Formation and Function of Circuitry for Vocal Learning

描述(由申请人提供)：这项建议的长期目标是发现社会学习的声音交流的神经基础，这是内隐学习的一种形式。中国的赤字 内隐学习，包括语言障碍，对社会融合具有毁灭性的后果。为了治疗或预防这些缺陷，目前尚不清楚的获得性语音交流的神经机制必须得到理解。语言是人类独有的，但其他物种拥有语言的亚成分，从而能够进行受控的分子、生理和行为研究。鸣禽是一个有用的模型，因为它们通过社会互动学习歌声，其方式与人类的语言发展有显著的相似之处。我们使用鸣禽来研究FoxP2-一种保守的转录因子，它的突变会导致严重的语言障碍，作为进入发声学习神经分子网络的入口点。人类和鸣禽都拥有全长和截短的FoxP2亚型。后者缺乏DNA结合域，但包括一个二聚化结构域，从而可能干扰转录活性。这些形式将作为增强或减少FoxP2功能的工具，并确定基因协同调节网络、神经生理学和行为的双向变化。除了组织大脑结构外，FoxP2还具有组织后的作用，正如在X区观察到的那样，X区是专门用于歌曲的基底节亚区。FoxP2区的水平在发育早期是强劲的，但当幼鸟或成年鸟练习它们的歌唱时，FoxP2的表达显著下调。我们假设，即使在成年人中，FoxP2也扮演着神经和行为可塑性的分子门：在歌曲学习和成人练习中，行为驱动的FoxP2减少使人能够调整声音。相反，高水平的FoxP2会促进大脑的组织，并在以后的生活中强化最佳的神经活动和行为。为了测试这一点， Foxp2的功能将通过病毒驱动的两种异构体在大脑组织期间、歌曲学习和成人维持期间的表达而增强和减少。分子网络将使用RNAseq和一种被称为加权基因共表达网络分析的强大系统级技术来识别，以突出行为上显著的关系。来自培养的神经元和急性脑片的电生理记录将用于检查紧急神经生理变化。将测试行为对歌曲学习的影响，以及对成年后因耳聋导致的歌曲质量下降的影响。这项工作与NIMH的计划目标有关，即开发和利用精神障碍的动物模型，其中社会学习缺陷是其中的一个主要组成部分，包括但不限于自闭症谱系障碍。通过研究一种学习发声的动物，我们可以解释与人类语言障碍有关的分子是如何扰乱神经功能的，为行为和药物干预的发展提供了关键的见解。这些研究将提供关于复杂的社会学习行为背后的神经过程的基本但关键的信息。

DESCRIPTION (provided by applicant): The long term objective of this proposal is to discover the neural basis for socially-learned vocal communication, a form of implicit learning. Deficits in implicit learning, including language disorders, have devastating consequences for social integration. To treat or prevent these deficits, the neural mechanisms for learned vocal communication, currently unknown, must be understood. Language is uniquely human, but other species possess subcomponents of language enabling controlled molecular, physiological and behavioral studies. Songbirds are a useful model because they learn their songs through social interactions in a manner that exhibits significant parallels to human speech development. We use songbirds to investigate FoxP2- a conserved transcription factor whose mutation causes a severe language disorder as an entry point into the neuromolecular networks for vocal learning. Humans and songbirds possess full length and truncated FoxP2 isoforms. The latter lacks the DNA binding domain but includes a dimerization domain whereby it could interfere with transcriptional activity. These forms will serve as tools to augment or decrease FoxP2 function and determine bidirectional changes in gene coregulatory networks, neurophysiology and behavior. In addition to organizing brain structures, FoxP2 has post-organizational roles, as observed within area X, the basal ganglia sub-region dedicated to song. Area X FoxP2 levels are robust early in development, but when juvenile or adult birds practice their songs, FoxP2 is acutely down-regulated. We hypothesize that FoxP2 acts as a molecular gate of neural and behavioral plasticity even in the adult: Behaviorally driven reduction of FoxP2 during song learning and adult practice enables vocal adjustments. Conversely, high FoxP2 levels promote brain organization and reinforce optimal neural activity and behavior later in life. To test this, FoxP2 function will be augmented and reduced via viral driven expression of the two isoforms during periods of brain organization, and during song learning and adult maintenance. Molecular networks will be identified using RNAseq and a powerful systems level technique known as weighted gene co-expression network analysis, to highlight behaviorally significant relationships. Electrophysiological recordings from cultured neurons and acute brain slices will be used to examine emergent neurophysiological changes. Behavioral effects on song learning and on deafening-induced song deterioration in adulthood will be tested. This work is relevant to the NIMH's programmatic goals of developing and exploiting animal models for mental disorders in which social-learning deficits are a major component, including but not limited to autism spectrum disorder. By investigating an animal that learns its vocalizations, we can illuminate how molecules linked to human language disorders disrupt neural function, providing critical insight for the development of be- havioral and pharmacological interventions. These studies will provide basic but critical information about the neural processes underlying a complex socially-learned behavior.