Summary: Astrocytes are important for uninterrupted slow wave sleep and brain rhythms that are essential for learning and memory, through mechanisms involving intracellular calcium signals.
Source: University of Oslo
Data presented by researchers from GliaLab at the Letten Centre at the University of Oslo lends further support that astrocytes are important to assure proper slow wave sleep. This finding that a non-neuronal cell type is crucial for appropriate slow wave sleep will guide future studies aimed at deciphering the mechanisms of and identifying novel treatment strategies for sleep disorders. The results have now been published in the journal Nature Communications and featured in Editors’ Highlights “From Brain to Behavior”.
Sleep is vital for our survival. Everyone can relate to how important sleep is for our optimal health simply by remembering how bad one feels after a single night of bad sleep. Yet even though sleep has been studied for over a century, the precise function of sleep and the mechanisms underlying many sleep disorders are still a mystery.
Sleep has mostly been investigated from the perspective of neurons, likely due to the lack of appropriate techniques to directly monitor non-neuronal cells in sleep. In the past couple of decades multiple studies have provided evidence that astrocytes, a star-shaped electrically non-excitable glial cell of the brain, as well might play a role in sleep, yet the signaling mechanisms that astrocytes employ in sleep have been mostly unknown.
The research group at University of Oslo formerly led by Professor Erlend A. Nagelhus, and now by Associate Professor Rune Enger, has demonstrated for the first time the activity patterns of astrocytes during natural sleep. One of the main signaling pathways of astrocytes are intracellular calcium increases. The team measured these calcium signals in astrocytes in the cortex of naturally sleeping mice using genetically encoded calcium indicators and in vivo two-photon microscopy. The authors found reduced calcium signaling during sleep as compared to when the mice are awake. However, there was still remaining activity during sleep which displayed different features in different sleep states.
Interestingly, astrocyte calcium activity increased upon sleep to wakefulness transitions and even preceded the neurophysiological (EEG) and behavioral (movement) signals upon waking from slow wave sleep. “This is a remarkable finding”, says shared first author Laura Bojarskaite, PhD candidate in neuroscience. “It demonstrates that astrocytes might be involved in orchestrating the waking up process”.
Such sleep-wake state specific activity suggests that astrocytes might be involved in sleep-wake state regulation. Therefore, the researchers next used a transgenic mouse line with impaired astrocyte calcium signaling and measured whether this would affect mice sleep patterns. The authors found that this manipulation disrupted slow wave sleep specifically and not rapid eye movement sleep. Mice with perturbed astrocyte calcium signaling had more microarousals (short awakenings) and shifted from one sleep state to another (slow wave sleep and intermediate state) more often, which interrupted their sleep and reduced its quality. “This means that astrocytic calcium signaling is important to maintain uninterrupted slow wave sleep and potentially to protect against waking up too often in the night”, says Bojarskaite. Interestingly, these mice also had more sleep spindles, which are signatures of particular type of neuronal activity associated with learning and memory. Too many sleep spindles are known to be associated with learning disabilities in humans and poor avoidance performance in rats.
Identifying new players involved in the regulation of slow wave sleep contributes to the understanding of the mechanisms and function of sleep as well as providing new targets for sleep disorders. One of the possible next steps for the group will be studying exactly how astrocyte calcium signals regulate slow wave sleep and sleep spindles.
Funding: This work was supported by the Research Council of Norway, the South-Eastern Norway Regional Health Authority, the European Union′s Seventh Framework Program, The National Association of Public Health, The Olav Thon Foundation and the Letten Foundation.
Astrocytic Ca 2+ signaling is reduced during sleep and is involved in the regulation of slow wave sleep
Astrocytic Ca2+ signaling has been intensively studied in health and disease but has not been quantified during natural sleep. Here, we employ an activity-based algorithm to assess astrocytic Ca2+ signals in the neocortex of awake and naturally sleeping mice while monitoring neuronal Ca2+ activity, brain rhythms and behavior. We show that astrocytic Ca2+ signals exhibit distinct features across the sleep-wake cycle and are reduced during sleep compared to wakefulness. Moreover, an increase in astrocytic Ca2+ signaling precedes transitions from slow wave sleep to wakefulness, with a peak upon awakening exceeding the levels during whisking and locomotion. Finally, genetic ablation of an important astrocytic Ca2+ signaling pathway impairs slow wave sleep and results in an increased number of microarousals, abnormal brain rhythms, and an increased frequency of slow wave sleep state transitions and sleep spindles. Our findings demonstrate an essential role for astrocytic Ca2+ signaling in regulating slow wave sleep.