in vivo imaging of transplanted human induced-Pluripotent Stem Cell (iPSC) derived neurons to model neurological and psychiatric disorders

对移植的人类诱导多能干细胞 (iPSC) 衍生的神经元进行体内成像，以模拟神经和精神疾病

• 批准号: 10132398
• 负责人: Krishnan Padmanabhan
• 金额: $ 49.83万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10132398
• 关键词: Action Potentials; Address; Affect; American; Anatomy; Animals; Antipsychotic Agents; Area; Attention; Autopsy; Brain; Calcium; Cell Differentiation process; Cell physiology; Cells; Code; Cognitive deficits; Complex; Computing Methodologies; Data; Delusions; Development; Disease; Disease Marker; Disease model; Early identification; Expressed Emotion; Fire - disasters; General Population; Goals; Hallucinations; Head; Health Care Costs; Homelessness; Human; Human Activities; Image; In Vitro; Individual; Induced pluripotent stem cell derived neurons; Label; Laser Scanning Microscopy; Life Expectancy; Memory; Mental disorders; Methods; Modeling; Monitor; Morphology; Mus; Neurites; Neurobiology; Neurological Models; Neurons; Pathology; Patients; Pattern; Physiological; Physiology; Pluripotent Stem Cells; Population; Process; Public Health; Research; Schizophrenia; Shapes; Structure; Substance abuse problem; Symptoms; Synapses; System; Technology; Testing; Time; Tissues; Transplantation; Validation; Work; area striata; awake; base; calcium indicator; gray matter; human disease; imaging modality; in vivo; in vivo calcium imaging; in vivo imaging; induced pluripotent stem cell; insight; nerve stem cell; nervous system disorder; neural circuit; neuropsychiatric disorder; novel; patient population; relating to nervous system; stem cells; suicidal risk; tool; two-photon

Project Summary Affecting over 1% of the world’s population, including 3 million Americans, schizophrenia is a debilitating psychiatric disorder characterized by an array of symptoms including hallucinations, delusions, difficulty expressing emotions, and deficits in attention and memory. Despite the currently available antipsychotics, patients suffering schizophrenia have a life expectancy 10 years lower than that of the general population, are prone to substance abuse, homelessness, and are at risk of suicide. As a result, both the toll exacted on the lives of individuals suffering from the disorder and the public health costs are substantial. There is currently no cure for schizophrenia, and research into the causes of the disease, including the anatomical and physiological disruptions in the brain, has been difficult because little is known about the underlying pathology of cells in patients. To elucidate the anatomical and physiological deficits found in the patients with schizophrenia, this proposal will develop a novel model for the disorder by transplanting reprogrammed human induced- Pluripotent Stem Cells (iPSCs) into an animal system and imaging the structure and function of these cells in vivo. In Aim 1, this project will develop the technologies needed to perform structural characteriation of human iPSC-derived neurons including developing methods to analyze neural circuit structure and anatomical dynamics. In Aim 2, this project will develop technologies needed to image the population calcium activity of human iPSC-derived neurons in vivo and develop new analysis methods for studying and characterizing this acitivity. In Aim 3, this project will apply these technologies to characterize the structure and spontaneous activity patterns of human iPSC-derived neurons in vivo. Taken together, this work will develop a powerful new platform for dissecting the structure and function of human neural circuits with the aims of understanding the neurobiological basis of schizophrenia.

项目概要 精神分裂症影响着世界上超过 1% 的人口，其中包括 300 万美国人。 使人衰弱的精神疾病，其特征是一系列症状，包括幻觉， 尽管存在妄想、难以表达情绪以及注意力和记忆力缺陷。 目前可用的抗精神病药物，精神分裂症患者的预期寿命为10岁 比一般人群年龄低，容易滥用药物、无家可归、 并面临自杀的危险，这对受苦受难的人造成了生命损失。 这种疾病造成的公共卫生成本巨大，目前尚无治愈方法。 精神分裂症，以及对该疾病的病因的研究，包括解剖学和 大脑的生理破坏一直很困难，因为人们对大脑的生理破坏知之甚少。 患者细胞的潜在病理学。 阐明在患有以下疾病的患者中发现的解剖学和生理学缺陷 精神分裂症，该提案将通过移植开发一种新的疾病模型 将人类诱导多能干细胞 (iPSC) 重新编程到动物系统中，并 在目标 1 中，该项目将开发这些细胞的体内结构和功能。 对人类 iPSC 衍生神经元进行结构表征所需的技术 包括开发分析神经回路结构和解剖动力学的方法。 目标 2，该项目将开发对人群钙活性进行成像所需的技术 人 iPSC 衍生的神经元体内研究和开发新的分析方法 在目标 3 中，该项目将应用这些技术来表征这一活动。 人 iPSC 衍生神经元在体内的结构和自发活动模式。 这项工作将共同开发一个强大的新平台来剖析结构和功能 人类神经回路的目的是了解神经生物学基础 精神分裂症。

项目成果

Centrifugal Inputs to the Main Olfactory Bulb Revealed Through Whole Brain Circuit-Mapping

通过全脑回路映射揭示主嗅球的离心输入

• DOI: 10.3389/fnana.2018.00115
• 发表时间: 2019
• 期刊: Frontiers in Neuroanatomy
• 影响因子: 2.9
• 作者: Padmanabhan, Krishnan;Osakada, Fumitaka;Tarabrina, Anna;Kizer, Erin;Callaway, Edward M.;Gage, Fred H.;Sejnowski, Terrence J.
• 通讯作者: Sejnowski, Terrence J.

From synapses to circuits and back: Bridging levels of understanding in animal models of Alzheimer's disease

• DOI: 10.1111/ejn.15636
• 发表时间: 2022-03-14
• 期刊: EUROPEAN JOURNAL OF NEUROSCIENCE
• 影响因子: 3.4
• 作者: Chockanathan，Udaysankar;Padmanabhan，Krishnan
• 通讯作者: Padmanabhan，Krishnan

Sex differences in head‐fixed voluntary running behavior in C57BL/6J mice

C57BL/6J 小鼠头部的性别差异固定自愿跑步行为

• DOI: 10.1111/ejn.14654
• 发表时间: 2019
• 期刊: European Journal of Neuroscience
• 影响因子: 3.4
• 作者: Warner, Emily J.;Padmanabhan, Krishnan
• 通讯作者: Padmanabhan, Krishnan