University of Lausanne, A groundbreaking study from researchers at the University of Lausanne has unveiled a significant role for the locus coeruleus (LC) in regulating sleep cycles and addressing sleep disruptions. This brain region is crucial for facilitating transitions between non-rapid eye movement (NREM) and rapid eye movement (REM) sleep, while also maintaining a level of unconscious vigilance to external stimuli. The study highlights how stress can impair the LC’s functions, leading to compromised sleep quality.
Sleep disorders are increasingly prevalent, posing serious health risks. While mammalian sleep consists of alternating cycles of NREM and REM sleep, the mechanisms governing these cycles have remained largely unclear. Led by Professor Anita Lüthi from the Department of Fundamental Neurosciences at the Faculty of Biology and Medicine, this research, published in Nature Neuroscience, marks the first identification of the LC’s involvement in sleep organization.
Historically, the LC has been recognized primarily for its role in regulating responses to stress during wakefulness. However, this study reveals that the LC is instrumental in determining the timing of transitions between sleep states, thus playing a vital role in maintaining the cyclic nature of sleep. The research team also found that daily experiences, particularly stress, disrupt the LC’s activity during sleep, resulting in fragmented sleep cycles and frequent awakenings. These findings offer critical insights into sleep disorders and may inform future treatment strategies.
The locus coeruleus is known as the primary source of noradrenaline, a hormone that enhances our ability to respond to environmental challenges. During sleep, the LC exhibits fluctuating activity, alternating between peaks and troughs approximately every 50 seconds. The significance of these fluctuations was not fully understood until now. Utilizing advanced technologies, the UNIL neuroscientists specifically targeted neuronal pathways within the LC in mice.
“We found that both peaks and troughs of the LC’s fluctuating activity play key roles in sleep organization, functioning like a clock,” said Georgios Foustoukos, one of the study’s lead authors.
The research indicates that sleep comprises previously unidentified structural units, with distinct functions coordinated sequentially. During peaks of LC activity, parts of the subcortical brain enter a wake-like state due to noradrenaline, enabling unconscious vigilance to potential dangers. Conversely, troughs in activity facilitate transitions to REM sleep.
In healthy individuals, NREM sleep consists of four distinct stages, culminating in deep sleep, while REM sleep—characterized by heightened brain activity and dreaming—accounts for about a quarter of total sleep time. A typical night features a coordinated alternation between NREM and REM states, allowing for physical and mental restoration. The UNIL study identifies the LC as a critical gatekeeper for these transitions, controlling the shift from NREM to REM sleep, particularly when its activity is low.
The researchers also discovered that heightened LC activity increases noradrenaline release, making certain brain areas more susceptible to arousal without fully waking the individual. This state represents a novel form of arousal that maintains vigilance during sleep, enabling rapid awakening in emergencies. “In other words, the brain is semi-awake at the subcortical level while being asleep at the cortical level,” explains Professor Lüthi.
A significant finding of this study is that stress experienced during wakefulness can disrupt sleep by elevating LC activity, which delays REM sleep onset and fragments NREM sleep due to excessive awakenings. This disruption affects both subcortical and cortical brain regions. Professor Lüthi suggests that these insights could lead to new clinical applications for individuals with sleep disorders: “Our discoveries enhance the understanding of sleep disturbances linked to mental health issues, such as anxiety. They also open avenues for innovative treatments, including using the LC as a biomarker to monitor and potentially correct sleep cycles.”
Collaborations with the Lausanne University Hospital (CHUV) are underway to explore whether the mechanisms identified in mice can be applied to human sleep.
Additionally, the study sheds light on the evolution of sleep across species. Unlike mammals with distinctly defined sleep states, some ancient species, such as reptiles, do not exhibit this duality. However, several reptiles display two types of sleep that alternate roughly every 50 seconds, suggesting that precursors to LC activity may have existed to structure their primitive sleep patterns.
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