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Developmental Continuity Of Individual Differences In Reactivity In Monkeys

猴子反应个体差异的发育连续性

基本信息

批准号：
7734719
负责人：
STEPHEN J. SUOMI
金额：
$ 98.33万
依托单位：
EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
依托单位国家：
美国
项目类别：
财政年份：
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/7734719
关键词：
Adolescent Adult Age-Years Alcohols Alleles Anterior Behavioral Binding Biological Biological Assay Biological Process Birth Brain Brain-Derived Neurotrophic Factor Candidate Disease Gene Cerebellar vermis structure Chicago Collaborations Condition Consumption Corticotropin-Releasing Hormone Data Collection Development Dorsal Environmental Risk Factor Exhibits Female Gender Gene Expression Genes Genetic Genetic Polymorphism Glucocorticoid Receptor Goals Grooming Hair Hand Handedness Hippocampus (Brain)Human Hydrocortisone Individual Differences Infant Life Longitudinal Studies Lymphocyte Macaca mulatta Magnetic Resonance Imaging Measures Medial Methylation Monkeys Monoamine Oxidase A Mothers National Institute on Alcohol Abuse and Alcoholism Neonatal Nerve Growth Factors Nurseries Opioid Receptor Pattern Peripheral Phenotype Plasma Positron-Emission Tomography Prefrontal Cortex Primates Process Receptor Gene Recording of previous events Relative (related person)Research Rest Rodent Sampling Serotonin Receptor 5-HT1A Shapes Social Environment Testing Universities Week behavior measurement biobehavior caregiving comparative genome wide association study infancy male neuroimaging peer preference receptor density response serotonin transporter social social separation teenage mother young adult

项目摘要

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.

在过去的一年中，我们的特点是发展变化的外周措施的脑源性神经营养因子（BDNF）和神经生长因子（NGF）在恒河猴与不同的早期社会养育背景的血浆BDNF和神经生长因子纵向收集从出生的猴子饲养无论是由他们的生物学母亲（MR）或在新生儿托儿所与随后的连续访问同龄人（PR）。我们重复了我们以前的发现，即BDNF水平在前2个月急剧下降，然后在第一年的剩余时间内逐渐下降，除了PR女性，其水平在前2个月保持较高水平。相比之下，NGF水平在前2个月保持相对稳定，然后从两个月到一岁急剧增加，基本上达到成人水平，除了PR男性，其NGF水平的增加发生得更早。在PR（但不是MR）婴儿血浆NGF和皮质醇水平显着相关。最后，在每个饲养组内，血浆NGF和BDNF值的个体差异在整个发育过程中基本上是稳定的，这表明可能的遗传影响。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得到表征。今年，我们在恒河猴群体中发现了一种功能相似的BDNF多态性，目前正在确定恒河猴BDNF基因的等位基因差异是否与血浆BDNF值和整个发育过程中生物行为功能的其他指标的个体差异相关。在过去的一年里，我们完成了其他几项研究，比较了MR和PR猴子在整个发育过程中的表现。对2岁MR和PR恒河猴幼猴进行了两项脑神经影像学研究。结构MRI显示，PR青少年有显着更大的体积小脑蚓部，内侧前额叶皮质，背侧前扣带皮质比MR青少年。此外，PR女性的海马体积显著低于PR男性和MR男性和女性。PET神经成像相同的猴子揭示了性别和饲养条件的影响：女性有显着降低5-HT 1A受体密度在整个大脑相对于男性，和女性和男性PR青少年有显着降低5-HT 1A受体密度比他们的MR同行。此外，雌性PR猴有显着更大的结合5-HT 1A结合潜力（BP）在前额皮质比MR女性，而PR男性有显着较低的BP比MR男性在内侧扣带皮层。另一项研究表明，早期抚养史的差异导致了偏侧性的差异：在青少年时期，MR猴子比PR猴子有更大的右手行为偏见。最后，PR猴在出生后的第一年，其毛发样本的检测结果显示，PR猴的皮质醇水平长期高于PR猴。我们继续对另外两个项目进行数据收集和分析，比较MR和PR恒河猴的生物功能的其他措施。第一个是与麦吉尔大学的同事合作，涉及评估从年轻成年MR和PR受试者中获得的海马和前额叶皮质中糖皮质激素受体基因的甲基化模式，以及从MR和PR猴在整个发育过程中纵向获得的颊样本和淋巴细胞中的甲基化模式;这些评估目前正在进行中。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，涉及从婴儿期开始纵向从MR和PR受试者中获得的淋巴细胞样本的全基因组扫描，以确定生命最初一周基因表达模式中可能的养育条件差异以及这些模式在整个发育过程中如何发生差异变化。该部门最近的研究的一个主要重点是表征几个候选基因（G X E相互作用）的差异早期社会养育和多态性之间的相互作用，最值得注意的是5-羟色胺转运蛋白基因（5-HTT）和MAO-A基因，在MR和PR恒河猴的整个发展过程中的行为和生物功能的各种措施。在过去的一年里，我们发现了显着的G x E相互作用，涉及5-HTT多态性MR婴儿的母亲在他们的照顾模式显着不同。婴儿的母亲表现出低水平的腹接触和梳理发声和探索较少，更被动的开放领域的测试，但只有当他们携带“短”5-HTT等位基因。此外，在合作与同事从NIAAA，我们确定了额外的功能多态性促肾上腺皮质激素释放因子（CRH）2A基因，和μ阿片受体基因和特征的特定G x E相互作用相对于行为反应的社会分离的青少年恒河猴，以及在几个措施的酒精偏好和消费的年轻成年猴。

项目成果

期刊论文数量（14）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Age-dependent variation in behavior following acute ethanol administration in male and female adolescent rhesus macaques (Macaca mulatta).

雄性和雌性青少年恒河猴（Macaca mulatta）急性乙醇注射后行为的年龄依赖性变化。

DOI：
10.1111/j.1530-0277.2006.00300.x
发表时间：
2007
期刊：
Alcoholism, clinical and experimental research
影响因子：
0
作者：
Schwandt,MelanieL;Barr,ChristinaS;Suomi,StephenJ;Higley,JamesD
通讯作者：
Higley,JamesD

Seasonal variation in CSF 5-HIAA concentrations in male rhesus macaques.

雄性恒河猴 CSF 5-HIAA 浓度的季节性变化。

DOI：
10.1016/s0893-133x(99)00097-4
发表时间：
2000
期刊：
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
影响因子：
0
作者：
Zajicek,KB;Price,CS;Shoaf,SE;Mehlman,PT;Suomi,SJ;Linnoila,M;Higley,JD
通讯作者：
Higley,JD

Association between the recombinant human serotonin transporter linked promoter region polymorphism and behavior in rhesus macaques during a separation paradigm.

重组人血清素转运蛋白连接启动子区多态性与恒河猴在分离范式中的行为之间的关联。

DOI：
10.1017/s095457940700048x
发表时间：
2007
期刊：
Development and psychopathology
影响因子：
3.3
作者：
Spinelli,Simona;Schwandt,MelanieL;Lindell,StephenG;Newman,TimothyK;Heilig,Markus;Suomi,StephenJ;Higley,JDee;Goldman,David;Barr,ChristinaS
通讯作者：
Barr,ChristinaS

Structural variation of the monoamine oxidase A gene promoter repeat polymorphism in nonhuman primates.

非人灵长类动物中单胺氧化酶 A 基因启动子重复多态性的结构变异。

DOI：
10.1111/j.1601-183x.2005.00130.x
发表时间：
2006
期刊：
Genes, brain, and behavior
影响因子：
0
作者：
Wendland,JR;Hampe,M;Newman,TK;Syagailo,Y;Meyer,J;Schempp,W;Timme,A;Suomi,SJ;Lesch,KP
通讯作者：
Lesch,KP

Rhesus monkeys with late-onset hydrocephalus differ from non-impaired animals during neonatal neurobehavioral assessments: six-year retrospective analysis.

患有迟发性脑积水的恒河猴在新生儿神经行为评估中与未受损的动物不同：六年回顾性分析。