Transgenesis in songbirds for the genetic manipulation of neuronal circuits

描述（由申请人提供）：几十年来，鸣禽一直是研究与人类健康相关的神经生物学问题的丰富实验系统。特别是，鸣禽是主要的非人类模型的研究的生物学基础的声乐学习，一个关键的行为基板语音习得。此外，鸣禽是研究大脑不对称性、大脑发育的激素控制、睡眠的生理功能、大脑中的性别特异性差异、行为诱导的基因表达和成年神经发生等问题的理想系统。尽管鸣禽在神经生物学上很重要，但由于缺乏遗传操作方法，鸣禽作为实验系统的实用性受到了限制。最近，我们已经成功地将慢病毒介导的转基因应用于斑胸草雀（Agate et al.，2009年）的报告。虽然这一成就证明了慢病毒介导的转基因在鸣禽中的可行性，但目前的方法效率低下，劳动密集且成本高昂。在这项提案中，我们计划优化现有的策略，并产生新的工具，以开发一个实用的鸟类转基因技术，可用于其他鸣禽神经生物学实验室。在鸣禽中进行基因操作的能力将为研究具有强大行为能力的动物物种中基因与大脑功能之间的关系提供前所未有的机会。转基因鸣禽将使我们能够产生影响复杂认知功能和交流障碍的人类疾病的动物模型，这些疾病只能在其他动物物种中不完全建模。 公共卫生相关性：人类许多神经和精神疾病的主要表现是行为改变。鸣禽表现出的丰富的行为技能使它们成为模仿人类疾病影响行为的理想动物模型。我们建议开发新的分子工具，允许对鸣禽进行遗传操作，以产生影响复杂认知功能和交流障碍的人类疾病的动物模型。

DESCRIPTION (provided by applicant): Songbirds have been a rich experimental system for studying neurobiological questions of relevance to human health for decades. In particular, songbirds are the leading non-human model for the investigation of the biological basis of vocal learning, a critical behavioral substrate for speech acquisition. In addition, songbirds are an ideal system for the study of brain asymmetry, hormonal control of brain development, physiological function of sleep, and sex-specific differences in the brain, behavioral-induced gene expression and adult neurogenesis, among other questions. Nonetheless despite their importance for neurobiology, the usefulness of songbirds as an experimental system has been restricted by a lack of genetic manipulation methods. Recently we have succeeded in applying lentiviral-mediated transgenesis to zebra finches (Agate et al., 2009). While this achievement proves the feasibility of lentiviral-mediated transgenesis in songbirds, the current method is inefficient, labor-intensive and costly. In this proposal we plan to optimize the existing strategy and to generate novel tools to develop a practical avian transgenic technique that could be used by other songbird neurobiology laboratories. The ability to perform genetic manipulations in songbirds will open unparalleled opportunities for the study of the relationship between genes and brain function in an animal species with a robust behavioral repertoire. Transgenic songbirds will allow us to generate animal models of human diseases affecting complex cognitive functions and communication disorders, which can only be incompletely modeled in other animal species. PUBLIC HEALTH RELEVANCE: The main manifestation of many neurological and psychiatric disorders in humans is altered behavior. The rich behavioral repertoires exhibited by songbirds make them ideal animal's nriodels in which to mimic human diseases that affect behavior. We propose to develop new molecular tools that will allow for genetic manipulation of songbirds to generate animal models of human diseases that affect complex cognitive functions and communication disorders.