Publishing a new report in Nature, University of California San Diego researchers, along with colleagues at The Scripps Research Institute and other institutions, have for the first time identified the genetic pathway between the heart and brain tied to fainting.

One of their unique approaches was to think of the heart as a sensory organ rather than the longstanding viewpoint that the brain sends out signals and the heart simply follows directions. School of Biological Sciences Assistant Professor Vineet Augustine, the paper’s senior author, applies a variety of approaches to better understand these neural connections between the heart and brain.

“What we are finding is that the heart also sends signals back to the brain, which can change brain function,” said Augustine. Information resulting from the study could be relevant to better understanding and treating various psychiatric and neurological disorders linked with 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 characteristics of human syncope at physiological, behavioral and neural network levels.”

Augustine, along with Biological Sciences Staff Research Associate Jonathan Lovelace and Graduate Student Jingrui Ma, the first authors of the paper, and their colleagues studied neural mechanisms related to Bezold-Jarisch reflex (BJR), a cardiac reflex first described in 1867. For decades researchers have hypothesized that the BJR, which features reduced heart rate, blood pressure and breathing, may be associated with fainting. But information lacked in proving the idea since 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 nerves that carry signals between the brain and visceral organs, including the heart. Specifically, vagal sensory neurons, or VSNs, project signals to the brainstem and are thought to be associated with BJR and fainting. In their search for a novel neural pathway they discovered that VSNs expressing the neuropeptide Y receptor Y2 (known as NPY2R) are tightly linked to the well-known BJR responses.

Studying this pathway in mice, the researchers were surprised to find that when they proactively triggered NPY2R VSNs using optogenetics, a method of stimulating and controlling neurons, mice that had been freely moving about immediately fainted. During these episodes they recorded from thousands of neurons in the brains of the mice, as well as heart activity and changes in facial features including pupil diameter and whisking. They also employed machine learning in several ways to analyze the data and pinpoint features of interest. Once NPY2R neurons were activated, they found, mice exhibited rapid pupil dilation and the classic “eye-roll” seen during human fainting, as well as suppressed heart-rate, blood pressure and breathing rate. 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 blown away when we saw how their eyes rolled back around the same time as brain activity rapidly dropped,” the researchers reported in a paper summary. “Then, after a few seconds, brain activity and movement returned. This was our eureka moment.”

Further testing showed that when NPY2R VSNs were removed from mice, the BJR and fainting conditions vanished. Previous studies had shown that fainting is caused by a reduction in brain blood flow, which the new study also found to be true, but the new evidence indicated that brain activity itself could be playing an important role. The findings therefore implicate the activation of the newly genetically identified VSNs and their neural pathways not only with BJR, but more centrally in overall animal physiology, certain brain networks and even behavior.

Such findings were difficult to tease out previously because neuroscientists study the brain and cardiologists study the heart, but many do so in isolation of the other. “Neuroscientists traditionally think the body just follows the brain, but now it is becoming very clear that the body sends signals to the brain and then the brain changes function,” said Augustine.

As a result of their findings, the researchers would like to continue tracking the precise conditions under which vagal sensory neurons are triggered into action.

“We also hope to more closely examine 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 fainting-associated conditions.

“About 60% of cats in the U.S. are overweight, which can lead to health problems such as diabetes and chronic inflammation. While many studies have investigated feline weight loss, there has been little focus on the opposite process, which is also important. In this study, we wanted to learn more about the metabolic and gastrointestinal changes that occur as a result of overeating and weight gain in cats,” says study co-author Kelly Swanson, professor in the Department of Animal Sciences and interim director of the Division of Nutritional Sciences (DNS), part of the College of Agricultural, Consumer and Environmental Sciences (ACES) at U. of I.

The study included 11 adult spayed female cats. They were fed a standard dry cat food and after two weeks of baseline measurements, they were allowed to eat as much as they wanted. The researchers collected blood and fecal samples at regular intervals and monitored physical activity.

Once the cats were able to overeat, they immediately increased their food intake substantially and started to gain weight. At the onset of the study, their average body condition score (BCS) was 5.41 on a 9-point scale. After 18 weeks of overfeeding, it had increased to 8.27, corresponding to being 30% overweight. BCS is equivalent to body mass index (BMI) for humans, and 6 or above is considered overweight, Swanson said.

The researchers analyzed changes in fecal output, gastrointestinal transit time, digestive efficiency (nutrient digestibility), and microbiota bacterial composition over the 20-week duration of the study.

“We found that as cats ate more and gained weight, gastrointestinal transit time was reduced, and so was digestive efficiency. When the body gets less food, it will be more efficient in extracting nutrients. But when the amount of food increases, it passes through the digestive system faster and fewer nutrients are extracted in the process,” Swanson explained.

The researchers also found significant changes in gut microbial composition between the lean cats at baseline and after 18 weeks of weight gain. The relative abundance of Bifidobacterium, which has antimicrobial activity, inhibits pathogens, and stimulates the immune system, increased, while Collinsella, which degrades fiber and has been linked to pro-inflammatory diseases, decreased. These results are opposite to what has been measured in overweight humans and suggest that their association to weight gain is complex, Swanson noted.

“The change in the gastrointestinal transit time was a novel finding and a potential reason for the change in fecal microbiota. Future studies should consider measuring transit time to better explain modifications to the microbiome of pets,” he added.

As the cats’ food consumption grew, so did their fecal output. In other words, as they ate more, they also pooped more. At the same time, fecal pH decreased, meaning that the stool became more acidic.

“In humans, a low fecal pH indicates poor absorption of carbohydrates and fat. Our findings correlate with this, as reduced fecal pH aligned with higher food intake and reduced digestibility,” Swanson said.

The researchers also measured the cats’ activity level with a monitor attached to a collar. The cats were housed in a group setting where they were able to interact with each other and play with toys, except for the days when stool samples were collected.

“We expected that weight gain might lead to decreased physical activity, but we did not observe any consistent changes in activity level. However, this could vary with individual cats and their environment, and how much their owners interact with them,” Swanson stated.

Understanding the metabolic and gastrointestinal changes that occur with weight gain and obesity in pets may help with future prevention and treatment plans, the researchers conclude.

Pet owners who want to help their cats lose weight can employ various strategies. In another new study, Swanson and his co-authors showed that restricted feeding can promote safe weight and fat loss in cats. The researchers also suggest pet parents encourage activity in their feline companions. For example, they can stimulate foraging by placing food around the home, or use food puzzles during mealtime to promote engagement and mental enrichment.

After the conclusion of the weight gain study, the 11 cats were put on a restricted-feeding diet that helped them return to normal weight.