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Articles, Neurobiology of Disease

Extended Wakefulness: Compromised Metabolics in and Degeneration of Locus Ceruleus Neurons

Jing Zhang, Yan Zhu, Guanxia Zhan, Polina Fenik, Lori Panossian, Maxime M. Wang, Shayla Reid, David Lai, James G. Davis, Joseph A. Baur and Sigrid Veasey
Journal of Neuroscience 19 March 2014, 34 (12) 4418-4431; https://doi.org/10.1523/JNEUROSCI.5025-12.2014
Jing Zhang
1Department of Respiratory and Critical Care Medicine, Peking University First Hospital, Beijing 100034, China,
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Yan Zhu
2Center for Sleep and Circadian Neurobiology, Department of Medicine,
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Guanxia Zhan
2Center for Sleep and Circadian Neurobiology, Department of Medicine,
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Polina Fenik
2Center for Sleep and Circadian Neurobiology, Department of Medicine,
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Lori Panossian
2Center for Sleep and Circadian Neurobiology, Department of Medicine,
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Maxime M. Wang
2Center for Sleep and Circadian Neurobiology, Department of Medicine,
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Shayla Reid
2Center for Sleep and Circadian Neurobiology, Department of Medicine,
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David Lai
2Center for Sleep and Circadian Neurobiology, Department of Medicine,
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James G. Davis
3Institute for Diabetes, Obesity and Metabolism, and
4Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104
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Joseph A. Baur
3Institute for Diabetes, Obesity and Metabolism, and
4Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104
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Sigrid Veasey
2Center for Sleep and Circadian Neurobiology, Department of Medicine,
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Abstract

Modern society enables a shortening of sleep times, yet long-term consequences of extended wakefulness on the brain are largely unknown. Essential for optimal alertness, locus ceruleus neurons (LCns) are metabolically active neurons that fire at increased rates across sustained wakefulness. We hypothesized that wakefulness is a metabolic stressor to LCns and that, with extended wakefulness, adaptive mitochondrial metabolic responses fail and injury ensues. The nicotinamide adenine dinucleotide-dependent deacetylase sirtuin type 3 (SirT3) coordinates mitochondrial energy production and redox homeostasis. We find that brief wakefulness upregulates SirT3 and antioxidants in LCns, protecting metabolic homeostasis. Strikingly, mice lacking SirT3 lose the adaptive antioxidant response and incur oxidative injury in LCns across brief wakefulness. When wakefulness is extended for longer durations in wild-type mice, SirT3 protein declines in LCns, while oxidative stress and acetylation of mitochondrial proteins, including electron transport chain complex I proteins, increase. In parallel with metabolic dyshomeostasis, apoptosis is activated and LCns are lost. This work identifies mitochondrial stress in LCns upon wakefulness, highlights an essential role for SirT3 activation in maintaining metabolic homeostasis in LCns across wakefulness, and demonstrates that extended wakefulness results in reduced SirT3 activity and, ultimately, degeneration of LCns.

  • acetylation
  • locus ceruleus
  • metabolics
  • mitochondria
  • oxidative stress
  • sleep deprivation
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The Journal of Neuroscience: 34 (12)
Journal of Neuroscience
Vol. 34, Issue 12
19 Mar 2014
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Extended Wakefulness: Compromised Metabolics in and Degeneration of Locus Ceruleus Neurons
Jing Zhang, Yan Zhu, Guanxia Zhan, Polina Fenik, Lori Panossian, Maxime M. Wang, Shayla Reid, David Lai, James G. Davis, Joseph A. Baur, Sigrid Veasey
Journal of Neuroscience 19 March 2014, 34 (12) 4418-4431; DOI: 10.1523/JNEUROSCI.5025-12.2014

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Extended Wakefulness: Compromised Metabolics in and Degeneration of Locus Ceruleus Neurons
Jing Zhang, Yan Zhu, Guanxia Zhan, Polina Fenik, Lori Panossian, Maxime M. Wang, Shayla Reid, David Lai, James G. Davis, Joseph A. Baur, Sigrid Veasey
Journal of Neuroscience 19 March 2014, 34 (12) 4418-4431; DOI: 10.1523/JNEUROSCI.5025-12.2014
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Keywords

  • acetylation
  • locus ceruleus
  • metabolics
  • mitochondria
  • oxidative stress
  • sleep deprivation

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