Formation and Function of Circuitry for Vocal Learning

描述(由申请者提供)：这项资助的长期目标是了解听觉引导的发声学习的神经机制。本申请的目的是确定发声运动学习功能回路的分子特征。鸣禽习得的歌声是发声学习的最典型的范例，然而，定义并在功能回路内运作的分子很少为人所知。传统的实验室物种不会改变它们与生俱来的发声方式，所以到目前为止，测试另一个动物群体的发声学习中确定的分子是否具有鸟鸣功能是不可能的。随着FOXP2被确定为人类语言障碍的第一个单基因位点，这种可能性发生了变化。携带FOXP2突变的人类的核心缺陷是准确性和一致性以及人类语音，以及在生成口腔面部肌肉系统的连续运动方面。这种行为表型伴随着参与言语的皮质-纹状体回路的异常结构和功能。总而言之，这些发现表明FOXP2沿着一条与语音有关的神经路径存在。我们建议在鸣禽中使用分子、行为和遗传干预技术来发现FoxP分子在斑马雀发声学习回路中的作用。鸣禽是这些研究的理想对象，因为大脑皮层纹状体回路是鸣禽产生和发育的基础。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，任何观察到的发声学习候选神经机制的发展相关性都可以被二次筛选，以确定这种相关性是否持续到实际年龄之后的行为状态。因此，鸣鸟在选择候选分子进行功能测试之前，提供了一个无与伦比的机会来筛选它们。具体目标1将决定FoxP神经表达模式在歌曲学习过程中是否受到调控。《特定目的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别相关的假设。特殊目的3使用改变的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发声学习回路的形成和功能的理解。在鸣禽身上发现FoxP功能，将额外提供与FOXP基因突变有关的人类疾病的基本信息

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