Neuroengineering a Robust Vocal Learning Phenotype in Mice as a Model for Treating Communication Disorders

摘要 这个变革性的R01项目的目标是为神经工程开发一种强大的遗传策略 小鼠的发声学习表型，这可能是治疗人类发声的第一个哺乳动物模型 沟通障碍。高达10%的人在一生中都有某种沟通障碍 (言语和语言障碍，NICHCY，2011)，但目前还没有遗传上容易处理的系统 增强或修复与语言有关的大脑回路。我们最近发现老鼠，这是高度的 易驯服，显示出初级发声学习表型的证据。具体地说，老鼠有一些特征 曾经被认为是人类和其他发声学习物种独有的能力，包括修改超声波的能力 基于上下文的发声(USV)；在发声过程中活跃的前脑发声回路，需要 频率调制和音节的组织，并直接连接到脑干运动神经元， 控制喉咙；当给予已知导致音素的FoxP2突变时，音节排序缺陷 对人类的运动障碍进行测序。然而，与人类和鸣禽相比，这些表型要多得多 更多的限制在老鼠身上。这些发现和其他发现导致我们假设，能力类似于自然变异 在发声学习者中，被认为不学习发声的人可能会表现出类似发声学习的表型 跨物种的复杂性的连续体。在这种情况下，考虑到存在于 在分类物种中，小鼠被认为是发声学习的专属动物，我们假设小鼠的发声系统 并且相关联的行为可能易于增强，从而为开发提供基础 提出了改善人类发声交流障碍的新的有效策略。要做到这一点， 我们将利用我们实验室的最新发现，在那里我们发现了收敛的专门化基因 ~50基因在包括人类和人类在内的几种发声学习物种发声脑区的表达 鸣禽，其中许多参与了大脑通路的发育。我们假设进化论 特征专门化基因调控的变化是更高级声乐出现的原因 可塑性和其他复杂的行为特征。我们的目标是总结独特的表达模式 这些基因在小鼠体内增强发声学习表型的连接性水平 电生理学和行为学。我们将使用病毒策略，引入人类神经干细胞， 以及转基因动物的产生。如果成功，我们的研究预计将对该领域产生以下影响：1) 确定发声学习的特殊基因如何塑造这个复合体的神经回路和生理 行为；2)开发一种新的、遗传上易处理的哺乳动物模型系统，用于揭示 人类语言的神经生物学细节和对其功能障碍的治疗；以及3)作为 神经工程学一般具有复杂的行为特征。

Abstract The goal of this Transformative R01 project is to develop genetic strategies for neuroengineering a robust vocal learning phenotype in mice, which may yield the first mammalian model for treating human vocal communication disorders. Up to 10% of humans have some sort of communication dysfunction in their lifetimes (Speech and Language Impairments, NICHCY, 2011), yet there is no genetically tractable system for enhancing or repairing brain circuits involved in speech. We recently discovered that mice, which are highly tractable, show evidence of a rudimentary vocal learning phenotype. Specifically, mice have some features once thought unique to humans and other vocal learning species, including the ability modify ultrasonic vocalizations (USVs) based on context; a forebrain vocal circuit that is active during vocalizing, is required for frequency modulation and organization of syllables, and that directly connects to brainstem motor neurons that control the larynx; and syllable sequencing deficits when given a FoxP2 mutation known to cause phoneme sequencing dyspraxia in humans. However, compared to humans and songbirds, these phenotypes are much more limited in mice. These and other findings led us to hypothesize that similar to natural variation in ability among vocal learners, presumed vocal non-learners may exhibit vocal learning-like phenotypes along a continuum of complexity across species. In this context, given the presence of the basic neuroarchitecture in mice considered obligate for vocal learning in categorical species, we postulate that the mouse vocal system and associated behaviors may be liable to enhancement, thereby providing a foundation for the development of novel and effective strategies for ameliorating disorders of human vocal communication. To accomplish this, we will exploit recent findings from our laboratory where we discovered convergent specialized gene expression of ~50 genes in vocal brain regions of several vocal learning species, including humans and songbirds, many of which are involved in brain pathway development. We hypothesize that evolutionary changes in the regulation of trait-specialized genes are responsible for the emergence of more advanced vocal plasticity and other complex behavioral traits. Our objective is to recapitulate the unique expression patterns of these genes in mice to enhance the vocal learning phenotype at the level of connectivity, in vivo electrophysiology, and behavior. We will do so using viral strategies, introduction of human neural stem cells, and the generation of transgenic animals. If successful, our studies are expected to impact the field by: 1) Establishing how vocal-learning specialized genes shape the neurocircuitry and physiology for this complex behavior; 2) Developing a novel, genetically tractable mammalian model system for unveiling the neurobiological details of human language and treatments for its dysfunction; and 3) Serving as a platform for neuroengineering complex behavioral traits in general.