Effect of maternal care on neurogenesis and behavior

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症的风险更大，在灵长类动物和啮齿类动物中也有类似的观察结果。在婴儿情感和认知发展中，父母与子女之间的相互作用具有保守性，这一点支持使用啮齿动物来研究这一过程的分子机制。迄今为止，大多数啮齿动物的研究都是使用大鼠进行的，只有少数研究使用小鼠进行的，并且没有一个小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已经证明，在啮齿动物中，低水平的产后母亲护理与持续到成年的神经发生和神经元存活减少有关。在这一点上，这种减少在成人神经发生的功能意义尚不清楚，但有趣的是，最近的数据显示成人神经发生，学习和压力的脆弱性之间的相关性。在这里，我们提出，一些行为后遗症的孕产妇护理是由于其能力，以调节神经发生在发展过程中和/或在成年期。为了检验这一假设，我们已经产生了转基因小鼠，表达胸苷激酶的神经干细胞（NSC），并显示，从这些小鼠的NSC暴露于更昔洛韦废除这些细胞的增殖。这些小鼠为我们提供了一个独特的工具，以评估产妇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这个问题的潜力。这个职业奖的提议反映了我的愿望，我希望联合收割机结合我作为细胞生物学家和临床医生的训练，了解基因和环境相互作用的分子细节，以影响遗传学上易于处理的和更简单的实验系统中的应激反应。我们的工作将被整合到NIH资助的发展中心，我们目前正在建立与琼博士考夫曼和正在进行的工作在儿童研究中心在耶鲁大学。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翻译工作，将产生新的治疗策略，在未来的情感障碍。

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.