Developing a Translational Monkey Model of Maternal Care

开发孕产妇护理的转化猴模型

• 批准号: 8302740
• 负责人: Erin Loraine Kinnally
• 金额: $ 7.69万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-08 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8302740
• 关键词: Adoption; Adrenal Glands; Affect; Age; Animal Model; Behavioral; Behavioral inhibition; Biological; Birth; Buffers; California; Caring; Child; Code; Cues; Data; Development; Early-life trauma; Emotional; Environment; Epigenetic Process; Ethics; Excision; Exhibits; Experimental Animal Model; Factor Analysis; Fostering; Genes; Genetic; Health; Human; Hydrocortisone; Hypothalamic structure; Individual; Infant; Infant Care; Infant Development; Intervention; Investigation; Investments; Life; Life Experience; Life Stress; Link; Macaca; Macaca mulatta; Mammals; Maternal Deprivation; Mediating; Methods; Modeling; Monkeys; Mothers; Outcome Measure; Parenting behavior; Parents; Physiological; Pituitary Gland; Population; Prevention strategy; Primates; Procedures; Quality of Care; Research; Resources; Risk; Role; Scheme; Sedation procedure; Stress; System; Testing; Translating; Urine; Validation; Variant; Weaning; Work; abuse neglect; base; biobehavior; biological adaptation to stress; caregiving; cohort; early experience; experience; improved; indexing; infant outcome; maltreatment; maternal separation; neglect; neurobehavioral; offspring; postnatal; psychologic; relating to nervous system; social group; social separation; stressor; trait

DESCRIPTION (provided by applicant): Early life stress is the most potent predictor of disadvantageous neurobehavioral development in human children. The validation of experimental translational animal models of early life stress will be essential to understanding how early experience affects infant development in positive and negative ways. The development of these strategies will be our best experimental avenue to develop informed intervention and prevention strategies for improving the lives of children that experience early trauma. Some well-characterized experimental animal models of early stress (e.g., maternal deprivation) are difficult to translate to the human experience. Many other manipulations exert their effects by reducing parental investment (e.g., variable foraging demand, repeated maternal separation). These manipulations work well because there are few more potent stressors for the developing infant than poor parental care (e.g., neglect or abuse). A related strategy is to observe the range of care individuals receive and determine its effects on variation in individual development. This is a powerful approach, as it allows us to determine the effects of moderate maltreatment, in addition to more extreme influences, on infant development. A significant drawback to this approach is that shared genes and environment between the mother and infant confound the investigation. Because of the potential for this "gene- environment correlation", it i impossible to know, for example, whether the experience of neglect and abuse leads to adverse neurobehavioral traits, or whether shared genes between parent and offspring are associated with both poor parenting and enhanced stress reactivity. Therefore, studies of the effects of early environment must include appropriate cross-fostered (FOSTER) conditions, when one group consists of infants reared by biologically unrelated mothers. If FOSTER dyads exhibit the same relationship between early care and infant neurobehavioral development as biologically related (BIO) dyads, we can focus on environmentally mediated maternal effects. This can only be accomplished in animal models, as experimental adoption studies in humans cannot be executed for ethical reasons, and naturalistic adoption studies are confounded by the fact that adoptive parents may be selected for greater psychological and physical resources than the normal population. Rhesus macaques (Macaca mulatta) are one of the best animal models of neurobehavioral development, as they are closely related to humans, and display comparable genetic, neural, and socio-emotional complexity. Importantly, rhesus macaque mothers, like all mammalian mothers studied to date, vary in the quality of care they give to infants. The only obstacle to the effective use of macaque FOSTER dyads is that some procedures for fostering infants to rhesus macaque mothers may reduce maternal care and enhance infant stress reactivity, making them poor controls for BIO dyads. The PI proposes to determine the effects of natural variation in maternal care quality on rhesus macaque infant development while testing new FOSTER procedures to reduce the differences between FOSTER and BIO dyads. If the relationship between maternal care and infant outcomes does not differ between BIO- and FOSTER- dyads, this will represent a new platform for understanding the genetic, epigenetic, neural and experiential bases of risk and resiliency in the most translatable animal model available. PUBLIC HEALTH RELEVANCE: Human children are at greater risk for poor health following early trauma. Understanding the role of early experience in infant development is best accomplished by observing how natural variation in care relates to infant outcomes. The proposed research will do so while introducing new methods for controlling for the role of genetic relatedness between parent and offspring, an approach that is impossible to take in human research for ethical reasons. This work will be therefore conducted in one of the best translational animal models available, the rhesus macaque.

描述(申请人提供)：早期生活压力是人类儿童神经行为发育不良的最有力的预测因子。验证早期生活压力的实验动物模型对于理解早期经历如何以积极和消极的方式影响婴儿发育至关重要。制定这些战略将是我们制定知情干预和预防战略的最佳试验性途径，以改善经历早期创伤的儿童的生活。一些具有良好特征的早期应激实验动物模型(例如，母体剥夺)很难转化为人类的经验。许多其他操作通过减少父母的投资发挥作用(例如，可变的觅食需求，反复的母体分离)。这些操作效果很好，因为对发育中的婴儿来说，没有什么比糟糕的父母照顾(例如，忽视或虐待)更有效的压力来源了。一个相关的策略是观察个人接受护理的范围，并确定其对个人发展差异的影响。这是一种强有力的方法，因为它允许我们确定中度虐待的影响，以及更极端的影响，对婴儿发育的影响。这种方法的一个重大缺陷是，母亲和婴儿之间共享的基因和环境混淆了调查。由于这种“基因-环境关联”的可能性，我不可能知道，例如，忽视和虐待的经历是否会导致不良的神经行为特征，或者父母和子女之间的共同基因是否与糟糕的父母教养和增强的压力反应能力有关。因此，对早期环境影响的研究必须包括适当的交叉养育(寄养)条件，当一组婴儿由生物上没有血缘关系的母亲抚养时。如果寄养双亲在早期护理和婴儿神经行为发育之间表现出与生物相关的(生物)双亲相同的关系，我们就可以专注于环境中介的母体效应。这只能在动物模型中完成，因为出于伦理原因，在人类身上进行的实验性收养研究不能进行，而自然主义的收养研究由于收养父母可能比正常人群更多的心理和身体资源而被选中，这一事实令人困惑。猕猴(Macaca Mulatta)是神经行为发育的最佳动物模型之一，因为它们与人类密切相关，并表现出类似的遗传、神经和社会情感复杂性。重要的是，恒河猴妈妈，就像迄今为止研究过的所有哺乳动物妈妈一样，对婴儿的护理质量各不相同。有效利用猕猴寄养二元体的唯一障碍是，一些将婴儿养育成猕猴母亲的程序可能会减少母体护理，增强婴儿的应激反应，使它们对生物二元体的控制能力很差。PI建议确定产妇护理质量的自然变化对恒河猴婴儿发育的影响，同时测试新的福斯特程序，以减少福斯特和生物二元体之间的差异。如果母婴保健和婴儿结局之间的关系在生物和养育二元体之间没有区别，这将代表一个新的平台，用于在最可翻译的动物模型中理解风险和弹性的遗传、表观遗传、神经和经验基础。 与公共卫生相关：人类儿童在早期创伤后健康状况不佳的风险更大。了解早期经验在婴儿发育中的作用最好通过观察护理中的自然变化与婴儿结局之间的关系来实现。拟议的研究将在这样做的同时，引入新的方法来控制父母和后代之间的遗传关系的作用，这是一种出于伦理原因而不可能在人类研究中采用的方法。因此，这项工作将在现有的最好的翻译动物模型之一-恒河猴中进行。