Microglia Regulate Sleep via Calcium-Dependent Modulation of Norepinephrine Transmission
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Abstract
Sleep interacts reciprocally with immune system activity, but its specific relationship with microglia – the resident immune cells in the brain – remains poorly understood. Here we show that microglia can regulate sleep through a mechanism involving Gi-coupled GPCRs, intracellular Ca 2+ signaling, and suppression of norepinephrine transmission. Chemogenetic activation of microglia Gi signaling strongly promoted sleep, whereas pharmacological blockade of Gi-coupled P2Y12 receptors decreased sleep. Two-photon imaging showed that P2Y12/Gi activation elevated microglia intracellular Ca 2+ , and blockade of this Ca 2+ elevation largely abolished the Gi-induced sleep increase. Microglia Ca 2+ level also increased at natural wake-to-sleep transitions, caused partly by reduced norepinephrine. Furthermore, imaging of norepinephrine activity with its biosensor showed that microglia P2Y12/Gi activation significantly reduced norepinephrine, partly by increasing the adenosine concentration. Thus, microglia can regulate sleep through reciprocal interactions with norepinephrine transmission.
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Recent studies have shown that during wakefulness microglia exhibit reduced motilitycompared to anesthetized states, likely due to suppression by NE38,39,59 . Here we show
One question I had throughout the paper is whether you observed changes in microglia motility in your experiments, both because of any biological significance of motility changes, as well as because of how motility could have affected your calcium dynamics results. I'd love to hear more!
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CNO-induced Gi activation in microglia caused astrong reduction of cortical extracellular NE concentration
What a dramatic response of extracellular NE! Do you know if CNO causes this kind of response in animals that don't express the DREADD?
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However, CNO-induced Gi activation caused a strong increase in Ca2+ activity,primarily in microglia processes
It's so cool that you saw in vivo calcium changes in the microglia processes with this manipulation. I can see from your analyses that there were significant changes in the processes compared to the soma, but I'm wondering whether you observed changes in the processes somewhat evenly distributed across cells, or whether there were particular microglia that had active processes while other cells did not. I know I might be able to answer this question if I could see the videos, but it could be an interesting descriptive analysis to show in addition to what's already in the figure. In addition, whether there's a change in other features of the calcium signal, like propagation, would also be interesting, and might necessitate an …
However, CNO-induced Gi activation caused a strong increase in Ca2+ activity,primarily in microglia processes
It's so cool that you saw in vivo calcium changes in the microglia processes with this manipulation. I can see from your analyses that there were significant changes in the processes compared to the soma, but I'm wondering whether you observed changes in the processes somewhat evenly distributed across cells, or whether there were particular microglia that had active processes while other cells did not. I know I might be able to answer this question if I could see the videos, but it could be an interesting descriptive analysis to show in addition to what's already in the figure. In addition, whether there's a change in other features of the calcium signal, like propagation, would also be interesting, and might necessitate an non-ROI-based analysis approach.
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mean duration of NREM sleepepisodes
I'm curious whether delta power during NREM sleep changed in addition to duration and % time. Especially since you later show that Gi and Gq activation in microglia have similar effects on NREM sleep, it might be a differentiating feature. For Gi vs Gq activation in astrocytes, we previously observed that Gi affected sleep depth while Gq changed sleep duration.
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Note, however, that the effect of these antagonists could be mediated either directly byadrenergic receptors on microglia or indirectly through their effects on neurons and astrocytes,which may in turn affect microglia Ca2+ activity
I think this is an important point to make, and I'm glad you did! You may want to include some citations here, especially because it may not be widely known that astrocytes can express high levels of adrenergic receptors, and that subtypes of astrocytic adrenergic receptors can be activated by dopamine, as well as norepinephrine, in the prefrontal cortex.
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we also elevatedmicroglia Ca2+ through Gq-mediated activation of PLC-IP3 signaling
I'd be curious to see how the Gi and the Gq activation differ in their activation of calcium, for example, to be able to compare any summary statistics here to those presented in Fig. 2g–k.
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