Microglia regulate sleep through calcium-dependent modulation of norepinephrine transmission

Chenyan Ma; Bing Li; Daniel Silverman; Xinlu Ding; Anan Li; Chi Xiao; Ganghua Huang; Kurtresha Worden; Sandra Muroy; Wei Chen; Zhengchao Xu; Chak Foon Tso; Yixuan Huang; Yufan Zhang; Qingming Luo; Kaoru Saijo; Yang Dan

doi:10.1038/s41593-023-01548-5

Microglia regulate sleep through calcium-dependent modulation of norepinephrine transmission

Nat Neurosci. 2024 Feb;27(2):249-258. doi: 10.1038/s41593-023-01548-5. Epub 2024 Jan 18.

Authors

Chenyan Ma^#¹, Bing Li^#¹, Daniel Silverman¹, Xinlu Ding¹, Anan Li^{2

3}, Chi Xiao⁴, Ganghua Huang⁴, Kurtresha Worden⁵, Sandra Muroy⁵, Wei Chen⁶, Zhengchao Xu², Chak Foon Tso^{1

7}, Yixuan Huang¹, Yufan Zhang¹, Qingming Luo^{2

3

4}, Kaoru Saijo⁵, Yang Dan⁸

Affiliations

¹ Division of Neurobiology, Department of Molecular and Cell Biology, Helen Wills Neuroscience Institute, Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, CA, USA.
² Biomedical Photonics, Wuhan National Laboratory for Optoelectronics, Huazhong University of Science and Technology, Wuhan, China.
³ Research Unit of Multimodal Cross Scale Neural Signal Detection and Imaging, Chinese Academy of Medical Sciences, HUST-Suzhou Institute for Brainmatics, JITRI, Suzhou, China.
⁴ Key Laboratory of Biomedical Engineering of Hainan Province, School of Biomedical Engineering, Hainan University, Haikou, China.
⁵ Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, CA, USA.
⁶ Department of Physics, University of California, Berkeley, Berkeley, CA, USA.
⁷ , Sunnyvale, CA, USA.
⁸ Division of Neurobiology, Department of Molecular and Cell Biology, Helen Wills Neuroscience Institute, Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, CA, USA. ydan@berkeley.edu.

^# Contributed equally.

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 G_i-coupled GPCRs, intracellular Ca²⁺ signaling and suppression of norepinephrine transmission. Chemogenetic activation of microglia G_i signaling strongly promoted sleep, whereas pharmacological blockade of G_i-coupled P2Y12 receptors decreased sleep. Two-photon imaging in the cortex showed that P2Y12-G_i activation elevated microglia intracellular Ca²⁺, and blockade of this Ca²⁺ elevation largely abolished the G_i-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-G_i 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.

MeSH terms

Animals
Calcium*
Mice
Microglia*
Norepinephrine
Signal Transduction / physiology
Sleep

Substances

Calcium
Norepinephrine