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Dynamic fluctuations of the locus coeruleus-norepinephrine system underlie sleep state transitions

View ORCID ProfileCelia Kjaerby, Mie Andersen, View ORCID ProfileNatalie Hauglund, View ORCID ProfileFengfei Ding, Wei Wang, Qiwu Xu, Saiyue Deng, Ning Kang, Sisi Peng, Qian Sun, Camilla Dall, Peter Kusk Jørgensen, View ORCID ProfileJiesi Feng, Yulong Li, View ORCID ProfilePia Weikop, View ORCID ProfileHajime Hirase, View ORCID ProfileMaiken Nedergaard
doi: https://doi.org/10.1101/2020.09.01.274977
Celia Kjaerby
1Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, University of Copenhagen, 2200 Copenhagen, Denmark
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  • ORCID record for Celia Kjaerby
  • For correspondence: celia.kjaerby@sund.ku.dk nedergaard@sund.ku.dk
Mie Andersen
1Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, University of Copenhagen, 2200 Copenhagen, Denmark
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Natalie Hauglund
1Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, University of Copenhagen, 2200 Copenhagen, Denmark
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  • ORCID record for Natalie Hauglund
Fengfei Ding
2Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester Medical Center, Rochester, NY 14642, USA
3Department of Neurology, Tongii Hospital, Tongii Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
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Wei Wang
3Department of Neurology, Tongii Hospital, Tongii Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
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Qiwu Xu
2Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester Medical Center, Rochester, NY 14642, USA
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Saiyue Deng
2Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester Medical Center, Rochester, NY 14642, USA
3Department of Neurology, Tongii Hospital, Tongii Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
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Ning Kang
2Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester Medical Center, Rochester, NY 14642, USA
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Sisi Peng
2Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester Medical Center, Rochester, NY 14642, USA
3Department of Neurology, Tongii Hospital, Tongii Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
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Qian Sun
2Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester Medical Center, Rochester, NY 14642, USA
3Department of Neurology, Tongii Hospital, Tongii Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
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Camilla Dall
1Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, University of Copenhagen, 2200 Copenhagen, Denmark
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Peter Kusk Jørgensen
1Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, University of Copenhagen, 2200 Copenhagen, Denmark
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Jiesi Feng
4State Key Laboratory of Membrane Biology, Peking University School of Life Sciences, Beijing 100871, China
5PKU-IDG/McGovern Institute for Brain Research, Beijing 100871, China
6Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China
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Yulong Li
4State Key Laboratory of Membrane Biology, Peking University School of Life Sciences, Beijing 100871, China
5PKU-IDG/McGovern Institute for Brain Research, Beijing 100871, China
6Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China
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Pia Weikop
1Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, University of Copenhagen, 2200 Copenhagen, Denmark
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Hajime Hirase
1Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, University of Copenhagen, 2200 Copenhagen, Denmark
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Maiken Nedergaard
1Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, University of Copenhagen, 2200 Copenhagen, Denmark
2Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester Medical Center, Rochester, NY 14642, USA
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  • ORCID record for Maiken Nedergaard
  • For correspondence: celia.kjaerby@sund.ku.dk nedergaard@sund.ku.dk
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Summary

We normally regard sleep and wake as two distinct opposing brain states, where sleep requires silence of wake-promoting structures such as the locus coeruleus (LC)-norepinephrine (NE) system. We set out to investigate how cortical NE dynamics and NE-related astrocytic activity relates to LC population activity during sleep states.

We show that LC displays regular phasic activity bouts during NREM sleep leading to a slow oscillatory pattern of prefrontal NE levels of which the majority of NE increases does not lead to awakening. NE troughs link to sleep spindles and continued NE decline transitions into REM sleep. Last, we show that prefrontal astrocytes have reduced sensitivity towards NE during sleep.

Our results suggest that dynamic changes in the activity of wake-promoting systems during sleep create alternation between crucial sleep processes and broadening of sensitivity towards incoming sensory input.

Highlights

  • Extracellular levels of norepinephrine display dynamic changes during NREM and REM sleep

  • Phasic activity of locus coeruleus neurons during NREM underlies slow norepinephrine oscillations

  • Spindles occur at norepinephrine troughs and are abolished by norepinephrine increases

  • Increased spindles prior to REM reflect the beginning of a long-lasting norepinephrine decline

  • REM episodes are characterized by a sub-threshold continuous norepinephrine decline

  • The responsiveness of astrocytic Ca2+ to norepinephrine is reduced during sleep

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • Lead Contact: Maiken Nedergaard (nedergaard{at}sund.ku.dk)

  • Further information should be directed to and will be fulfilled by the Lead Contact, Maiken Nedergaard (nedergaard{at}sund.ku.dk).

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted September 02, 2020.
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Dynamic fluctuations of the locus coeruleus-norepinephrine system underlie sleep state transitions
Celia Kjaerby, Mie Andersen, Natalie Hauglund, Fengfei Ding, Wei Wang, Qiwu Xu, Saiyue Deng, Ning Kang, Sisi Peng, Qian Sun, Camilla Dall, Peter Kusk Jørgensen, Jiesi Feng, Yulong Li, Pia Weikop, Hajime Hirase, Maiken Nedergaard
bioRxiv 2020.09.01.274977; doi: https://doi.org/10.1101/2020.09.01.274977
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Dynamic fluctuations of the locus coeruleus-norepinephrine system underlie sleep state transitions
Celia Kjaerby, Mie Andersen, Natalie Hauglund, Fengfei Ding, Wei Wang, Qiwu Xu, Saiyue Deng, Ning Kang, Sisi Peng, Qian Sun, Camilla Dall, Peter Kusk Jørgensen, Jiesi Feng, Yulong Li, Pia Weikop, Hajime Hirase, Maiken Nedergaard
bioRxiv 2020.09.01.274977; doi: https://doi.org/10.1101/2020.09.01.274977

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