Development of a whole-brain cellular mapping approach in a genetic model of autism and intellectual disability

自闭症和智力障碍遗传模型中全脑细胞图谱方法的开发

• 批准号: 9263018
• 负责人: Konstantinos Meletis
• 金额: $ 19.8万
• 依托单位: SCRIPPS FLORIDA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-15 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9263018
• 关键词: Animal Experimentation; Animal Model; Animals; Antibodies; Archives; Area; Autistic Disorder; Award; Bayesian Analysis; Behavior; Bioinformatics; Brain; Brain Diseases; Brain Mapping; Brain region; Cognition; Collaborations; Communities; Comorbidity; Computer software; Computers; DNA Sequence Alteration; Data; Data Set; Detection; Development; Disease; Disease model; Ecosystem; Epilepsy; Funding; Future; Genes; Genetic Models; Genotype; Goals; Health; Image; Imagery; Individual; Instruction; Intellectual functioning disability; Knockout Mice; Label; Maps; Measures; Mental disorders; Microscopy; Modeling; Molecular; Mus; Neurons; Neurosciences; Online Systems; Pattern; Play; Procedures; Process; Protocols documentation; Reporter; Research; Risk Factors; Schizophrenia; Scientist; Signal Transduction; Social Behavior; Social Interaction; Statistical Data Interpretation; Synapses; System; Technology; Testing; Time; Tracer; activity marker; alpha-SNAP; autism spectrum disorder; brain research; cell type; data visualization; design; developmental neurobiology; digital; experience; experimental study; genetic risk factor; high resolution imaging; mouse model; neural circuit; neuropsychiatric disorder; novel; prevent; programs; public health relevance; reconstruction; relating to nervous system; response; skills; social; software development; tool; web based interface

 DESCRIPTION (provided by applicant): Whole-brain mapping of cellular data in animal models will revolutionize our understanding of neural circuits and behavior. Microscopy hardware has progressed to a point where it is becoming routine to archive labeled whole animal brains. Furthermore, computing power and the software ecosystem are now mature enough that very large datasets can be managed. However, bioinformatics tools specifically designed for whole-brain mapping of cellular signals in animal models are lacking. Our collaborative group has recently created a suite of bioinformatics tools capable of reconstructing and then analyzing whole-brain data sets. However, because of their complexity, these tools can only be used by computer scientists in their current form. Thus, the goal of this project is to optimize a streamlined approach to digitally archive mouse brains so that whole-brain cellular measures can be more easily reconstructed and then analyzed. The results of such experiments are expected to vastly increase understanding of brain function. This will be accomplished by developing a seamless protocol for immunolabeling the mouse brain, followed by digital archiving of the brains, detection of cellular signals and analysis of these signals across the entire mouse brain. As part of developing this protocol, a web-based portal will be created that users around the world will be able to utilize to perform 3D reconstructions and subsequent analysis of their own mouse brain digital sections. Importantly, this system will be amenable to any form of cellular labeling, such as signals arising from any number of fluorescent reporters. In order to optimize this workflow and to test the utility of the web-based portal, mapping of whole brain activity is proposed in a mouse model of autism spectrum disorders and intellectual disability in response to social novelty. These would be the first whole brain cellular activation maps in a model of a developmental brain disorder. It is expected that these maps will advance our understanding of the neurobiology of developmental brain disorders by revealing brain areas that are dysfunctional during abnormal social behaviors. Importantly, the web-based portal will make whole brain mapping of cellular signals more accessible to the neuroscience community. This would enable other labs to map whole brain cellular data in any neuropsychiatric disease model. Collectivity, whole-brain mapping data from numerous distinct disease models by labs throughout the world would be expected to reveal common systems-level substrates of severe brain disorders.

 描述（由适用提供）：动物模型中细胞数据的全脑映射将彻底改变我们对神经回路和行为的理解。显微镜硬件已经发展到将整个动物大脑标记的日常档案变成常规的地步。此外，计算能力和软件生态系统现在已经足够成熟，可以管理非常大的数据集。但是，缺乏专门设计用于动物模型中细胞信号全脑映射的生物信息学工具。我们的协作小组最近创建了一套能够重建的生物信息学工具，然后分析全脑数据集。但是，由于它们的复杂性，这些工具只能由计算机科学家以当前形式使用。那，这个项目的目标是 优化用于数字归档小鼠大脑的流线型方法，以便更容易重建全脑细胞测量，然后进行分析。这种实验的结果有望大大增加对大脑功能的理解。这将通过开发一种无缝的协议来实现用于免疫标记的小鼠大脑，然后进行大脑的数字归档，检测细胞信号以及对整个小鼠大脑中这些信号的分析。作为开发此协议的一部分，将创建一个基于Web的门户，世界各地的用户将能够使用3D重建以及随后对自己的鼠标脑数字段的分析。重要的是，该系统将适合任何形式的细胞标记，例如由任意数量的荧光记者引起的信号。为了优化此工作流程并测试基于Web的门户的实用性，在自闭症谱系障碍的鼠标模型和智力残疾的鼠标模型中提出了整个大脑活动的映射，以响应社会新颖性。这些将是第一个整体 发育性脑部疾病模型中的脑细胞激活图。预计这些地图将通过揭示在异常的社会行为过程中脑部功能失调的大脑区域来提高我们对发展脑疾病的神经生物学的理解。重要的是，基于网络的门户将使神经科学社区更容易访问细胞信号的整个大脑映射。这将使其他实验室能够在任何神经精神疾病模型中绘制全脑细胞数据。全世界实验室的众多不同疾病模型的集体，全脑映射数据有望揭示严重脑部疾病的常见系统级底物。