Neurodevelopment of Tourette syndrome

抽动秽语综合征的神经发育

• 批准号: 10302287
• 负责人: FLORA M VACCARINO
• 金额: $ 45.98万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-19 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10302287
• 关键词: Anatomy; Architecture; Astrocytes; Autopsy; Basal Ganglia; Biological Markers; Blood specimen; Brain; Calcium Channel; Cell Line; Cell Nucleus; Cells; ChIP-seq; Child; Chronic; Clinical Trials; Clinical assessments; Complex; Corpus striatum structure; Development; Disease; Disease model; Electrophysiology (science); Enhancers; Environmental Risk Factor; Epigenetic Process; Fluorescence; Functional disorder; Gene Expression; Gene Expression Regulation; Genes; Genetic Enhancer Element; Gilles de la Tourette syndrome; Heritability; Human; Immune; Immunologics; In Vitro; Individual; Inflammatory; Interneurons; Longitudinal cohort study; Maps; Metabolic; Metabolism; Microglia; Modeling; Molecular; Mutation; Neurobiology; Neuroglia; Neuronal Differentiation; Neurons; Nitric Oxide Synthase; Nuclear; Oligodendroglia; Organoids; Outcome; Parvalbumins; Pathway Analysis; Pathway interactions; Patients; Pattern; Potassium Channel; Predisposing Factor; Recurrence; Research Personnel; Somatostatin; Sorting - Cell Movement; Subgroup; Synapses; Therapeutic; Time; Tissue-Specific Gene Expression; Tissues; Transcript; Variant; Work; autism spectrum disorder; base; brain tissue; cell type; cholinergic; cholinergic neuron; clinical biomarkers; developmental genetics; epigenome; epigenomics; experimental study; follow-up; gamma-Aminobutyric Acid; gene network; gene regulatory network; genetic variant; genome-wide; immunocytochemistry; induced pluripotent stem cell; longitudinal analysis; mind control; morphogens; network dysfunction; neurodevelopment; neuroimaging; neuropeptide Y; neuropsychiatric disorder; neurotransmission; proband; progenitor; putamen; recruit; relating to nervous system; response; stem cell model; transcriptome; transcriptome sequencing; transcriptomics

Tourette syndrome (TS) is a common disorder that afflicts as many as 1 in 150 children. Despite the high familiar recurrence rate, no significant causative or predisposing factor has yet emerged in TS. Neuroimaging and anatomical studies have implicated the striatum within the basal ganglia in TS. In postmortem brain tissue of patients with severe TS we found a decrease in striatal cholinergic neurons (CH/TAN) and two types of GABA interneurons, the parvalbumin+ (PV) and Somatostatin/Nitric Oxide Synthase /Neuropeptide Y+ (SST/NOS/NPY) by immunocytochemistry. Transcriptome profiling by RNA sequencing highlighted a decrease in synaptic neurotransmission and metabolism-related biofunctions in TS, as well as a prominent increase in inflammatory transcripts, as compared to matched normal controls (NC) brains. However, these signatures are an average of a complex cellular mixture and most likely miss changes occurring in cell subpopulations, particularly interneurons. We now seek to identify the transcriptome of striatal medium spiny neuron (MSN), interneuron (INT), astrocytes & microglia (AST/MICR) and oligodendrocytes (OLIG) cell subpopulations by fluorescence-activated nuclear sorting (FAN) as well as single neuronal nuclei in TS and NC postmortem brain tissue. Correspondingly, the epigenome of these cell types will be characterized by chromatin immunoprecipitation and sequencing (ChIP-seq) in the same cellular fractions. Differentially active enhancer regions will be mapped in the striatum of TS vs NC and a gene regulatory network encompassing changes in gene expression and corresponding enhancer activities will be built. Network modules differentially active in TS will be used to construct a model of dysfunctional striatal circuitry in TS. To understand the origin and potential causes of this network dysfunction, we will recapitulate early telencephalic development in vitro using a human induced pluripotent stem cell (iPSC) model of the disorder. Basal ganglia and cortical organoids from chronic TS patients, recovered TS patients and NC will be longitudinally analyzed and compared on the cellular, transcriptomic, epigenomic and electrophysiological levels to reveal cell fate, neuronal differentiation, molecular and functional abnormalities that underlie the disorder and its outcome. These complementary experiments will define the likely time of origin, pathophysiology, and molecular underpinnings of TS and provide a disease model where genetic and epigenetic changes can be perturbed to assess their neurobiological effects.

Tourette综合征（TS）是一种常见的疾病，患有多达150名儿童中的1个。尽管很高 熟悉的复发率，TS中尚未出现明显的病因或易感因素。神经影像学 解剖学研究暗示了TS基底神经节内的纹状体。在死后脑组织 在严重TS的患者中，我们发现纹状体胆碱能神经元（CH/TAN）和两种类型 GABA中间神经元，白蛋白+（PV）和生长抑素 /一氧化氮合酶 /神经肽Y+ （SST/NOS/NPY）通过免疫细胞化学。 RNA测序的转录组分析突出显示了 TS中的突触神经传递和代谢相关的生物功能的减少以及突出 与匹配的正常对照（NC）大脑相比，炎症转录本的增加。但是，这些 签名平均是复杂的细胞混合物，很可能会错过细胞中发生的变化 亚群，尤其是中间神经元。我们现在寻求识别纹状体介质的转录组 神经元（MSN），中间神经元（INT），星形胶质细胞和小胶质细胞（AST/MICR）和少突胶质细胞（Olig）细胞 TS和NC中的荧光激活核分子（FAN）以及单个神经元核的亚群 尸体后脑组织。相应地，这些细胞类型的表观组将由 在同一细胞级分中的染色质免疫沉淀和测序（CHIP-SEQ）。差异性活跃 增强剂区域将在TS vs NC的纹状体和基因调节网络中映射 将建立基因表达和相应增强剂活动的变化。网络模块差异化 TS中的活性将用于构建TS中功能失调的纹状体电路模型。了解起源 以及该网络功能障碍的潜在原因，我们将在体外概括早期脑脑发育 使用人类诱导的多能干细胞（IPSC）模型。基底神经节和皮质 来自慢性TS患者，康复的TS患者和NC的器官将进行纵向分析，并将 在细胞，转录组，表观基因组和电生理水平上进行比较，以揭示细胞命运， 神经元分化，分子和功能异常，这些异常是该疾病及其结果的基础。 这些互补实验将定义可能的起源时间，病理生理学和分子的时间 TS的基础，并提供疾病模型，其中遗传和表观遗传学变化可能会受到干扰 评估他们的神经生物学作用。