Sudden infant death syndrome or SIDS (also known as “cot death” or “crib death”) is the leading cause of death of young infants in the western world. Although the link between serotonin-producing neurons and their role in the regulation of breathing has been at the heart of SIDS research for many years, the cause of SIDS has remained elusive.

Now, new research from Harvard Medical School looked specifically at the role of serotonin-producing neurons and their role in the autoresuscitation response—a process that triggers a series of gasps and raises the heart rate to restore healthy levels when breathing temporarily stops and oxygen levels in cells fall too low and carbon dioxide levels rise too high.

An infant’s failure of autoresuscitation may underlie SIDS. But heart rate monitor readings in some SIDS infants support the hypothesis that this fail-safe mechanism doesn’t always kick in, and that its failure can lead to SIDS. Some of those infants show abnormalities in the brain cells that produce serotonin. The researchers, led by Susan Dymecki, M.D., Ph.D., professor of genetics at Harvard Medical School, asked the question “Does the autoresuscitation recovery response rely on serotonin-producing neurons?”

The results of the study titled “Acute perturbation of Pet1-neuron activity in neonatal mice impairs cardiorespiratory homeostatic recovery,” published this week in eLife, suggest that the dysfunction of serotonin-producing neurons could actually contribute to SIDS deaths.

Dr. Dymecki states, “If we can determine whether serotonin-producing neurons play an active and necessary role in regulating breathing, heart rate, and the recovery response to apneas in young mouse pups, it could provide a plausible biological explanation for at least some SIDS cases.”

Serotonin-producing neurons in a mouse brain [Dymecki lab/Harvard Medical School]
To do this, the researchers used one-week-old mouse pups (similar in age to an infant at risk of SIDS) that had been genetically engineered to respond to an injected drug by rapidly inhibiting their serotonin neurons. In these mice, the serotonin neurons can be quickly inhibited while other neurons remain unaffected. Specifically, the authors used an inducible (clozapine-N-oxide (CNO)-triggered) neuronal inhibition strategy involving the cognate, synthetic inhibitory G protein-coupled receptor hM4Di (also referred to as Di) to disrupt at P8 the activity of a raphe neuron population defined by expression of a Pet1 BAC transgene.

This system was key to analyzing the linkage between the neurons and the breathing ability of the mice. “Although initially technically challenging, this novel approach allowed for precise brain cell manipulation and real-time measurement of cardiac and respiratory activity,” says Ryan Dosumu-Johnson, a graduate student in Dr. Dymecki’s lab and first author of the paper.

Inhibiting the serotonin neurons resulted in altered baseline cardiorespiratory properties and diminished apnea survival. Although their heart rate showed largely normal recovery—at least at first—their breathing did not. Disordered gasp recovery from the initial apnea distinguished mice that would go on to die during subsequent apneas, meaning that the mice that took fewer gasps were more likely to die following such episodes. The results provide evidence that the serotonergic neurons play an active role in maintaining normal neonatal cardiorespiratory function and provide mechanistic plausibility for the serotonergic abnormalities associated with SIDS.

“This possible explanation might provide some hope, even if minutely, for the profound grief experienced by families who have lost a child to SIDS, and may one day help researchers prevent SIDS altogether,” Dr. Dymecki says. She adds, “these results indicate a vital role for serotonin neurons at an early age after birth.”

Interestingly, the heart rates in the mice with inhibited serotonin neurons recovered normally, at least initially, even though their breathing was impaired. “This uncoupling of the breathing and heart-rate recovery responses was unexpected,” says Dr. Dymecki. “It suggests that these two vital physiological responses—heart rate and breathing—could be more separable at the level of brain cells and circuits than previously anticipated, despite their interwoven physiology.”

Most SIDS deaths occur in babies between 1 month and 4 months of age, and the majority (90%) of SIDS deaths occur before a baby reaches 6 months of age. However, SIDS deaths can occur anytime during a baby’s first year

The authors conclude that “these findings shed new light on cardiorespiratory control systems and, more specifically, support a potential pathoetiological role for the SIDS-associated finding of postmortem brainstem serotonergic neuron abnormalities.” Further, the results suggest that gasp features might potentially help define a physiological profile associated with a higher risk likelihood for SIDS, leading to improved screening tools to identify infants at risk for SIDS and to develop new drug therapies for those infants.

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