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（由申请人提供）：早期生活压力是人类儿童不利神经行为发育的最有效预测因子。早期生活压力的实验转化动物模型的验证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实验途径，以改善经历早期创伤的儿童的生活。一些表征良好的早期应激实验动物模型（例如，母亲的匮乏）很难转化为人类的经验。许多其他操纵通过减少亲本投资来发挥其作用（例如，多变的觅食需求，反复的母亲分离）。这些操作效果很好，因为对发育中的婴儿来说，很少有比父母照顾不周更有效的压力源（例如，忽视或虐待）。一个相关的策略是观察个人接受的护理范围，并确定其对个人发展变化的影响。这是一个强有力的方法，因为它使我们能够确定除了更极端的影响外，中度虐待对婴儿发育的影响。这种方法的一个显著缺点是，母亲和婴儿之间共有的基因和环境使调查变得混乱。由于这种“基因与环境相关性”的潜在性，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，或者父母和后代之间的共享基因是否与不良的养育和增强有关。压力反应。因此，早期环境影响的研究必须包括适当的交叉寄养（FOSTER）条件，当一组婴儿由生物学上无关的母亲抚养时。如果FOSTER二元组表现出与生物相关（BIO）二元组相同的早期护理和婴儿神经行为发育之间的关系，我们可以专注于环境介导的母体效应。这只能在动物模型中完成，因为出于伦理原因，无法在人类中进行实验性收养研究，而自然主义收养研究则被养父母可能比正常人群更大的心理和身体资源所混淆。恒河猴（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，并显示出可比的遗传，神经和社会情感复杂性。重要的是，恒河猴母亲，像迄今为止研究的所有哺乳动物母亲一样，在照顾婴儿的质量方面有所不同。有效使用猕猴FOSTER二联体的唯一障碍是，将婴儿寄养给恒河猴母亲的一些程序可能会减少孕产妇护理并增强婴儿的应激反应，使其成为BIO二联体的不良对照。PI建议确定孕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FOSTER程序，以减少FOSTER和BIO二元体之间的差异。如果母亲护理和婴儿结局之间的关系在BIO-和FOSTER-二元体之间没有区别，这将代表一个新的平台，用于理解最可翻译的动物模型中风险和弹性的遗传，表观遗传，神经和经验基础。 公共卫生相关性：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，最好是通过观察护理中的自然变化与婴儿结局的关系来实现。拟议的研究将这样做，同时引入新的方法来控制父母和后代之间的遗传相关性的作用，这种方法由于伦理原因不可能在人类研究中采用。因此，这项工作将在最好的翻译动物模型之一，恒河猴。