Neurodevelopment of Tourette syndrome

抽动秽语综合症的神经发育

• 批准号: 10063046
• 负责人: FLORA M VACCARINO
• 金额: $ 52.05万
• 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/10063046
• 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; Regulator Genes; 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; 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.

抽动秽语综合征（TS）是一种常见的疾病，每150名儿童中就有1名患有这种疾病。尽管高 虽然复发率相似，但TS中尚未出现显著的致病或诱发因素。神经影像 解剖学研究表明，基底神经节内的纹状体与TS有关。在死后的脑组织中 在严重TS患者中，我们发现纹状体胆碱能神经元（CH/TAN）和两种类型的 GABA中间神经元、小清蛋白+（PV）和生长抑素/一氧化氮合酶/神经肽Y+ (SST/NOS/NPY）。通过RNA测序进行的转录组分析强调了 TS中突触神经传递和代谢相关生物功能的减少，以及显著的 与匹配的正常对照（NC）脑相比，炎性转录物增加。但这些 签名是复杂细胞混合物的平均值，并且很可能错过细胞中发生的变化 亚群，特别是中间神经元。我们现在试图确定纹状体中棘的转录组， 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 通过荧光激活的核分选（FAN）以及TS和NC中的单个神经元核的亚群 死后的脑组织相应地，这些细胞类型的表观基因组的特征在于： 染色质免疫沉淀和测序（ChIP-seq）在相同的细胞级分。差异活性 增强子区域将在TS与NC的纹状体中进行定位，以及一个基因调控网络，包括 将建立基因表达和相应增强子活性的变化。网络模块差异化 将用于构建TS中功能障碍的纹状体回路的模型。为了了解 以及这种网络功能障碍的潜在原因，我们将在体外重现端脑的早期发育。 使用该疾病的人诱导多能干细胞（iPSC）模型。基底神经节和皮质 将纵向分析来自慢性TS患者、恢复的TS患者和NC的类器官， 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、作为疾病及其结果基础的分子和功能异常。 这些补充实验将确定可能的起源时间，病理生理学和分子生物学。 TS的基础，并提供了一种疾病模型，其中遗传和表观遗传变化可以被干扰， 评估其神经生物学效应。