This past year we continued our collaborative project with investigators from the Istituto di Sanita Superiore (Rome, Italy) characterizing developmental changes in nerve growth fThis past year we expanded our efforts to characterize developmental changes in peripheral measures of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) in rhesus monkeys with different early social rearing backgrounds by assaying plasma for NGF and BDNF collected longitudinally from monkeys reared from birth either by their biological mother (MR) or in the neonatal nursery with subsequent continuous access to peers (PR). We replicated our previous findings that plasma NGF levels increase sharply from two weeks to one year of age for both MR and PR subjects, essentially achieving adult levels at that point, with a significant age by rearing condition interaction: MR and PR infants initially have equivalent NGF levels, but as they grow older levels for PR infants increase more than do those of their MR counterparts. We found the opposite developmental pattern for BDNF: plasma levels for both sets of infants are highest at 2 weeks of age and thereafter decrease dramatically with increasing age. MR subjects have much higher 2-week levels than PR infants, but by 60 days of age this difference is reversed, with MR levels dropping more precipitously than those of PR infants. In addition, female infants consistently exhibit higher plasma BDNF levels than do males. Among PR (but not MR) infants plasma NGF and cortisol levels are significantly correlated. Finally, within each rearing group, individual differences in both plasma NGF and BDNF values are 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 human and rodent samples. In the coming year we plan to test whether the same or functionally similar polymorphisms are present in rhesus monkeys and whether any polymorphic differences in the rhesus monkey BDNF gene are associated with individual differences in plasma BDNF values throughout development. We initiated two other collaborative project comparing MR and PR rhesus monkeys on additional measures of biological functioning. The first involved researchers from UCSF, who have demonstrated differences in telomere length, thought to be a marker of relative cellular age, in adult humans as a function of differences in social status and cumulative social stress. These researchers hypothesized that such differences may have their origin in differential experiences with social stress during the childhood years, a period when telomere length shortens rapidly. Accordingly we have been providing them with DNA extracted from whole blood samples collected from both MR and PR monkeys throughout their first two years of life, a developmental period during which we have previously demonstrated major differences between MR and PR monkeys in the behavioral and biological responses to social stress. The DNA is currently being analyzed by our UCSF colleagues with respect to telomere length. The second collaboration is with colleagues from McGill University, who in an elegant series of studies have demonstrated that differential rates of maternal licking and grooming of rat pups during their second week of life result in different patterns of expression in the glucocorticoid receptor gene in hippocampal brain regions as a consequence of differential methylation, which in turn are associated with different patterns of behavioral and neuroendocrine response to social stress not only throughout the lifetime of the pups but in their own progeny as well. The collaboration involves assessing methylation patterns in hippocampal glucocorticoid receptor genes and in buccal samples and lymphocytes obtained from MR and PR monkeys throughout development; Those assessments are currently underway. A major focus of the Sections recent research has involved 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 the MAO-A gene, for a variety of measures of behavioral and biological functioning, including physical aggression, HPA reactivity, and central serotonin metabolism, throughout development in rhesus monkeys. This past year, in collaboration with colleagues from NIAAA, we characterized additional functional polymorphisms in the neuropeptide Y (NPY) promoter gene, the corticotrophin releasing factor (CRH)2A gene, and the mu opoid receptor gene and 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) have 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. Last year we published data characterizing the 5-HTT and MAO-A genes in 6 other macaque species: Barbary (M.sylvanis), crab-eating (M. fasicularis), pigtail (M. nemestrina), stumptail (M. arctoides), Tibetan (M. thibetanna), and Tonkenan (M. tonkeana). Unlike the case for rhesus monkeys, we found no functional polymorphisms for these two genes in any of these other macaque species. Moreover, for the 5-HTT gene, there was 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.This year we collected behavioral data and also obtained CSF samples from the Barbary, crab-eating, and Tonkenan macaque subjects whom we had previously genotyped for the 5-HTT gene in order to determine whether the strong inverse relationship between CSF 5-HIAA concentrations and levels of aggressive behavior previously demonstrated for humans and for rhesus and pigtail macaques also holds for these other macaque species and whether species differences in these measures parallel the species differences seen in promoter region length of the 5-HTT gene.