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

基本信息

批准号：
10241317
负责人：
Erich D Jarvis
金额：
$ 106.12万
依托单位：
ROCKEFELLER UNIVERSITY
依托单位国家：
美国
项目类别：
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/10241317
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

项目摘要

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.

抽象的这个变革性R01项目的目的是开发神经工程的遗传策略小鼠的声带学习表型，这可能产生第一个用于治疗人声的哺乳动物模型沟通障碍。多达10％的人在其一生中患有某种沟通功能障碍（言语和语言障碍，Nichcy，2011年），但没有可用于的基因处理系统增强或修复涉及语音的脑电路。我们最近发现，老鼠很高可处理的，显示了基本声音学习表型的证据。具体来说，鼠标具有一些特征曾经认为人类和其他声带学习物种独有的认为，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声电路是必需的音节的频率调制和组织，并直接连接到脑干运动神经元控制喉；当给出已知引起音素的FOXP2突变时，音节测序缺陷在人类中测序障碍。但是，与人类和鸣禽相比，这些表型很多小鼠更有限。这些发现和其他发现使我们假设与能力自然变化相似在声乐学习者中，假定的人声非学习者可能会表现出类似人声学习的表型物种之间复杂性的连续性。在这种情况下，鉴于存在基本神经结构的存在被认为是分类物种中声学学习的小鼠，我们假设鼠标声音系统并且相关的行为可能有责任增强，从而为发展提供了基础新颖有效的策略，用于改善人声交流的疾病。为此，我们将利用实验室发现的最新发现，在那里我们发现了收敛的专业基因在包括人类在内的几种声音学习物种的声带区域中表达了〜50个基因鸣禽，其中许多参与大脑通路的发展。我们假设这种进化特质特有基因调节的变化是导致出现更先进的人声的原因可塑性和其他复杂的行为特征。我们的目标是概括独特的表达模式这些基因在小鼠中以增强连通性水平的声带学习表型，体内电生理学和行为。我们将使用病毒策略，引入人类神经干细胞，这样做，以及转基因动物的产生。如果成功的话，我们的研究将通过以下方式影响该领域：1）确定声音学习专业基因如何塑造这种复合物的神经记录和生理学行为; 2）开发一种新颖的，可探针的哺乳动物模型系统，用于揭幕人类语言和治疗障碍的神经生物学细节； 3）作为一个平台神经工程的复杂行为特征一般。