Developmental Continuity Of Individual Differences In Reactivity In Monkeys

在过去的一年里，我们通过分析从其亲生母亲(MR)或随后连续接触同伴(PR)的新生托儿所中纵向收集的血浆中脑源性神经营养因子(BDNF)和神经生长因子(NGF)的血浆，来表征具有不同早期社会养育背景的恒河猴外周神经营养因子(BDNF)和神经生长因子(NGF)的发育变化。我们重复了我们之前的发现，即BDNF水平在前两个月显著下降，然后在第一年的其余时间更缓慢地下降，除了PR女性，她们的水平在前两个月保持在较高水平。相比之下，NGF水平在前两个月保持相对稳定，然后从两个月到一岁急剧上升，基本上达到成年水平，但PR雄性除外，他们的NGF水平上升要早得多。在PR(但不是MR)婴儿中，血浆NGF和皮质醇水平显着相关。最后，在每个饲养群体中，血浆NGF和BDNF值的个体差异在整个发育过程中基本上是稳定的，这表明可能存在遗传影响。一个潜在的候选基因是BDNF基因，其功能多态在人类和啮齿动物中都有特征。今年，我们在恒河猴群体中发现了一种功能相似的BDNF多态，目前正在确定恒河猴BDNF基因的等位基因差异是否与血浆BDNF值和其他生物行为功能指标在整个发育过程中的个体差异有关。 在过去的一年里，我们完成了其他几项研究，比较了MR和PR猴子在整个发育过程中的差异。对2岁的MR和PR猕猴幼猴进行了两项脑神经成像研究。结构MRI显示，PR青少年的小脑鞭、内侧前额叶皮质和背侧前扣带回的体积明显大于MR青少年。此外，PR女性的海马体体积显著小于PR男性以及MR男性和女性。对同一只猴子的宠物神经成像显示了性别和养育条件的影响：与雄性相比，雌性显著降低了大脑中5-HT1A受体的密度，雌性和雄性PR幼猴的5-HT1A受体密度都显著低于它们的MR同龄人。此外，雌性PR猴在前额叶皮质的5-HT1a结合电位(BP)显著高于MR雌性猕猴，而PR雄性猕猴在内侧扣带回皮质的BP显著低于MR雄性猕猴。另一项研究表明，早期养育历史的差异导致了偏侧性的差异：在青少年时期，MR猴子比PR猴子有更大的右撇子行为偏见。最后，在毛发样本的分析中，公关猴子的皮质醇水平长期高于公关猴子在其生命的第一年。 我们继续对另外两个项目的数据收集和分析，比较MR和PR猕猴对生物功能的其他衡量标准。第一项是与麦吉尔大学的同事合作，包括评估从年轻成年MR和PR受试者的海马体和前额叶皮质中获得的糖皮质激素受体基因的甲基化模式，以及从发育过程中纵向获得的MR和PR猴子的口腔样本和淋巴细胞中的甲基化模式；这些评估目前正在进行中。第二个项目是与加州大学洛杉矶分校和芝加哥大学的同事合作，对从婴儿时期起从MR和PR受试者那里纵向获得的淋巴细胞样本进行全基因组扫描，以确定在生命最初一周的基因表达模式中可能存在的养育条件差异，以及这些模式在整个发育过程中可能发生的不同变化。 这些部分的一个主要焦点是最近的研究涉及表征不同的早期社会教养与几个候选基因(G×E相互作用)之间的相互作用，其中最著名的是5-羟色胺转运体基因(5-HTT)和MAO-A基因，用于衡量MR和PR猕猴整个发育过程中的行为和生物功能的各种指标。在过去的一年里，我们在母亲照顾方式明显不同的MR婴儿中发现了涉及5-HTT多态的显著G x E交互作用。那些腹部接触和打扮水平较低的母亲的婴儿发声和探索较少，在野外测试中更被动，但只有在携带“短”的5-HTT等位基因的情况下。此外，我们与NIAAA的同事合作，在促肾上腺皮质激素释放因子(CRH)2A基因和Mu阿片受体基因中发现了额外的功能多态性，并表征了与幼年恒河猴对社交分离的行为反应有关的特定G x E相互作用，以及在幼年成年猕猴的酒精偏好和消费的几个指标中。

This past year we characterized developmental changes in peripheral measures of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in rhesus monkeys with different early social rearing backgrounds by assaying plasma for BDNF and NGF 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 BDNF levels decrease dramatically over the first 2 months and then more gradually over the rest of the first year, except for PR females, whose levels remain high throughout their first 2 months. In contrast, NGF levels remains relatively stable for the first 2 months and then increases sharply from two months to one year of age, essentially achieving adult levels at that point, except for PR males whose increases in NGF levels occur much earlier. 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 humans and rodents. This year we identified a functionally similar BDNF polymorphism in our rhesus monkey colony and are now in the process of determining whether allelic differences in the rhesus monkey BDNF gene are associated with individual differences in plasma BDNF values and other measures of biobehavioral functioning throughout development. This past year we completed several other studies comparing MR and PR monkeys throughout development. Two brain neuroimaging studies were carried out on 2-yr-old MR and PR rhesus monkey juveniles. Structural MRI revealed that PR juveniles had significantly greater volume of cerebellar vermis, medial prefrontal cortex, and dorsal anterior cingulated cortex than MR juveniles. In addition, PR females had significantly lower hippocampal volume than PR males and both MR males and females. PET neuroimaging of the same monkeys revealed both gender and rearing condition effects: females had significantly reduced 5-HT1A receptor densities throughout the brain relative to males, and both female and male PR juveniles had significantly lower 5-HT1A receptor densities than their MR counterparts. In addition, female PR monkeys had significantly greater binding 5-HT1A binding potential (BP) in prefrontal cortex than MR females, whereas PR males had significantly lower BP than MR males in the medial cingulated cortex. Another study demonstrated that differences in early rearing history resulted in differences in laterality: as adolescents, MR monkeys had a greater right-handed behavioral bias than did PR monkeys. Finally, PR monkeys had chronically higher levels of cortisol, as assessed in assays of hair samples, than did PR monkeys throughout their first year of life. We continued data collection and analysis on two other projects comparing MR and PR rhesus monkeys on additional measures of biological functioning. The first, a collaboration with colleagues from McGill University, involves assessing methylation patterns in glucocorticoid receptor genes in hippocampus and prefrontal cortex obtained from young adult MR and PR subjects and in buccal samples and lymphocytes obtained longitudinally from MR and PR monkeys throughout development; those assessments are currently underway. The second project, a collaboration with colleagues from UCLA and the University of Chicago, involves whole genome scanning of lymphocyte samples obtained longitudinally from MR and PR subjects from infancy onward in order to identify possible rearing condition differences in patterns of gene expression in the initial week of life and how those patterns might change differentially throughout development. 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 throughout development in MR and PR rhesus monkeys. This past year we identified significant G x E interactions involving the 5-HTT polymorphism among MR infants whose mothers differed significantly in their care-giving patterns. Infants whose mothers exhibited low levels of ventral contact and grooming vocalized and explored less and were more passive in an open field test but only if they carried the "short" 5-HTT allele. In addition, in collaboration with colleagues from NIAAA, we identified additional functional polymorphisms in the corticotrophin releasing factor (CRH)2A gene, and the mu opioid receptor gene and characterized 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.