Our research involves broad-based investigation of primate biobehavioral development through comparative longitudinal studies of rhesus monkeys and other nonhuman primate species. Our primary goals are to characterize distinct biobehavioral phenotypes in our rhesus monkey colony, determine how genetic and environmental factors interact to shape the development of these primates, and 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 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, Lutz, Novak, Ruggiero, Shannon, Sheldon, Suomi; in collaboration with Alleva, Cirulli
In collaboration with Enrico Alleva and Francesca Cirulli, we investigated, in rhesus monkeys with different early social rearing backgrounds, possible developmental changes in the two neurotrophic factors: nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF). Plasma NGF levels increased sharply from one month to one year for both mother-reared (MR) and peer-reared (PR) subjects, essentially achieving adult levels at that point. We also observed a significant age-by-rearing-condition interaction: PR infants had marginally lower NGF values at one month but significantly higher levels at one year. We found the opposite developmental pattern for plasma BDNF: one-month levels were much higher in MR than PR infants, and values for both rearing groups dropped to adult levels by one year of age. Cerebrospinal (CSF) fluid assays for NGF and BDNF revealed the same general pattern of developmental change and interaction with rearing condition as for plasma samples.
During prepubertal development of PR monkeys, we documented consistent (from infancy to adolescence) deficits in CSF concentrations of 5-hydroxyindoleacetic acid (5-HIAA), the primary central serotonin metabolite, as compared with MR monkeys. Individual differences in CSF 5-HIAA concentrations were highly stable throughout development within both rearing groups. Second, we demonstrated 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. A third study documented early-rearing-condition differences in measures of social dominance and impulse control during the juvenile years. We also found significantly lower levels of serotonin transporter ligand binding potential and in cerebral blood flow, as determined by PET, in raphe, thalamus, striatum, frontal, and parietal brain regions of PR subjects.
In addition, we characterized interactions between differential early social rearing and a polymorphism in the serotonin transporter gene (5-HTT) on a variety of measures of behavioral and biological functioning throughout development in rhesus monkeys. Last year, we published a report of a specific gene-environment (G/E) interaction in rhesus monkey hypothalamic-pituitary-adrenal (HPA) responsiveness to short-term social separation at seven months. Monkeys with the “short” (LS) 5-HTT allele exhibited heightened ACTH responsiveness compared with those with the “long” (LL) allele, but only if the animals had been peer-reared. In contrast, LS monkeys reared by their biological mother did not differ in ACTH responsiveness from MR LL subjects, suggesting a “buffering” effect of maternal rearing. We found a parallel pattern of G/E interaction involving a polymorphism in the MAOA gene for levels of aggressive behavior exhibited by MR and PR rhesus monkey juveniles. We are now in the process of determining whether these and other functional polymorphisms in several candidate genes are associated with specific G/E interactions with respect to a variety of behavioral and biological measures obtained throughout development in our rhesus monkey colony.
As a species, rhesus monkeys are notoriously aggressive compared with most other primates. We genotyped 5-HTT for six other species of macaques: Barbary (M. sylvanis), crab-eating (M. fasicularis), pigtail (M. nemestrina), stumptail (M. arctoides), Tibetan (M. thibetanna), and Tonkean (M. tonkeana) macaques. Unlike in rhesus monkeys, we found no polymorphisms for the 5-HTT gene in any of these macaque species. Moreover, there was 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. Thus, all Barbary macaques sampled 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; all 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. Subsequent comparisons of potential polymorphisms in three other “candidate” genes among these seven 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 the candidate genes. Rhesus monkeys also differ from the other macaque species in terms of the size of their overall natural populations and the range of physical, social, and climatic environments in which they reside in nature, raising the possibility 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, Shannon C, Parker C, Dvoskin RL, Becker ML, Schwandt M, Champoux M, Lesch KP, Goldman D, Suomi SJ, Higley JD. Rearing condition and rh5-HTTLPR interact to influence LHPA-axis response to stress in infant macaques. Biol Psychiatry 2004;55:733-738.
Erickson K, Gabry KE, Schulkin J, Gold P, Lindell SG, Higley JD, Champoux M, Suomi SJ. Social withdrawal behaviors in nonhuman primates and changes in neuroendocrine and monoamine concentrations during a separation paradigm. Dev Psychobiol 2005;46:331-339.
Newman TK, Syagaiol Y, Barr CS, Wendland J, Champoux M, Graessle M, Suomi SJ, Higley JD, Lesch KP. Monoamine oxidase A gene promoter polymorphism and infant rearing experience interact to influence aggression and injuries in rhesus monkeys. Biol Psychiatry 2005;57:167-172.
Shannon C, Schwandt ML, Champoux M, Shoaf SE, Suomi SJ, Linnoila M, Higley JD. Maternal absence and stability of individual differences in CSF 5-HIAA concentrations in rhesus monkey infants. Am J Psychiatry 2005;162:1658-1664.
Wendland JR, Lesch KP, Newman TK, Timme A, Gachot-Neveu A, Thierry B, Suomi SJ. Differential functional variability of serotonin transporter and monoamine oxidase A genes in macaque species displaying contrasting levels of aggression-related behavior. Behav Genet 2005 [Epub ahead of print].
Adaptation of laboratory-reared monkeys to field environments
Kenney, Kerekes, Miller, Morin, Novak, O’Neill Wagner, Robbins, Semnani, Shannon, 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 investigate the cognitive, behavioral, and social processes involved in adaptation to new settings and circumstances.
We have continued to monitor maternal and fetal heart rate and blood pressure throughout the third trimester of pregnancy in several rhesus monkey females who had been surgically implanted with indwelling catheters that enabled us to record heart rate and blood pressure online continuously via a tethering device that permitted unimpeded locomotor and exploratory activity within the caging unit. Each pregnant female subsequently delivered an infant that exhibited normal neurological and behavioral postnatal development. Analyses of the prenatal data 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 produced comparable short-term increases in maternal heart rate. Significant increases in maternal heart rate in the context of cage restraint were associated with increases in both maternal and fetal blood pressure and significant decreases in fetal heart rate, whose recovery to baseline values essentially tracked those of maternal heart rate (albeit in the opposite direction). In contrast, significant increases in maternal heart rate following presentation of food treats were not associated with any significant changes in maternal blood pressure or in either fetal heart rate or blood pressure.
We also expanded our initial efforts to determine if rhesus monkey neonates are capable of “imitating” specific facial expressions and hand movements of a human “model.” 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. We found that, by two to three days after birth, some (but not all) of the newborns were able to mimic facial expressions involving mouth and tongue movements. Interestingly, infants that demonstrated this imitative capacity spent significantly more time focusing on facial stimuli on Day 1 than those who 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 subsequent biobehavioral functioning.
We completed 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. Additional analyses of CSF monoamine metabolite concentrations obtained throughout the study are currently under way.
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 veterinary trapping revealed significant relationships 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 offspring of more dominant mothers. The findings demonstrate that differences in maternal rank can have significant consequences not only for an offspring’s social and emotional development but also for its immune and adrenocortical functioning.
We investigated the relationship between social dominance ranking and food consumption as a function of food novelty and 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 was true for low-ranking subjects. Rates of aggressive threats by high-ranking monkeys toward lower-ranking individuals 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 (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 social threat behavior. However, despite these obvious social influences, the subjects’ behavior in restricted food choice situations appears to be motivated more by the experience of frustration than by aversion resulting from perceived social inequality.
Roma PG, Champoux M, Suomi SJ. Environmental control, social context, and individual differences in behavioral and cortisol responses to novelty in infant rhesus monkeys. Child Dev (in press).
Roma PG, Silberberg A, Ruggiero A, Suomi SJ. Capuchin monkeys, inequality aversion, and the frustration effect. J Comp Psychol (in press).
Suomi SJ. Aggression and social behaviour in rhesus monkeys. Novartis Found Symp 2005;268:216-226.
Suomi SJ. Animal research and its relevance to psychiatry. In: Saddock BJ, Saddock VA, eds. Comprehensive Textbook of Psychiatry (Vol. 1). Philadelphia: Lippincott Williams & Wilkins, 2005;692-700.
Suomi SJ. Mother-infant attachment, peer relationships, and the development of social networks in rhesus monkeys. Hum Dev 2005;48:67-79.
COLLABORATORS
Enrico Alleva, MD, Istituto Superiore di Sanità, Rome, Italy
Christina Barr, PhD, DVM, Laboratory of Clinical and Translational Studies, NIAAA, Poolesville, MD
Michelle Becker, PhD, Laboratory of Clinical and Translational Studies, 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
Barbara DeVinney, PhD, Office of Behavioral and Social Science Research, NIH, Bethesda, MD
Pier Ferrari, PhD, Università di Parma, Parma, Italy
Phillip W. Gold, MD, Clinical Neuroendocrinology Branch, NIMH, Bethesda, MD
David A. Goldman, MD, Laboratory of Neurogenetics, NIAAA, Bethesda, MD
James D. Higley, PhD, Laboratory of Clinical and Translational Studies, NIAAA, Poolesville, 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
Timothy K. Newman, PhD, Laboratory of Clinical and Translational Studies, NIAAA, Poolesville, MD
Melinda A. Novak, PhD, University of Massachusetts, Amherst, MA
Eric Phoebus, PhD, University of Puerto Rico, Mayaguez, PR
Melanie L. Schwandt, PhD, Laboratory of Clinical and Translational Studies, NIAAA, Poolesville, MD
Susan E. Shoaf, PhD, Laboratory of Clinical and Translational Studies, NIAAA, Bethesda, 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, NIMH, Bethesda, MD
For further information and publications, contact suomis@mail.nih.gov.