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

基本信息

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
项目类别：
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

项目摘要

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数百种神经元类型的活性，这些神经元类型嵌入了复杂的网络中神经回路。尽管神经回路的形成是由紧急活动的指导，但许多初始活动 “接线说明”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，导致持久功能缺陷。我们的总体目标是确定控制的分子和细胞机制神经元细胞类型规范及其早期连通性偏好。疾病相关的突变服务作为可能破坏连通性的分子机制的发现平台。在这个项目中，我们专注于人丘脑的发展和丘脑皮层途径形成的早期阶段。鉴于丘脑皮质途径在感觉，运动和认知任务中的中心作用，了解其人脑中的发展对于研究建模突变的后果将是基础与多种神经精神症状有关。小鼠和人之间的显着差异丘脑皮层途径的发展提出了研究通用影响的科学挑战关于人丘脑皮层途径发育的变体，尤其是在其早期形成期间。创新诱导多能干细胞的体外分化方案最近已实现了早期的研究使用类器官形成人丘脑皮层途径。作为一个典范，我们建议调查从22q11.2的患者衍生的类器官中丘脑皮质和皮质丘脑轴突的生长微缺失综合征与精神分裂症，自闭症，运动障碍，发育性有关延迟和情节。 22q11缺失综合征（22q11ds）患者的神经影像学研究已经鉴定患者与健康对照之间的功能性丘脑皮质连通性差异，建立科学前提，用于检查具有微骨骼22q11.2细胞中丘脑皮质途径的发育。使用干细胞模型对神经发育缺陷的研究将通过平行努力来完成使用人类22q11.2微缺失的小鼠模型。我们将确定细胞脂肪的分子变化丘脑神经元的规范，并比较对照和细胞中的轴突生长表型 22Q11.2微骨骼。我们的初步数据暗示FOXP2转录因子活性在介导 22q11.2 ds丘脑神经元中的丘脑皮质途径生长表型。拟议的项目将建立研究基础，以研究发现的稀有遗传突变列表的较高效果尺寸已发现通过对自闭症，多动症和精神分裂症患者在大脑发育中作用的大规模研究，专注于丘脑皮层途径的发展。