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| Single-Cell Transcriptomics of Tongue-Innervating Trigeminal Neurons Reveals Distinct Populations of Pruriceptors and Mechanonociceptors Afshin Faridiesfanjani1, Katherine Chacon1, Mark Gradwell2, Michael Kissner3, Joriene De Nooij4, Yalda Moayedi1. 1Pain Research Center, Department of Molecular Pathobiology, New York University-College of Dentistry, New York, NY, New York, NY, USA.2Cell Biology and Neuroscience Department, Rutgers University, The State University of New Jersey, New Brunswick, NJ, USA W.M.Keck Center for Collaborative Neuroscience, Rutgers University, The State University of New Jersey, New Brunswick, NJ, USA., New Jersey, NJ, USA.3Columbia Stem Cell initiative, Columbia University Irving Medical Center., New York, NY, USA.4Department of Neurology Columbia University Medical Center, BB305 650 west 168th Street New York, NY 10032, New York, NY, USA |
Abstract
Tongue somatosensation supports several oral functions including eating, speaking and social bonding; however, the molecular identities of the peripheral sensory afferents mediating these processes remain incompletely understood. Deeper insight into lingual innervation will improve our ability to treat tongue pathologies and sensory disorders. Here, we molecularly define tongue-innervating trigeminal neurons using RNA-seq, genetic labeling, and functional imaging. Tongues of C57BL/6J mice were injected with a fluorescent retrograde tracer, and labelled trigeminal neurons were sorted for PLATE-Seq. Data were analyzed in Seurat through four steps: preprocessing, CCA-based integration with published trigeminal atlases, clustering, and visualization. Cluster markers were histologically validated. These analyses revealed eleven clusters of tongue-innervating trigeminal neurons, including peptidergic and non-peptidergic nociceptors, thermoreceptors, and mechanoreceptors. Several peptidergic populations also showed Piezo2 co-expression, consistent with a high-threshold mechanoreceptor (HTMR) identity. Among these, two clusters co-expressed Nefh, indicative of an Ad identity. Notably, a single low threshold mechanoreceptor (LTMR) population was identified. MRGPRD-expressing pruriceptors were abundant, while MRGPRA3+ pruriceptors were completely absent. Consistent with this molecular profile, in vivo trigeminal calcium imaging revealed that tongue-innervating trigeminal neurons responded to b-alanine but not chloroquine. Overall, these findings clarify the molecular basis of tongue somatosensation, suggesting presence of not only myelinated rapidly adapting LTMRs, but also myelinated and unmyelinated HTMRs, and provide a compelling reason why lingual itch differs in prevalence from itch in other tissues.
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No part of this publication may be reproduced, distributed, or transmitted in any form or by any means, including photocopying, recording, or other electronic or mechanical methods, without the prior written permission of the author.