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      Neuronal heterogeneity and stereotyped connectivity in the auditory afferent system

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          Abstract

          Spiral ganglion (SG) neurons of the cochlea convey all auditory inputs to the brain, yet the cellular and molecular complexity necessary to decode the various acoustic features in the SG has remained unresolved. Using single-cell RNA sequencing, we identify four types of SG neurons, including three novel subclasses of type I neurons and the type II neurons, and provide a comprehensive genetic framework that define their potential synaptic communication patterns. The connectivity patterns of the three subclasses of type I neurons with inner hair cells and their electrophysiological profiles suggest that they represent the intensity-coding properties of auditory afferents. Moreover, neuron type specification is already established at birth, indicating a neuronal diversification process independent of neuronal activity. Thus, this work provides a transcriptional catalog of neuron types in the cochlea, which serves as a valuable resource for dissecting cell-type-specific functions of dedicated afferents in auditory perception and in hearing disorders.

          Abstract

          Spiral ganglion neurons (SGNs) of the cochlea receive input from hair cells and project to the auditory brainstem. Here, the authors perform single-cell RNA sequencing to identify four SGN subclasses and characterize their molecular profile, electrophysiological properties and connectivity.

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          Most cited references54

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          Noise-induced cochlear neuropathy is selective for fibers with low spontaneous rates.

          Acoustic overexposure can cause a permanent loss of auditory nerve fibers without destroying cochlear sensory cells, despite complete recovery of cochlear thresholds (Kujawa and Liberman 2009), as measured by gross neural potentials such as the auditory brainstem response (ABR). To address this nominal paradox, we recorded responses from single auditory nerve fibers in guinea pigs exposed to this type of neuropathic noise (4- to 8-kHz octave band at 106 dB SPL for 2 h). Two weeks postexposure, ABR thresholds had recovered to normal, while suprathreshold ABR amplitudes were reduced. Both thresholds and amplitudes of distortion-product otoacoustic emissions fully recovered, suggesting recovery of hair cell function. Loss of up to 30% of auditory-nerve synapses on inner hair cells was confirmed by confocal analysis of the cochlear sensory epithelium immunostained for pre- and postsynaptic markers. In single fiber recordings, at 2 wk postexposure, frequency tuning, dynamic range, postonset adaptation, first-spike latency and its variance, and other basic properties of auditory nerve response were all completely normal in the remaining fibers. The only physiological abnormality was a change in population statistics suggesting a selective loss of fibers with low- and medium-spontaneous rates. Selective loss of these high-threshold fibers would explain how ABR thresholds can recover despite such significant noise-induced neuropathy. A selective loss of high-threshold fibers may contribute to the problems of hearing in noisy environments that characterize the aging auditory system.
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            Auditory-nerve response from cats raised in a low-noise chamber.

            A litter of four cats, born and raised in a soundproofed chamber, was studied in an attempt to determine which, if any, features of the auditory-nerve response from routinely available cats might be due to the chronic effects of noise exposure. Two features of routine-normal response were especially suspect in this regard: (1) a "notch" in the distribution of single-unit thresholds centered at characteristic frequencies (CF's) near 3 kHz and (2) a compression of the distribution of rates of spontaneous discharge for units with CF above 10 kHz. A third feature of response in routine animals was the presence of a small number (roughly 10%) of units with virtually no spontaneous discharge and very high thresholds, sometimes 80 dB less sensitive than high-spontaneous units of similar CF. In the data from chamber-raised animals, the high-spontaneous units showed exceptionally low thresholds at all CF regions, however, there were signs of the midfrequency notch in the threshold distribution of at least two of these animals. The compression of the spontaneous rate distribution was not seen in any of the three most sensitive animals. The data suggest that there is a significant amount of "normal pathology" in the high-CF units from routine animals. Low-spontaneous, high-threshold units were present in all four chamber-raised ears with the same characteristics as in routine animals (exceptionally narrow tuning curves and exceptionally low maximum discharge rates) and at roughly the same percentage of the unit sample. A class of units with medium spontaneous rates and intermediate thresholds could also be identified. The possible significance of a classification of auditory-nerve units according to spontaneous rate is discussed.
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              Kv3 channels: voltage-gated K+ channels designed for high-frequency repetitive firing.

              Analysis of the Kv3 subfamily of K(+) channel subunits has lead to the discovery of a new class of neuronal voltage-gated K(+) channels characterized by positively shifted voltage dependencies and very fast deactivation rates. These properties are adaptations that allow these channels to produce currents that can specifically enable fast repolarization of action potentials without compromising spike initiation or height. The short spike duration and the rapid deactivation of the Kv3 currents after spike repolarization maximize the quick recovery of resting conditions after an action potential. Several neurons in the mammalian CNS have incorporated into their repertoire of voltage-dependent conductances a relatively large number of Kv3 channels to enable repetitive firing at high frequencies - an ability that crucially depends on the special properties of Kv3 channels and their impact on excitability.
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                Author and article information

                Contributors
                francois.lallemend@ki.se
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                12 September 2018
                12 September 2018
                2018
                : 9
                : 3691
                Affiliations
                [1 ]ISNI 0000 0004 1937 0626, GRID grid.4714.6, Department of Neuroscience, , Karolinska Institutet, Biomedicum, ; Stockholm, 171 77 Sweden
                [2 ]ISNI 0000 0004 0598 4854, GRID grid.462081.9, Aix-Marseille Université, CNRS UMR7288, Institut de Biologie du Développement de Marseille (IBDM), ; 13009, Marseille, France
                [3 ]ISNI 0000 0001 2297 6811, GRID grid.266102.1, Department of Physiology, , University of California–San Francisco, ; San Francisco, CA 94158 USA
                Author information
                http://orcid.org/0000-0002-7442-8494
                http://orcid.org/0000-0002-1769-1966
                http://orcid.org/0000-0001-6822-1246
                http://orcid.org/0000-0001-9964-505X
                Article
                6033
                10.1038/s41467-018-06033-3
                6135759
                30209249
                f0e8f8db-2e71-4068-bf12-b051f3d608c1
                © The Author(s) 2018

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 23 January 2018
                : 31 July 2018
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