Neurodevelopment of Tourette syndrome

抽动秽语综合症的神经发育

• 批准号: 10529308
• 负责人: FLORA M VACCARINO
• 金额: $ 42.62万
• 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 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10529308
• 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; Disease remission; Electrophysiology (science); Enhancers; Environmental Risk Factor; Epigenetic Process; Fluorescence; Functional disorder; Gene Expression; Gene Expression Regulation; Genes; Genetic; 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; Subgroup; Synapses; Therapeutic; Time; Tissue-Specific Gene Expression; Tissues; Transcript; Variant; Work; autism spectrum disorder; brain tissue; cell type; cholinergic; cholinergic neuron; chromatin immunoprecipitation; clinical biomarkers; 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; neural; neurodevelopment; neuroimaging; neuropeptide Y; neuropsychiatric disorder; neurotransmission; proband; progenitor; putamen; recruit; response; stem cell model; transcriptome; transcriptome sequencing; transcriptomic profiling; 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.

多发性抽动症(TS)是一种常见的疾病，每150名儿童中就有一名患有这种疾病。尽管有很高的 熟悉的复发率，TS尚未出现明显的病因或诱因。神经成像 解剖学研究表明，TS患者的纹状体位于基底节内。在死后的脑组织中 在重度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、小白蛋白+和生长抑素/一氧化氮合酶/神经肽Y+ (SST/NOS/NPY)免疫细胞化学染色。通过RNA测序进行转录组分析突出了 TS的突触神经传递和代谢相关的生物功能降低，以及显著的 与匹配的正常对照组(NC)相比，炎性转录增加。然而，这些 签名是复杂细胞混合物的平均值，很可能遗漏了细胞中发生的变化 亚群，特别是中间神经元。我们现在试图鉴定纹状体中间刺的转录组。 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 荧光激活核分选(FAN)亚群以及TS和NC中单个神经元核的研究 死后脑组织。相应地，这些细胞类型的表观基因组将被表征为 染色质免疫沉淀和测序(CHIP-SEQ)。差异化活跃 增强子区将被定位在TS和NC的纹状体中，并包含一个基因调控网络 基因表达的变化和相应的增强子活性将被建立。不同的网络模块 在TS中的活性将被用于构建TS中纹状体回路功能障碍的模型。要了解起源 以及这种网络功能障碍的潜在原因，我们将简要回顾一下端脑早期的体外发育 使用人类诱导的多能干细胞(IPSC)模型来研究这种疾病。基底节和皮质 将对慢性TS患者、康复TS患者和NC的有机化合物进行纵向分析和 在细胞、转录、表观基因组和电生理水平上进行比较，以揭示细胞的命运， 神经元分化、分子和功能异常是导致这种疾病及其后果的基础。 这些互补的实验将确定可能的起源时间、病理生理学和分子 TS的基础，并提供了一种疾病模型，在该模型中，遗传和表观遗传变化可以被干扰 评估它们的神经生物学效应。

项目成果

Role of SHH in Patterning Human Pluripotent Cells towards Ventral Forebrain Fates.

• DOI: 10.3390/cells10040914
• 发表时间: 2021-04-16
• 期刊: Cells
• 影响因子: 6
• 作者: Brady MV;Vaccarino FM
• 通讯作者: Vaccarino FM

Antibodies From Children With PANDAS Bind Specifically to Striatal Cholinergic Interneurons and Alter Their Activity.

• DOI: 10.1176/appi.ajp.2020.19070698
• 发表时间: 2021-01-01
• 期刊: The American journal of psychiatry
• 作者: Xu J;Liu RJ;Fahey S;Frick L;Leckman J;Vaccarino F;Duman RS;Williams K;Swedo S;Pittenger C
• 通讯作者: Pittenger C

Analysis of somatic mutations in 131 human brains reveals aging-associated hypermutability.

• DOI: 10.1126/science.abm6222
• 发表时间: 2022-07-29
• 期刊: SCIENCE
• 影响因子: 56.9
• 作者: Bae, Taejeong;Fasching, Liana;Wang, Yifan;Shin, Joo Heon;Suvakov, Milovan;Jang, Yeongjun;Norton, Scott;Dias, Caroline;Mariani, Jessica;Jourdon, Alexandre;Wu, Feinan;Panda, Arijit;Pattni, Reenal;Chahine, Yasmine;Yeh, Rebecca;Roberts, Rosalinda C.;Huttner, Anita;Kleinman, Joel E.;Hyde, Thomas M.;Straub, Richard E.;Walsh, Christopher A.;Network, Brain Somatic Mosaicism;Urban, Alexander E.;Leckman, James F.;Weinberger, Daniel R.;Vaccarino, Flora M.;Abyzov, Alexej
• 通讯作者: Abyzov, Alexej

Mispatterning and interneuron deficit in Tourette Syndrome basal ganglia organoids.

• DOI: 10.1038/s41380-022-01880-5
• 发表时间: 2022-12
• 期刊: MOLECULAR PSYCHIATRY
• 影响因子: 11
• 作者: Brady, Melanie V.;Mariani, Jessica;Koca, Yildiz;Szekely, Anna;King, Robert A.;Bloch, Michael H.;Landeros-Weisenberger, Angeli;Leckman, James F.;Vaccarino, Flora M.
• 通讯作者: Vaccarino, Flora M.