Scientists at the FBM-UNIL have identified a new role for the locus coeruleus in sleep and sleep disorders. This brain region enables the transition between sleep states and the maintenance of essential unconscious vigilance. Stress disrupts its functions and impacts sleep quality.
Sleep disorders affect a growing number of people, with potentially serious consequences for their health. Mammalian sleep is made up of cycles between two states: deep sleep (called ’NREM’ sleep) and REM sleep (called ’REM’ sleep). But little is known about the rules that govern these cycles. A study conducted by the team of Anita Lüthi , a researcher in the Department of Basic Neuroscience at the Faculty of Biology and Medicine (FBM) at the University of Lausanne (UNIL), shows for the first time that the locus coeruleus (LC), a region of the brain stem, is involved in the organization of sleep.
The LC was previously known as the major regulator of the ability to react to a dangerous situation during wakefulness. The study conducted by Anita Lüthi’s team and published in Nature Neuroscience, shows that the LC determines the moments when the transition between the two sleep states is permitted and thus maintains the normal cyclicity of sleep. According to the researcher, ’daytime experiences, particularly stress, disrupt the function of the LC and can lead to disruptions in the sleep cycle and frequent awakenings.’ These findings offer crucial clues to a better understanding of sleep disorders, with a view to improving treatments.
The structure of sleep redefined
The LC, long recognized as the production center of noradrenaline - the main hormone governing our ability to react to environmental adversities by mobilizing the brain and body - is essential for cognitive arousal. During sleep, its activity fluctuates, alternating between peaks and troughs at intervals of around 50 seconds. Until now, the role of this activity has remained poorly understood. Using cutting-edge technologies, neuroscientists at the University of Lausanne have succeeded in investing neuronal pathways in this region of the brain in mice. We found that the peaks and troughs of fluctuating LC activity each play a key role in the organization of sleep. It’s a new structural element of sleep, it works a bit like a clock", explains one of the study’s three lead authors, Georgios Foustoukos.
Their results show that sleep consists of previously unknown structural units, during which two functions are sequentially coordinated. During peaks, part of the subcortical brain is put into a more awake state, thanks to noradrenaline, allowing unconscious alertness to the environment and potential dangers. During troughs, on the other hand, transitions to REM sleep are possible.
Two key functions for restful sleep
Under normal conditions, human NREM sleep is divided into four distinct stages corresponding to the deepest periods of sleep. REM sleep, on the other hand, is characterized by high brain activity associated with dreaming, and occupies around a quarter of the night. A typical night alternates, in a coordinated fashion, between NREM and REM sleep states, allowing the body and mind to rest and recuperate. Neuroscientists have identified the LC as the gatekeeper to these transitions, precisely controlling the moments when the switch from NREM to REM sleep can occur, i.e. at activity troughs.
However, scientists have discovered that when LC activity is high, it leads to increased production of noradrenaline, which makes certain areas of the brain more sensitive to arousal, without waking the organism. This state represents a hitherto unknown type of arousal, enabling a degree of vigilance towards the environment and the body to be maintained during sleep, and thus facilitating full and rapid awakening in the event of an emergency. In other words, the brain is semi-awake at the subcortical level, whereas it is asleep at the cortical level", explains Anita Lüthi.
Hope for sleep disorders
Based on these findings, the study shows that stressful conditions in mice can disrupt sleep by increasing LC activity, thereby delaying the onset of REM sleep and fragmenting NREM sleep by too many arousals engaging subcortical and cortical areas. For Anita Lüthi, these results open the way to new clinical applications for people affected by sleep disorders: ’Our findings may help to better understand anxiety or other sleep-related disorders. In addition, they offer avenues for new treatments, such as using LC as a biomarker to monitor and possibly correct sleep cycles. A strong aspect of our work is that we are bringing the neuronal activities of sleep very close to the sleep measurements used in the hospital.’ Clinical collaborations with the Centre Hospitalier Universitaire Vaudois (CHUV) have thus been initiated to assess whether the mechanisms identified in mice can be applied to human sleep.
Finally, the study also opens up new avenues for understanding sleep through the evolution of species. Unlike mammals, which have two distinct sleep states, some archaic species, such as reptiles, do not have this well-defined duality. However, many reptiles exhibit two types of sleep that alternate over a period of around 50 seconds. This suggests that precursors of LC activity already existed to structure their ancient sleep.
