Developmental Continuity Of Individual Differences

该项目通过对恒河猴和其他猴子物种的纵向比较研究来调查灵长类动物的生物行为发育，特别强调对环境新奇性和挑战的不同行为和生理反应的个体模式的特征，并确定在不同的物理和社会环境中饲养的不同遗传背景的个体的长期发育后果。CBGS中的几项正在进行的研究集中在5-HTT多态性（由于启动子区域的长度变化）（一种受损的β-羟色胺能功能的候选基因）与不同的早期社会经验之间可能的相互作用。在过去的一年里，我们发表了一份关于恒河猴出生后第一个月内基因与环境相互作用的报告：相对于那些携带“长”（LL）等位基因的婴儿，携带“短”（LS）等位基因的婴儿在状态控制和视觉定向方面表现出缺陷，但只有在他们被托儿所抚养的情况下;相反，由其生物学母亲抚养的LS猴表现出正常的状态控制和视觉定向，表明母亲抚养的“缓冲”效应。其他研究显示，LS恒河猴在婴儿后期对社会分离的促肾上腺皮质激素反应方面，在青少年时期冲动攻击和社会游戏行为的表达方面，以及在青春期“快乐时光”情况下饮酒倾向方面，母亲缓冲的其他例子。一个平行模式的基因-环境相互作用，涉及在单胺氧化酶-A基因的多态性被发现的水平表现出的母亲和同龄人饲养的恒河猴少年的攻击行为。在过去的一年里，我们还确定和表征了CRH基因和神经肽Y基因中的其他多态性，以及多巴胺转运蛋白基因中的SNP，我们现在正在确定这些多态性中的任何一个或全部是否与特定的基因-环境相互作用有关，这些相互作用与我们恒河猴种群在整个发育过程中获得的各种行为和生物学指标有关。 相对于其他猕猴（事实上，相对于大多数其他灵长类动物），恒河猴作为一个物种是众所周知的侵略性;相比之下，巴巴利猕猴的侵略性相对较低，这是不寻常的。去年，我们能够对一组自由放养的巴巴利猕猴的5-HTT基因进行基因分型，与恒河猴的情况不同，我们没有发现具有LS或LL等位基因的个体。相反，所有的巴巴利猕猴样本都有一个“超长”（XL）等位基因，这种形式在迄今为止基因分型的恒河猴中发现不到2%。随后，我们对来自不同地理区域的巴巴利猕猴进行了基因分型，并复制了我们的初步发现，这表明XL等位基因确实代表了整个物种，而不是反映了特定的创始人效应。我们还对不同的巴巴利猕猴种群的MAO-A基因进行了基因分型，再次未能发现以前在恒河猴种群中观察到的多态性。我们现在正在对其他三种猕猴的5-HTT基因和MAO-A基因进行基因分型。我们还表征了大量其他非人灵长类动物物种中的5-HTT基因，这些物种代表了整个灵长类目的全部分类群，这是模拟灵长类动物中5-HTT进化史的第一步。在过去的一年里，我们还发表了一篇论文，证明脑室内（ICV）CRH输注与单独和熟悉的社会群体中的年轻成年恒河猴的焦虑样和焦虑导向行为的增加有关，以及社会群体环境中抑郁样行为的增加。ICV输注CRH也与杏仁核、垂体/漏斗和海马的葡萄糖代谢率显著增加相关，表明边缘系统脑活动增强。相比之下，CRH-R1受体拮抗剂antalarmin的给药不仅降低了具有高CRH-R1浓度的脑区域中的结合，而且还显著降低了右后颞叶皮层、丘脑和左右纹状体中的5 HT-2A结合，沿着左右前颞叶皮层、左右眶皮层和左右背外侧前额叶皮层中的边界降低，从而将灵长类动物脑中的HPA活性和肾上腺素能功能联系起来。最后，密歇根大学的同事对我们的一些母亲和同伴饲养的年轻成年恒河猴进行了死后研究，结果显示，由于早期饲养历史的差异，大脑结构和功能都存在显着差异。具体而言，同龄人饲养的猴子表现出显着较低的MR mRNA水平在海马，但有点矛盾，显着较高的MR mRNA水平在前额皮质，相对于他们的母亲饲养的同行。此外，同龄人饲养的猴子有显着较低的5-HT 1A mRNA水平和5-HTT结合在前额皮质。这些研究人员还发现，具有LS 5-HTT多态性的同龄人饲养的猴子与具有LL多态性的同龄人饲养的猴子相比，5-HT 1A mRNA水平显着降低，5-HTT结合减少，而LS和LL母亲饲养的受试者之间在这两项指标上均无显着差异，从而证明了在大脑结构和功能水平上的基因-环境相互作用。

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.