Neurodevelopmental defects of the thalamocortical pathway as a convergent feature of psychiatric disorders

丘脑皮质通路的神经发育缺陷是精神疾病的共同特征

• 批准号: 10655225
• 负责人: Tomasz Nowakowski
• 金额: $ 75.82万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10655225
• 关键词: 22q11; 22q11.2; Attention deficit hyperactivity disorder; Axon; Benchmarking; Biological Assay; Brain; Calcium; Cell Line; Cell Nucleus; Cells; Cerebral cortex; Clustered Regularly Interspaced Short Palindromic Repeats; Complement; Complex; DNA Sequence Alteration; Data; Data Set; Defect; Dejerine Roussy Syndrome; Development; Developmental Delay Disorders; DiGeorge Syndrome; Disease; Epilepsy; FOXP2 gene; Fiber; Functional disorder; Gene Expression; Genes; Genetic study; Glutamates; Goals; Growth; Heterozygote; Human; Human Development; Image; In Vitro; Individual; Instruction; Investigation; Mediating; Mental disorders; Modeling; Molecular; Motor; Movement Disorders; Mus; Mutation; Neurodevelopmental Disorder; Neuroglia; Neuronal Differentiation; Neurons; Organoids; Pathway interactions; Patients; Phenotype; Pluripotent Stem Cells; Process; Protocols documentation; Radial; Role; Schizophrenia; Sensory; Series; Specific qualifier value; Specificity; Study models; Syndrome; Technology; Testing; Thalamic structure; Tissue Model; Tissues; Work; autism spectrum disorder; cell fate specification; cell type; cognitive task; differentiation protocol; epigenomics; exome sequencing; genetic variant; genomic data; human model; human pluripotent stem cell; human tissue; in vivo; induced pluripotent stem cell; innovation; knock-down; microdeletion; mouse development; mouse model; neural; neural circuit; neural patterning; neuroimaging; neuropsychiatric symptom; overexpression; preference; single cell sequencing; single-cell RNA sequencing; stem; stem cell model; stem cell technology; thalamocortical tract; tool; transcription factor; transcriptomics

PROJECT SUMMARY Brain function emerges from the activity of hundreds of neuronal types embedded within a complex network of neural circuits. Although the formation of neural circuits is guided by the emergent activity, many of the initial ‘wiring instructions’ are genetically encoded. Mutations in genes associated with neurodevelopmental psychiatric disorders may disrupt the early stages of cell type and circuit development, leading to long-lasting deficits in function. Our overarching goal is to identify the molecular and cellular mechanisms that govern neuronal cell type specification and their early connectivity preferences. Disease associated mutations serve as a discovery platform of molecular mechanisms that likely disrupt connectivity. In this project, we focus on the development of the human thalamus and early stages of thalamocortical pathway formation. Given the central role of the thalamocortical pathway in sensory, motor, and cognitive tasks, understanding its development in the human brain would be fundamental to studies modeling the consequences of mutations associated with multiple neuropsychiatric symptoms. Remarkable differences between mouse and human development of the thalamocortical pathway pose a scientific challenge for studying the impact of genetic variants on human thalamocortical pathway development, especially during its early formation. Innovations of in vitro differentiation protocols for induced pluripotent stem cells have recently enabled studies of early formation of the human thalamocortical pathway using organoids. As an exemplar, we propose to investigate thalamocortical and corticothalamic axon outgrowth in organoids derived from patients with 22q11.2 microdeletion syndrome, which is associated with schizophrenia, autism, movement disorders, developmental delays, and epilepsies. Neuroimaging studies in 22Q11 Deletion Syndrome (22Q11DS) patients have identified differences in functional thalamocortical connectivity between patients and healthy control, establishing a scientific premise for examining thalamocortical pathway development in cells with 22q11.2 microdeletion. Investigations of neurodevelopmental defects using stem cell models will be complemented by a parallel effort using a mouse model of human 22q11.2 microdeletion. We will identify molecular changes in cell fate specification of thalamic neurons, and compare axonal outgrowth phenotypes in control and cells with the 22q11.2 microdeletion. Our preliminary data implicate FOXP2 transcription factor activity in mediating thalamocortical pathway growth phenotypes in 22q11.2 DS thalamic neurons. The proposed project will establish groundwork for studying the growing list of rare genetic mutations with high effect size discovered through large scale studies of Autism, ADHD, and schizophrenia patients for their role in brain development, focusing on the development of the thalamocortical pathway.

项目摘要 大脑功能来自于数百种神经元的活动，这些神经元嵌入在一个复杂的神经网络中。 神经回路虽然神经回路的形成是由涌现的活动指导的，但许多最初的神经回路是由涌现的活动指导的。 “接线指令”是基因编码的。与神经发育相关的基因突变 精神疾病可能会破坏细胞类型和电路发育的早期阶段，导致长期的 功能缺陷。我们的首要目标是确定分子和细胞机制， 神经元细胞类型特化和它们的早期连接偏好。疾病相关突变 作为一个发现可能破坏连接的分子机制的平台。在这个项目中，我们专注于 人类丘脑的发育和丘脑皮质通路形成的早期阶段。鉴于 丘脑皮层通路在感觉、运动和认知任务中的中心作用，了解其 人类大脑的发育将是研究突变后果的基础 与多种神经精神症状有关小鼠和人类之间的显著差异 丘脑皮质通路的发展对研究遗传因素的影响提出了科学挑战。 人类丘脑皮质通路的发展，特别是在其早期形成的变体。创新 用于诱导多能干细胞的体外分化方案最近使得能够进行早期分化的研究。 使用类器官形成人类丘脑皮质通路。作为一个范例，我们建议调查 来自22q11.2患者的类器官中的丘脑皮质和皮质丘脑轴突生长 微缺失综合征，与精神分裂症，自闭症，运动障碍，发育障碍， 延迟和癫痫22Q11缺失综合征（22Q11DS）患者的神经影像学研究已经确定 患者和健康对照之间功能性丘脑皮质连接的差异，建立了一个 研究22q11.2微缺失细胞中丘脑皮质通路发育的科学前提。 使用干细胞模型的神经发育缺陷的调查将得到平行努力的补充 使用人类22q11.2微缺失的小鼠模型。我们将识别细胞命运的分子变化 丘脑神经元的规格，并比较对照组和细胞中的轴突生长表型与 22q11.2微缺失。我们的初步数据表明FOXP2转录因子的活性介导了 22q11.2 DS丘脑神经元的丘脑皮质途径生长表型。拟议项目将 为研究越来越多的发现高效应量的罕见基因突变奠定基础 通过对自闭症、多动症和精神分裂症患者的大规模研究，了解他们在大脑发育中的作用， 专注于丘脑皮质通路的发展。