Investigating the role of CNTNAP2 gene in vocal learning in mutant songbirds

研究 CNTNAP2 基因在突变鸣禽声音学习中的作用

基本信息

批准号：
8413323
负责人：
CARLOS LOIS
金额：
$ 24.91万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-13 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8413323
关键词：
Acute Adolescent Affect Anatomy Animal Model Animals Area Autistic Disorder Behavior Behavioral Birds Boxing Brain Cell Nucleus Communication Communication impairment Development Disease Dissection Down-Regulation Engineering Exhibits Genes Genetic Hearing Human Impairment Laboratories Language Language Development Lead Learning Lentivirus Vector Link Maps Mediating Memory Messenger RNA Methods Modeling Modification Molecular Mutation Neurodevelopmental Disorder Pathway interactions Patients Performance Play Predisposition Production Property Proteins RNA Interference Research Research Personnel Role Series Signal Transduction Songbirds Speech System Transgenic Organisms autism spectrum disorder base communication behavior contactin critical period developmental disease forkhead protein genetic manipulation mutant prevent social specific language impairment tool vocal learning vocalization zebra finch

项目摘要

DESCRIPTION (provided by applicant): Communication impairments are some of the most debilitating consequences of a number of neurodevelopmental disorders, including autism spectrum disorders (ASD). It is thought that the communication impairments associated with neurodevelopmental disorders may be due to the perturbed assembly of brain areas involved in vocal communication. In recent years a number of genes, including the transcription factor FoxP2 and its target CNTNAP2, have been linked to language specific impairments and to ASD in humans, suggesting that they could play a direct role in speech and language acquisition. However, the lack of adequate animal models to specifically study vocal learning and communication has prevented the dissection of the genetic components involved in communication behaviors. Songbirds are currently the best animal model to study vocal communication because song learning in these animals shares critical features with speech acquisition in humans. Moreover, songbirds have a dedicated brain circuit that is required for the learning and production of vocal signals. Finally, both Foxp2 and CNTNAP2 are expressed in the song system suggesting that speech acquisition in humans and song learning in songbirds involves similar molecular pathways. Thus, songbirds could be an excellent model to study the genetic basis of communication-related aspects of neurodevelopmental disorders, as they represent the ideal system to study how genes orchestrate the assembly of a brain circuit dedicated to vocal learning and production. Our laboratory has developed new methods for the genetic modification of songbirds that will enable us and other researchers to generate genetic animal models for vocal communication disorders. In this proposal we describe a plan to generate genetically-engineered songbirds deficient in CNTNAP2, which will open a new avenue for investigating the role of genes on the assembly and function of the brain circuits involved in vocal communication. This approach should lead to a better understanding on how mutations in this and other genes result in communication deficits such as the ones observed in patients with ASD and other neurodevelopmental disorders. PUBLIC HEALTH RELEVANCE: Impaired vocal communication is one of the most debilitating deficits observed in a number of diseases due to abnormal brain development, such as autism. Recent studies have identified several genes associated with autism and other disorders that impair communication. Songbirds are currently the best animal model to study vocal communication because song learning in these animals shares several critical features with speech acquisition in humans. We propose to generate a genetically-engineered songbird in which one of these autism-related genes is disrupted to investigate how genes orchestrate the assembly of the brain circuits involved in vocal communication.

描述（由申请人提供）：沟通障碍是许多神经发育障碍（包括自闭症谱系障碍（ASD））最严重的后果之一。人们认为，与神经发育障碍相关的沟通障碍可能是由于参与声音沟通的大脑区域的扰动造成的。近年来，包括转录因子 FoxP2 及其靶标 CNTNAP2 在内的许多基因已与人类语言特异性障碍和自闭症谱系障碍 (ASD) 有关，这表明它们可能在言语和语言习得中发挥直接作用。然而，缺乏足够的动物模型来专门研究声音学习和交流，阻碍了对交流行为所涉及的遗传成分的剖析。鸣禽是目前研究声音交流的最佳动物模型，因为这些动物的鸣叫学习与人类的语音习得具有共同的关键特征。此外，鸣禽有学习和产生声音信号所需的专用大脑回路。最后，Foxp2 和 CNTNAP2 均在鸣叫系统中表达，表明人类的语音习得和鸣禽的鸣叫学习涉及相似的分子途径。因此，鸣禽可能是研究神经发育障碍的交流相关方面的遗传基础的绝佳模型，因为它们代表了研究基因如何编排致力于发声学习和产生的大脑回路组装的理想系统。我们的实验室开发了对鸣禽进行基因改造的新方法，这将使我们和其他研究人员能够生成声音交流障碍的遗传动物模型。在这项提案中，我们描述了一项通过基因工程培育缺乏 CNTNAP2 的鸣禽的计划，这将为研究基因对涉及声音交流的大脑回路的组装和功能的作用开辟一条新途径。这种方法应该有助于更好地理解该基因和其他基因的突变如何导致沟通缺陷，例如在自闭症谱系障碍和其他神经发育障碍患者中观察到的沟通缺陷。公共健康相关性：声音交流受损是在许多由于大脑发育异常（例如自闭症）引起的疾病中观察到的最严重的缺陷之一。最近的研究发现了一些与自闭症和其他损害沟通的疾病相关的基因。鸣禽是目前研究声音交流的最佳动物模型，因为这些动物的鸣叫学习与人类的语音习得有几个关键特征。我们建议培育一种基因工程鸣禽，其中一个与自闭症相关的基因被破坏，以研究基因如何协调参与声音交流的大脑回路的组装。