Genetic dissection of cortical projection neurons in social brain circuits

社会脑回路中皮质投射神经元的基因解剖

• 批准号: 10452678
• 负责人: Winrich Freiwald
• 金额: $ 21.19万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10452678
• 关键词: Advanced Development; Affinity Chromatography; Amygdaloid structure; Animal Model; Animals; Area; Behavior; Bioinformatics; Biological Models; Brain; Brain imaging; Brain region; Callithrix; Candidate Disease Gene; Catalogs; Cells; Cerebral cortex; Characteristics; Complement; Data; Defect; Dependovirus; Development; Diffusion Magnetic Resonance Imaging; Disease; Disease model; Dissection; Etiology; Exhibits; Face; Face Processing; Foundations; Functional Imaging; Functional Magnetic Resonance Imaging; Functional disorder; Future; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Generations; Genes; Genetic; Genetic Variation; Genetic study; Glutamates; Goals; Grant; Human; Impairment; Individual; Knowledge; Label; Link; Macaca; Maps; Measures; Mediating; Messenger RNA; Methodology; Modeling; Molecular Profiling; Monkeys; Mus; Mutation; Neurons; Outcome Study; Pathway interactions; Pattern; Polyribosomes; Population; Primates; Procedures; Property; Protocols documentation; Rattus; Research; Ribosomes; Rodent; Social Behavior; Social Functioning; Social Identification; Specificity; System; Techniques; Temporal Lobe; Time; Transgenic Organisms; Translating; Variant; Viral; autism spectrum disorder; base; behavioral phenotyping; cell type; central coherence; connectome; diffusion weighted; experimental study; genetic analysis; genetic variant; imaging study; improved; neural circuit; nonhuman primate; novel; novel strategies; programs; rational design; risk variant; social; theories; tool; tractography

The autism spectrum disorders (ASDs) are characterized by impairments of social and communicative behavior. The different, yet specific behavioral phenotypes of autism suggest impairments of specific neural circuits of the social brain. Yet, as genetic studies of autism implicate several hundred gene variants, it remains unclear how these genetic variants cause the behavioral phenotypes of autism. Several studies have implicated dysregulation of gene expression in the cerebral cortex in the pathophysiology of ASD. However, they do not address the specificity of cell types involved, how genetic changes alter brain function, or the involvement of functionally specific brain areas. Thus, we do not know whether and how they are altering social brain function selectively or what it is about social brain function that makes it particularly vulnerable in autism. In order to understand autism and its causes, we need to understand how genetic alterations cause the specific changes in the brain circuits that mediate the social and communicative behaviors altered in the condition. The current proposal aims to establish a new approach and a new model system to answer these questions. Using an animal model close to humans, gene expression patterns in functionally defined circuits of the social brain will be characterized. As in human functional magnetic resonance imaging (fMRI) studies, functionally specific regions of the social brain will be localized. This pilot proposal will focus on face-selective brain regions, but the overall approach, once established, will easily translate to other systems. The functional characterizations of the social brain will be complemented by the determination of the connectome of face areas through diffusion-weighted brain imaging. With this knowledge, long-range projection neurons within this functionally defined network will be labeled through a retrograde adeno-associated virus and cell-type specific gene expression patterns will be measured using the Translating Ribosome Affinity Purification (TRAP). The approach will allow for the determination of these expression patterns in glutamatergic cortical projection neurons located in the supra- and infra-granular cortical layers. These are the exact neurons which two recent studies have found to be highly correlated with ASD risk genes. Gene expression patterns of projection neurons will be compared in functionally defined social brain areas to known catalogs of autism-associated gene variations and pathways. The main expected outcome of this study will be the first determination of autism-risk gene expression patterns of functionally identified nodes of the social brain. The rationale of this study is that it will allow us to link autism risk genes to social brain circuits, advance the development of etiological models of autism, and provide crucial information for the generation of transgenic non-human primate autism models. In doing so, critical new links will be forged between the genetic analysis of ASD and functional imaging of brain function in ASD.

自闭症谱系障碍 (ASD) 的特点是社交和沟通障碍 行为。自闭症的不同但特定的行为表型表明特定的神经损伤 社会大脑的回路。然而，由于自闭症的遗传学研究涉及数百种基因变异，因此 目前尚不清楚这些基因变异如何导致自闭症的行为表型。多项研究已 ASD 病理生理学中涉及大脑皮层基因表达失调。然而， 它们没有解决所涉及细胞类型的特异性、基因变化如何改变大脑功能，或者 涉及特定功能的大脑区域。因此，我们不知道它们是否以及如何改变 社会性大脑功能有选择性地发挥作用，或者社会性大脑功能为何使其在以下情况下特别脆弱： 自闭症。为了了解自闭症及其病因，我们需要了解基因改变如何导致 调节社交和交流行为的大脑回路的特定变化 健康）状况。当前的提案旨在建立一种新的方法和新的模型系统来回答这些问题 问题。使用接近人类的动物模型，功能定义的电路中的基因表达模式 社会大脑将被表征。正如在人体功能磁共振成像 (fMRI) 研究中一样， 社交大脑的功能特定区域将被定位。该试点提案将重点关注面部选择性 大脑区域，但总体方法一旦建立，将很容易转化为其他系统。功能性的 面部连接组的确定将补充社交大脑的特征 通过扩散加权脑成像的区域。有了这些知识，这个区域内的远程投射神经元 功能定义的网络将通过逆行腺相关病毒和细胞类型特异性进行标记 基因表达模式将使用翻译核糖体亲和纯化 (TRAP) 进行测量。这 该方法将允许确定谷氨酸能皮质投射中的这些表达模式 位于颗粒上皮层和颗粒下皮层的神经元。这些正是最近两个研究的神经元 研究发现与 ASD 风险基因高度相关。投影的基因表达模式 神经元将在功能定义的社交大脑区域与已知的自闭症相关目录进行比较 基因变异和途径。本研究的主要预期结果将是首次确定 社交大脑功能识别节点的自闭症风险基因表达模式。这样做的理由 研究表明，它将允许我们将自闭症风险基因与社交大脑回路联系起来，促进自闭症的发展 自闭症的病因学模型，并为转基因非人类的产生提供重要信息 灵长类自闭症模型。在此过程中，自闭症谱系障碍的遗传分析和 自闭症谱系障碍 (ASD) 患者脑功能的功能成像。