Scientists Discover Genetic Link Between Heart and Brain Responsible for Fainting

1. Cardiac Sensory Neurons and Homeostasis: Cardiac sensory neurons, particularly NPY2R VSNs, play a crucial role in maintaining homeostasis, regulating heart function, and influencing the brain.

2. Syncope and NPY2R VSNs: Stimulation of NPY2R VSNs can induce syncope-like responses, including bradycardia, hypotension, cerebral hypoperfusion, and reduced respiration, mirroring the physiological changes associated with syncope in humans.

3. Unique Organ Innervation: NPY2R VSNs exhibit a one-to-one map for organ innervation, with distinct subsets projecting to the heart, lungs, and gut, indicating the complexity of the cardiac sensory network.

4. Neural Circuit Mechanisms of Syncope: Besides reduced cerebral blood flow, there may be neural circuit mechanisms involved in the induction and maintenance of syncope, including the paraventricular nucleus (PVZ) in the hypothalamus.

5. Translational Promise: Understanding the neurobiology of the heart and its interaction with the brain has the potential for significant translational applications in addressing cardiovascular diseases, the leading cause of morbidity worldwide.

The human body is an intricately woven tapestry of reflexes, responses, and connections that govern our survival, motivation, and emotional expression. One of the most critical systems involved in this intricate web is the homeostatic reflex, which is responsible for maintaining the body's internal balance. These reflexes rely on sensory neurons distributed throughout the body, continuously sending vital signals to the brain for interpretation and processing. When these signals go awry, it can lead to a cascade of issues, not only affecting our physiological well-being but also playing a role in the development of psychiatric and neurological disorders.

The Heart: A Crucial Organ in the Symphony of Body and Mind

The heart, often seen as the symbol of love and emotion, is not just a pump that circulates blood. It is also a central player in the orchestration of autonomic physiology and the modulation of emotions and cognition. Yet, the intricate connection between the heart and the brain remains a topic of mystery and intrigue. The key to unraveling this enigma lies in a lesser-known network of cardiac sensory neurons, which transmit beat-to-beat information to the central nervous system.

At the core of this network are PIEZO ion channels, responsible for mediating the baroreflex. These channels, particularly PIEZO2 VSNs, form claw-like structures around the aortic arch, regulating this critical reflex. But the story doesn't end there. There are more homeostatic reflex arcs associated with different anatomical cardiac locations, such as the atrial Bainbridge reflex and the ventricular BJR. These reflexes play their roles in regulating heart rate, causing tachycardia or bradycardia, respectively. However, due to the closed-loop nature of the cardiovascular system, understanding these reflexes and their individual contributions has been a formidable challenge.

The Quest to Decode Cardiac Sensory Pathways

To gain a deeper understanding of the heart's influence on the brain and behavior, it is imperative to genetically dissect cardiac sensory pathways. One critical aspect is identifying the transcriptomic identities, anatomical organization, and functional roles of cardiac ventral sensory neurons (VSNs). Notably, the cardiac ventricles are primarily innervated by VSNs with unmyelinated c-fibers, known for triggering the cardioinhibitory BJR, leading to bradycardia and syncope.

Shedding Light on the Mystery of Syncope

Syncope, often referred to as the 'little faint,' is a common yet enigmatic condition characterized by a transient loss of consciousness, followed by rapid recovery. Despite its prevalence, mechanistic investigations have been limited due to the lack of genetically tractable animal models. However, researchers are now on a quest to address this issue by genetically identifying and characterizing the VSNs responsible for the BJR. These VSNs play a pivotal role in syncope induction and influence the networks in the central nervous system.

The Intricate Web of Genetic and Anatomical Heart-Brain Links

The ventricular wall and the aortic arch are anatomically separate, suggesting the possibility of genetic segregation within the cardiac sensory network. Recent advances in single-cell RNA sequencing have revealed the existence of a distinct genetic cluster of VSNs, the NPY2R VSNs. These VSNs not only differ genetically but have also been shown to modulate autonomic function.

Intriguingly, these VSNs project to the brainstem, forming dense terminals in the nucleus of the solitary tract (NTS) and the area postrema (AP). A challenge in understanding cardiac innervation lies in the thin and spread-out nature of the fibers, coupled with the heart's density and opacity. Researchers have overcome this obstacle using innovative techniques, such as whole-organ tissue clearing followed by high-resolution light sheet microscopy. This approach has revealed the presence of a substantial number of NPY2R VSN fibers in the ventricular wall. These fibers exhibit two distinct types of putative sensory endings: end nets and flower sprays.

Mapping the Complexity of Organ Innervation

To investigate whether a single VSN projects to multiple organs, researchers have performed paired injections of retro-AAVs with distinct fluorophores into the heart-lung and heart-gut of NPY2R-Cre mice. The results have indicated that distinct subsets of NPY2R VSNs project differentially to the heart, lungs, and gut. Within the brainstem, there is a spatial segregation of heart, lung, and gut NPY2R VSN terminals. Notably, the area postrema predominantly receives innervation from heart VSNs, while the nucleus of the solitary tract is labeled by heart, lung, and gut VSNs.

This one-to-one map for organ innervation by VSNs indicates the complexity of the cardiac sensory network and its potential implications for various physiological responses.

The Unveiling of Vagal Sensory Neurons in Syncope

The impact of cardiac VSN manipulation on behavior has remained a subject of limited exploration. Researchers have embarked on a journey to uncover the influence of ventricular VSNs on cardiovascular physiology and behavior in awake, freely moving animals. This exploration has revealed that stimulation of these neurons can induce syncope-like responses, including spontaneous falls and immobility.

Unbiased electrophysiological investigations, involving the recording of electroencephalograms (EEGs) alongside ventricular VSN stimulation, have unveiled sudden, significant drops in EEG power, particularly in the gamma range. These findings correlate with reduced brain oscillations observed in EEGs of human patients with syncope.

Unraveling the Physiological Impact of Vagus Nerve Stimulation

To delve deeper into the physiological effects of vagus nerve stimulation in the heart, researchers employed a multi-faceted approach, combining optogenetics with high-resolution ultrasonography. This method allowed them to visualize real-time changes in cardiovascular parameters. Photostimulation was found to induce a time-locked slowing of the electrocardiogram (ECG), with higher frequencies causing more pronounced heart rate reductions.

The novel opto-ultrasound technique enabled the quantification of various cardiovascular parameters, revealing significant decreases in cardiac output, ejection fraction, ascending aorta diameter, aortic valve peak blood-flow velocity, and increases in left ventricular volume, area, and aortic acceleration time. Blood pressure and respiration exhibited rapid, time-locked changes, further mirroring the physiological changes associated with syncope in humans. Importantly, this triad of responses—bradycardia, hypotension, and reduced respiration rate—strongly resembles the physiological changes attributed to the Bainbridge reflex.

Concluding Thoughts: The Fascinating Intersection of Cardiac Sensory Neurons and Syncope

In the pursuit of understanding the intricate relationship between the heart and the brain, researchers have unveiled the roles played by cardiac sensory neurons, particularly the NPY2R VSNs. These neurons have been found to have a one-to-one map for organ innervation, predominantly targeting the ventricular wall and influencing the area postrema.

Furthermore, their role in syncope induction is becoming increasingly clear, as their stimulation leads to syncope-like responses in animal models. The physiological changes induced by vagus nerve stimulation closely resemble those observed during human syncope.

FAQs

1. What are cardiac sensory neurons, and what is their role in the body?

   • Cardiac sensory neurons are nerve cells located in the heart that play a crucial role in maintaining homeostasis, regulating heart function, and sending signals to the brain. They help control heart rate, blood pressure, and other physiological processes.

2. What is syncope, and how are cardiac sensory neurons related to it?

   • Syncope, often referred to as fainting, is a transient loss of consciousness followed by a rapid recovery. Cardiac sensory neurons, particularly NPY2R VSNs, can induce syncope-like responses when stimulated, including bradycardia, hypotension, cerebral hypoperfusion, and reduced respiration.

3. What is the significance of the NPY2R VSNs' one-to-one map for organ innervation?

   • The one-to-one map of NPY2R VSNs for organ innervation reveals the complexity of the cardiac sensory network. Different subsets of these neurons project to the heart, lungs, and gut, indicating a precise and specialized control system for various physiological responses.

4. What are the neural circuit mechanisms of syncope, and how do they differ from reduced cerebral blood flow?

   • In addition to reduced cerebral blood flow, there may be neural circuit mechanisms involved in the induction and maintenance of syncope. The paraventricular nucleus (PVZ) in the hypothalamus is suggested to have a role in regulating syncope, with both excitation and inhibition affecting arousal and the syncope state.

5. How can the understanding of cardiac sensory neurons and their role benefit medical research and treatment?

   • Understanding the neurobiology of the heart and its interaction with the brain holds promise for addressing cardiovascular diseases, which are a leading cause of morbidity worldwide. This research may lead to innovative approaches in the diagnosis and treatment of heart-related conditions and syncope.

Reference Article

Lovelace, J.W., Ma, J., Yadav, S. et al. Vagal sensory neurons mediate the Bezold–Jarisch reflex and induce syncope. Nature (2023). https://doi.org/10.1038/s41586-023-06680-7

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