Genetic profiles and physiological heterogeneity of oligodendrocytes

项目概要/摘要 少突胶质细胞（Oligodendrocytes，OL）通过产生髓磷脂来支持神经元。OL被认为是 同源群体编程为被动髓鞘轴突。然而，最近的研究表明， OL是具有能够检测和响应神经元信号的OL子集的异质性群体。 活动为了理解OL异质性，有必要解决基因表达的变异， 独特的OL亚群的生理功能。我们的长期目标是确定 对应于异源OL群体的功能特征的谱，其最终将 阐明OL亚群在发育和疾病过程中的不同作用。分类的能力 分离的OL亚型将增强我们对细胞多样性在神经组织中的作用的认识， 功能和疾病。 OL响应神经元活动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需求，并有助于神经系统的可塑性。OLS 显示出对神经元活动具有不同反应的不同生理特征。但 OL整合神经元信号以驱动髓鞘形成的机制仍不清楚。我们最近的研究 确定了一种新的可兴奋的OL，其传导功能性电压激活的Na+通道（Nav）电流，足以 诱发动作电位，并显示对脑干神经元活动的Ca 2+反应。客观 这项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在其他脑区以外的存在。 脑干我们假设OL谱系细胞中的Nav通道表达区分了可兴奋的 在发育中的大脑中，具有对神经活动的独特反应和独特功能的OL亚群。 为了验证这一假设，我们将使用创新的技术，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将描述 使用patch-seq的可兴奋和不可兴奋的OL的生理和遗传概况。目标2将确定 在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， 控制神经胶质细胞的沟通和适应性髓鞘形成，并将扩大我们对神经胶质细胞的理解。 在发育和成人大脑中，控制髓鞘生长、稳定和修复的机制。

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.