Formation and Function of Circuitry for Vocal Learning

描述（由申请人提供）：该基金的长期目标是了解神经元引导的声乐学习的神经机制。本申请的目的是确定发声运动学习功能回路的分子特征。鸣禽的学习歌曲是声音学习的最佳特征范例，然而很少有人知道在功能回路中定义和操作的分子。传统的实验室物种不会改变它们天生的发声能力，所以直到现在，测试在另一个动物群体的发声学习中发现的分子的鸟鸣功能是不可能的。这种不可能性随着FOXP 2被鉴定为人类语言障碍的第一个单基因位点而改变。携带FOXP 2突变的人类的核心缺陷在于准确性和一致性以及人类语言和产生面部肌肉组织的顺序运动。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。总之，这些发现表明FOXP 2位于沿着一条与语言相关的神经通路上。我们建议使用分子，行为和遗传干预技术在鸣禽中发现FoxP分子在斑胸草雀发声学习回路中的作用。鸣禽是这些研究的理想对象，因为皮层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，观察到的候选发声学习的神经机制的任何发育相关性，可以二次筛选，以确定是否持续超过实足年龄的行为状态的相关性。因此，鸣禽提供了一个无与伦比的机会，筛选候选分子之前，选择他们的功能测试。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。具体目标2测试的假设，即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。Specific Aim 3使用FoxP分子的基因表达改变来测试它们是否是感觉运动学习和歌曲维持所必需的。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。在鸣禽中发现FoxP功能，这是唯一实验上易于处理的发声学习者，将另外提供与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