Sleep regulation by neuron-astrocyte interactions

Sleep is essential for our healthy lives. Abnormalities in sleep are associated with neurodegenerative and neuropsychiatric diseases. It is important to better understand the mechanism underpinning sleep control.

Sleep exhibits cycles of two major sleep states, called rapid eye movement (REM) sleep and non-REM (NREM) sleep. Despite previous studies over the past decades, compared to NREM sleep, it is less clear how REM sleep is controlled.

REM sleep is characterized by vivid dreaming, rapid eye movement, muscle atonia and other body homeostatic signatures. REM sleep-controlling circuits are widespread throughout the brainstem and the hypothalamus and involve a range of neurotransmitters and neuropeptides. Of these brain areas, a brainstem nucleus, called the sublaterodorsal nucleus (SLD) has been implicated in REM sleep induction and muscle atonia. However, it is unclear how the SLD controls REM sleep. In this project, we will focus on non-neuronal cells in the SLD, called astrocytes.

A current theory predicts that intracellular calcium activity in astrocytes increases during wakefulness and decreases during NREM sleep. Thereby astrocytes act as a 'wakefulness integrator' to contribute to sleep homeostasis. However, we recently discovered that calcium signals increase during NREM sleep in SLD astrocytes. Based on this unexpected finding, we hypothesize that SLD astrocytes play a role in REM sleep control.

By combining various in vivo technologies in mice, we will specifically investigate how calcium signals in SLD astrocytes are controlled and what is the functional consequence of the increased calcium signals in SLD astrocytes. The outcome of this project will contribute to a better understanding of the mechanisms of sleep control and ultimately to the development of novel sleep medicine.

A better understanding of neurobiology in sleep is extremely important for our health. However, the regulatory mechanism of REM sleep remains elusive compared to NREM sleep. Previous studies have suggested that the sublaterodorsal nucleus (SLD) plays a central role in REM sleep regulation. However, it remains unclear how SLD neurons are regulated across the sleep-wake cycle in vivo. Although accumulating evidence also suggests that astrocytes are involved in sleep homeostasis as a wakefulness integrator, our preliminary results show higher calcium signals during NREM sleep in SLD astrocytes, implying that SLD astrocytes play a role in NREM sleep maintenance and REM sleep induction.

To investigate the regulatory mechanism of calcium signals in SLD astrocytes across the sleep-wake cycle, we will test the hypothesis that activity of GABAergic neurons in the ventrolateral periaqueductal gray (vlPAG) modifies calcium signals in SLD astrocytes across the sleep-wake cycle. By combining optogenetic and calcium imaging approaches in mice, we will investigate how SLD-projecting vlPAG GABAergic neurons ('vlPAG->SLD GABAergic neurons') are active across the sleep-wake cycle, and whether the optogenetic activation of vlPAG->SLD GABAergic neurons can increase calcium level in SLD astrocytes.

To explore the functional role of calcium signals in SLD astrocytes, with respect to sleep regulation, we will test the hypothesis that calcium signals in SLD astrocytes play a role in NREM sleep maintenance and REM sleep genesis. By combining chemogenetic, calcium extruder and calcium imaging, we will investigate how artificial manipulations of calcium level in SLD astrocytes affects sleep architecture.

This study will shed new light on the importance of astrocyte for sleep regulation.