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）：在早期发育过程中受到虐待或忽视的儿童在以后的生活中患焦虑和抑郁的风险更大，并且在灵长类动物和啮齿类动物中也有类似的观察结果。婴儿情绪和认知发展中亲子互动的保守性支持利用啮齿类动物来研究这一过程背后的分子机制。迄今为止，大多数啮齿类动物的研究都使用了大鼠，只有少数研究使用了小鼠，而且没有研究组使用转基因动物来研究这个问题。我们的工作以及其他几个实验室的工作表明，在啮齿类动物中，产后母亲护理水平低与神经发生和神经元存活率的下降有关，这种下降一直持续到成年期。目前，成人神经发生减少的功能意义尚不清楚，但考虑到最近的数据显示成人神经发生、学习和压力脆弱性水平之间的相关性，这一点很有趣。在这里，我们提出，孕产妇护理的一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。为了检验这一假设，我们培育了在神经干细胞（NSC）中表达胸苷激酶的转基因小鼠，并表明将这些小鼠的 NSC 暴露于更昔洛韦可消除这些细胞的增殖。这些小鼠为我们提供了一种独特的工具来评估母亲护理对神经发生的行为影响，并证明使用转基因动物研究这个问题的潜力。这项职业奖的提议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，以了解基因和环境相互作用以影响遗传易处理和更简单的实验系统中的应激反应的分子细节。我们的工作将被纳入美国国立卫生研究院 (NIH) 资助的发展中心，目前我们正在与琼·考夫曼 (Joan Kaufman) 博士合作建立该中心，并在耶鲁大学儿童研究中心开展正在进行的工作。我们相信，临床医生和基础行为神经科学之间的这种密切合作提供了一种转化工作，将在未来产生情感障碍的新治疗策略。