Effect of maternal care on neurogenesis and behavior

描述(由申请人提供)：在早期发育期间受到虐待或忽视的儿童在以后的生活中发展为焦虑和抑郁的风险更大，在灵长类动物和啮齿动物中也有类似的观察结果。亲子相互作用在婴儿情绪和认知发育中的保守性支持利用啮齿动物来研究这一过程的分子机制。到目前为止，大多数啮齿类动物的研究都是使用大鼠，只有少数研究使用小鼠，还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表明，在啮齿动物中，出生后低水平的母婴护理与持续到成年的神经发生和神经元存活的减少有关。成人神经发生减少的功能意义目前尚不清楚，但令人感兴趣的是，最近的数据显示，成人神经发生、学习和对压力的脆弱性之间存在相关性。在这里，我们认为，母亲护理的一些行为后遗症是由于其在发育和/或成年期调节神经发生的能力所致。为了验证这一假设，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体护理对神经发生的行为后果，并展示了使用转基因动物研究这一问题的潜力。这个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，以了解在一个基因易处理和更简单的实验系统中，基因和环境相互作用影响应激反应的分子细节。我们的工作将被整合到NIH资助的发展中心，该中心目前正在与Joan Kaufman博士合作建立，并在耶鲁这里的儿童研究中心进行正在进行的工作。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，将在未来产生新的情感障碍治疗策略。

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.