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

神经工程小鼠强大的声音学习表型作为治疗沟通障碍的模型

• 批准号: 10472693
• 负责人: Erich D Jarvis
• 金额: $ 108.02万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10472693
• 关键词: Animal Model; Animals; Apraxias; Behavior; Behavioral; Biological Models; Birds; Brain; Brain Stem; Brain region; Categories; Communication; Communication impairment; Complex; Development; Disease; Electrophysiology (science); Engineered Gene; Engineering; Exhibits; FOXP2 gene; Foundations; Frequencies; Functional disorder; Gene Expression; Gene Expression Profile; Generations; Genes; Genetic; Genetic Engineering; Goals; Human; Individual; Institutes; Knowledge; Laboratories; Language; Language Development; Language Disorders; Larynx; Learning; Life Style; Maintenance; Measures; Modeling; Molecular; Motor Neurons; Mus; Mutation; Neurobiology; Phenotype; Physiology; Population; Preclinical Testing; Prosencephalon; Regulation; Resolution; Shapes; Songbirds; Speech; Speech Disorders; Study models; System; Techniques; Testing; Therapeutic; Time; Transgenic Animals; Ultrasonics; Uncertainty; Variant; Viral; axon guidance; base; behavioral phenotyping; brain circuitry; brain pathway; brain repair; classical conditioning; differential expression; effective therapy; experience; genetic approach; genetic manipulation; genetic testing; human model; in vivo; innovation; insight; interest; language impairment; learning ability; mutant; nerve stem cell; neural circuit; neurobehavioral; neurogenetics; neurophysiology; non-invasive imaging; novel; reconstitution; relating to nervous system; repaired; tool; trait; transcription factor; treatment strategy; vocal learning; vocalization

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.

抽象的 这个 Transformative R01 项目的目标是开发神经工程的遗传策略 小鼠的声乐学习表型，这可能会产生第一个治疗人类声乐的哺乳动物模型 沟通障碍。多达 10% 的人一生中存在某种沟通障碍 （言语和语言障碍，NICCHCY，2011），但尚无可遗传处理的系统 增强或修复与言语有关的大脑回路。我们最近发现，小鼠具有高度 易于处理，显示出基本的声音学习表型的证据。具体来说，老鼠有一些特征 曾经被认为是人类和其他声音学习物种所独有的，包括修改超声波的能力 基于上下文的发声 (USV)；前脑发声回路在发声过程中处于活跃状态，是 频率调制和音节组织，并直接连接到脑干运动神经元 控制喉部；当给予已知会导致音素的 FoxP2 突变时，音节顺序缺陷 对人类运动障碍进行测序。然而，与人类和鸣禽相比，这些表型要大得多。 在小鼠中更有限。这些和其他发现使我们推测，能力的自然变化类似于 在声乐学习者中，假定的声乐非学习者可能会表现出类似声乐学习的表型 跨物种的复杂性的连续体。在这种情况下，考虑到基本神经结构的存在 小鼠被认为在分类物种中必须进行发声学习，我们假设小鼠发声系统 相关行为可能会得到增强，从而为发展提供基础 改善人类声音交流障碍的新颖有效的策略。为了实现这一目标， 我们将利用我们实验室的最新发现，我们发现了趋同的特殊基因 多个发声学习物种（包括人类和 鸣禽，其中许多参与大脑通路的发育。我们假设进化 性状特化基因调控的变化是导致更高级发声能力出现的原因 可塑性和其他复杂的行为特征。我们的目标是重现独特的表达模式 在小鼠体内研究这些基因，以在体内连接水平上增强发声学习表型 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，我们的研究预计将通过以下方式影响该领域：1) 确定声乐学习专用基因如何塑造这一复合体的神经回路和生理学 行为; 2）开发一种新颖的、遗传上易于处理的哺乳动物模型系统，以揭示 人类语言的神经生物学细节及其功能障碍的治疗； 3）作为一个平台 神经工程一般复杂的行为特征。