Effect of maternal care on neurogenesis and behavior

母亲护理对神经发生和行为的影响

• 批准号: 7101199
• 负责人: ARIE KAFFMAN
• 金额: $ 17.94万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7101199
• 关键词: animal developmental psychology; anxiety; behavior test; behavioral /social science research tag; cell proliferation; dentate gyrus; depression; developmental neurobiology; early experience; ganciclovir; genetic strain; genetically modified animals; green fluorescent proteins; laboratory mouse; maternal behavior; neurogenesis; neuropharmacology; newborn animals; parent offspring interaction; stem cells; thymidine kinase

DESCRIPTION (provided by applicant): Children that have been abused or neglected during early development are at greater risk for developing anxiety and depression later in life and similar observations have also been documented in primates and rodents. The conserved nature of the parent-offspring interaction in infant emotional and cognitive development supports the use of rodents to study the molecular mechanisms that underlie this process. Most of the work to date in rodents has used rats with only a few studies using mice, and no group has used transgenic animals to study this problem. Our work, and work from several other labs, has demonstrated that, in rodents, low levels of postnatal maternal care are associated with a decrease in neurogenesis and neuronal survival that persist into adulthood. The functional significance of this decrease in adult neurogenesis is unclear at this point, but is intriguing given recent data showing a correlation between levels of adult neurogenesis, learning, and vulnerability to stress. Here we propose that some of the behavioral sequelae of maternal care are due to its ability to regulate neurogenesis during development and/or in adulthood. In order to test this hypothesis we have generated transgenic mice that express thymidine kinase in neural stem cells (NSC) and show that exposure of NSC from these mice to Ganciclovir abolishes proliferation of these cells. These mice provide us with a unique tool to assess the behavioral consequences of maternal care on neurogenesis and demonstrate the potential of using transgenic animals to study this problem. This proposal for a Career Award reflects my wish to combine my training as a cell biologist and a clinician to understand the molecular details by which genes and environment interact to affect stress reactivity in a genetically-tractable and a simpler experimnetal system. Our work will be integrated into an NIH funded Development Center that we are currently establishing in collaboration with Dr. Joan Kaufman and ongoing work done at the Child Study Center here at Yale. We believe that such close collaboration between clinicians and basic behavioral-neuroscience provides the kind of translational work that will yield new treatment strategies for affective disorders in the future.

描述（由申请人提供）：早期发育期间滥用或忽视的儿童在生命以后患焦虑和抑郁的风险更大，并且在灵长类动物和啮齿动物中也有类似的观察结果。婴儿情绪和认知发展中父源性相互作用的保守性质支持啮齿动物来研究这一过程构成的分子机制。迄今为止，啮齿动物的大多数工作都使用了使用小鼠进行少量研究的大鼠，并且没有人使用转基因动物来研究这一问题。我们的工作以及其他几个实验室的工作表明，在啮齿动物中，产后孕产妇护理水平较低与神经发生和神经元生存的降低有关，而神经元的生存一直持续到成年。目前尚不清楚这种降低的成人神经发生的功能意义，但是鉴于最近的数据显示了成人神经发生，学习和压力脆弱性之间的相关性，这很有趣。在这里，我们建议某些行为后遗症是由于其在发育和/或成年期间调节神经发生的能力所致。为了检验该假设，我们已经产生了在神经干细胞（NSC）中表达胸苷激酶的转基因小鼠，并表明NSC从这些小鼠暴露于Ganciclovir到Ganciclovir废除了这些细胞的增殖。这些小鼠为我们提供了一种独特的工具来评估母体护理对神经发生的行为后果，并证明了使用转基因动物研究此问题的潜力。这项职业奖的提案反映了我希望将我作为细胞生物学家和临床医生的培训结合起来，以了解基因和环境通过这些细节相互作用，以影响遗传上可吸引和更简单的实验系统中的压力反应性。我们的工作将集成到NIH资助的开发中心中，我们目前正在与Joan Kaufman博士合作建立，并在耶鲁大学的儿童学习中心进行的持续工作。我们认为，临床医生与基本行为神经科学之间的这种紧密合作提供了一种转化工作，将为未来的情感障碍提供新的治疗策略。