Formation and Function of Circuitry for Vocal Learning

描述（由申请人提供）：这项资助的长期目标是了解听觉引导的声乐学习的神经机制。本应用程序的目的是识别发声运动学习功能电路的分子特征。鸣禽的习得歌声是声音学习的最佳特征范例，然而，在功能电路中定义和操作的分子却很少为人所知。传统的实验室物种不会改变它们天生的发声方式，所以直到现在，还不太可能测试一种在另一动物群体的发声学习中发现的分子，因为它的功能是鸟鸣。这种不可能性随着FOXP2作为人类语言障碍的第一个单基因位点的鉴定而改变。携带FOXP2突变的人类的核心缺陷是人类语言的准确性和一致性，以及产生面部肌肉组织的顺序运动。这种行为表型伴随着参与语言的皮质纹状体回路的结构和功能异常。总之，这些发现表明FOXP2位于一条与语言相关的神经通路上。我们建议利用鸣禽分子、行为和基因干预技术来发现FoxP分子在斑胸草雀声乐学习回路中的作用。鸣禽是这些研究的理想对象，因为皮质纹状体回路是歌曲产生和发展的基础。此外，歌曲学习的三个阶段中的每一个都可以通过操纵听觉输入来扩展或夸大。因此，任何观察到的候选声音学习神经机制的发育相关性都可以进行二次筛选，以确定这种相关性是否持续存在于实足年龄之后的行为状态。因此，在选择候选分子进行功能测试之前，鸣禽为筛选候选分子提供了无与伦比的机会。具体目标1将确定FoxP神经表达模式是否在歌曲学习过程中受到调节。特异性目标2验证了FoxP表达的变化与歌曲学习和歌曲维持的感觉运动阶段特异性相关的假设。特异性目的3通过改变FoxP分子的基因表达来测试它们是否对感觉运动学习和歌曲维持是必要的。这些发现将极大地促进我们对声音学习回路的形成和功能的理解。鸣禽是唯一一种实验上可控制的声乐学习者，发现鸣禽的FoxP功能，将额外提供与FoxP突变相关的人类疾病的重要信息

DESCRIPTION (provided by applicant): The long-term goal of this grant is to understand the neural mechanisms for auditory-guided vocal learning. The objective addressed in this application is to identify molecular signatures of functional circuits for vocal motor learning. The learned song of songbirds is the best characterized exemplar of vocal learning, however few of the molecules that define and operate within the functional circuitry are known. Traditional laboratory species do not modify their innate vocalizations, so it has been improbable, until now, to test a molecule identified in the vocal learning of another animal group for its function birdsong. This improbability has changed with the identification of FOXP2 as the first monogenetic locus for a human language disorder. The core deficit of humans bearing a FOXP2 mutation is in the accuracy and consistency and human speech and in generating sequential movements of the orpfacial musculature. This behavioral phenotype is accompanied by abnormal structure and function of a cortical-striatal circuit that participates in speech. Together, these findings indicate that FOXP2 lies along one neural path linked to speech. We propose to use molecular, behavioral, and genetic intervention techniques in songbirds to discover the role of FoxP molecules in the vocal learning circuit of the zebra finch. Songbirds are ideal for these studies as a corticalstriatal circuit underlies song production and development. Further, each of the three phases of song learning can be extended or exaggerated by manipulating auditory input. Therefore, any developmental correlations observed for candidate neural mechanisms of vocal learning can be secondarily screened to determine whether the correlation persists beyond chronological age to behavioral state. The songbird thereby offers an unrivalled opportunity for screening candidate molecules prior to selecting them for functional tests. Specific Aim 1 will determine whether FoxP neural expression patterns are regulated during song learning. Specific Aim 2 tests the hypothesis that changes in FoxP expression correlate specifically with the sensorimotor phase of song learning and song maintenance. Specific Aim 3 uses altered genetic expression of FoxP molecules to test whether they are necessary for sensorimotor learning and song maintenance. These findings will significantly advance our understanding of the formation and function of vocal-learning circuitry. Discovery of FoxP function in songbirds, the only experimentally tractable vocal learner, will additionally provide essential information regarding human disorders linked to FOXP mutations