Developmental Continuity Of Individual Differences In Reactivity In Monkeys

在过去的一年里，我们研究了不同早期社会抚养背景的恒河猴的脑源性神经营养因子（BDNF）和神经生长因子（NGF）的外周测量的发育变化，通过纵向分析从出生后由其生母（MR）饲养或在新生儿保育室中连续接触同伴（PR）饲养的猴子的血浆BDNF和NGF。我们重复了之前的发现，BDNF水平在头两个月急剧下降，然后在第一年剩下的时间里逐渐下降，除了PR雌性，它们的水平在头两个月保持很高。相比之下，NGF水平在头2个月保持相对稳定，然后从2个月到1岁急剧上升，基本上达到成人水平，除了PR男性的NGF水平增加得更早。在PR（而非MR）婴儿中，血浆NGF和皮质醇水平显著相关。最后，在每个饲养组中，血浆NGF和BDNF值的个体差异在整个发育过程中基本稳定，这表明可能存在遗传影响。一个潜在的候选基因是BDNF基因，其功能多态性已在人类和啮齿动物中被表征。今年，我们在恒河猴群体中发现了功能相似的BDNF多态性，现在正在确定恒河猴BDNF基因的等位基因差异是否与血浆BDNF值的个体差异以及整个发育过程中生物行为功能的其他指标有关。

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.