Genetic profiles and physiological heterogeneity of oligodendrocytes

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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.