Formation and Function of Circuitry for Vocal Learning

描述（由申请人提供）：本提案的长期目标是发现社会学习的声音交流的神经基础，这是一种内隐学习的形式。赤字 内隐学习，包括语言障碍，对社会融合具有破坏性后果。为了治疗或预防这些缺陷，必须了解目前未知的习得性声音交流的神经机制。语言是人类独有的，但其他物种也拥有语言的子成分，从而可以进行受控的分子、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曲，这种方式与人类语言发展有着显著的相似之处。 我们使用鸣禽来研究FoxP 2-一种保守的转录因子，其突变导致严重的语言障碍，作为进入发声学习神经分子网络的切入点。人类和鸣禽拥有全长和截短的FoxP 2同种型。后者缺乏DNA结合结构域，但包括二聚化结构域，由此它可以干扰转录活性。这些形式将作为增加或减少FoxP 2功能的工具，并确定基因共调节网络，神经生理学和行为的双向变化。除了组织大脑结构外，FoxP 2还具有组织后的作用，如在X区（专门用于歌曲的基底神经节子区域）内观察到的。X区的FoxP 2水平在发育早期是稳定的，但当幼鸟或成年鸟练习唱歌时，FoxP 2会急剧下调。我们假设FoxP 2作为神经和行为可塑性的分子门，即使在成年人中：行为驱动的FoxP 2减少在歌曲学习和成人练习，使声乐调整。相反，高水平的FoxP 2促进大脑组织，并在以后的生活中加强最佳的神经活动和行为。 为了验证这个， FoxP 2功能将通过在大脑组织期间以及在歌曲学习和成人维持期间病毒驱动的两种亚型表达而增强和减少。分子网络将使用RNAseq和一种强大的系统水平技术（称为加权基因共表达网络分析）来识别，以突出行为上的重要关系。来自培养的神经元和急性脑切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和成年后对催眠诱导的歌曲退化的影响。 这项工作与NIMH的开发和利用精神障碍动物模型的计划目标有关，其中社会学习缺陷是主要组成部分，包括但不限于自闭症谱系障碍。通过研究学习发声的动物，我们可以阐明与人类语言障碍相关的分子如何破坏神经功能，为开发生物和药物干预提供关键的见解。这些研究将提供有关复杂的社会习得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.