PKU-Nanjing Institute of Translational Medicine, Nanjing Raygen Health, Nanjing, China; National Platform for Medical Engineering Education Integration, Southeast University, Nanjing, China; Jiangsu Key Laboratory of Molecular and Functional Imaging, Department of Radiology, Zhongda Hospital, Medical School, Southeast University, Nanjing, China; Key Laboratory of Developmental Genes and Human Diseases, Department of Histology Embryology, Medical School, Southeast University, Nanjing, China
Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China; Research Unit of Mitochondria in Brain Diseases, Chinese Academy of Medical Sciences, PKU-Nanjing Institute of Translational Medicine, Nanjing, China
Xueli Chen
Research Unit of Mitochondria in Brain Diseases, Chinese Academy of Medical Sciences, PKU-Nanjing Institute of Translational Medicine, Nanjing, China
Lifeng Zhang
Research Unit of Mitochondria in Brain Diseases, Chinese Academy of Medical Sciences, PKU-Nanjing Institute of Translational Medicine, Nanjing, China
Huaqiang Fang
Research Unit of Mitochondria in Brain Diseases, Chinese Academy of Medical Sciences, PKU-Nanjing Institute of Translational Medicine, Nanjing, China
PKU-Nanjing Institute of Translational Medicine, Nanjing Raygen Health, Nanjing, China
Shenghong Ju
Jiangsu Key Laboratory of Molecular and Functional Imaging, Department of Radiology, Zhongda Hospital, Medical School, Southeast University, Nanjing, China
Weizheng Gao
Academy of Advanced Interdisciplinary Study, College of Engineering, Peking University, Beijing, China
Xiaoyu Qian
Academy of Advanced Interdisciplinary Study, College of Engineering, Peking University, Beijing, China
Research Unit of Mitochondria in Brain Diseases, Chinese Academy of Medical Sciences, PKU-Nanjing Institute of Translational Medicine, Nanjing, China; State Key Laboratory of Membrane Biology, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking-Tsinghua Center for Life Sciences, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing, China
Jue Zhang
Academy of Advanced Interdisciplinary Study, College of Engineering, Peking University, Beijing, China
Research Unit of Mitochondria in Brain Diseases, Chinese Academy of Medical Sciences, PKU-Nanjing Institute of Translational Medicine, Nanjing, China; State Key Laboratory of Membrane Biology, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking-Tsinghua Center for Life Sciences, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing, China; National Biomedical Imaging Center, State Key Laboratory of Membrane Biology, Peking-Tsinghua Center for Life Sciences, College of Future Technology, Peking University, Beijing, China
Microglia surveillance manifests itself as dynamic changes in cell morphology and functional remodeling. Whether and how microglia surveillance is coupled to brain state switches during natural sleep-wake cycles remains unclear. To address this question, we used miniature two-photon microscopy (mTPM) to acquire time-lapse high-resolution microglia images of the somatosensory cortex, along with EEG/EMG recordings and behavioral video, in freely-behaving mice. We uncovered fast and robust brain state-dependent changes in microglia surveillance, occurring in parallel with sleep dynamics and early-onset phagocytic microglial contraction during sleep deprivation stress. We also detected local norepinephrine fluctuation occurring in a sleep state-dependent manner. We showed that the locus coeruleus-norepinephrine system, which is crucial to sleep homeostasis, is required for both sleep state-dependent and stress-induced microglial responses and β2-adrenergic receptor signaling plays a significant role in this process. These results provide direct evidence that microglial surveillance is exquisitely tuned to signals and stressors that regulate sleep dynamics and homeostasis so as to adjust its varied roles to complement those of neurons in the brain. In vivo imaging with mTPM in freely behaving animals, as demonstrated here, opens a new avenue for future investigation of microglia dynamics and sleep biology in freely behaving animals.
