Developmental Continuity Of Individual Differences In Re

本项目通过恒河猴和其他猴类的纵向比较研究来研究灵长类动物的生物行为发育。本研究的主要目的是表征恒河猴群体中不同的生物行为表型，确定遗传和环境因素如何相互作用影响它们的发育，并评估来自不同遗传背景的猴子在不同的物理和社会环境中饲养时的长期行为和生物学后果。在过去的一年里，我们继续与意大利罗马高等卫生研究所的研究人员合作，研究不同早期社会抚养背景下恒河猴神经生长因子（NGF）和脑源性神经营养因子（BDNF）的发育变化。最初的研究检查了从出生起由其亲生母亲（MR）或在新生儿托儿所不断接触同伴（PR）饲养的猴子的血浆和脑脊液（CSF）中的NGF和BDNF水平；婴儿在1个月和1岁时再次取样，并将其值与单独成人样本的值进行比较。从一个月到一年，MR和PR受试者血浆NGF水平急剧上升，基本达到成人水平。养育条件的相互作用对年龄也有显著影响：MR婴儿在1个月时NGF值略高，但在1岁时水平显著降低。血浆BDNF的发育模式则相反：MR组1个月时的BDNF水平远高于PR组，两组在1岁时均降至成人水平。脑脊液中NGF和BDNF的检测结果与血浆样品中发现的发育变化和饲养条件相互作用的一般模式相同。第二项研究分别在14、30和60日龄的MR和PR婴儿中检测了血浆NGF和BDNF水平，基本上复制了NGF和BDNF的不同发展趋势。此外，PR婴儿在第60天的NGF值显著较高（但在第14天和第30天没有），而对于BDNF， MR婴儿在第14天的NGF值较高，但到第60天，其值已被PR婴儿超过。最后，在每个饲养组内，血浆NGF和BDNF值的个体差异在整个研究期间基本稳定。

This project investigates primate biobehavioral development through comparative longitudinal studies of rhesus macaques and other monkey species. Our primary goals in this research are to characterize different distinctive biobehavioral phenotypes in our rhesus monkey colony, to determine how genetic and environmental factors interact to shape their development, and to assess the long-term behavioral and biological consequences for monkeys from different genetic backgrounds when they are reared in different physical and social environments. This past year we continued our collaborative project with investigators from the Istituto di Sanita Superiore (Rome, Italy) characterizing 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 1 month and again at 1 year of age, and their values were 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: MR infants had marginally higher NGF values at one month but significantly lower levels at 1 year. The opposite developmental pattern was found for plasma BDNF: MR subjects had much higher 1-month levels than PR infants, and values for both rearing groups dropped to adult levels by 1 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, respectively, and it basically replicated 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 but by 60 days their values had been surpassed by those of PR infants. Finally, within each rearing group, individual differences in both plasma NGF and BDNF values were basically stable throughout the period of study. Long-term effects of differential early social rearing were also examined 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 6 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, respectively, whereas MR monkeys did not. Significant differences between MR and PR juveniles in serotonin transporter ligand binding potential and in cerebral blood flow, as determined by PET, were found in raphe, thalamus, striatum, frontal and parietal brain regions, with PR subjects exhibiting significantly lower levels for both measures in each region. Significant differences were found between young adult MR and PR monkeys? behavioral responses to a major change in social housing, with PR monkeys exhibiting greater behavioral disruption. Significant differences between MR and PR young adult monkeys were also seen in their behavioral and serotonergic response to chronic fluxotine treatment, as assessed in a standardized acoustic startle paradigm. In contrast, no differences were found in the maternal behavior of MR vs. PR mothers, nor did their offspring differ in their behavioral and adrenocortical responses to maternal separation at 6 months, indicating that the numerous biobehavioral consequences of differential early social rearing apparently were not being transmitted to the next generation of monkeys. A major focus of the Section?s recent research has involved characterizing interactions between differential early social rearing and polymorphisms in several ?candidate? genes (G x E interactions). Most notably, 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, HPA reactivity, and central serotonin metabolism, throughout development in rhesus monkeys. This past year, in collaboration with colleagues from the LCS, 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. This past 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. For example, all of the Barbary macaques sampled had an ?extra long? (XL) allele; this species is notably nonaggressive in both naturalistic and captive settings. All of the crab-eating, pigtail, stumptail, and Tonkean macaques sampled had the LL allele; these species are generally considered to be less aggressive than rhesus macaques. Finally, all of 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 are 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 CSF samples for 5-HIAA concentrations in order to determine if 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 these 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 if they are predictive of individual differences in aggression, as is the case with rhesus and pigtail macaques.