Bernstein members involved: Juan Luis Riquelme

In mammals, birds and some reptiles, sleep can be divided into two primary states: slow-wave sleep (SWS) and rapid eye movement sleep (REMS). SWS is characterized by slow brain waves and occurs first as we fall asleep, while REMS is characterized by brain activity similar to that seen when awake, along with rapid eye movements and occasional muscle twitches. The alternation of SWS and REMS forms what is known as the ultradian sleep rhythm, whose temporal features vary significantly across species. In humans, for example, a sleep cycle of SWS followed by REMS lasts about 1 to 1.5 hours, resulting in five to six cycles per typical night.

Eight years ago, the research group led by Max Planck director Gilles Laurent discovered a REM-like state in a reptile, the Australian dragon (Pogona vitticeps), well after REM had been discovered first in mammals and later, in birds. This finding suggested that REM sleep may be an ancestral trait that is shared by reptiles, birds and mammals (collectively called amniotes), and may have existed already in their common ancestor 320 million years ago.

The lizard’s sleep had another intriguing feature: its REMS is about as long as its SWS, with both phases lasting about one minute per cycle. This pattern results in 200 to 250 sleep cycles per night, allowing the research team, including postdoctoral researchers Lorenz Fenk and Luis Riquelme, to explore the mechanisms behind the brain’s alternating states during sleep. Understanding what drives these changes has remained a challenging task, despite decades of sleep research in different species.

In their study, published this week in the journal Nature, the researchers found that the features of the lizard’s ultradian sleep rhythm are consistent with the output of a central pattern generator (CPG) —specialized neural circuits that generate rhythmic motor outputs such as walking or breathing. Although CPGs are generally known for their role in motor control, the researchers reasoned that they were well suited also to control the alternation of REM/SW sleep states. “This idea of a sleep CPG was completely counterintuitive because CPGs control motor output, whereas sleep is characterized by the near absence of motor activity,” Laurent notes.

Taking advantage of the unique features of Pogona’s sleep, the researchers looked for hallmarks of CPGs, such as phase-dependent reset, and entrainment. “Phase-dependent reset means that if the rhythm is affected by a short external perturbation (akin to tripping on a stone while walking, which interrupts the walking cycle), the rhythm is immediately affected in a way that depends on the time (or phase) at which the perturbation occurred”, explains Riquelme. Entrainment is somewhat related, and describes the effects of forcing the rhythm away from its natural frequency (a little faster or a little slower) by a rhythmic input. “We found evidence for both, building on the key observation that brief light pulses delivered to the closed eyes of sleeping animals reliably reset the REM-SW cycle,” Fenk explains. The scientists also discovered that this rhythm could be affected even when the animals were awake, suggesting that the underlying circuits could be activated under the right conditions. “This is important because it suggests that sleep and the alternation between SWS and REMS are at least partially independent,” Fenk adds.

In addition, the researchers found that while the alternation between SWS and REMS occurs on both sides of the brain, the rhythm can be reset and affected on one side only. After such a unilateral perturbation, the sleep rhythms on both sides quickly re-synchronize, indicating the existence of two CPGs – one for each side of the brain – that must be interconnected to synchronize.

These findings are exciting because they link neural circuits traditionally associated with motor activity to the regulation of sleep states when the body is at rest. They also raise many questions: What are the exact components of these circuits, which are thought to reside in the brainstem? Do these findings apply to other vertebrates, such as mammals and birds? If so, how could these circuits be flexible enough to account for the different sleep patterns observed in different species? Finally, they raise important questions about the evolution of sleep and could potentially help address one of the most important questions about sleep: how did it come about, and for what?