Developmental Continuity Of Individual Differences In Reactivity In Monkeys

猴子反应个体差异的发育连续性

• 批准号: 8941456
• 负责人: STEPHEN J. SUOMI
• 金额: $ 103.24万
• 依托单位: EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8941456
• 关键词: 8 year old; Adolescence; Adolescent; Adult; Affect; Age; Age-Months; Alcohol consumption; Alleles; Antibacterial Response; Antiviral Response; Behavioral; Binding; Biological; Birth; Brain; Brain region; Brain-Derived Neurotrophic Factor; Buffers; Cell Proliferation; Childhood; Chronic; Collaborations; Competence; DRD1 gene; Data; Data Analyses; Development; Environment; Environmental Risk Factor; Epigenetic Process; Exhibits; Fostering; Genetic; Genetic Polymorphism; Genetic Transcription; Glucocorticoids; Goals; Hair; Hand; Hour; Housing; Hydrocortisone; Hydroxyindoleacetic Acid; Individual; Individual Differences; Infant; Inflammation; Intervention; Leukocytes; Life; Longitudinal Studies; Lymphocyte; Lymphocyte Activation; Macaca mulatta; Magnetic Resonance Imaging; Measures; Metabolism; Methylation; Monkeys; Mothers; Naloxone; Neonatal; Nurseries; Opioid; Outcome; Outcome Measure; Pattern; Phenotype; Physical environment; Plasma; Play; Positron-Emission Tomography; Prefrontal Cortex; Primates; Puberty; Publishing; Reaction; Regulation; Reporting; Research; Research Project Grants; Sampling; Serotonin; Shapes; Social Behavior; Social Dominance; Social Environment; Specificity; Structure; Surrogate Mothers; T-Lymphocyte; Time; Tissues; Universities; biobehavior; comparative; environmental intervention; genome wide methylation; genome-wide; grandparent; indexing; mRNA Expression; male; neuropeptide Y; peer; physical conditioning; promoter; prospective; response; risk variant; serotonin transporter; social; social separation; stressor; treatment effect

As in previous years, a major focus of this project has been detailed longitudinal study of the behavioral and biological consequences of differential early social rearing, most notably comparing rhesus monkey infants reared by their biological mothers in pens containing adult males and other mothers with same-age infants for their first 6-7 months of life (MR), with monkeys separated from their mothers at birth, hand-reared in the labs neonatal nursery for their first month and then raised in small groups of same-age peers for their next 6 months (PR). In a third standard rearing environment, surrogate-peer rearing (SPR), infants are separated from their mothers and nursery reared just like PR infants, but then at 1 month are housed in individual cages containing an inanimate surrogate mother and additionally are placed in a play cage with 3 other like-reared peers for 2 hours daily for the next are 6 months. At 7-8 months of age, MR, PR, and SPR infants are all moved into one large pen, where they all live together until puberty. Thus, the differential social rearing occurs only for the first 7-8 months; thereafter MR, PR, and SPR all share the same physical and social environment. We previously demonstrated that PR monkeys cling more, play less, tend to be more impulsive and aggressive, and exhibit much greater behavioral and biological disruption during and immediately following short-term social separation at 6 months of age than MR monkeys, and they also exhibit deficits in serotonin metabolism (as indexed by chronically low values of CSF 5-HIAA), as do SPR monkeys, and they also have significantly lower levels of 5-HTT binding throughout many brain regions than do MR subjects. Many of these differences between MR and PR monkeys persist throughout the childhood years in the absence of experimental interventions. More recently we published data extending these rearing condition differences to include patterns of brain lateralization, cortisol concentrations in hair (a measure of chronic HPA activity), and measures of brain structure and function, as assessed by structural MRI and PET, respectively. Additional differences in measures of social dominance status, maternal competence, and physical health during childhood, adolescence, and adulthood were also documented. Somewhat surprisingly, however, MR and PR juveniles did not exhibit differential behavioral responses to chronic fluxotine treatment, and as adolescents their pattern of serotonin transporter distribution throughout their brains did not differ as a function of differential rearing but did reflect highly significant fluxotine treatment effects. Another major focus of recent research for this project has involved characterizing interactions between differential early social rearing and polymorphisms in several candidate genes (G X E interactions), most notably the 5HTTLPR gene. During the past year we expanded the range of outcomes for which G x E interactions involving the 5-HTTLPR polymorphism and early rearing condition differences appear, including social play, and behavioral reactions to a variety of social stressors, and in epigenetic regulation of brain activity. In addition, we recently reported significant G x E interactions between early MR vs.PR rearing and polymorphisms for several other candidate genes, including DRD1, neuropeptide Y, mu opioid (OPRMI), BDNF, NOS-1, and a SNP in the glucocorticoid gene, with outcome measures including play behavior, social buffering, behavioral and HPA reaction to an unfamiliar conspecific, naloxone treatment, alcohol consumption, and plasma BDNF concentrations. In virtually every case a similar pattern was observed: The less efficient (transcription-wise) allele was associated with a negative outcome ammong PR reared monkeys but a neutral or, in some cases, even an optimal outcome for MR reared subjects carrying that same less efficient allele, suggesting an overall buffering effect of MR rearing for individuals carrying these so-called risk alleles. Finally, we recently published the results of two sets of studies investigating the effects of differences in early social rearing (MR vs. SPR) on genome-wide patterns of mRNA expression in leukocytes, and on methylation patterns in prefrontal cortex and in T-cell lymphocytes. Our research involving mRNA expression, carried out in collaboration with Steven Cole and James Heckman, examined expression patterns in differentially reared 4-month-old infants. In all, 521 different genes were significantly more expressed in MR infants than in SPR infants, whereas the reverse was the case for another 717 genes. In general, SPR- reared infants showed enhanced expression in genes involved in inflammation, T-lymphocyte activation and cell proliferation, and suppression of antiviral and antibacterial responses, a pattern curiously also seen in leukocyte expression in adult humans who perceive themelves as socially isolated. Since that initial study we have completed a prospective longitudinal study in which differentially reared subjects are being sampled at 14 days, 30 days, 6-7 months, and every 4 months thereafter until they reach puberty. Data analyzed to date have revealed that the above rearing condition diffferences in genome-wide patterns of mRNA expression in leukocytes continue to be pervasive and persistent throughout development. The other set of studies, carried out in collaboration with Moshe Szyf and his lab at McGill University, involved genome-wide analyses of methylation patterns in differentially reared monkeys when they were adults. The initial study compared such patterns in prefrontal cortex tissue and T-cell lymphocytes obtained from 8-year-old monkeys differentially reared for their initial 6-7 weeks of life and thereafter maintained under identical conditions until adulthood. These analyses revealed that (a) more than 4,400 genes were differentially methylated in both PFC and lymphocytes, (b) although there was considerable tissue specificity, approximately 25% of the affected genes were identical in both PFC and lymphocytes, and (c) in both PFC and lymphocytes methylated promoters tended to cluster both by chromosomal region and gene function. Thuis past year we completed a prospective longitudinal study of genome-wide methylation patterns in lymphocytes, collecting samples from exactly the same MR and SPR monkeys at exactly the same time points as in the afore-mentioned longitudinal study of mRNA expression. Preliminary finding suggest that, at least in lymphocites, extensive rearing conditions are present within the first month of life but can at least in part be significantly minimized and/or re-directed subsequently following a social environmental intervention utilizing "foster" grandparents.

与往年一样，该项目的一个主要重点是对早期社会养育差异的行为和生物学后果进行详细的纵向研究，最值得注意的是，比较了由其亲生母亲在成年雄性和其他母亲与同龄婴儿的围栏中抚养的恒河猴婴儿在生命的前 6-7 个月（MR），以及在出生时与母亲分开，在实验室新生儿保育室中手工抚养的猴子的第一次出生。 一个月，然后在接下来的 6 个月内以同龄同龄人的小组形式长大（PR）。在第三种标准饲养环境中，即代理同伴饲养（SPR），婴儿与母亲分开，像 PR 婴儿一样在托儿所中饲养，但在 1 个月大时，被安置在装有无生命代理母亲的单独笼子中，另外与其他 3 个类似饲养的同伴一起被放置在游戏笼中，在接下来的 6 个月中每天 2 小时。 7-8 个月大时，MR、PR 和 SPR 婴儿都会被转移到一个大围栏中，在那里它们一起生活直到青春期。因此，差别化的社会教养只发生在最初的7-8个月；此后 MR、PR 和 SPR 都共享相同的物理和社会环境。我们之前证明，与 MR 猴相比，PR 猴在 6 个月大时更粘人，更少玩耍，更容易冲动和更具攻击性，并且在短期社会分离期间和之后表现出更大的行为和生物破坏，而且它们还表现出血清素代谢缺陷（以 CSF 5-HIAA 值长期较低为指标），SPR 猴也是如此，而且它们的血清素代谢水平也显着降低。 与 MR 受试者相比，5-HTT 结合遍及许多大脑区域。在没有实验干预的情况下，MR 和 PR 猴子之间的许多差异在整个童年时期持续存在。最近，我们发表的数据扩展了这些饲养条件差异，包括大脑偏侧化模式、头发中的皮质醇浓度（慢性 HPA 活动的衡量标准）以及大脑结构和功能的衡量标准（分别通过结构 MRI 和 PET 进行评估）。还记录了儿童期、青春期和成年期社会支配地位、母亲能力和身体健康指标的其他差异。然而，有些令人惊讶的是，MR 和 PR 青少年对长期氟索汀治疗并没有表现出不同的行为反应，并且作为青少年，他们整个大脑中的血清素转运蛋白分布模式并没有因差异饲养而有所不同，但确实反映了非常显着的氟索汀治疗效果。 该项目最近研究的另一个主要焦点涉及表征差异性早期社会教养与多个候选基因（G X E 相互作用）的多态性之间的相互作用，最显着的是 5HTTLPR 基因。在过去的一年里，我们扩大了涉及 5-HTTLPR 多态性和早期饲养条件差异的 G x E 相互作用的结果范围，包括社交游戏、对各种社会压力源的行为反应以及大脑活动的表观遗传调节。此外，我们最近报道了早期 MR 与 PR 饲养之间的显着 G x E 相互作用以及其他几个候选基因的多态性，包括 DRD1、神经肽 Y、μ 阿片类药物 (OPRMI)、BDNF、NOS-1 和糖皮质激素基因中的 S​​NP，结果测量包括游戏行为、社交缓冲、对不熟悉的同种纳洛酮的行为和 HPA 反应 治疗、饮酒和血浆 BDNF 浓度。几乎在每种情况下都观察到类似的模式：效率较低（转录方面）的等位基因与 PR 饲养的猴子的负面结果相关，但对于携带同样效率较低的等位基因的 MR 饲养的受试者来说，中性甚至在某些情况下甚至是最佳结果，这表明 MR 饲养对携带这些所谓的风险等位基因的个体具有总体缓冲作用。 最后，我们最近发表了两组研究的结果，调查了早期社会养育（MR 与 SPR）差异对白细胞全基因组 mRNA 表达模式以及前额皮质和 T 细胞淋巴细胞甲基化模式的影响。我们与 Steven Cole 和 James Heckman 合作进行了涉及 mRNA 表达的研究，检查了差异饲养的 4 个月大婴儿的表达模式。总共有 521 个不同基因在 MR 婴儿中的表达显着高于 SPR 婴儿，而另外 717 个基因的情况则相反。一般来说，SPR 喂养的婴儿表现出与炎症、T 淋巴细胞活化和细胞增殖以及抗病毒和抗菌反应抑制相关的基因表达增强，奇怪的是，在认为自己与社会隔离的成年人的白细胞表达中也发现了这种模式。自那项初步研究以来，我们完成了一项前瞻性纵向研究，其中对差异饲养的受试者在 14 天、30 天、6-7 个月以及此后每 4 个月进行一次采样，直到他们进入青春期。迄今为止分析的数据表明，上述饲养条件下白细胞 mRNA 表达模式的差异在整个发育过程中仍然普遍存在并持续存在。 另一组研究是与 Moshe Szyf 和他在麦吉尔大学的实验室合作进行的，涉及对不同饲养的猴子成年后的甲基化模式进行全基因组分析。最初的研究比较了前额皮质组织和 T 细胞淋巴细胞的这种模式，这些模式取自 8 岁的猴子，这些猴子在生命最初 6-7 周内进行了不同的饲养，此后一直保持在相同的条件下直到成年。这些分析表明，(a) PFC 和淋巴细胞中超过 4,400 个基因被差异甲基化，(b) 尽管存在相当大的组织特异性，但 PFC 和淋巴细胞中大约 25% 的受影响基因是相同的，(c) PFC 和淋巴细胞中甲基化启动子倾向于按染色体区域和基因功能聚类。去年，我们完成了一项淋巴细胞全基因组甲基化模式的前瞻性纵向研究，在与上述 mRNA 表达纵向研究完全相同的时间点从完全相同的 MR 和 SPR 猴子收集样本。初步发现表明，至少在淋巴细胞中，在生命的第一个月内存在广泛的饲养条件，但在利用“寄养”祖父母进行社会环境干预后，至少可以部分地显着最小化和/或重新定向。