined plasma NGF and BDNF levels in a larger group of MR and PR infants at 14, 30, and 60 days of age, basically replicating the different developmental trends for NGF and BDNF. In addition, PR infants had significantly higher NGF values at 60 days (but not at 14 and 30 days), whereas, for BDNF, MR infants had higher values at 14 days; by 60 days, however, their values had been surpassed by those of PR infants. Finally, within each rearing group, individual differences in both plasma NGF and BDNF values remained essentially stable throughout the period of study.

We also examined long-term effects of differential early social rearing in several other studies comparing MR and PR rhesus monkeys throughout prepubertal development. One study demonstrated significant early rearing condition differences in biobehavioral response profiles following short-term social separations at six months of age: whereas MR monkeys showed strong links between adrenocortical and behavioral responses to separation, those links were largely absent in PR monkeys. In contrast, PR monkeys showed comparably strong links between behavioral responses to separation and CSF levels of the metabolites for dopamine, norepinepherine, and serotonin, whereas MR monkeys did not. We found significant differences between MR and PR juveniles in serotonin transporter ligand-binding potential and in cerebral blood flow, as determined by PET, in raphe, thalamus, striatum, and frontal and parietal brain regions, with PR subjects exhibiting significantly lower levels for both measures in each region. We found significant differences between young adult MR and PR monkeys' behavioral responses to a major change in social housing, with PR monkeys exhibiting greater behavioral disruption. We also observed significant differences between MR and PR young adult monkeys in their behavioral and serotonergic response to chronic fluxotine treatment, as assessed in a standardized acoustic startle paradigm. In contrast, we found no differences in the maternal behavior of MR versus PR mothers, and their offspring did not differ in their behavioral and adrenocortical responses to maternal separation at six months, indicating that the numerous biobehavioral consequences of differential early social rearing were apparently not transmitted to the next generation of monkeys.

A major focus of our recent research has involved characterization of interactions between differential early social rearing and polymorphisms in several "candidate" genes (G x E interactions). Most notably, throughout development in rhesus monkeys, we have demonstrated significant G x E interactions involving functional polymorphisms in the serotonin transporter gene (5-HTT) and the MAO-A gene for a variety of measures of behavioral and biological functioning, including physical aggression, hypothalamic pituitary axis (HPA) reactivity, and central serotonin metabolism. This past year, in collaboration with colleagues from the Laboratory of Clinical Sciences, NIAAA, we characterized additional functional polymorphisms in the neuropeptide Y (NPY) promoter gene, the corticotrophin releasing factor (CRH)2A gene, and the mu opioid receptor gene. We demonstrated specific G x E interactions with respect to behavioral responses to social separation by juvenile rhesus monkeys as well as in several measures of alcohol preference and consumption among young adult monkeys.

As previously mentioned, rhesus macaques (and humans) exhibit functional polymorphisms in the 5-HTT and MAO-A genes, and in both species interactions of these polymorphisms with differential early experiences have been linked to developmentally stable individual differences in aggressiveness. This past year, we published data characterizing the 5-HTT and MAO-A genes in six other macaque species: Barbary (M. sylvanis), crab-eating (M. fasicularis), pigtail (M. nemestrina), stumptail (M. arctoides), Tibetan (M. thibetana), and Tonkenan (M. tonkeana). Unlike the case for rhesus monkeys, we found no functional polymorphisms for the two genes in any of the other macaque species. Moreover, for the 5-HTT gene, we observed an apparent inverse relationship between the relative length of the promoter region and the relative level of aggressiveness that has been reported from field observations of each species. For example, all the sampled Barbary macaques had an "extra long" (XL) allele; this species is notably nonaggressive in both naturalistic and captive settings. All the sampled crab-eating, pigtail, stumptail, and Tonkean macaques had the LL allele; these species are generally considered less aggressive than rhesus macaques. Finally, all the Tibetan macaques had an "extra short" (XS) allele not seen in any of the other species; recent field data suggest that these monkeys are even more aggressive than most rhesus monkeys. This past year, we collected CSF samples from the Barbary, crab-eating, and Tonkean macaque subjects who provided some of the above genotypic data. We are currently assaying these samples for 5-HIAA concentrations to determine whether species differences in characteristic 5-HTT genotypes parallel species differences in CSF 5-HIAA concentrations, as we previously showed in rhesus-pigtail macaque comparisons. We are also collecting additional samples of CSF 5-HIAA in each of Barbary, crab-eating, and Tonkean macaque species as well as observational data on aggression and other behavioral patterns to determine whether individual differences in 5-HIAA are stable over time and predictive of individual differences in aggression, as is the case with rhesus and pigtail macaques.

Selected Publications

Barr CS, Schwandt ML, Lindell SG, Suomi SJ, Goldman D, Heilig M, Higley JD. Mu opioid receptor gene variation is associated with alcohol response and consumption in rhesus monkeys. Arch Gen Psychiat (in press).

Adaptation of laboratory-reared monkeys to field environments

Ionica, Kenney, Kerekes, Miller, Morin, Novak, O'Neill Wagner, Paukner, Robbins, Suomi, Unkefer, in collaboratin with Champoux, Ferrari, Novak, Visalberghi

We assess adaptation in our monkeys by examining their behavioral repertoires and monitoring a variety of physiological systems throughout their 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 investigate the cognitive, behavioral, and social processes involved in adaptation to new settings and circumstances.

We continued our research program investigating prenatal development by monitoring maternal and fetal heart rate and blood pressure throughout the third trimester of pregnancy in rhesus monkey females surgically implanted with indwelling catheters. This preparation enables us to record these measures continuously online via a tethering device that permits unimpeded locomotor and exploratory activity within the caging unit. To date, each implanted female subsequently has successfully delivered an infant that exhibited normal neurological and behavioral postnatal development. Analyses of the prenatal data collected to date focused on changes in maternal and fetal heart rate and blood pressure following two types of short-term experimental manipulations: cage restraints and presentation of food treats, which each reliably produced comparable short-term increases in maternal heart rate. Throughout the period of prenatal study, changes in maternal blood pressure following each manipulation were reliably associated with parallel changes in fetal blood pressure. In contrast, significant increases in maternal heart rate in the context of cage restraint were associated with concomitant decreases in fetal heart rate, whose recovery to baseline values essentially tracked those of maternal heart rate (albeit in the opposite direction).

This past year we published our initial efforts to characterize how effectively rhesus monkey neonates can imitate 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 and chimpanzee 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. We found that some (but not all) tested newborns were able to mimic specific facial expressions involving mouth and tongue movements, but not until day 2 or 3 of life; after day 10, the human model could no longer elicit these imitative responses. Interestingly, those infants who demonstrated the 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 carrying out follow-up behavioral observations and biological sampling of these infants to determine if individual differences in their early imitative capabilities are predictive of individual differences in their biobehavioral functioning throughout subsequent development.

We also expanded an ongoing program of research designed to assess emerging cognitive capabilities in nursery-reared monkeys during their initial months of life. We have long assessed infants on a variety of tests of neurobehavioral functioning throughout their first five weeks of life, but this past year we began assessing the development of object permanence in nursery-reared infants, starting in their sixth week. In addition, we introduced the infants to a different cognitive assessment paradigm that used a WGTA test battery. Some infants began adaptation testing at two months of age, others at three months, and the remainder at four months. The infants that began adaptation training at two months took longer to complete the training regimen than those that started at older ages, but once trained, they solved the initial discrimination task more rapidly than the other groups, suggesting that some degree of latent learning may have occurred during their adaptation training. Across all age groups, performance on the object permanence task appeared to be unrelated to performance on discrimination tasks in the WGTA test battery, suggesting that the two test paradigms are assessing qualitatively different aspects of rhesus monkey cognitive development.

Preventing the development of self-injurious behavior (SIB), currently exhibited by as many as 10 percent of the rhesus monkeys maintained in the eight National Primate Centers across the United States, represents a major challenge for primate veterinarians and colony managers alike. Prospective longitudinal research has indicated that virtually all monkeys who engage in SIB as adults began exhibiting non-injurious self-biting behavior during their juvenile years. This past year, we completed a study designed to identify risk factors for and early predictors of self-biting behavior in our colony. We observed incidents of self-biting in only a small subset of rhesus monkeys that had been reared in the nursery with artificial surrogate "mothers" and limited (two hours per day) access to peers; we never observed any self-biting in infants reared by their biological mothers or with continuous contact with peers during their first six months of life. Among the surrogate-peer-reared monkeys, those that engaged in the lowest level of physical contact with peers during their daily interaction sessions were the most likely to develop self-biting behavior during their juvenile years.

Finally, this past year we developed and pilot-tested surrogate "mothers" designed to generate infant-initiated movement in nursery-reared monkeys by hanging the surrogates from the top of the infant's rearing cage rather than using the standard floor-mounted design that has been in use in most primate nurseries for the past half-century. Initial comparisons of infants reared on hanging surrogates with those reared on the standard model revealed that hanging surrogate-reared infants had superior visual and auditory orienting capabilities during their first month, developmentally accelerated crawling behavior and greater activity levels in novel settings during their second month, superior performance on object permanence tests during their third month, and higher levels of locomotion and environmental exploration during months six to eight. We are currently collecting additional behavioral and biological data from these infants during their second and third years of life to determine if these developmental advantages persist throughout the childhood years.

Selected Publications

COLLABORATORS

Enrico Alleva, MD, Istituto Superiore di Sanità, Rome, Italy
Christina Barr, PhD, DVM, Laboratory of Clinical Sciences, NIAAA, Poolesville, MD
Michelle Becker, PhD, Laboratory of Clinical Sciences, NIAAA, Poolesville, MD
Allyson J. Bennett, PhD, Wake Forest University School of Medicine, Winston-Salem, NC
Gayle D. Byrne, PhD, University of Maryland, College Park, MD
Maribeth Champoux, PhD, Center for Scientific Review, NIH, Bethesda, MD
Francesca Cirulli, PhD, Istituto Superiore di Sanità, Rome, Italy
Pier Ferrari, PhD, Università di Parma, Parma, Italy
Melissa Gerald, PhD, Caribbean Primate Research Center, Punta Santiago, PR
David A. Goldman, MD, Laboratory of Neurogenetics, NIAAA, Bethesda, MD
Markus Heilig, MD, Laboratory of Clinical Studies, 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, Universität Würzburg, Würzburg, Germany
E. Nelson, PhD, Neurobiology Non-Human Primate Core, NIMH, Bethesda, MD
Timothy K. Newman, PhD, Laboratory of Clinical Sciences, NIAAA, Poolesville, MD
Melinda A. Novak, PhD, University of Massachusetts, Amherst, MA
Melanie L. Schwandt, PhD, Laboratory of Clinical Sciences, NIAAA, Poolesville, MD
Susan E. Shoaf, PhD, Laboratory of Clinical Sciences, NIAAA, Poolesville, MD
Alan Silberberg, PhD, American University, Washington, DC
Simona Spinelli, PhD, Laboratory of Clinical Sciences, NIAAA, Poolesville, MD
Bernard Thierry, PhD, Centre d' Ecologie, Physiologie et Ethologie, CNRS, Strasbourg, France
Angelika Timme, PhD, Freie Universität Berlin, Berlin, Germany
Elisabetta Visalberghi, PhD, Istituto de Scienze e Technologie della Cognizione, CNR, Rome, Italy
Jens Wendland, PhD, Laboratory of Clinical Sciences, NIAAA, Poolesville, MD
James T. Winslow, PhD, Neurobiology Non-Human Primate Core, NIMH, Bethesda, MD

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