Vagal sensory neurons mediate the Bezold–Jarisch reflex and induce syncope

Jonathan W. Lovelace, Jingrui Ma, Saurabh Yadav, Karishma Chhabria, Hanbing Shen, Zhengyuan Pang, Tianbo Qi, Ruchi Sehgal, Yunxiao Zhang, Tushar Bali, Thomas Vaissiere, Shawn Tan, Yuejia Liu, Gavin Rumbaugh, Li Ye, David Kleinfeld, Carsen Stringer and Vineet Augustine ()
Additional contact information
Jonathan W. Lovelace: University of California
Jingrui Ma: University of California
Saurabh Yadav: University of California
Karishma Chhabria: University of California
Hanbing Shen: Scripps Research
Zhengyuan Pang: Scripps Research
Tianbo Qi: Scripps Research
Ruchi Sehgal: Scripps Research
Yunxiao Zhang: Scripps Research
Tushar Bali: Scripps Research
Thomas Vaissiere: University of Florida–Scripps Biomedical Research
Shawn Tan: Scripps Research
Yuejia Liu: Scripps Research
Gavin Rumbaugh: University of Florida–Scripps Biomedical Research
Li Ye: Scripps Research
David Kleinfeld: University of California
Carsen Stringer: HHMI Janelia Research Campus
Vineet Augustine: University of California

Nature, 2023, vol. 623, issue 7986, 387-396

Abstract: Abstract Visceral sensory pathways mediate homeostatic reflexes, the dysfunction of which leads to many neurological disorders1. The Bezold–Jarisch reflex (BJR), first described2,3 in 1867, is a cardioinhibitory reflex that is speculated to be mediated by vagal sensory neurons (VSNs) that also triggers syncope. However, the molecular identity, anatomical organization, physiological characteristics and behavioural influence of cardiac VSNs remain mostly unknown. Here we leveraged single-cell RNA-sequencing data and HYBRiD tissue clearing4 to show that VSNs that express neuropeptide Y receptor Y2 (NPY2R) predominately connect the heart ventricular wall to the area postrema. Optogenetic activation of NPY2R VSNs elicits the classic triad of BJR responses—hypotension, bradycardia and suppressed respiration—and causes an animal to faint. Photostimulation during high-resolution echocardiography and laser Doppler flowmetry with behavioural observation revealed a range of phenotypes reflected in clinical syncope, including reduced cardiac output, cerebral hypoperfusion, pupil dilation and eye-roll. Large-scale Neuropixels brain recordings and machine-learning-based modelling showed that this manipulation causes the suppression of activity across a large distributed neuronal population that is not explained by changes in spontaneous behavioural movements. Additionally, bidirectional manipulation of the periventricular zone had a push–pull effect, with inhibition leading to longer syncope periods and activation inducing arousal. Finally, ablating NPY2R VSNs specifically abolished the BJR. Combined, these results demonstrate a genetically defined cardiac reflex that recapitulates characteristics of human syncope at physiological, behavioural and neural network levels.

Date: 2023
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DOI: 10.1038/s41586-023-06680-7

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