This project investigates primate biobehavioral development through comparative longitudinal studies of rhesus macaques and other monkey species, with special emphasis on characterizing individual patterns of differential behavioral and physiological responses to environmental novelty and challenge and on determining long-term developmental consequences for individuals of different genetic backgrounds reared in different physical and social environments. Several ongoing studies in the CBGS 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. This past year we published a report of a specific gene-environment interaction in rhesus monkeys during their first month of life: infants with the """"""""short"""""""" (LS) allele exhibited deficits in measures of state control and visual orienting relative to those with the """"""""long"""""""" (LL) allele, but only if they had been nursery-reared; in contrast, LS monkeys reared by their biological mother showed normal state control and visual orienting, suggesting a """"""""buffering"""""""" effect of maternal rearing. Other studies revealed additional examples of maternal buffering for LS rhesus monkeys with respect to ACTH response to social separation in late infancy, in the expression of impulsive aggression and social play behavior during the juvenile years, and in propensity to consume alcohol in a """"""""happy hour"""""""" situation during adolescence. A parallel pattern of gene-environment interaction involving a polymorphism in the MAO-A gene was found for levels of aggressive behavior exhibited by mother- and peer-reared rhesus monkey juveniles. This past year we also identified and characterized additional polymorphisms in the CRH gene and in the Neuropeptide Y gene, as well as a SNP in the dopamine transporter gene, and we are now in the process of determining whether any or all of these 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. Rhesus monkeys are notoriously aggressive as a species, relative to other macaques (indeed, relative to most other primates); by contrast, Barbary macaques are unusual in their relatively low levels of aggression. Last year we were able to genotype members of a group of free-ranging Barbary macaques with respect to the 5-HTT gene and, unlike the case for rhesus monkeys, we found no individuals with either the LS or the LL allele. Instead, all of the Barbary macaques sampled had an """"""""extra long"""""""" (XL) allele, a form found in less than 2% of the rhesus monkeys genotyped to date. We subsequently genotyped additional Barbary macaques who came from different geographic regions than our original group and replicated our initial findings, suggesting that this XL allele is indeed representative of the species as a whole rather than reflecting a specific founder effect. We also genotyped the different Barbary macaque populations with respect to the MAO-A gene and once again failed to find the polymorphism previously seen in our rhesus monkey population. We are now genotyping both the 5-HTT gene and the MAO-A gene in three other species of macaques. We are also characterizing the 5-HTT gene in a large number of other nonhuman primate species representing the full range of taxa across the entire primate order as a first step in modelling the evolutionary history of 5-HTT in primates. This past year we also published a paper demonstrating that intracebroventricular (ICV) infusions of CRH were associated with increases in both anxiety-like and observer-directed behaviors in young adult rhesus monkeys housed both individually and in familiar social groups, as well as increases in depressive-like behaviors in the social group setting. ICV infusions of CRH were also associated with significant increases in glucose metabolism rates in amygdala, pituitary/infundibulum, and hippocampus, indicating enhanced limbic brain activity. In contrast, administration of the CRH-R1 receptor antagonist antalarmin not only decreased binding in brain regions with high CRH-R1 concentrations but also significantly decreased 5HT-2A binding in right posterior temporal cortex, thalamus, and left and right striatum, along with borderline decreases in left and right anterior temporal cortex, left and right orbital cortex, and left and right dorsolateral prefrontal cortex, thus linking HPA activity and serotonergic function in the primate brain. Finally, postmortem studies of some of our mother- and peer-reared young adult rhesus monkeys conducted by colleagues at the University of Michigan revealed significant differences in both brain structure and function as a result of differential early rearing history. Specifically, peer-reared monkeys exhibited significantly lower MR mRNA levels in hippocampus but, somewhat paradoxically, significantly higher MR mRNA levels in prefrontal cortex, relative to their mother-reared counterparts. In addition, peer-reared monkeys had significantly lower 5-HT1A mRNA levels and less 5-HTT binding in prefrontal cortex. These investigators also found that peer-reared monkeys with the LS 5-HTT polymorphism had significantly lower 5-HT1A mRNA levels and less 5-HTT binding than peer-reared monkeys with the LL polymorphism, whereas there were no significant differences between LS and LL mother-reared subjects in either measure, thus demonstrating a gene-environment interaction at the level of brain structure and function.
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