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:10002032
- 负责人:
- 金额:$ 102.6万
- 依托单位:
- 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:
- 关键词:Animal ModelAnimalsApraxiasBehaviorBehavioralBiological ModelsBirdsBrainBrain StemBrain regionCategoriesCommunicationCommunication impairmentComplexDevelopmentDiseaseElectrophysiology (science)Engineered GeneEngineeringExhibitsFOXP2 geneFoundationsFrequenciesFunctional disorderGene ExpressionGene Expression ProfileGenerationsGenesGeneticGenetic EngineeringGoalsHumanIndividualInstitutesKnowledgeLaboratoriesLanguageLanguage DevelopmentLanguage DisordersLarynxLearningLife StyleMaintenanceMeasuresModelingMolecularMotor NeuronsMusMutationNeurobiologyPhenotypePhysiologyPopulationPreclinical TestingProsencephalonRegulationResolutionShapesSongbirdsSpeechSpeech DisordersStudy modelsSystemTechniquesTestingTherapeuticTimeTransgenic AnimalsUltrasonicsUncertaintyVariantViralaxon guidancebasebehavioral phenotypingbrain circuitrybrain pathwaybrain repairclassical conditioningdifferential expressioneffective therapyexperiencegenetic approachgenetic manipulationgenetic testinghuman modelin vivoinnovationinsightinterestlanguage impairmentlearning abilitymutantnerve stem cellneural circuitneurobehavioralneurogeneticsneurophysiologynon-invasive imagingnovelreconstitutionrelating to nervous systemrepairedtooltraittranscription factortreatment strategyvocal learningvocalization
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.
摘要
这个变革R 01项目的目标是开发神经工程的遗传策略,
小鼠的发声学习表型,这可能产生第一个治疗人类发声的哺乳动物模型。
沟通障碍多达10%的人在一生中有某种沟通障碍
(Speech and Language Impairments,NICHCY,2011),但没有遗传上易于处理的系统,
增强或修复与语言有关的大脑回路。我们最近发现,
易处理,显示出基本的发声学习表型的证据。具体来说,老鼠有一些特征
曾经被认为是人类和其他发声学习物种所独有的,包括改变超声波的能力。
发声(USVs)基于上下文;在发声过程中活跃的前脑发声回路,
频率调制和音节的组织,并直接连接到脑干运动神经元,
控制喉部;以及当给予已知引起音素的FoxP 2突变时音节序列缺陷
对人类的运动障碍进行排序然而,与人类和鸣禽相比,这些表型
更局限于小鼠。这些和其他发现使我们假设,类似于能力的自然变化,
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,沿着a
跨物种的复杂性的连续体。在这种情况下,鉴于存在的基本神经结构,
小鼠被认为是专为声乐学习的分类物种,我们假设,小鼠的声乐系统,
和相关的行为可能易于增强,从而为发展提供基础
新的和有效的策略来改善人类的声音交流障碍。为了实现这一点,
我们将利用我们实验室的最新发现,
在几种发声学习物种的发声脑区域中,包括人类和
鸣禽,其中许多参与大脑通路的发展。我们假设进化论
特化基因调节的变化是导致更高级发声的原因。
可塑性和其他复杂的行为特征。我们的目标是概括出
这些基因在小鼠体内增强发声学习表型的连接水平,
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,
和转基因动物的产生。如果成功,我们的研究预计将影响该领域:1)
建立声音学习专门基因如何塑造这种复合体的神经回路和生理学
行为; 2)开发一种新的,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,
神经工程复杂的行为特征。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Erich D Jarvis其他文献
Erich D Jarvis的其他文献
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{{ truncateString('Erich D Jarvis', 18)}}的其他基金
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:
10685974 - 财政年份:2019
- 资助金额:
$ 102.6万 - 项目类别:
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 - 财政年份:2019
- 资助金额:
$ 102.6万 - 项目类别:
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:
10241317 - 财政年份:2019
- 资助金额:
$ 102.6万 - 项目类别:
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:
9789421 - 财政年份:2019
- 资助金额:
$ 102.6万 - 项目类别:
Auditory Protein Regulation in Normal & Abnormal States
正常情况下的听觉蛋白质调节
- 批准号:
7254135 - 财政年份:2006
- 资助金额:
$ 102.6万 - 项目类别:
Molecular Mechanisms of Basal Ganglia Regeneration in Songbirds
鸣禽基底神经节再生的分子机制
- 批准号:
7473240 - 财政年份:2006
- 资助金额:
$ 102.6万 - 项目类别:
Auditory Protein Regulation in Normal & Abnormal States
正常情况下的听觉蛋白质调节
- 批准号:
7148247 - 财政年份:2006
- 资助金额:
$ 102.6万 - 项目类别:
Molecular Mechanisms of Basal Ganglia Regeneration in Songbirds
鸣禽基底神经节再生的分子机制
- 批准号:
7264657 - 财政年份:2006
- 资助金额:
$ 102.6万 - 项目类别:
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