Genetic profiles and physiological heterogeneity of oligodendrocytes

少突胶质细胞的遗传谱和生理异质性

• 批准号: 10058072
• 负责人: Jun Hee Kim
• 金额: $ 38.97万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10058072
• 关键词: Action Potentials; Adult; Architecture; Area; Auditory; Axon; Brain; Brain Stem; Brain region; Cell Lineage; Cells; Cerebellum; Characteristics; Classification; Communication; Data; Development; Disease; Down-Regulation; Electrophysiology (science); Environment; Exhibits; Gene Expression; Genetic; Genetic Transcription; Goals; Growth; Heterogeneity; Impairment; Ion Channel; Learning; Molecular; Molecular Profiling; Morphology; Mus; Myelin; Nervous system structure; Neuraxis; Neuroglia; Neurons; Neurotransmitter Receptor; Neurotransmitters; Oligodendroglia; Physiological; Play; Population; Population Heterogeneity; Production; Property; RNA analysis; Role; Shapes; Specific qualifier value; Synapses; Techniques; Testing; Variant; biophysical properties; cell type; differential expression; expectation; genetic profiling; information processing; innovation; insight; mRNA Differential Displays; myelination; neural circuit; neurotransmission; novel; oligodendrocyte lineage; oligodendrocyte progenitor; patch clamp; patch sequencing; population based; postnatal; relating to nervous system; repaired; response; single-cell RNA sequencing; stem cells; tool; transcriptomics; voltage

Project summary/Abstract Oligodendrocytes (OLs) support neurons through the production of myelin. OLs were considered to be a homogenous population programmed to passively myelinate axons. However, recent studies indicate that OLs are a heterogeneous population with a subset of OLs that are able to detect and respond to neuronal activity. To understand OL heterogeneity, it is necessary to resolve variations in gene expression that specify the physiological functions of unique OL subpopulations. Our long-term goal is to determine the genetic profiles corresponding to functional characteristics of the heterologous OL population, which will eventually elucidate the diverse roles of OL subpopulations during development and disease. The ability to classify discrete subtypes of OL will enhance our perspective of the role of cellular diversity in neural organization, function, and disease. OLs respond to neuronal activity and support neuronal function through adaptive myelination that shapes circuit timing to meet functional requirements and contributes to nervous system plasticity. OLs display differential physiological profiles with differential responses to neuronal activity. However, the mechanisms whereby OLs integrate neuronal signals to drive myelination remain unclear. Our recent studies identified a novel excitable OL that conducts functional voltage-activated Na+ channel (Nav) currents sufficient to evoke action potentials, and displays a Ca2+ response to neuronal activity in the brainstem. The objective of the proposed study is to determine the molecular signature of excitable OLs for distinguishing them from non-excitable OLs, and to investigate the presence of excitable OLs in other brain areas beyond the brainstem. We hypothesize that Nav channel expression in OL lineage cells distinguishes an excitable subpopulation of OLs with unique responses to neural activity and a distinct function in the developing brain. To test the hypothesis we will use the innovative technique incorporating patch-clamp recording and single cell RNA analysis from the same cells, which is referred to patch-seq transcriptomics. Aim 1 will characterize the physiological and genetic profiles of excitable and non-excitable OLs using patch-seq. Aim 2 will identify the presence of excitable OL in other brain areas, and compare their genetic and physiological profiles with excitable OLs in the brainstem. The findings will provide novel insights on excitable oligodendroglia that govern neuron-glia communication and adaptive myelination, and will expand our understanding of the mechanisms that controls myelin growth, stability, and repair in the developing and adult brain.

项目摘要/摘要 少突胶质细胞通过产生髓鞘来支持神经元。OL被认为是一种 同质的群体被编程为被动地髓鞘轴突。然而，最近的研究表明， OL是一个具有能够检测和响应神经元的OL子集的异质群体 活动。为了了解OL的异质性，有必要解决基因表达的变异，这些变异表明 独特的OL亚群的生理功能。我们的长期目标是确定基因 与异源OL群体的功能特征相对应的配置文件，最终将 阐明OL亚群在发育和疾病过程中的不同作用。分类的能力 不连续的OL亚型将增强我们对细胞多样性在神经组织中作用的看法， 功能和疾病。 OL通过自适应髓鞘形成对神经元活动做出反应并支持神经元功能 塑造电路时序以满足功能要求，并有助于神经系统的可塑性。运营服务商 显示不同的生理特征和对神经元活动的不同反应。然而， OL整合神经元信号以驱动髓鞘形成的机制尚不清楚。我们最近的研究 发现了一种新的可兴奋的OL，它能充分传导功能电压激活的Na+通道(NAV)电流 以唤起动作电位，并对脑干中的神经元活动显示出钙反应。目标是 拟议的研究的目的是确定可兴奋的OL的分子特征，以区分它们与 非兴奋性OL，并调查兴奋性OL在大脑其他区域的存在 脑干。我们假设，在OL系细胞中NAV通道的表达区分了可兴奋性 对神经活动有独特反应的OL亚群，在发育中的大脑中具有独特的功能。 为了验证这一假设，我们将使用结合了膜片钳记录和单次记录的创新技术 来自相同细胞的细胞RNA分析，称为Patch-Seq转录组学。目标1将描述 用PATCH-SEQ研究兴奋性和非兴奋性OL的生理和遗传学特征。目标2将确定 其他脑区可兴奋性OL的存在，并将其遗传学和生理学特征与 脑干中的易激动的老头。这些发现将为研究兴奋性少突胶质细胞提供新的见解 管理神经元-神经胶质细胞通讯和适应性髓鞘形成，并将扩大我们对 控制发育中和成人大脑中髓鞘生长、稳定和修复的机制。