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，我们发起了一个合作项目，调查两种神经营养因子可能的发育变化。神经生长因子（NGF）和脑源性神经营养因子（BDNF）在不同早期社会抚养背景恒河猴中的作用。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）饲养的猴子血浆和脑脊液（CSF）中的NGF和BDNF水平。研究人员分别在猴子1个月大时和1岁时对它们进行采样，并将它们的值与单独的成年样本进行比较。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也存在显著的年龄差异：PR婴儿在1个月时NGF值略低，但在1岁时水平显著较高。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。目前正在进行一项复制研究，在更大的MR和PR受试者样本中检查生命第一年的几个时间点。在其他几项比较MR和PR猕猴青春期前发育的研究中，进一步研究了不同早期社会养育的影响。一项研究记录了PR猴脑脊液中5-羟基吲哚乙酸（5-HIAA）（主要的中枢血清素代谢物）浓度与MR猴相比，从婴儿期到青春期一直存在一致的缺陷。两个饲养组脑脊液5-HIAA浓度的个体差异在整个发育过程中高度稳定。第二项研究表明，在6个月大的时候，短期社会分离后，早期饲养条件在生物行为反应方面存在差异：MR猴在肾上腺皮质和分离行为反应之间表现出强烈的联系，而PR猴在很大程度上没有这种联系。第三项研究记录了幼年时期社会支配和冲动控制的早期抚养条件差异。最后，通过PET测定，MR和PR青少年在中叶、丘脑、纹状体、额叶和顶叶脑区血清素转运体结合电位和脑血流量方面存在显著差异，PR受试者在每个区域的这两项测量水平都明显较低。

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 initiated a collaborative project investigating possible developmental changes in two neurotrophic factors ? 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 plasma and in 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 monkey subjects were sampled at 1 month and again at 1 year of age, and their values were compared with those of 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: PR infants had marginally lower NGF values at one month but significantly higher 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 replication study examining several time points within the first year of life in a larger sample of MR and PR subjects is currently underway. The effects of differential early social rearing were further investigated in several other studies comparing MR and PR rhesus monkeys during prepubertal development. One study documented consistent deficits among PR monkeys in CSF concentrations of 5-hydroxyindoleacetic acid (5-HIAA), the primary central serotonin metabolite, relative to those of MR monkeys, from infancy to adolescence. Individual differences in CSF 5-HIAA concentrations were highly stable throughout development within both rearing groups. A second study demonstrated 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. A third study documented early rearing condition differences in measures of social dominance and impulse control during the juvenile years. Finally, 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. A major focus of the Section?s recent research has involved characterizing 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. This past year we published a report of a specific gene-environment (G x E) interaction in rhesus monkey HPA responsiveness to short-term social separation at 7 months of age. Monkeys with the ?short? (LS) 5-HTT allele exhibited heightened ACTH responsiveness relative to those with the ?long? (LL) allele, but only if they 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. A parallel pattern of G x E interaction involving a polymorphism in the MAOA gene was found 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 x E interactions with respect to a variety of behavioral and biological measures obtained throughout development in our rhesus monkey colony. Gene x environment interactions were further investigated from a comparative perspective. Rhesus monkeys are notoriously aggressive as a species, relative to other macaques (indeed, relative to most other primates). Last year we were able to genotype for 5-HTT biological samples obtained from 6 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 the case for rhesus monkeys, we found no polymorphisms for this gene in any of these other 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 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 most rhesus monkeys. Subsequent comparisons of potential polymorphisms in three other ?candidate? genes among these 7 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 these different candidate genes. Rhesus monkeys also differ from these 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 intriguing possibility that their relative ?success? as a species may be somehow related to their genetic variability, at least with respect to these particular genes.