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: 7968558
• 负责人: STEPHEN J. SUOMI
• 金额: $ 156.8万
• 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/7968558
• 关键词: Acoustics; Adolescent; Adult; Affect; Age; Age-Months; Alcohols; Alleles; Antibody Formation; Antiviral Response; B-Lymphocytes; BDNF gene; Behavioral; Binding; Biological; Biological Process; Birth; Blood; Brain region; Brain-Derived Neurotrophic Factor; Candidate Disease Gene; Cell Proliferation; Chicago; Childhood; Collaborations; Consumption; Corticotropin-Releasing Hormone; DRD1 gene; Data; Data Collection; Development; Elderly; Environment; Environmental Risk Factor; Exhibits; Gene Expression; Genes; Genetic; Genetic Polymorphism; Genome; Goals; Grooming; Growth; Hair; Hand; Hematopoietic; Hour; Housing; Hydrocortisone; Hydroxyindoleacetic Acid; IL8 gene; Immunoglobulins; Individual; Individual Differences; Infant; Inflammatory; Interferons; Leukocytes; Life; Longitudinal Studies; Lymphocyte; Macaca mulatta; Measures; Mediating; Metabolism; Methylation; Monkeys; Monoamine Oxidase A; Mothers; NPY gene; National Institute on Alcohol Abuse and Alcoholism; Neonatal; Nurseries; Opioid Receptor; Pathway interactions; Pattern; Phenotype; Plasma; Play; Primates; Proteins; Puberty; Publishing; Receptor Gene; Relative (related person); Research; Research Project Grants; Sampling; Scanning; Serotonin; Shapes; Social Environment; Surrogate Mothers; T memory cell; T-Lymphocyte; Testing; Tissue Sample; Transcript; Universities; behavior measurement; biobehavior; caregiving; comparative; cytokine; early experience; forest; genome wide association study; genome-wide; indexing; male; monoamine; monocyte; peer; preference; response; social; social separation; transcription factor; young adult

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 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 6-7 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 much more 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. Research in collaboration with colleagues from NIAAA has demonstrated that both PR and SPR monkeys also consume significantly more alcohol when placed in a happy hour situation as adolescents and young adults. This past year we published data extending these rearing condition differences to include developmental changes in plasma concentrations of BDNF and NGF (6), behavioral lateralization (4), acoustic startle response patterns following fluxotine treatment (11), and structural differences in various brain regions (15). Finally, we found that PR monkeys had chronically higher levels of cortisol obtained from hair samples than did MR and SPR monkeys throughout their first year of life, whereas during the second year SPR monkeys had higher levels than the other two rearing groups. During the past year we finished data collection and preliminary analyses for two projects comparing the results of genome-wide scans of blood and tissue samples collected from differentially reared monkeys. First, in collaboration with colleagues from McGill and Wake Forest Universities, we assessed methylation patterns in lymphocyte T cells and pfc obtained from 8 yr-old adult MR and SPR subjects who had been living in the same or comparable physical and social environments since 7 months of age. Over 4,000 genes, i.e. almost 1/5 of the entire genome, showed significant differences in methylation as a function of early experience in both T cells and pfc, with approximately half of the affected genes significantly more methylated in MR-derived samples and the remaining half significantly more methylated in SPR-derived samples. Additionally, there was considerable overlap among the specific genes in T cell and pfc that were differentially methylated: about 30% of the genes showed the same pattern of significant rearing condition differences in both T cells and pfc, whereas approximately 25% of the genes showed exactly the opposite pattern in T cells vs. pfc. Furthermore, there were a substantial number of genes in specific known pathways (e.g., various IL, monoamine transporter, and CRH pathways) that were differentially methylated as a function of differential early experience again in both T cells and pfc. The second project utilizing genome-wide scans of samples obtained from differentially reared monkeys, a collaboration with colleagues from UCLA and the University of Chicago, involved microarray scanning of leukocyte samples obtained from MR, PR, and SPR infants at 7 months of age to determine possible differences in gene expression. As in the afore-mentioned case of differential methylation patters, significant differences in gene expression as a function of differential early experience were found throughout the entire genome. Relative to those of MR infants, genes upregulated in leukocytes from PR infants included the pro-inflammatory cytokine IL8, a diverse array of transcription factors, regulators of cell proliferation, and multiple T cell-associated transcripts. Genes notably suppressed in leukocytes from PR infants included those involved in Type 1 Interferon mediated antiviral responses, several immunoglobulin-encoding genes involved in B cell antibody production, several hematopoietic growth regulators, monocyte-associated gene products, and a variety of memory T cell-related markers. Analyses of gene expression patterns in SPR infants yielded results qualitatively similar to those of PR monkeys, but with differences with MR subject generally quantitatively less pronounced than those of PR subjects, albeit with a number of exceptions. Taken together, these two sets of genome-wide analyses demonstrate that the consequences of differential early experience for monkeys clearly extend to the level of gene methylation patterns and actual expression. 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 5-HTT-LPR gene 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-LPR 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-LPR allele. In addition, in collaboration with colleagues from NIAAA and the University of Wurzburg, we identified additional functional polymorphisms in the corticotrophin releasing factor (CRH)2A gene (1), the mu opioid receptor gene (3) , the NPY gene (10), the DRD1 5UTR gene (12), the BDNF gene, and the NOS-1 gene. We were also able to characterized specific G x E interactions with respect to behavioral responses to social separation by juvenile rhesus monkeys for the 5-HTT-LPR and NPY polymorphisms, as well as in several measures of alcohol preference and consumption among young adult monkeys for the CRH, NPY, and DRD1 5UTR polymorphisms (1, 10, 12).

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 个月大时，MR、PR 和 SPR 婴儿都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 6-7 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，玩耍更少，往往更具攻击性，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 的长期低值为指标），SPR 猴也是如此，而且它们的 5-HTT 结合水平也显着降低 比 MR 受试者更遍及许多大脑区域。 MR 猴和 PR 猴之间的许多差异在整个童年时期都持续存在。与 NIAAA 的同事合作进行的研究表明，当处于青少年和年轻人的欢乐时光时，PR 和 SPR 猴子也会消耗更多的酒精。去年，我们发表了数据，扩展了这些饲养条件差异，包括 BDNF 和 NGF 血浆浓度的发育变化 (6)、行为偏侧化 (4)、氟索汀治疗后的声惊吓反应模式 (11) 以及不同大脑区域的结构差异 (15)。最后，我们发现，从毛发样本中获得的 PR 猴在其生命的第一年中，其皮质醇水平长期高于 MR 和 SPR 猴，而在第二年，SPR 猴的皮质醇水平高于其他两个饲养组。 在过去的一年里，我们完成了两个项目的数据收集和初步分析，比较了从差异饲养的猴子收集的血液和组织样本的全基因组扫描结果。首先，我们与麦吉尔大学和维克森林大学的同事合作，评估了从 7 个月大起就生活在相同或类似的物理和社会环境中的 8 岁成人 MR 和 SPR 受试者中获得的淋巴细胞 T 细胞和 pfc 的甲基化模式。超过 4,000 个基因，即整个基因组的近 1/5，在 T 细胞和 pfc 中显示出作为早期经验的函数的甲基化显着差异，其中大约一半受影响的基因在 MR 衍生样本中显着更高甲基化，而其余一半在 SPR 衍生样本中显着更高甲基化。此外，T细胞和pfc中差异甲基化的特定基因之间存在相当大的重叠：大约30%的基因在T细胞和pfc中显示出相同的显着饲养条件差异模式，而大约25%的基因在T细胞与pfc中显示出完全相反的模式。此外，在特定的已知途径（例如，各种 IL、单胺转运蛋白和 CRH 途径）中，有大量基因根据 T 细胞和 pfc 中的早期差异经历而被差异甲基化。 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，利用对差异饲养的猴子样本进行全基因组扫描，对从 7 个月大的 MR、PR 和 SPR 婴儿获得的白细胞样本进行微阵列扫描，以确定基因表达可能存在的差异。与上述差异甲基化模式的情况一样，在整个基因组中发现了基因表达作为差异早期经验的函数的显着差异。相对于 MR 婴儿，PR 婴儿白细胞中上调的基因包括促炎细胞因子 IL8、多种转录因子、细胞增殖调节因子和多种 T 细胞相关转录物。 PR婴儿的白细胞中显着受到抑制的基因包括那些参与1型干扰素介导的抗病毒反应的基因、一些参与B细胞抗体产生的免疫球蛋白编码基因、一些造血生长调节剂、单核细胞相关基因产物和各种记忆T细胞相关标记。对 SPR 婴儿基因表达模式的分析得到的结果在质量上与 PR 猴子相似，但与 MR 受试者的差异通常在数量上不如 PR 受试者明显，尽管有一些例外。总而言之，这两组全基因组分析表明，猴子早期经历差异的后果显然延伸到了基因甲基化模式和实际表达的水平。 该项目近期研究的另一个主要焦点涉及表征早期社会养育差异与多个候选基因（G X E 相互作用）多态性之间的相互作用，最著名的是 5-HTT-LPR 基因和 MAO-A 基因，用于 MR 和 PR 恒河猴整个发育过程中行为和生物功能的各种测量。去年，我们在 MR 婴儿中发现了涉及 5-HTT-LPR 多态性的显着 G x E 相互作用，这些婴儿的母亲的护理方式存在显着差异。母亲表现出低水平的腹侧接触和梳理行为的婴儿在旷场测试中发声和探索较少且更加被动，但前提是他们携带“短”5-HTT-LPR等位基因。此外，我们与 NIAAA 和维尔茨堡大学的同事合作，发现了促肾上腺皮质激素释放因子 (CRH)2A 基因 (1)、mu 阿片受体基因 (3)、NPY 基因 (10)、DRD1 5UTR 基因 (12)、BDNF 基因和 NOS-1 基因中的其他功能多态性。我们还能够针对 5-HTT-LPR 和 NPY 多态性，以及针对 CRH、NPY 和 DRD1 5UTR 多态性的年轻成年猴的酒精偏好和消费的几种测量方法，表征关于幼年恒河猴对社会分离的行为反应的特定 G x E 相互作用 (1, 10, 12)。