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      A large fraction of neocortical myelin ensheathes axons of local inhibitory neurons

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          Abstract

          Myelin is best known for its role in increasing the conduction velocity and metabolic efficiency of long-range excitatory axons. Accordingly, the myelin observed in neocortical gray matter is thought to mostly ensheath excitatory axons connecting to subcortical regions and distant cortical areas. Using independent analyses of light and electron microscopy data from mouse neocortex, we show that a surprisingly large fraction of cortical myelin (half the myelin in layer 2/3 and a quarter in layer 4) ensheathes axons of inhibitory neurons, specifically of parvalbumin-positive basket cells. This myelin differs significantly from that of excitatory axons in distribution and protein composition. Myelin on inhibitory axons is unlikely to meaningfully hasten the arrival of spikes at their pre-synaptic terminals, due to the patchy distribution and short path-lengths observed. Our results thus highlight the need for exploring alternative roles for myelin in neocortical circuits.

          DOI: http://dx.doi.org/10.7554/eLife.15784.001

          eLife digest

          The brain is far away from the muscles that it controls. In humans, for example, the brain must be able to trigger the contraction of muscles that are more than a meter away. This task falls to specialized motor neurons that stretch from the brain to the spinal cord, and from the spinal cord to the muscles.

          Neurons transmit information (in the form of electrical nerve impulses) along their length through cable-like structures called axons. The axons of the motor neurons are so long that, if they were ‘naked’, it would take at least a second for nerve impulses to travel their entire length. Such a long delay between thoughts and actions would make rapid movement impossible.

          Nerve impulses are able to travel from the brain to the muscles much more quickly, because they are wrapped with a substance called myelin that acts like electrical insulation. Myelin helps the nerve impulses travel up to 100 times faster down the axon. Not surprisingly, diseases that damage myelin, such as multiple sclerosis, severely disrupt movement and sensation.

          Not all of the brain’s myelin is found around the long axons of motor neurons. The outer layer of the brain, known as the cerebral cortex, also contains myelin. However, most neurons within the cerebral cortex are only a few millimeters long. So what exactly is myelin doing there?

          Micheva et al. have now used electron microscopy and light microscopy to study the neurons in the cortex of the mouse brain. This revealed that up to half of the myelin in some layers of the cortex surrounds the axons of inhibitory neurons (which reduce the activity of the neurons they signal to). Moreover, one particular subtype of inhibitory neuron accounts for most of the myelinated inhibitory axons, namely inhibitory neurons that contain a protein called parvalbumin.

          Exactly why parvalbumin-containing neurons are myelinated remains a mystery. Myelin covers only short segments of the axons of these neurons, so it would speed up the transmission of signals by less than a millisecond – probably not enough to make a meaningful difference. Parvalbumin-containing neurons often signal frequently, and thus require large amounts of energy. One possibility therefore is that myelin helps to meet these energy requirements or to reduce energy consumption. Further research will be needed to test this and other ideas.

          DOI: http://dx.doi.org/10.7554/eLife.15784.002

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          Most cited references86

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          Interneurons of the neocortical inhibitory system.

          Mammals adapt to a rapidly changing world because of the sophisticated cognitive functions that are supported by the neocortex. The neocortex, which forms almost 80% of the human brain, seems to have arisen from repeated duplication of a stereotypical microcircuit template with subtle specializations for different brain regions and species. The quest to unravel the blueprint of this template started more than a century ago and has revealed an immensely intricate design. The largest obstacle is the daunting variety of inhibitory interneurons that are found in the circuit. This review focuses on the organizing principles that govern the diversity of inhibitory interneurons and their circuits.
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            A resource of Cre driver lines for genetic targeting of GABAergic neurons in cerebral cortex.

            A key obstacle to understanding neural circuits in the cerebral cortex is that of unraveling the diversity of GABAergic interneurons. This diversity poses general questions for neural circuit analysis: how are these interneuron cell types generated and assembled into stereotyped local circuits and how do they differentially contribute to circuit operations that underlie cortical functions ranging from perception to cognition? Using genetic engineering in mice, we have generated and characterized approximately 20 Cre and inducible CreER knockin driver lines that reliably target major classes and lineages of GABAergic neurons. More select populations are captured by intersection of Cre and Flp drivers. Genetic targeting allows reliable identification, monitoring, and manipulation of cortical GABAergic neurons, thereby enabling a systematic and comprehensive analysis from cell fate specification, migration, and connectivity, to their functions in network dynamics and behavior. As such, this approach will accelerate the study of GABAergic circuits throughout the mammalian brain. Copyright © 2011 Elsevier Inc. All rights reserved.
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              Petilla terminology: nomenclature of features of GABAergic interneurons of the cerebral cortex.

              Neuroscience produces a vast amount of data from an enormous diversity of neurons. A neuronal classification system is essential to organize such data and the knowledge that is derived from them. Classification depends on the unequivocal identification of the features that distinguish one type of neuron from another. The problems inherent in this are particularly acute when studying cortical interneurons. To tackle this, we convened a representative group of researchers to agree on a set of terms to describe the anatomical, physiological and molecular features of GABAergic interneurons of the cerebral cortex. The resulting terminology might provide a stepping stone towards a future classification of these complex and heterogeneous cells. Consistent adoption will be important for the success of such an initiative, and we also encourage the active involvement of the broader scientific community in the dynamic evolution of this project.
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                Author and article information

                Contributors
                Role: Reviewing editor
                Journal
                eLife
                Elife
                eLife
                eLife
                eLife
                eLife Sciences Publications, Ltd
                2050-084X
                06 July 2016
                2016
                : 5
                : e15784
                Affiliations
                [1 ]deptDepartment of Molecular and Cellular Physiology , Stanford University , Stanford, United States
                [2 ]Janelia Research Campus, Howard Hughes Medical Institute , Ashburn, United States
                [3]Tel Aviv University , Israel
                [4]Tel Aviv University , Israel
                Author notes
                [†]

                Allen Institute for Brain Science, Seattle, United States.

                Author information
                http://orcid.org/0000-0002-5012-1690
                http://orcid.org/0000-0002-8218-7926
                Article
                15784
                10.7554/eLife.15784
                4972537
                27383052
                c69b2c65-2385-459b-a7ab-857c5e73a6a7
                © 2016, Micheva et al

                This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

                History
                : 04 March 2016
                : 05 July 2016
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: R21MH099797
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: R01NS75252
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: R01NS092474
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000011, Howard Hughes Medical Institute;
                Award Recipient :
                The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
                Categories
                Neuroscience
                Research Article
                Custom metadata
                2.5
                Parvalbumin-positive inhibitory neurons in the cortex have insulating myelin sheathes, despite forming only short-range connections.

                Life sciences
                array tomography,electron microscopy,myelin,cortex,basket cells,interneurons,mouse
                Life sciences
                array tomography, electron microscopy, myelin, cortex, basket cells, interneurons, mouse

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