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Nearly 40 percent of people experience syncope or fainting at least once in their lives. These brief losses of consciousness, caused by pain, anxiety, heat, hyperventilation, or other causes, account for a significant portion of hospital emergency department visits. Yet the exact underlying mechanisms at play when people “faint” have largely remained a mystery.
Publishing a new report in Nature, researchers from the University of California San Diego, along with colleagues from the Scripps Research Institute and other institutions, have identified for the first time the genetic pathway between the heart and brain linked to fainting .
One of their unique approaches was to view the heart as a sensory organ rather than the long-standing view that the brain sends out signals and the heart simply follows directions. Assistant Professor Vineet Augustine of the School of Biological Sciences, senior author of the paper, applies a variety of approaches to better understand these neural connections between the heart and brain.
“What we find is that the heart also sends signals back to the brain, which can change brain function,” says Augustinus. Information emerging from the study could be relevant to better understanding and treating several psychiatric and neurological disorders related to brain-heart connections, the researchers note in their paper. “Our study is the first comprehensive demonstration of a genetically defined cardiac reflex, which faithfully recapitulates the characteristics of human syncope at physiological, behavioral and neural network levels.”
Augustine, together with Jonathan Lovelace, the first author of the paper, and his colleagues Biological Sciences Staff Research Associate and Graduate Student Jingrui Ma, and their colleagues studied neural mechanisms related to the Bezold-Jarisch reflex (BJR), a cardiac reflex which was first described in 1867. For decades, researchers have hypothesized that BJR, which is associated with decreased heart rate, blood pressure, and breathing, may be associated with fainting. But information was lacking to prove the idea because the neural pathways involved in the reflex were not well known.
The researchers focused on the genetics behind a sensory cluster known as the nodose ganglia, which are part of the vagus nerve that carry signals between the brain and visceral organs, including the heart. Specifically, vagal sensory neurons, or VSNs, project signals to the brain stem and are thought to be related to BJR and fainting. In their search for a new neural pathway, they discovered that VSNs expressing the neuropeptide Y receptor Y2 (known as NPY2R) are closely linked to the known BJR responses.
Studying this pathway in mice, the researchers were surprised to find that when they proactively activated NPY2R VSNs using optogenetics, a method of stimulating and controlling neurons, mice that were running freely immediately fainted. During these episodes, they recorded thousands of neurons in the mice’s brains, as well as heart activity and changes in facial features, including pupil diameter and beating. They also used machine learning in various ways to analyze the data and identify features of interest. Once the NPY2R neurons were activated, they found that mice showed rapid pupil dilation and the classic “eye roll” seen during human fainting episodes, as well as depressed heart rate, blood pressure and breathing. They also measured reduced blood flow to the brain, an area of collaboration with Professor David Kleinfeld’s laboratory in the UC San Diego Departments of Neurobiology and Physics.
“We were overwhelmed to see their eyes roll back at the same time as brain activity dropped rapidly,” the researchers reported in a paper summary. “Then, after a few seconds, the brain activity and movement returned. This was our eureka moment.”
Further testing showed that when NPY2R VSNs were deleted from mice, the BJR and fainting disappeared. Previous studies had shown that fainting is caused by a reduction in blood flow in the brain, which the new study found to be true, but the new evidence indicated that brain activity itself could play an important role. The findings therefore imply the activation of the newly genetically identified VSNs and their neural pathways not only with BJR, but more centrally in general animal physiology, certain brain networks and even behavior.
Such findings were previously difficult to uncover because neuroscientists study the brain and cardiologists study the heart, but many do so separately. “Neuroscientists traditionally think that the body just follows the brain, but now it is becoming very clear that the body sends signals to the brain and the brain then changes function,” says Augustinus.
As a result of their findings, the researchers would like to continue monitoring the precise conditions under which vagal sensory neurons are fired into action.
“We also hope to further investigate cerebral blood flow and neural pathways in the brain during the moment of syncope, to better understand this common but mysterious condition,” they note.
They also hope to use their research as a model to develop targeted treatments for conditions associated with fainting.
The co-authors of the Nature article 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 Augustinus.
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