The locus coeruleus is a region of the brain that is instrumental in coordinating our mental processing and is the primary source of noradrenaline in the brain, which acts to regulate arousal states and adaptive behavior. Now, researchers at the University of Lausanne (UNIL) have identified a new role for the locus coeruleus in sleep and its disruptions.
The findings in mice are published in Nature Neuroscience in an article titled, “Infraslow noradrenergic locus coeruleus activity fluctuations are gatekeepers of the NREM–REM sleep cycle,” and demonstrates that the locus coeruleus facilitates the transition between NREM and REM sleep states while maintaining an unconscious vigilance toward the external world.
“The noradrenergic locus coeruleus (LC) regulates arousal levels during wakefulness, but its role in sleep remains unclear,” the researchers wrote. “Here, we show in mice that fluctuating LC neuronal activity partitions non-rapid-eye-movement sleep (NREMS) into two brain–autonomic states that govern the NREMS–REMS cycle over ~50-s periods; high LC activity induces a subcortical–autonomic arousal state that facilitates cortical microarousals, whereas low LC activity is required for NREMS-to-REMS transitions.”
The study, led by Anita Lüthi, PhD, a researcher at the department of fundamental neurosciences at the faculty of biology and medicine at UNIL, shows that the LC determines when the transition between the two sleep states is possible, indicating that this brain area is crucial for the normal cyclicity of sleep states. The team also discovered that experiences during the day, particularly stress, disrupt the activity of the LC during sleep and result in a disorganized sleep cycle and too frequent awakenings.
The LC, long recognized as the center of noradrenaline production—the primary hormone governing our ability to respond to environmental challenges by mobilizing the brain and body—is essential for cognitive wakefulness. During sleep, its activity becomes fluctuating, alternating between peaks and troughs at intervals of about 50 seconds. The role of this activity has remained poorly understood until now.
The UNIL neuroscientists specifically targeted neuronal pathways in this brain region in mice. “We found that both peaks and troughs of the LC’s fluctuating activity play key roles in sleep organization. This is a new structural element of sleep; it functions somewhat like a clock,” explained Georgios Foustoukos, PhD, one of the study’s lead authors, and a postdoctoral researcher in the laboratory of Lüthi.
Their results show that sleep is composed of previously unknown structural units, during which two functions are sequentially coordinated. During peaks of LC activity, part of the subcortical brain enters a more wake-like state, thanks to noradrenaline, allowing unconscious vigilance toward the environment and potential dangers. Conversely, during troughs, transitions to REM sleep are possible.
Under normal conditions, human NREM sleep consists of four distinct stages that include the deepest stages of sleep. REM sleep, on the other hand, is characterized by high brain activity associated with dreams and occupies about a quarter of the night. A typical night alternates, in a coordinated manner, between NREM and REM states, allowing the body and mind to rest and recover.
UNIL’s neuroscientists have identified the LC as the gatekeeper of these transitions, precisely controlling when the shift from NREM to REM sleep can occur, notably at moments when its activity is low.
Conversely, the scientists discovered that when LC activity is elevated, more noradrenaline is released into the brain, making certain areas of the brain more prone to become aroused, yet without actually waking up the organism. This state represents a previously unknown type of arousal that generates vigilance toward the environment and body during sleep, facilitating a complete and rapid awakening in case of emergency. “In other words, the brain is semi-awake at the subcortical level while being asleep at the cortical level,” explained Lüthi.
These discoveries provide crucial insights for a better understanding of sleep disorders and could lead to improved treatments.
“Our discoveries can help better understand sleep disturbances associated with mental health disorders such as anxiety or other sleep disorders,” said Lüthi. “Moreover, they offer avenues for new treatments, like using the LC as a biomarker to monitor and potentially correct sleep cycles. The strength of our work is that we bring the neural activity of the sleeping brain a big step closer to human sleep measures that we know from the hospital.”
Clinical collaborations with the Lausanne University Hospital (CHUV) have been initiated to assess whether the mechanisms identified in mice can be applied to human sleep.
