Though widely known as the “sleep hormone,” melatonin’s exact role in sleep is far from fully understood. We know of many links between melatonin and sleep: the hormone’s levels rise at night and fall during the day, regulated by the same circadian rhythms that help govern sleep. Disruptions in melatonin levels go hand in hand with sleep problems. But how, exactly does melatonin influence sleep, and our sleep and wake cycles? That, we do not yet really understand. Scientists at Caltech sought to find out more about melatonin’s precise role in sleep, and recently shared their results. Their findings shed some new light on how important melatonin is to sleep, and how it may function to bring sleep about.
To explore in detail the effects of melatonin on sleep, the researchers investigated the sleep-related functions of melatonin in zebrafish larvae. These tiny organisms have a circadian cycle similar to humans. They are awake during daylight hours, and sleep at night, during which time melatonin levels are at their highest. Researchers compared the sleep-wake patterns of normal zebrafish larvae to zebrafish larvae that were unable to produce melatonin, due to a gene mutation. The melatonin-deficient fish larvae slept significantly less than their melatonin-making counterparts, about half as long. The fish larvae without melatonin also took twice as long to fall asleep.
Researchers went a step further, and temporarily prevented the normal zebrafish larvae from making melatonin, by impairing cells in their pineal gland. (The pineal gland is also where melatonin is produced in humans.) Without the ability to generate melatonin, the zebrafish larvae displayed drastic changes to their sleep patterns. They began sleeping the same reduced amount as the genetically-mutated fish larvae, about half as much as they had slept when they were able to make melatonin. When researchers stopped preventing the fish larvae from making melatonin and they began to produce it again naturally, their sleep returned to its normal levels.
These results strongly suggest there is a direct role for melatonin in both falling asleep and in sleeping for a normal, healthy duration throughout the night.
The researchers also looked into how melatonin functioned in relation to the zebrafish larvae’s circadian clocks and their sleep-wake cycles. They first exposed both the normal zebrafish larvae and the genetically-mutated zebrafish larvae to a regular pattern of day and night—14 hours of light and 10 hours of darkness. This established the larvae with circadian clocks that operated in sync with the light and darkness. Then they moved both types of fish larvae to an environment of complete darkness. The fish that produced melatonin naturally maintained their normal circadian cycle of sleep and wakefulness, even in the absence of routine light exposure.
But the genetically-mutated zebrafish, which were incapable of producing any melatonin, lost all circadian pattern or rhythmicity to their sleep. Without melatonin, the fish larvae could not maintain circadian cycles of sleep and wakefulness. This was a surprise to researchers, and strongly suggests that melatonin is not just useful and helpful to circadian sleep-wake cycles, but essential to them.
Working with this understanding, that melatonin is required for circadian sleep cycles to function, researchers next sought to learn how melatonin goes about exerting this regulatory influence. They investigated the relationship between melatonin and adenosine, a neurotransmitter that in humans is thought to play an important part in the body’s homeostatic sleep system—our internal drive to sleep. In humans, adenosine levels rise in the brain throughout the day. This build-up of adenosine is associated with increasing feelings of tiredness and need for sleep. Adenosine levels decrease during sleep.
Researchers gave both normal zebrafish larvae and the melatonin-deficient larvae doses of a drug that stimulated adenosine. The two groups of fish reacted in very different ways. The adenosine had no effect on the normal zebrafish larvae. But among the melatonin-deficient fish larvae, researchers observed significant changes to their sleep. The genetically-mutated fish larvae began sleeping normally, in patterns like the fish that were able to produce melatonin.
This phase of their experiment suggests that one function of melatonin may be to help trigger the adenosine build up in the brain that in turn leads to feeling the need for sleep.
These findings also suggest that melatonin may be a bridge between the two powerful systems that govern sleep: the circadian system and the homeostatic sleep system. We know these two systems both exert influence over sleep, and together create our basic 24-hour cycle of a long, consolidated period of sleep followed by an extended period of wakefulness. But science has yet to establish or uncover a direct, concrete link between these two systems. This research offers a lot of new detail about how melatonin actually may work on behalf of sleep, as well as the first evidence of a direct connection between our two sleep systems.
Next, we’ll examine recent scientific breakthroughs in understanding how melatonin may influence health and disease, and new therapeutic possibilities for melatonin.
Michael J. Breus, PhD
The Sleep Doctor™