Genetic profiles and physiological heterogeneity of oligodendrocytes

少突胶质细胞的遗传谱和生理异质性

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要少突胶质细胞 (OL) 通过生成髓磷脂来支持神经元。 OL被认为是同质群体被编程为被动地使轴突有髓鞘。然而，最近的研究表明 OL 是一个异质群体，其中一部分 OL 能够检测神经元并对其做出反应活动。为了理解 OL 异质性，有必要解决基因表达的变化，这些变化指定独特的 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概况，最终将阐明 OL 亚群在发育和疾病过程中的不同作用。分类能力 OL 的离散亚型将增强我们对细胞多样性在神经组织中的作用的看法，功能、疾病。 OL 对神经元活动做出反应，并通过适应性髓鞘形成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。 OL 显示不同的生理特征以及对神经元活动的不同反应。然而， OL 整合神经元信号来驱动髓鞘形成的机制仍不清楚。我们最近的研究确定了一种新型可兴奋 OL，它能够传导足够的功能性电压激活 Na+ 通道 (Nav) 电流激发动作电位，并对脑干神经元活动显示出 Ca2+ 反应。目标拟议研究的目的是确定可兴奋 OL 的分子特征，以将它们与非兴奋性 OL，并研究兴奋性 OL 在大脑以外的其他脑区的存在。脑干。我们假设 OL 谱系细胞中的 Nav 通道表达区分了兴奋性 OL 亚群，对神经活动有独特的反应，并且在发育中的大脑中具有独特的功能。为了检验这一假设，我们将使用创新技术，结合膜片钳记录和单来自相同细胞的细胞RNA分析，这被称为patch-seq转录组学。目标 1 将表征使用 patch-seq 分析可兴奋和不可兴奋 OL 的生理和遗传特征。目标 2 将确定其他大脑区域中存在兴奋性 OL，并将其遗传和生理特征与脑干中的兴奋性 OL。这些发现将为兴奋性少突胶质细胞提供新的见解控制神经元-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磷脂生长、稳定性和修复的机制。