Summary: Researchers have identified a genetic pathway linking the heart and brain that explains why people faint. By treating the heart as a sensory organ that sends signals back to the brain, the team mapped specific neural circuits that trigger the sudden loss of consciousness known as syncope.
The work focuses on the Bezold–Jarisch reflex (BJR) and on vagal sensory neurons in the nodose ganglia. The findings clarify how cardiac signals travel to the brain to produce fainting episodes and point toward potential targeted therapies for syncope and related disorders.
Key Facts:
- Scientists demonstrated that the heart actively sends sensory signals to the brain that can alter brain activity and behavior.
- Genetic analysis of the nodose ganglia revealed that a subset of vagal sensory neurons (VSNs) expressing the neuropeptide Y receptor Y2 (NPY2R) are linked to the Bezold–Jarisch reflex.
- Optogenetic activation of NPY2R-expressing VSNs in mice produced hallmark features of syncope—pupil dilation and eye-roll, suppressed heart rate, lower blood pressure, reduced breathing, and temporary loss of consciousness—while removing these neurons eliminated the reflex.
Source: UCSD
Nearly 40 percent of people experience syncope, or fainting, at least once in their lives. Brief losses of consciousness—triggered by pain, fear, heat, hyperventilation or other causes—account for many emergency room visits. Despite their frequency, the precise mechanisms that produce fainting have remained poorly understood.
In a new report published in Nature, researchers from the University of California San Diego, The Scripps Research Institute and other institutions provide the first clear genetic and circuit-level description of a heart-to-brain pathway that induces syncope.
Breaking with the conventional view that the brain simply commands the heart, the team treated the heart as an active sensory organ that can send information back to the brain. Vineet Augustine, Assistant Professor in the School of Biological Sciences and the paper’s senior author, led experiments that combine genetics, high-resolution recording techniques and behavioral analysis to map those neural connections.
“We found that the heart sends signals to the brain that can change how the brain functions,” Augustine said. The researchers emphasize that these findings could improve understanding of brain–heart interactions relevant to neurological and psychiatric conditions and could inform future treatments for syncope-related disorders.
The team focused on the Bezold–Jarisch reflex, a cardiac reflex first described in 1867 and long suspected to play a role in fainting because it produces slowed heart rate, lowered blood pressure and reduced breathing. Progress was limited previously because the specific neural pathways mediating the reflex were not well defined.
To address that gap, the researchers examined the nodose ganglia, sensory clusters that are part of the vagus nerves and relay information from visceral organs—including the heart—to the brainstem. They used single-cell RNA sequencing and tissue-clearing methods to identify molecularly distinct populations of vagal sensory neurons (VSNs).
Their analysis revealed that VSNs expressing the neuropeptide Y receptor Y2 (NPY2R) preferentially connect the ventricular wall of the heart to brainstem regions implicated in autonomic control. Using optogenetics to stimulate these NPY2R VSNs in freely moving mice, the researchers observed immediate fainting episodes that mirrored clinical syncope.
During these events, the team recorded activity from thousands of neurons across the brain with Neuropixels probes while simultaneously tracking cardiac function and facial indicators such as pupil diameter and whisker movement. They also measured cerebral blood flow with laser Doppler flowmetry and high-resolution echocardiography.
Activation of NPY2R VSNs produced a consistent set of responses: rapid pupil dilation and an eye-roll reminiscent of human fainting, a drop in heart rate and blood pressure, reduced respiration, and decreased cerebral perfusion. Machine-learning analyses helped the team identify and quantify the neural and behavioral signatures of the induced syncope.
Large-scale brain recordings showed widespread suppression of neuronal activity across distributed brain networks during the induced syncope, effects that could not be explained solely by reduced movement. The investigators also manipulated a periventricular brain region to demonstrate bidirectional influence: inhibition lengthened syncope episodes, while activation promoted arousal and recovery.
Crucially, selective ablation of NPY2R-expressing VSNs abolished the Bezold–Jarisch reflex and prevented the fainting response in mice, providing causal evidence that this genetically defined group of cardiac sensory neurons mediates the reflex.
Together, these results define a specific heart-to-brain circuit that reproduces the physiological, behavioral and neural-network features of human syncope. The study highlights how peripheral sensory neurons shape central brain activity and behavior and underscores the importance of integrating cardiovascular and neural perspectives when studying autonomic reflexes.
Moving forward, the researchers plan to clarify the precise triggers that activate vagal sensory neurons in natural settings and to map the detailed neural pathways and blood-flow dynamics during spontaneous syncope. They hope this work will serve as a framework to develop targeted interventions for fainting-related conditions.
Coauthors of the Nature paper include: Jonathan 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.
About this genetics research news
Author: Mario Aguilera
Source: UCSD
Contact: Mario Aguilera – UCSD
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Vagal sensory neurons mediate the Bezold–Jarisch reflex and induce syncope” by Vineet Augustine et al. Nature
Abstract
Vagal sensory neurons mediate the Bezold–Jarisch reflex and induce syncope
Visceral sensory pathways support homeostatic reflexes, and dysfunction of these pathways contributes to many neurological disorders. The Bezold–Jarisch reflex (BJR), described in 1867, is a cardioinhibitory reflex thought to be mediated by vagal sensory neurons (VSNs) and capable of triggering syncope. Yet the molecular identity, anatomy, physiology and behavioral influence of cardiac VSNs have remained largely undefined.
Using single-cell RNA sequencing and HYBRiD tissue clearing, the authors show that NPY2R-expressing VSNs predominantly connect the heart’s ventricular wall to the area postrema. Optogenetic activation of these neurons elicits the classic BJR triad—hypotension, bradycardia and reduced respiration—and produces fainting in animals.
High-resolution echocardiography and laser Doppler flowmetry combined with behavioral observation revealed clinical-like features of syncope, including reduced cardiac output, decreased cerebral perfusion, pupil dilation and eye-roll. Large-scale Neuropixels recordings and machine-learning models demonstrated that this manipulation suppresses activity across a broad neuronal population beyond effects explained by movement.
Bidirectional manipulation of a periventricular zone produced opposite effects: inhibition prolonged syncope and activation promoted arousal. Finally, selective ablation of NPY2R VSNs abolished the BJR. Altogether, these results define a genetically specified cardiac reflex that recapitulates human syncope at physiological, behavioral and neural-network levels.