Research in mice sheds light on how brain senses, responds to low oxygen levels

New research from the lab of Peng Li, Ph.D., at the University of Michigan Life Sciences Institute has uncovered the neural circuit in mice that activates sighing in response to low oxygen levels.

The findings, published Feb. 6 in Current Biology, reveal a unique signaling pathway that improves the blood oxygen levels by linking the body’s oxygen monitoring center, the carotid body, to the breathing control center in the brain.   

Li’s lab at the LSI investigates how interwoven neural pathways produce various forms of breathing and sighing, and how disruptions in these pathways lead to diseases. The team previously identified the neural circuit that produces emotional sighs in mice under stress conditions. In this newest study, they wanted to determine how the brain’s breathing control center responds to low oxygen in the body, or hypoxia. 

“It’s known that hypoxia can change breathing. But what has not been characterized in detail is how it induces more sighing,” says Li, a faculty member at the LSI and assistant professor of biologic and materials sciences at the School of Dentistry.  “We wanted a better understanding of how low oxygen level is sensed and what neurocircuits in the brain are driving the cardio-respiratory responses.”

The team began by analyzing the range of breathing changes that rodents exhibited in low-oxygen conditions. They found that, while normal breath rate increased by about 10% to 20%, the rate of sighs increased by five-fold. The increased sighing also lasted much longer than the adjusted breathing rate.

“There is definitely a difference in the respiratory response to hypoxic conditions, in terms of the respiratory rate versus the sigh rate, and we propose that the brain is preferentially inducing sighs to combat hypoxia,” says Li, who is also an assistant professor of molecular and integrative physiology at the Medical School. “So then we traced this response up to the brain to see how the neurocircuits modulated these hypoxia-induced sighs.”

They found that a nerve linked to the carotid body — a group of oxygen-sensing cells located where the carotid artery branches in two — sends signals to a group of neurons in the NTS (nucleus of the solitary tract) region of the mouse’s brain whenever oxygen levels drop. These NTS neurons connect directly to the area of the brain known to control all forms of sighing, including the regular sighs that occur as part of normal breathing patterns as well as emotional sighs.

We are beginning to really see how different types of inputs all converge onto the same site in the brainstem to regulate the same behavior — sighing — in response to very different conditions.
Peng Li, Ph.D.

When the researchers activated the NTS neurons directly, sighing rates increased regardless of oxygen levels. Similarly, when they silenced the NTS neurons, the increased sigh rate diminished under low-oxygen conditions, even while the breath rate increased.

“We now have a map showing how the periphery oxygen sensor in the body connects to the breathing control center to regulate this hypoxia sighing,” Li says. “And we are beginning to really see how different types of inputs all converge onto the same site in the brainstem to regulate the same behavior — sighing — in response to very different conditions.”

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Abstract illustration of a signaling tower, representing the carotid body (left), sending signals through the ganglion neurons (fluorescent imaging, right) to induce sighing.

Disclosure & Authorship

The research was supported by the National Institutes of Health, the American Thoracic Society and the Parker B. Francis Fellowship Program.

Study authors are: Yilong Yao, Jingwen Chen, Xingyu Li, and Peng Li, University of Michigan; and Zhou-Feng Chen, Washington University School of Medicine.

Go to Article

A carotid body-brainstem neural circuit mediates sighing in hypoxia,” Current Biology. DOI: 10.1016/j.cub.2023.01.019