Gaining insight into psychiatric disease by engineering piece by piece the human brain in vitro.

通过在体外对人脑进行逐个改造，深入了解精神疾病。

• 批准号: 10418740
• 负责人: Sergiu Pasca
• 金额: $ 59.67万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10418740
• 关键词: 16p11.2; 3-Dimensional; Acetylcholine; Affect; Anatomy; Award; Brain; Brain Diseases; Brain Stem; Brain region; CRISPR/Cas technology; Calcium; Cell Communication; Cell Line; Cells; Cerebral cortex; Communication; Coupled; Coupling; Defect; Development; Disease; Disease model; Dopamine; Electrophysiology (science); Engineering; Functional disorder; Gene Expression; Genes; Genetic; Glutamates; Goals; Growth Factor; High Pressure Liquid Chromatography; Human; Human Biology; Hybrids; Image; In Vitro; Instruction; Interneurons; Investigation; Laboratories; Lentivirus; Measurement; Mental disorders; Methods; Modeling; Molecular; Names; National Institute of Mental Health; Nervous system structure; Neuraxis; Neurobiology; Neurodevelopmental Disorder; Neuromodulator; Neurons; Neurosciences; Opsin; Organ; Organoids; Pathogenesis; Patients; Pattern; Pharmaceutical Preparations; Pharmacology; Phenotype; Physiological; Play; Pluripotent Stem Cells; Positioning Attribute; Preparation; Process; Property; Prosencephalon; Rodent Model; Role; Selective Serotonin Reuptake Inhibitor; Serotonergic System; Serotonin; Signal Transduction; Slice; Synapses; Syndrome; System; Technology; Testing; Therapeutic; Viral; Work; atypical antipsychotic; axon guidance; brain tissue; cohort; directed differentiation; experimental study; human model; human pluripotent stem cell; immunocytochemistry; insight; migration; neural network; neurodevelopment; neuropsychiatric disorder; neuropsychiatry; neuroregulation; next generation; novel; novel strategies; optogenetics; patch clamp; progenitor; programs; rabies viral tracing; raphe nuclei; receptor; relating to nervous system; social deficits; stem cell biology; stem cell model; three dimensional structure; transcriptomics

ABSTRACT A critical challenge in understanding the intricate programs underlying development, assembly, function, and dysfunction of the human nervous system is the lack of direct access to intact, functioning human brain tissue for detailed investigation by imaging, recording, and stimulation. My laboratory has been developing methods for directed differentiation of region-specific brain organoids and we have shown that these can combined two by two to study cell-cell interactions and circuit formation in preparations called brain assembloids. However, current in vitro brain models derived from stem cells do not capture neuromodulatory input, which restrict broader applications in neuroscience and modeling of disease. Here, we propose to develop a human 3D cellular platform that includes neuromodulatory projections. More specifically, we will derive from pluripotent stem cells regionalized brain organoids resembling the nucleus raphe in the brainstem and containing serotonergic neurons, and subsequently assemble them with cortical organoids. Using state-of-the-art live imaging, transcriptomics, pharmacology, viral tracing and electrophysiological methods, we plan to study serotonergic input into the cerebral cortex and use this platform to investigate defects in neuronal cross-talk in a severe genetic form of neurodevelopmental disease.

摘要 理解开发、组装、 功能，而人体神经系统的功能障碍是缺乏完整的直接进入， 通过成像、记录和刺激对功能正常的人脑组织进行详细研究。 我的实验室一直在开发针对特定区域大脑的定向分化方法， 我们已经证明，这些细胞可以两两结合起来研究细胞间的相互作用， 和回路形成的过程中。然而，目前的体外脑 来自干细胞的模型不能捕获神经调节输入，这限制了更广泛的神经调节输入。 在神经科学和疾病建模中的应用。在这里，我们建议开发一个人类3D 包括神经调节投射的细胞平台。更具体地说，我们将得到 从多能干细胞区域化的脑类器官类似于中缝核， 脑干和含有多巴胺能神经元，随后将它们与皮质 类器官使用最先进的实时成像，转录组学，药理学，病毒追踪和 电生理学方法，我们计划研究进入大脑皮层的肾上腺素能输入，并使用 这个平台，以调查缺陷的神经元串扰在一个严重的遗传形式， 神经发育疾病