Astroglial Calcium Signaling Encodes Sleep Need inDrosophila

Abstract

<jats:title>SUMMARY</jats:title><jats:p>Sleep is under homeostatic control, whereby increasing wakefulness generates sleep need and triggers sleep drive. However, the molecular and cellular pathways by which sleep need is encoded are poorly understood. In addition, the mechanisms underlying both how and when sleep need is transformed to sleep drive are unknown. Here, using <jats:italic>ex vivo</jats:italic> and <jats:italic>in vivo</jats:italic> imaging, we show in <jats:italic>Drosophila</jats:italic> that astroglial Ca<jats:sup>2+</jats:sup> signaling increases with sleep need. We demonstrate that this signaling is dependent on a specific L-type Ca<jats:sup>2+</jats:sup> channel and is required for homeostatic sleep rebound. Thermogenetically increasing Ca<jats:sup>2+</jats:sup> in astrocytes induces persistent sleep behavior, and we exploit this phenotype to conduct a genetic screen for genes required for the homeostatic regulation of sleep. From this large-scale screen, we identify TyrRII, a monoaminergic receptor required in astrocytes for sleep homeostasis. TyrRII levels rise following sleep deprivation in a Ca<jats:sup>2+</jats:sup>-dependent manner, promoting further increases in astrocytic Ca<jats:sup>2+</jats:sup> and resulting in a positive-feedback loop. These data suggest that TyrRII acts as a gate to enable the transformation of sleep need to sleep drive at the appropriate time. Moreover, our findings suggest that astrocytes then transmit this sleep need to the R5 sleep drive circuit, by upregulation and release of the interleukin-1 analog Spätzle. These findings define astroglial Ca<jats:sup>2+</jats:sup> signaling mechanisms encoding sleep need and reveal dynamic properties of the sleep homeostatic control system.</jats:p>

Circadian regulation of endoplasmic reticulum calcium response in cultured mouse astrocytes

“…This finding aligns with studies showing heightened stimulus-evoked Ca 2+ activity in astrocytes during wakefulness, which diminishes during sleep (Bojarskaite et al, 2020;Ingiosi et al, 2020). In flies, Ca 2+ activity in astrocytes is correlated with the duration of wakefulness, suggesting that astrocytic Ca 2+ is a key factor in the homeostatic regulation of sleep (Blum et al, 2021). Our findings provide a mechanistic explanation for differential Ca 2+ levels observed between wake and sleep states, with circadian regulation of ITPR2 by HERP being a key factor in this process.…”

Role of astrocytes in sleep deprivation: accomplices, resisters, or bystanders?

“…Astrocytic tumor necrosis factor-alpha (TNF-α), a pro-inflammatory cytokine, is an important sleep regulator. Several studies have shown that astrocyte-derived cytokines, including TNF-α and interleukin (IL)-1, support sleep and immunity (Krueger et al, 2011;Olivadoti et al, 2011;Blum et al, 2021), even though the function of TNF-α in sleep remains debatable (Szentirmai and Kapás, 2019). IL-6 can enhance adenosine A(1) receptor mRNA expression and signaling in astrocytes (Biber et al, 2001), and as mentioned above, adenosine is an established inhibitory neuromodulator that supports sleep homeostasis.…”

“…Additionally, after SD, less astrocyte synchronization occurred at both the network and single-cell levels during nonrapid eye movement sleep (Ingiosi et al, 2020). Another study on a Drosophila model indicated that specific astrocytic L-type Ca 2+ channel-dependent Ca 2+ signals increase to enhance sleep drive so that sleep demand can be met; moreover, increased levels of TyrRll (a monoaminergic receptor) in a Ca 2+ -dependent manner following SD can evoke further elevation of astrocytic Ca 2+ levels and promote a positive feedback loop that contributes to sleep homeostasis (Blum et al, 2021).…”