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Cited by 92Sleep and Wakefulness ResearchNeuroscience of respiration and sleepSleep and related disorders

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A noradrenergic-hypothalamic neural substrate for stress-induced sleep disturbances

Open access
Antila, Hanna, Kwak, Iris, Choi, Ashley, Pisciotti, Alexa, Covarrubias, Ivan, Baik, Justin, Eisch, Amelia, Beier, Kevin, Thomas, Steven, Weber, Franz, Chung, Shinjae·2022·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.2123528119PMC PMC9659376
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Abstract

In our daily life, we are exposed to uncontrollable and stressful events that disrupt our sleep. However, the underlying neural mechanisms deteriorating the quality of non-rapid eye movement sleep (NREMs) and REM sleep are largely unknown. Here, we show in mice that acute psychosocial stress disrupts sleep by increasing brief arousals (microarousals [MAs]), reducing sleep spindles, and impairing infraslow oscillations in the spindle band of the electroencephalogram during NREMs, while reducing REMs. This poor sleep quality was reflected in an increased number of calcium transients in the activity of noradrenergic (NE) neurons in the locus coeruleus (LC) during NREMs. Opto- and chemogenetic LC-NE activation in naïve mice is sufficient to change the sleep microarchitecture similar to stress. Conversely, chemogenetically inhibiting LC-NE neurons reduced MAs during NREMs and normalized their number after stress. Specifically inhibiting LC-NE neurons projecting to the preoptic area of the hypothalamus (POA) decreased MAs and enhanced spindles and REMs after stress. Optrode recordings revealed that stimulating LC-NE fibers in the POA indeed suppressed the spiking activity of POA neurons that are activated during sleep spindles and REMs and inactivated during MAs. Our findings reveal that changes in the dynamics of the stress-regulatory LC-NE neurons during sleep negatively affect sleep quality, partially through their interaction with the POA.

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  • NREM sleep is characterized by regular oscillations in brain norepinephrine levels with a frequency of approximately 0.02 Hz.

    “NREM sleep is characterized by regular oscillations in brain norepinephrine (NE) levels with a frequency in the range of ~0.02 Hz32–34.”

    From Norepinephrine-mediated slow vasomotion drives glymphatic clearance during sleep (2025) · cites this paper as [34]

    The Results section, “The Activity of LC-NE Neurons Rhythmically Fluctuates during NREMs” (page unavailable), reports rhythmic LC noradrenergic-neuron activity in sleeping mice peaking at 0.017 ± 0.005 Hz, approximately 0.02 Hz. A separate Results section measures norepinephrine levels in the preoptic area during NREM sleep, but does not establish that the levels themselves oscillate at that frequency throughout the brain. (LLM, conf=0.85)

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Research works printed but not linked: 100

  1. 10.1093/oxfordjournals.aje.a009241 · DOI
  2. 10.1001/jama.1989.03430110069030 · DOI · Paper page
  3. 10.1007/7854_2015_367 · DOI
  4. 10.1080/15402000701557383 · DOI · Paper page
  5. L. D. Sanford, D. Suchecki, P. Meerlo, “Stress, arousal, and sleep” in Sleep, Neuronal Plasticity and Brain Function. Current Topics in Behavioral Neurosciences, v. 25, P. Meerlo, R. M. Benca, T. Abel, Eds. (Springer, 2015), pp. 379–410.
  6. 10.1093/sleep/30.1.52 · DOI
  7. 10.1073/pnas.1015633108 · DOI
  8. 10.1016/j.bbr.2008.08.035 · DOI
  9. 10.1038/nn.2253 · DOI · Paper page
  10. 10.1016/0006-3223(94)91152-5 · DOI
  11. 10.1152/physrev.00046.2019 · DOI
  12. 10.1159/000446284 · DOI
  13. 10.1007/s12264-020-00473-y · DOI
  14. 10.3389/fnins.2019.00322 · DOI
  15. 10.3389/fnsys.2020.00006 · DOI
  16. 10.3389/fnbeh.2017.00227 · DOI
  17. 10.1016/j.physbeh.2014.01.010 · DOI
  18. 10.1016/S0006-8993(01)02603-8 · DOI
  19. 10.1016/j.ynstr.2016.03.002 · DOI
  20. 10.1523/JNEUROSCI.0885-17.2017 · DOI
  21. 10.1146/annurev.neuro.28.061604.135709 · DOI · Paper page
  22. 10.1016/j.smrv.2011.12.003 · DOI
  23. 10.1523/JNEUROSCI.1164-19.2019 · DOI
  24. 10.1038/s41583-020-0360-9 · DOI · Paper page
  25. 10.1016/j.ejphar.2007.11.062 · DOI · Paper page
  26. 10.1523/JNEUROSCI.01-08-00887.1981 · DOI
  27. 10.1111/j.1460-9568.2004.03526.x · DOI
  28. 10.1523/JNEUROSCI.2446-04.2004 · DOI
  29. 10.1093/cercor/bhn020 · DOI · Paper page
  30. 10.1016/0301-0082(86)90008-0 · DOI
  31. 10.1016/j.neuron.2015.07.002 · DOI · Paper page
  32. 10.1016/0361-9230(94)90175-9 · DOI
  33. 10.1016/0006-8993(86)90370-7 · DOI
  34. 10.1111/j.1460-9568.1995.tb01108.x · DOI
  35. 10.1038/npp.2015.289 · DOI
  36. 10.1523/JNEUROSCI.1809-08.2008 · DOI
  37. 10.1016/j.cub.2021.09.041 · DOI · Paper page
  38. 10.1038/s41467-020-19076-2 · DOI
  39. 10.1016/j.cub.2021.10.030 · DOI
  40. 10.1523/JNEUROSCI.20-10-03830.2000 · DOI
  41. 10.1126/science.160.3833.1253 · DOI
  42. 10.1126/science.271.5246.216 · DOI · Paper page
  43. 10.1016/S0006-8993(98)00631-3 · DOI
  44. 10.1037/0735-7044.115.1.165 · DOI
  45. 10.1016/j.cub.2021.06.031 · DOI
  46. 10.1016/0168-0102(94)90006-X · DOI
  47. 10.1523/JNEUROSCI.01-08-00876.1981 · DOI · Paper page
  48. 10.1126/sciadv.aaz4232 · DOI
  49. 10.1016/j.neuroscience.2010.06.009 · DOI
  50. 10.1016/j.jneumeth.2018.12.002 · DOI · Paper page
  51. 10.1016/j.cub.2017.12.049 · DOI
  52. P. Halász, O. Kundra, P. Rajna, I. Pál, M. Vargha, Micro-arousals during nocturnal sleep. Acta Physiol. Acad. Sci. Hung. 54, 1–12 (1979).
  53. 10.1038/s41598-019-42100-5 · DOI
  54. 10.1016/j.neuron.2016.03.036 · DOI · Paper page
  55. 10.1152/physrev.00042.2018 · DOI · Paper page
  56. 10.1371/journal.pcbi.1009316 · DOI
  57. 10.1016/j.brainres.2016.02.023 · DOI
  58. C. Wissing M. Maheu S. Wiegert A. Dieter Targeting noradrenergic neurons of the locus coeruleus: A comparison of model systems and strategies. bioRxiv Preprint (2022). https://doi.org/10.1101/2022.01.22.477348. · DOI
  59. 10.1523/JNEUROSCI.1303-17.2017 · DOI · Paper page
  60. J. Traut Effects of clozapine-N-oxide and compound 21 on sleep in laboratory mice. bioRxiv Preprint (2022). https://doi.org/10.1101/2022.02.01.478652. · DOI
  61. C. Varin, P.-H. Luppi, P. Fort, Melanin-concentrating hormone-expressing neurons adjust slow-wave sleep dynamics to catalyze paradoxical (REM) sleep. Sleep (Basel) 41, zsy068 (2018).
  62. 10.7554/eLife.65835 · DOI
  63. 10.1038/35010109 · DOI · Paper page
  64. 10.1016/j.neuroscience.2005.05.045 · DOI · Paper page
  65. 10.1016/j.neuron.2019.02.037 · DOI · Paper page
  66. 10.1016/j.cell.2015.07.015 · DOI · Paper page
  67. 10.1038/nature14979 · DOI
  68. 10.1016/j.neuroscience.2009.02.075 · DOI
  69. 10.1038/s41593-022-01102-9 · DOI · Paper page
  70. 10.1038/s41467-017-02765-w · DOI
  71. P. Franken, A. Malafosse, M. Tafti, Genetic determinants of sleep regulation in inbred mice. Sleep 22, 155–169 (1999).
  72. 10.1073/pnas.0408242101 · DOI
  73. 10.1038/380639a0 · DOI
  74. 10.1038/nn.2682 · DOI · Paper page
  75. 10.3389/fnbeh.2015.00152 · DOI
  76. 10.1016/j.biopsych.2018.07.027 · DOI
  77. 10.1016/j.neuron.2014.12.036 · DOI
  78. 10.1002/gene.20065 · DOI
  79. 10.1016/0169-328X(94)90011-6 · DOI
  80. 10.1523/JNEUROSCI.0760-05.2005 · DOI
  81. 10.1016/j.cub.2016.07.054 · DOI
  82. 10.3389/fnins.2021.645877 · DOI
  83. 10.1523/JNEUROSCI.3217-07.2007 · DOI
  84. M. S. Hunsley, R. D. Palmiter, Norepinephrine-deficient mice exhibit normal sleep-wake states but have shorter sleep latency after mild stress and low doses of amphetamine. Sleep 26, 521–526 (2003).
  85. 10.1016/0006-8993(77)90948-9 · DOI
  86. 10.1016/0006-8993(74)90109-7 · DOI
  87. 10.1016/S0166-4328(05)80275-X · DOI
  88. 10.1093/sleep/11.4.370 · DOI
  89. 10.1152/jn.00226.2004 · DOI
  90. 10.1038/s41467-018-07566-3 · DOI
  91. 10.1523/JNEUROSCI.4827-05.2006 · DOI
  92. 10.1523/JNEUROSCI.22-11-04568.2002 · DOI
  93. 10.1038/s41593-020-00784-3 · DOI
  94. 10.1093/sleep/8.2.137 · DOI
  95. 10.1016/S1388-2457(03)00136-6 · DOI
  96. 10.1016/j.ijpsycho.2013.04.002 · DOI
  97. 10.1016/j.smrv.2007.09.003 · DOI · Paper page
  98. 10.1176/appi.ajp.158.8.1227 · DOI · Paper page
  99. 10.1097/00004714-200202000-00013 · DOI
  100. 10.1111/j.1365-2869.2004.00388.x · DOI

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Metadata

Authors
Antila, H., Kwak, I., Choi, A., Pisciotti, A., Covarrubias, I., Baik, J., Eisch, A., Beier, K., Thomas, S., Weber, F., & Chung, S.
Affiliations
  • University of Pennsylvania (US)
  • Children's Hospital of Philadelphia (US)
  • University of California, Irvine (US)
Corresponding author
Chung, Shinjae
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2022-11-04
Volume
119
Issue
45
Pages
e2123528119-e2123528119
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.2123528119
PMC
PMC9659376
OpenAlex
W4308343127
Cited by
92
References
16
Citations by year
2026: 28 · 2025: 30 · 2024: 22 · 2023: 11 · 2022: 1
FWCI
7.11
Type
journal article
Language
en
Open access
Licence
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
  • National Institute on Aging (RF1AG066905)
  • National Heart, Lung, and Blood Institute (R01HL149133)
  • National Institute of Neurological Disorders and Stroke (R01NS110865)
Topics
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Sleep and Wakefulness Research
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Neuroscience of respiration and sleep
  • Social Sciences › Psychology › Experimental and Cognitive Psychology › Sleep and related disorders
Keywords
psychosocial stress, sleep disruption, noradrenergic neurons, locus coeruleus, preoptic area, hypothalamus, sleep spindles, REM sleep, microarousals, infraslow oscillations, sleep quality, calcium transients, optogenetics, chemogenetics, sleep microarchitecture
MeSH terms
Animals, Electroencephalography, Hypothalamus, Norepinephrine, Sleep, Sleep Wake Disorders, Sleep, REM, Mice

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