Inhaled carbon dioxide triggers group of neurons responsible for arousal

Breathing too much carbon dioxide can be deadly, but it can happen during sleep if a particular sleeping position causes an obstructed airway or because of a medical condition like sleep apnea. Fortunately, inhaled carbon dioxide normally triggers sensitive brain mechanisms that prevent suffocation. Researchers have long believed that inhaled carbon dioxide activates neurons responsible for breathing and the physical effect of increased deep breathing then triggers waking from sleep (arousal).

But a new study by researchers with the Iowa Neuroscience Institute at the University of Iowa challenges that idea. The UI study identifies a group of neurons responsible for arousal that are directly triggered by carbon dioxide and cause mice to wake up without any changes to breathing. The findings were published Jan. 29 in the Journal of Neuroscience.

"Carbon dioxide-induced arousal is critical to diseases like sleep apnea and sudden infant death syndrome (SIDS), and is probably important in sudden unexpected death in epilepsy (SUDEP). However, exactly how carbon dioxide triggers waking from sleep (arousal) has not been well understood," says Gordon Buchanan, MD, PhD, senior study author and assistant professor of neurology at the UI Carver College of Medicine. "We show that neurons that should have nothing to do with breathing cause arousal from sleep when they are directly stimulated with carbon dioxide. This represents a departure from the previous thinking and may change preventive management of these diseases where disruption of carbon dioxide-induced arousal plays a role."

Previous research by Buchanan and his colleagues showed that serotonin (5-HT) neurons are important for carbon dioxide-induced arousal, because mice without serotonin neurons do not wake up when they inhale carbon dioxide. However, there are two major groups of serotonin neurons: one in the midbrain involved in sleep-wake regulation and one in the medulla involved in the regulation of breathing. The new study separates the effects of these two groups of serotonin neurons.

The team showed that applying carbon dioxide-enriched artificial cerebrospinal fluid directly to the serotonin neurons in mice in an area of the midbrain known as the dorsal raphe nucleus (DRN) causes arousal from sleep. This arousal was lost if these midbrain serotonin neurons were blocked either by genetic manipulation or with chemical inhibitors. Moreover, applying the carbon dioxide-enriched artificial cerebrospinal fluid directly to the serotonin neurons in the medulla increased breathing but did not cause arousal in mice.

"We propose that serotonin neurons in the DRN can be activated directly by carbon dioxide to cause waking independently of respiratory activation," Buchanan says. "A better understanding of the mechanisms that underlie this protective reflex of waking up when too much carbon dioxide is inhaled might improve strategies for reducing death and disability caused by sleep apnea and SIDS."

Carbon dioxide-induced arousal plays a role in both SIDS and sleep apnea, but in the case of SIDS, the arousal mechanism is thought to be impaired, while in the sleep apnea the arousal mechanism works well, but that leads to a host of secondary health problems.

Babies that are susceptible to SIDS are not awakened by increased carbon dioxide when airway obstruction occurs. This might happen if the baby is sleeping face down, or their nose and mouth are covered by soft bedding, a plush toy, or a co-sleeping parent. In contrast, carbon-dioxide-induced arousal causes people with sleep apnea to awake frequently - in many cases hundreds of times during a night. This sleep disruption is associated with significant health problems, including poor cognitive function, excessive sleepiness, and cardiovascular and metabolic complications.

"While our findings are far from ready for clinical application, this work suggests that there should be ways to prevent apnea by maintaining normal carbon dioxide during sleep without causing arousal or to augment the arousal mechanisms in babies thought to be at higher risk for SIDS. Similar approaches might also help prevent SUDEP," Buchanan says.

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