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: 9796745
• 负责人: STEPHEN J. SUOMI
• 金额: $ 15.21万
• 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/9796745
• 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 methylation; 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 showedenhanced 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. Recently, 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.

与前几年一样，该项目的主要重点是对不同早期社会养育方式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由亲生母亲抚养的恒河猴婴儿和其他年龄相同的婴儿在出生后6-7个月（MR）的情况下与母亲分离的猕猴。第一个月在实验室新生儿托儿所手工饲养，然后在接下来的6个月里在同龄同伴的小组中饲养，或者在单独的笼子里饲养一个没有生命的代孕母亲，每天与相似饲养的同伴（NR）互动2小时。在7-8个月大的时候，MR和NR婴儿都被转移到一个大围栏里，在那里他们都住在一起，直到青春期。因此，差别社会养育只发生在头7-8个月；此后，MR和NR都共享相同的物理和社会环境。我们之前的研究表明，NR猴在6个月大的时候比MR猴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，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，他们在许多大脑区域的5-HTT结合水平明显低于MR受试者。

项目成果

Suppression of alcohol preference by naltrexone in the rhesus macaque: a critical role of genetic variation at the micro-opioid receptor gene locus.

• DOI: 10.1016/j.biopsych.2009.07.026
• 发表时间: 2010-01-01
• 期刊: Biological psychiatry
• 影响因子: 10.6
• 作者: Barr CS;Chen SA;Schwandt ML;Lindell SG;Sun H;Suomi SJ;Heilig M
• 通讯作者: Heilig M

Exploratory factor analysis of human infant temperament in the rhesus monkey.

• DOI: 10.1016/j.infbeh.2009.11.005
• 发表时间: 2010-02
• 期刊: INFANT BEHAVIOR & DEVELOPMENT
• 影响因子: 2.1
• 作者: Kay, Daniel B.;Marsiske, Michael;Suomi, Stephen J.;Higley, J. Dee
• 通讯作者: Higley, J. Dee

Do capuchin monkeys (Sapajus apella) prefer symmetrical face shapes?

• DOI: 10.1037/com0000052
• 发表时间: 2017-02
• 期刊: Journal of comparative psychology (Washington, D.C. : 1983)
• 作者: Paukner A;Wooddell LJ;Lefevre CE;Lonsdorf E;Lonsdorf E
• 通讯作者: Lonsdorf E

Who's my little monkey? Effects of infant-directed speech on visual retention in infant rhesus macaques.

• DOI: 10.1111/desc.12519
• 发表时间: 2018-03
• 期刊: Developmental science
• 影响因子: 3.7
• 作者: Slonecker EM;Simpson EA;Suomi SJ;Paukner A
• 通讯作者: Paukner A

Effect of mother's dominance rank on offspring temperament in infant rhesus monkeys (Macaca mulatta).

母亲的统治地位对幼年恒河猴（Macaca mulatta）后代气质的影响。

• DOI: 10.1002/ajp.22081
• 发表时间: 2013
• 期刊: American journal of primatology
• 影响因子: 2.4
• 作者: Suarez-Jimenez,Benjamin;Hathaway,Amanda;Waters,Carlos;Vaughan,Kelli;Suomi,StephenJ;Noble,PamelaL;Pine,DanielS;Fox,NathanA;Nelson,EricE
• 通讯作者: Nelson,EricE