An animal model of parental care: Manipulating social environments with V1aR-RNAi

描述（由申请人提供）：最近试图理解基因和环境对人类发展的动态贡献，强调需要考虑不同尺度的环境；最简单的区别是直接的家庭环境和学校、社区、社会经济和文化的远端影响之间的区别。啮齿类动物已经证明了研究这些更近端的过程（即母性照顾）在大脑和行为发育中的作用的强大模型。然而，关于亲代抚育如何与远端影响相互作用的研究在很大程度上仅限于人类的相关研究和非人类灵长类动物的操纵性研究。虽然这两种数据来源都很重要，但都不能提供啮齿动物模型中存在的神经元操作能力。我们建议将啮齿动物神经科学扩展到半自然环境中，使用基因治疗、RNA干扰（RNAi）、无线电遥测和焦点视频采样的新组合。我们概述了一项研究计划，该计划将对一种独特的啮齿动物——草原田鼠——进行研究，草原田鼠以其配偶结合和双亲照顾而闻名。我们建议使用RNAi方法来操纵腹侧白球中抗利尿激素1a受体（V1aR）的表达，这是雄性配对所必需的大脑区域。我们建议将V1aR降低的雄性（V1Ai）、对照组（CONT）雄性和未被控制的雌性放置在半自然的围栏中，不同频率的V1Ai和CONT雄性形成不同的“社区”。然后，我们将检查父亲的V1Ai表型，社会邻居，和父母照顾的年轻人之间的关系。最后，我们将检查来自这些巢穴的后代的应激反应措施，这是一种在啮齿动物，人类和非人类灵长类动物中由亲代照顾形成的特征明显的表型。结果数据将独特地解决近端和远端环境对神经和行为结果的相互影响。同样重要的是，该研究将开发出解决基因组和社会环境如何相互作用以影响广泛表型的方法。公共卫生相关性：儿童与其照料者之间的互动对儿童发展至关重要。对啮齿动物的研究已经阐明了神经和激素机制，通过这种机制，护理可以转化为生理和行为的终身变化，包括对肥胖、心脏病和抑郁症的易感性。我们建议开发一种独特的分子和行为工具的组合，使研究人员能够解决社会环境、基因表达、神经生物学和行为发育之间更复杂的相互作用。

DESCRIPTION (provided by applicant): Recent attempts to understand the dynamic contributions of genes and environments to human development have emphasized the need to consider environments at different scales; the simplest such distinction is between the immediate home environment and the more distal influences of school, neighborhood, socioeconomics and culture. Rodent species have proved powerful models for investigating the role of these more proximal processes, namely maternal care, on the development of brains and behavior. The examination of how parental care interacts with more distal influences, however, has largely been limited to correlational studies in humans and manipulative studies in non-human primates. Although both sources of data are important, neither provides the capacity for neuronal manipulation present in rodent models. We propose to extend rodent neuroscience into semi-natural settings using a novel combination of gene therapy, RNA interference (RNAi), radiotelemetry and focal video sampling. We outline a research plan that would do so with a unique rodent species, the prairie vole, known for its pairbonding and bi-parental care. We propose to use RNAi methods to manipulate the expression of the vasopressin 1a receptor (V1aR) in the ventral pallidum, a brain area necessary for male pairbonding. We propose to place males with reduced V1aR (V1Ai), control (CONT) males, and unmanipulated females in semi-natural enclosures, with different frequencies of V1Ai and CONT males forming different "neighborhoods." We will then examine the relationship between paternal V1Ai phenotype, social neighborhood, and the parental care received by young. Lastly, we will examine offspring from these nests on measures of stress reactivity, a well-characterized phenotype shaped by parental care in rodents, humans and non-human primates. The resulting data will uniquely address the reciprocal influences of proximal and distal environments on neural and behavioral outcomes. No less importantly, the study will develop methods that address how genomes and social environments interact to influence a broad range of phenotypes. PUBLIC HEALTH RELEVANCE: The interactions between children and their caregivers are critical to child development. Work on rodents has clarified the neuronal and hormonal mechanisms through which care can be translated into lifelong changes in physiology and behavior, including susceptibility to obesity, heart disease and depression. We propose to develop a unique combination of molecular and behavioral tools that would allow researchers to address more complex interactions between social environment, gene expression, and neurobiological and behavioral development.