Adenosine-independent regulation of the sleep-wake cycle by astrocyte activity

Wanling Peng; Xiaotong Liu; Guofen Ma; Zhaofa Wu; Ziyue Wang; Xiang Fei; Meiling Qin; Lizhao Wang; Yulong Li; Siyu Zhang; Min Xu

doi:10.1038/s41421-022-00498-9

Adenosine-independent regulation of the sleep-wake cycle by astrocyte activity

Cell Discov. 2023 Feb 7;9(1):16. doi: 10.1038/s41421-022-00498-9.

Authors

Wanling Peng^#^{1

2}, Xiaotong Liu^#^{3

4}, Guofen Ma^#^{5

6}, Zhaofa Wu^{7

8}, Ziyue Wang^{5

6}, Xiang Fei^{3

4}, Meiling Qin³, Lizhao Wang^{5

6}, Yulong Li^{7

8

9}, Siyu Zhang^{10

11}, Min Xu^{12

13

14}

Affiliations

¹ Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China. wlpeng@ion.ac.cn.
² University of Chinese Academy of Sciences, Beijing, China. wlpeng@ion.ac.cn.
³ Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China.
⁴ University of Chinese Academy of Sciences, Beijing, China.
⁵ Center for Brain Science of Shanghai Children's Medical Center, Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁶ Songjiang Institute and Songjiang Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁷ State Key Laboratory of Membrane Biology, Peking University School of Life Sciences, Beijing, China.
⁸ Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China.
⁹ PKU-IDG/McGovern Institute for Brain Research, Beijing, China.
¹⁰ Center for Brain Science of Shanghai Children's Medical Center, Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China. zhang_siyu@sjtu.edu.cn.
¹¹ Songjiang Institute and Songjiang Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. zhang_siyu@sjtu.edu.cn.
¹² Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China. mxu@ion.ac.cn.
¹³ University of Chinese Academy of Sciences, Beijing, China. mxu@ion.ac.cn.
¹⁴ Shanghai Center for Brain Science and Brain-Inspired Intelligence Technology, Shangha, China. mxu@ion.ac.cn.

^# Contributed equally.

Abstract

Astrocytes play a crucial role in regulating sleep-wake behavior, and adenosine signaling is generally thought to be involved. Here we show multiple lines of evidence supporting that modulation of the sleep-wake behavior by astrocyte Ca²⁺ activity could occur without adenosine signaling. In the basal forebrain and the brainstem, two brain regions that are known to be essential for sleep-wake regulation, chemogenetically-induced astrocyte Ca²⁺ elevation significantly modulated the sleep-wake cycle. Although astrocyte Ca²⁺ level positively correlated with the amount of extracellular adenosine, as revealed by a genetically encoded adenosine sensor, we found no detectable change in adenosine level after suppressing astrocyte Ca²⁺ elevation, and transgenic mice lacking one of the major extracellular ATP-adenosine conversion enzymes showed similar extracellular adenosine level and astrocyte Ca²⁺-induced sleep modulation. Furthermore, astrocyte Ca²⁺ is dependent primarily on local neuronal activity, causing brain region-specific regulation of the sleep-wake cycle. Thus, neural activity-dependent astrocyte activity could regulate the sleep-wake behavior independent of adenosine signaling.