Microglia regulate sleep through calcium-dependent modulation of norepinephrine transmission 

Chenyan Ma1,8, Bing Li1,8, Daniel Silverman1, Xinlu Ding1, Anan Li2,3, Chi Xiao4, Ganghua Huang4, Kurtresha Worden5, Sandra Muroy5, Wei Chen6, Zhengchao Xu2, Chak Foon Tso1,7, Yixuan Huang1, Yufan Zhang1,

Qingming Luo2,3,4, Kaoru Saijo5 & Yang Dan1

1Division of Neurobiology, Department of Molecular and Cell Biology, Helen Wills Neuroscience Institute, Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, CA, USA.

2Biomedical Photonics, Wuhan National Laboratory for Optoelectronics, Huazhong University of Science and Technology, Wuhan, China.

3Research Unit of Multimodal Cross Scale Neural Signal Detection and Imaging, Chinese Academy of Medical Sciences,

HUST-Suzhou Institute for Brainmatics, JITRI, Suzhou, China.

4Key Laboratory of Biomedical Engineering of Hainan Province, School of Biomedical Engineering, Hainan University, Haikou, China.

5Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, CA, USA.

6Department of Physics, University of California, Berkeley, Berkeley, CA, USA.

7Sunnyvale, CA, USA.

8These authors contributed equally: Chenyan Ma, Bing Li.

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 in mice that microglia can regulate sleep through a mechanism involving Gi-coupled GPCRs, intracellular Ca2+ 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 in the cortex showed that P2Y12–Gi activation elevated microglia intracellular Ca2+, and blockade of this Ca2+ elevation largely abolished the Gi-induced sleep increase. Microglia Ca2+ level also increased at natural wake-to-sleep transitions, caused partly by reduced norepinephrine levels. Furthermore, imaging of norepinephrine with its biosensor in the cortex showed that microglia P2Y12–Gi activation significantly reduced norepinephrine levels, partly by increasing the adenosine concentration. These findings indicate that microglia can regulate sleep through reciprocal interactions with norepinephrine transmission. 

The paper: https://www.nature.com/articles/s41593-023-01548-5