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: 9553308
• 负责人: STEPHEN J. SUOMI
• 金额: $ 35.51万
• 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/9553308
• 关键词: 2 year old; 8 year old; Adolescence; Adolescent; Adult; Affect; Age; Age-Months; Aggressive behavior; Alcohol consumption; Alleles; Antibacterial Response; Antiviral Response; Attention; Behavior; Behavioral; Binding; Biological; Birth; Brain; Brain region; Brain-Derived Neurotrophic Factor; Buffers; Candidate Disease Gene; Cell Proliferation; Childhood; Childhood Acute Lymphocytic Leukemia; Chronic; Collaborations; DRD1 gene; Data Analyses; Data Reporting; Development; Disease; Environmental Risk Factor; Epigenetic Process; Exhibits; Female; Fostering; Generations; Genes; Genetic; Genetic Polymorphism; Genetic Transcription; Genome; Glucocorticoids; Goals; Hand; Health; Hour; Hydroxyindoleacetic Acid; Impulsivity; Individual; Individual Differences; Infant; Infection; Inflammation; Intervention; Leukocytes; Life; Longitudinal Studies; Longitudinal prospective study; Lymphocyte; Lymphocyte Activation; Macaca mulatta; Mediating; Metabolism; Monkeys; Mothers; Naloxone; Neonatal; Nurseries; Opioid; Outcome; Outcome Measure; Paper; Pattern; Phenotype; Physical environment; Placenta; Plasma; Play; Prefrontal Cortex; Primates; Puberty; Publications; Publishing; Reaction; Recording of previous events; Reporting; Research; Research Project Grants; Sampling; Serotonin; Sex Characteristics; Shapes; Social Dominance; Social Environment; Social status; Specificity; Sum; Surrogate Mothers; T-Lymphocyte; Time; Tissues; Universities; Weaning; attenuation; behavioral study; biobehavior; comparative; emerging adult; environmental intervention; epigenetic regulation; gene function; genome-wide; genome-wide analysis; grandparent; indexing; infancy; mRNA Expression; male; methylation pattern; neuropeptide Y; offspring; peer; prepuberty; promoter; risk variant; sex; social; social group; social separation; stressor; telomere; transmission process; virtual

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 and others 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 or housed in individual cages containing an inanimate surrogate mother and given 2 hours of daily interaction with like-reared peers (NR). At 7-8 months of age, MR and NR 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 and NR all share the same physical and social environment. We previously demonstrated that NR 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).. Additionally, they have significantly lower levels of 5-HTT binding throughout many brain regions than do MR subjects. Many of these differences between MR and NR monkeys persist throughout the childhood years in the absence of experimental interventions. For example, this past year we published data reporting that adult female NR monkeys had shorter lymphocyte telomeres than their MR counterparts, We have also found that NR monkeys required greater veterinary attention with respect to treatment for G-I disorders, infections, and wounds than MR monkeys during adolescence and early adulthood 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 two years 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.NR 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 aggression, 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 has been observed: The less efficient (transcription-wise) allele was associated with a negative outcome among NR 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. Additionally, we recently published the results of two sets of studies investigating the effects of differences in early social rearing (MR vs. NR) 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, NR infants showed enhanced expression in genes involved in inflammation, T-lymphocyte activation and cell proliferation, and suppression of antiviral and antibacterial responses. 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 3 months thereafter until they reach puberty. Data analyzed to date have revealed that the above rearing condition differences in genome-wide patterns of mRNA expression in leukocytes persist throughout development in the absence of any changes in the social environment but change dramatically whenever the social environment is altered during the juvenile years. These new findings are currently being prepared for publication. 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 monthsand 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. This 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 study of mRNA expression. Finding published this past year suggest that, at least in lymphocytes, extensive rearing conditions are present within the first month of life but can at least be significantly reversed following a social environmental intervention utilizing "foster" grandparents. This past year we also published the results of a long-term longitudinal study detailing genome-wide epigenetic changes in some of these MR and PR monkeys over their first 2 years of life. We found dramatic changes in methylation patterns in MR monkeys from infancy to 6 months in both males and females, affecting wide swaths of the genome, but sex differences in infancy were largely reversed prior to weaning. These differences continued after weaning, albeit with some attenuation, but increased again by 2 years of age. Both sexes of NR monkeys exhibited very different developmental trajectories in infancy, showing many of the same genome-wide patterns seen in post-weaning MP monkeys, with parallel sex differences. In sum, genome-wide patterns of methylation in lymphocytes were highly dynamic throughout pre-pubertal development and varied dramatically as a function of setting, sex and early social rearing history. Finally, in another collaboration with the Szyf lab, we published a paper that examined the epigenetic consequences of being high vs. low-ranking in established social groups of adult female monkeys and their offspring, whose relative social dominance status matched that of their mothers. It appeared that the cross-generational transmission of social status was mediated by, at least in part, the placenta, in that the genome-wide pattern of methylation in tissues collected from placentas immediately after birth differed dramatically between offspring of high- vs. low-ranking females, and not only did the order of magnitude of these differences match that of the above-mentioned rearing condition differences but also many of the same sets of genes were involved, suggesting the existence of a subset of "adversity" genes sensitive to a range of early social adversities.

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，将由其亲生母亲和其他人抚养的恒河猴婴儿与同龄婴儿在生命的前 6-7 个月（MR）进行比较，其中猴子在出生时与母亲分开，在实验室新生儿保育室中手工抚养第一个月，然后以小组形式饲养 在接下来的 6 个月内，将其与同龄的同伴饲养在一起，或者将其安置在装有无生命代孕母亲的单独笼子中，并每天与同样抚养的同伴进行 2 小时的互动 (NR)。 7-8 个月大时，MR 和 NR 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 和 NR 都共享相同的物理和社会环境。我们之前证明，与 MR 猴相比，NR 猴更粘人，玩耍更少，往往更冲动和更具攻击性，并且在 6 个月大的短期社会分离期间和之后表现出更大的行为和生物破坏，并且它们还表现出血清素代谢缺陷（以 CSF 5-HIAA 的长期低值为指标）。此外，它们在许多情况下的 5-HTT 结合水平显着降低 比 MR 受试者的大脑区域更重要。 在没有实验干预的情况下，MR 和 NR 猴子之间的许多差异在整个童年时期持续存在。例如，去年我们发表的数据报告称，成年雌性 NR 猴的淋巴细胞端粒比 MR 猴短。我们还发现，在青春期和成年早期，NR 猴在 G-I 疾病、感染和伤口的治疗方面比 MR 猴需要更多的兽医关注 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。在过去的两年中，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，我们最近报告了早期 MR 与 NR 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，结果测量包括攻击性、游戏行为、社交缓冲、对不熟悉的同种动物的行为和 HPA 反应， 纳洛酮治疗、饮酒和血浆 BDNF 浓度。几乎在每种情况下都观察到了类似的模式：效率较低（转录方面）的等位基因与 NR 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。 此外，我们最近发表了两组研究的结果，调查了早期社会养育差异（MR 与 NR）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，NR 婴儿的炎症、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基因的表达增强。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 3 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，在社会环境没有任何变化的情况下，白细胞全基因组mRNA表达模式的上述饲养条件差异在整个发育过程中持续存在，但只要在幼年期间社会环境发生变化，就会发生显着变化。这些新发现目前正在准备出版。 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，这些猴子在最初的 6-7 个月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，我们完成了一项关于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 表达研究完全相同的时间点从完全相同的 MR 和 SPR 猴子中收集了样本。去年发表的研究结果表明，至少在淋巴细胞中，出生后第一个月内存在广泛的养育条件，但在利用“寄养”祖父母进行社会环境干预后，至少可以显着逆转。 去年，我们还发表了一项长期纵向研究的结果，详细介绍了一些 MR 和 PR 猴子在生命的头两年内的全基因组表观遗传变化。我们发现雄性和雌性 MR 猴从婴儿期到 6 个月大的甲基化模式发生了巨大变化，影响了大范围的基因组，但婴儿期的性别差异在断奶前基本逆转。这些差异在断奶后仍然存在，尽管有所减弱，但在 2 岁时再次增加。 NR 猴的两性在婴儿期表现出非常不同的发育轨迹，显示出许多与断奶后 MP 猴相同的全基因组模式，并具有平行的性别差异。总之，淋巴细胞的全基因组甲基化模式在整个青春期前的发育过程中是高度动态的，并且随着环境、性别和早期社会养育历史的变化而发生巨大变化。 最后，在与 Szyf 实验室的另一项合作中，我们发表了一篇论文，研究了成年雌性猴子及其后代的既定社会群体中高地位与低地位的表观遗传后果，这些群体的相对社会统治地位与其母亲相匹配。社会地位的跨代传递似乎至少部分是由胎盘介导的，因为出生后立即从胎盘收集的组织中的全基因组甲基化模式在高地位女性与低地位女性的后代之间存在显着差异，不仅这些差异的数量级与上述饲养条件差异的数量级相匹配，而且还涉及许多相同的基因组， 表明存在对一系列早期社会逆境敏感的“逆境”基因子集。