@article{2056920fea144b0db177975fb6c33f58,
title = "Sneezing reflex is mediated by a peptidergic pathway from nose to brainstem",
abstract = "Sneezing is a vital respiratory reflex frequently associated with allergic rhinitis and viral respiratory infections. However, its neural circuit remains largely unknown. A sneeze-evoking region was discovered in both cat and human brainstems, corresponding anatomically to the central recipient zone of nasal sensory neurons. Therefore, we hypothesized that a neuronal population postsynaptic to nasal sensory neurons mediates sneezing in this region. By screening major presynaptic neurotransmitters/neuropeptides released by nasal sensory neurons, we found that neuromedin B (NMB) peptide is essential for signaling sneezing. Ablation of NMB-sensitive postsynaptic neurons in the sneeze-evoking region or deficiency in NMB receptor abolished the sneezing reflex. Remarkably, NMB-sensitive neurons further project to the caudal ventral respiratory group (cVRG). Chemical activation of NMB-sensitive neurons elicits action potentials in cVRG neurons and leads to sneezing behavior. Our study delineates a peptidergic pathway mediating sneezing, providing molecular insights into the sneezing reflex arc.",
keywords = "caudal ventral respiratory group, nasal sensory neurons, neuropeptide, sneeze, sneeze-evoking region",
author = "Fengxian Li and Haowu Jiang and Xiaolei Shen and Weishan Yang and Changxiong Guo and Zhiyao Wang and Maolei Xiao and Lian Cui and Wenqin Luo and Kim, {Brian S.} and Zhoufeng Chen and Huang, {Andrew J.W.} and Qin Liu",
note = "Funding Information: We thank Qiufu Ma, Michael Panneton, Ru-Rong Ji, and Guo Huang for their helpful comments on the manuscript and Feixue Liang and Fengrui Zhang for their help with audio recording. This work was supported by the National Institutes of Health (grants R01AI125743 and R01EY024704) and the Pew Scholar Award (to Q.L.). B.S.K. is supported by NIAMS (grants K08-AR065577, R01AR070116, and R01AR077007), the American Skin Association, and the Doris Duke Charitable Foundation. F.L. established the mouse sneezing model and performed behavioral tests, immunofluorescence staining, AEN bilateral rhizotomies, chemical ablation of Trpv1+ nasal sensory fiber, allergic rhinitis model, cell picking, the NMB-siRNA study, neuronal ablation by NMB-saporin, genetic axonal tracing, retrograde neuronal tracing, NMB peptide microinjection into the cVRG, and data analysis and participated in paper preparation. H.J. performed behavioral tests, immunofluorescence staining, genetic axonal tracing, retrograde tracing, brainstem preparation, electrophysiological recordings, and data analysis and participated in paper preparation. X.S. performed behavioral tests, EMG recordings, immunofluorescence staining, retrograde tracing, and data analysis and participated in paper preparation. W.Y. performed chemical ablation of Trpv1+ fibers, allergic rhinitis model, cell picking, sneezing and pain behavior assays, and data analysis. C.G. performed single-cell PCR assay and genetic mouse line generation. Z.W. conducted immunofluorescence staining. M.X. helped conduct sneezing behavioral tests. L.C. and W.L. conducted electrophysiological recordings and data analysis. Z.C. provided Nmb−/−, Nmbr−/−, and NmbreGFP/+ mice and contributed to manuscript preparation. B.S.K. and A.J.W.H. contributed to experimental design and manuscript preparation. Q.L. planned and directed all the experiments and wrote the paper. The authors declare no competing interests. B.S.K. has noncompeting financial interests unrelated to this work and has served as a consultant for AbbVie, ABRAX Japan, Almirall, Cara Therapeutics, Maruho, Menlo Therapeutics, Pfizer, and Third Rock Ventures. He has participated on the advisory board for Almirall, Boehringer Ingelheim, Cara Therapeutics, Kiniksa Pharmaceuticals, Menlo Therapeutics, Regeneron Pharmaceuticals, Sanofi Genzyme, and Trevi Therapeutics. He is also founder, chief scientific officer, and stockholder of Nuogen Pharma and stockholder of Locus Biosciences. Funding Information: We thank Qiufu Ma, Michael Panneton, Ru-Rong Ji, and Guo Huang for their helpful comments on the manuscript and Feixue Liang and Fengrui Zhang for their help with audio recording. This work was supported by the National Institutes of Health (grants R01AI125743 and R01EY024704 ) and the Pew Scholar Award (to Q.L.). B.S.K. is supported by NIAMS (grants K08-AR065577 , R01AR070116 , and R01AR077007 ), the American Skin Association , and the Doris Duke Charitable Foundation . Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",
year = "2021",
month = jul,
day = "8",
doi = "10.1016/j.cell.2021.05.017",
language = "English",
volume = "184",
pages = "3762--3773.e10",
journal = "Cell",
issn = "0092-8674",
number = "14",
}