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Sleep is known to be essential for survival, as it allows both humans and other animals to rest, while the brain consolidates memories and clears out metabolic waste products. For many people worldwide, however, falling asleep at a reasonable time every evening and sleeping enough hours is challenging, due to various conditions such as insomnia, circadian rhythm disorders, depression and anxiety.
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While there are now various treatment options for those who are struggling to fall asleep, many existing medications can cause dependence or undesirable side effects, such as next-day drowsiness and rebound insomnia. Better understanding the neurological processes associated with sleep could potentially help to devise more effective and non-addictive medications that induce sleep.
Researchers at the Chinese Academy of Sciences and other institutes in China recently showed that a naturally occurring molecule called tryptamine (TrpA) could contribute to a gradual increase in the brain's drive to sleep.
Their paper, published in Nature Neuroscience, reports that activating the receptor that detects this molecule could increase the duration and boost the quality of sleep in both mice and pigs.
"Wakefulness produces sleep-promoting substances and the cerebrospinal fluid contains substances that reflect homeostatic sleep pressure," wrote Huateng Cao, Kui Wang and their colleagues in their paper.
"However, the identities of such molecules, and the neural mechanisms for producing and sensing them, remain mysterious. We show that cerebrospinal fluid levels of TrpA track homeostatic sleep pressure in nocturnal mice and diurnal pigs, reflecting physical activity history independently of light–dark cycles."
How tryptamine signals the brain's need for sleep
The familiar feeling of becoming increasingly sleepy after spending several hours awake is scientifically known as "sleep pressure." This drive to sleep is a key component of sleep homeostasis, or in other words, the biological process that balances the time animals spend awake and asleep.
To identify chemicals that contribute to the gradual increase in sleep pressure during waking hours, the researchers examined nocturnal mice and diurnal pigs. More specifically, they used a molecular tool they developed to measure levels of TrpA in the animals' cerebrospinal fluid across different stages of the sleep-wake cycle.
"We developed a ratiometric fluorescent sensor for TrpA and showed that TrpA is produced by wake-active monoaminergic nuclei in the diencephalon and brainstem and is secreted in an activity-dependent manner," wrote the authors.
"We showed that released TrpA binds to G-protein-coupled receptor 139 (GPR139) and enhances neuronal excitability in the hypothalamic preoptic area to promote sleep. TrpA–GPR139 signaling was necessary for homeostatic sleep rebound and small-molecule GPR139 agonists promoted sleep duration and quality."
Essentially, Cao, Wang and their colleagues found that TrpA levels in the cerebrospinal fluid of mice and pigs increased as they spent more hours awake, reflecting a growing sleep pressure. Notably, TrpA levels reflected the animals' history of being awake and active, independently of what time it was.
The team observed that some neurons that are only active while mammals are awake naturally produced and released TrpA. The molecule then appeared to activate a receptor called GPR139, which in turn increased the activity of neurons in the hypothalamic preoptic area, a brain region known to promote sleep.
A possible target for treating sleep disorders
Inspired by their initial findings, the researchers carried out further experiments aimed at testing the effects of compounds that activated the GPR139 receptor. Remarkably, they found that these experimental compounds increased the duration of sleep and boosted the quality of sleep in both mice and pigs.
"Together, our study reveals TrpA as a signal related to sleep homeostasis and GPR139 as a druggable target against its disruption," wrote Cao, Wang and their colleagues.
The fact that the team could replicate their findings in both mice and pigs suggests that the mechanism they identified may be conserved across various mammalian species. Future studies confirming that the same mechanism is also present in humans could potentially lead to new treatments for insomnia or for other conditions associated with difficulties sleeping and poor sleep quality.
Written for you by our author Ingrid Fadelli,edited by Sadie Harley, and fact-checked and reviewed by Robert Egan—thisarticle is the result of careful human work. We rely on readers like you to keep independent science journalism alive.If this reporting matters to you,please consider a donation (especially monthly).
More information: Huateng Cao et al, Tryptamine from wake-active monoaminergic neurons regulates sleep homeostasis, Nature Neuroscience (2026). DOI: 10.1038/s41593-026-02332-x.
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This story was originally published on Medical Xpress.
