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，鸣禽是研究声乐学习生物学基础的主要非人类模型，声乐学习是语言习得的关键行为基础。此外，鸣禽是研究大脑不对称、大脑发育的激素控制、睡眠的生理功能、大脑性别差异、行为诱导的基因表达和成人神经发生等问题的理想系统。尽管鸣禽对神经生物学很重要，但由于缺乏基因操作方法，鸣禽作为实验系统的有效性受到限制。最近，我们成功地将慢病毒介导的转基因应用于斑胸草雀（Agate et al., 2009）。虽然这一成就证明了慢病毒介导的鸣禽转基因的可行性，但目前的方法效率低、劳动密集且成本高。在本提案中，我们计划优化现有的策略，并产生新的工具，以开发一种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技能的动物物种的基因与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进行不完整的建模。

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.