New molecule could be the key to regulating sleep

Sleep is vital for rest and recovery, allowing the brain to consolidate memories and eliminate metabolic waste. However, millions of people struggle with insomnia, circadian rhythm disorders, depression, and anxiety, making it difficult to fall asleep and maintain quality sleep. Existing medications often lead to addiction or undesirable side effects, such as daytime drowsiness or recurrent insomnia. Therefore, understanding the precise neurobiological mechanisms of sleep holds the potential for developing safer and more effective treatments.

To find the chemicals involved in the buildup of sleep pressure, the researchers worked with night-active mice and day-active pigs. They developed a special radiometric fluorescent sensor for TRPA1 and used it to track the level of the molecule in the cerebrospinal fluid at different stages of the sleep-wake cycle. They found that the level of TRPA1 increased as the animals became more awake and physically active, regardless of the light cycle.

The key link is the GPR139 receptor, a G-protein-coupled receptor that TRPA1 binds to. This molecule is produced in the monoaminergic nuclei of the diencephalon and brainstem, which are active during wakefulness, and is released based on the level of activity. When TRPA1 enters the appropriate areas, it activates GPR139, increasing the excitability of neurons in the preoptic area of the hypothalamus, a region of the brain that is directly involved in the initiation and maintenance of sleep.

Experiments have shown that the TRPA1-GPR139 signaling pathway is necessary for restorative sleep after sleep deprivation. Moreover, the use of small molecule GPR139 receptor agonists led to increased sleep duration and improved sleep quality in mice and pigs.

The fact that this effect was observed in two different species of mammals with different daily activity patterns suggests that this mechanism is conserved, meaning it may be common to many mammals. If further research confirms that the same system works in humans, it will open up prospects for new methods of treating insomnia and other sleep disorders, instead of affecting the general inhibitory systems of the brain, it will be possible to purposefully strengthen the natural signal about the need for sleep.

According to the authors of the work, the study is the first to link a specific endogenous signal (TRPA1) with the mechanism of sleep homeostasis and at the same time points to a potentially drug target, the GPR139 receptor, the impact of which can correct sleep disorders.