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Series GSE211538 Query DataSets for GSE211538
Status Public on Apr 15, 2024
Title Brainstem Dbh+ Neurons Control Chronic Allergen-Induced Airway Hyperreactivity
Organism Mus musculus
Experiment type Expression profiling by high throughput sequencing
Summary Exaggerated airway constriction triggered by exposure to irritants such as allergen, also called hyperreactivity, is a hallmark of asthma and can be life-threatening. Aside from immune cells, vagal sensory neurons are important for airway hyperreactivity 1-4. However, the identity and signature of the downstream nodes of this adaptive circuit remains poorly understood. Here we show that Dbh+ neurons in the nucleus of the solitary tract (nTS) of the brainstem, and downstream neurons in the nucleus ambiguus (NA), are both necessary and sufficient for chronic allergen-induced airway hyperreactivity. We found that repeated exposures of mice to inhaled allergen activates nTS neurons in a mast cell-, interleukin 4 (IL-4)- and vagal nerve-dependent manner. Single-nucleus RNA-seq followed by RNAscope quantification of the nTS at baseline and following allergen challenges reveals that a Dbh+ population is preferentially activated. Ablation or chemogenetic inactivation of Dbh+ nTS neurons blunted, while chemogenetic activation promoted hyperreactivity. Viral tracing indicates that Dbh+ nTS neurons, capable of producing norepinephrine, project to the NA, and NA neurons are necessary and sufficient to relay allergen signals to postganglionic neurons that then directly drive airway constriction. Focusing on transmitters, delivery of norepinephrine antagonists to the NA blunted allergen-induced hyperreactivity. Together, these findings provide molecular, anatomical and functional definitions of key nodes of a canonical allergen response circuit. The knowledge opens the possibility of targeting neural modulation as an approach to control refractory allergen-induced airway constriction.
Overall design We dissected the GFP+ NA region from 7 Chat-cre; CAG-Sun1/sfGFP mice brainstem under the fluorescence microscope. Mice were euthanized using CO2 inhalation. Brains were acutely harvested. Dissected NA were put in liquid N2 immediately and stored at -80°C or proceeded directly to nuclei isolation. NA nuclei were processed into cDNA libraries using Chromium Single Cell 3' v3 kit (10XGenomics). Sequencing was carried out on NovaSeq (Illumina) platform. CellRanger package (version 3.0.2) was used to align the raw reads onto the mouse reference genome (GRCm38) and generate the feature-barcode matrix. R package Seurat (version 4.0) was used to perform data quality control, normalization, principal components analysis and uniform manifold approximation and projection (UMAP method).
Contributor(s) Su Y, Zhu Z, Ji C, Xu L, Yu H
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Submission date Aug 18, 2022
Last update date Apr 16, 2024
Contact name Yujuan Su
Phone 18583092532
Organization name UCSD
Street address 9500 Gilman Dr. MC0766 CMME, Room 1087
City San Diego
State/province CALIFORNIA
ZIP/Postal code 92093
Country USA
Platforms (1)
GPL24247 Illumina NovaSeq 6000 (Mus musculus)
Samples (1)
GSM6475220 Chat-cre; CAG-Sun1/sfGFP mice NA
BioProject PRJNA870768

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Supplementary file Size Download File type/resource
GSE211538_RAW.tar 86.8 Mb (http)(custom) TAR (of H5, RDS)
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Raw data are available in SRA
Processed data provided as supplementary file

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