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)以社交和沟通障碍为特征 行为。自闭症的不同但特定的行为表型表明特定的神经损害 社会性大脑的回路。然而，由于自闭症的基因研究涉及数百个基因变异，它 目前尚不清楚这些基因变异是如何导致自闭症的行为表型的。几项研究已经 在ASD的病理生理学机制中，大脑皮层基因表达异常。然而， 它们没有解决所涉及的细胞类型的特殊性，也没有说明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 有选择性的社会性脑功能，或使其特别脆弱的社会性脑功能是什么 自闭症。为了了解自闭症及其原因，我们需要了解基因改变是如何引起的。 调节社会和交流行为的大脑回路中的特定变化在 条件。目前的提案旨在建立一种新的方法和新的模式体系来回答这些问题 问题。使用接近人类的动物模型，基因在功能定义的环路中的表达模式 社交大脑将被特色化。正如在人类功能磁共振成像(FMRI)研究中一样， 社交大脑的特定功能区域将被本地化。这项试点提案将重点放在面部选择上 但是，一旦建立了整体方法，就很容易将其转化为其他系统。功能界别 社交大脑的特征将通过确定面孔的连接体来补充 通过弥散加权脑部成像。有了这些知识，大脑中的长程投射神经元 将通过逆行腺相关病毒和细胞类型特异性标记功能定义的网络 基因表达模式将使用翻译核糖体亲和纯化(TRAP)来测量。这个 方法将允许确定这些谷氨酸能皮质投射的表达模式 神经元位于颗粒上和颗粒下皮质层。这些正是两个新近发现的 研究发现，ASD风险基因与ASD高度相关。投影的基因表达模式 研究人员将把功能定义的社交脑区中的神经元与已知的自闭症相关类别进行比较 基因变异和途径。这项研究的主要预期结果将是第一次确定 社交大脑功能识别节点的自闭症风险基因表达模式。这样做的理由是 研究表明，这将使我们能够将自闭症风险基因与社会大脑回路联系起来，促进 自闭症的病因模型，并为转基因非人类的产生提供关键信息 灵长类自闭症模型。在这样做的过程中，将在ASD的基因分析和 ASD患者脑功能的功能成像。