Memory-enhancing properties of sleep depend on the oscillatory amplitude of norepinephrine
Open accessPublished version of a preprint
Abstract
Sleep has a complex micro-architecture, encompassing micro-arousals, sleep spindles and transitions between sleep stages. Fragmented sleep impairs memory consolidation, whereas spindle-rich and delta-rich non-rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep promote it. However, the relationship between micro-arousals and memory-promoting aspects of sleep remains unclear. In this study, we used fiber photometry in mice to examine how release of the arousal mediator norepinephrine (NE) shapes sleep micro-architecture. Here we show that micro-arousals are generated in a periodic pattern during NREM sleep, riding on the peak of locus-coeruleus-generated infraslow oscillations of extracellular NE, whereas descending phases of NE oscillations drive spindles. The amplitude of NE oscillations is crucial for shaping sleep micro-architecture related to memory performance: prolonged descent of NE promotes spindle-enriched intermediate state and REM sleep but also associates with awakenings, whereas shorter NE descents uphold NREM sleep and micro-arousals. Thus, the NE oscillatory amplitude may be a target for improving sleep in sleep disorders. Kjaerby and Andersen et al. show that norepinephrine (NE) plays profound roles in shaping sleep micro-architecture. NE slowly oscillates during sleep, with NE oscillatory amplitude being a major determinant of spindle-dependent memory consolidation and awakenings.
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The occurrence of spindles during non-REM sleep fluctuates with an infra slow rhythm of 0.02 Hz, and recent research indicates this rhythm possibly reflects modulation via LC-NA activity.
“Interestingly, the occurrence of spindles during non-REM sleep fluctuates with an infra slow rhythm of 0.02 Hz 203 and recent research indicates that this rhythm possibly reflects a modulation via LC-NA activity.204,205”
From Sleep—A brain-state serving systems memory consolidation (2023) · cites this paper as [204]
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References 89 · Cited by 306
Research works printed but not linked: 3
- [24]Osorio-Forero A Infraslow locus coeruleus activity coordinates spindle rhythms and heart rate to gate fluctuating non-REM sleep substates. bioRxiv 2021.03.08.434399 (2021) doi: 10.1101/2021.03.08.434399. · DOI
- [28]Aston-Jones G & Bloom FE Activity of norepinephrine-containing locus coeruleus neurons in behaving rats anticipates fluctuations in the sleep-waking cycle. J Neurosci 1, 876– 886 (1981). 7346592 PMC6564235
- [46]Gottesmann C The transition from slow-wave sleep to paradoxical sleep: Evolving facts and concepts of the neurophysiological processes underlying the intermediate stage of sleep. Neuroscience and Biobehavioral Reviews 20, 367– 387 (1996). 8880730
- Authors
- Kjaerby, C., Andersen, M., Hauglund, N., Untiet, V., Dall, C., Sigurdsson, B., Ding, F., Feng, J., Li, Y., Weikop, P., Hirase, H., & Nedergaard, M.
- Affiliations
- University of Copenhagen (DK)
- Peking University (CN)
- Corresponding author
- Nedergaard, Maiken
- ORCID
- Venue
- Nature Neuroscience
- Published
- 2022-07-07
- Volume
- 25
- Issue
- 8
- Pages
- 1059-1070
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC9817483
- OpenAlex
- W4284675681
- Semantic Scholar
- 205c760a710aeba67b26310dacf142dcdf8ad254
- Cited by
- 306
- References
- 89
- Citations by year
- 2026: 63 · 2025: 91 · 2024: 65 · 2023: 64 · 2022: 17 · 2021: 5 · 2020: 1
- FWCI
- 30.47
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- Nature Neuroscience (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion, other-oa)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion, cc-by-nc-nd)
- Funders
- Lundbeckfonden (R386--2021--165, R287‐2018‐2046, R155-2016–552)
- Novo Nordisk
- Augustinus Fonden
- Novo Nordisk Fonden (NNF13OC0004258, NNF21OC0066419)
- H. Lundbeck A/S
- National Institute of Neurological Disorders and Stroke (U01NS120824, U01NS113358, RF1NS110049)
- National Center for Complementary and Integrative Health (R01AT011439)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Sleep and Wakefulness Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Neuroscience of respiration and sleep
- Keywords
- norepinephrine, sleep spindles, microarousals, memory consolidation, infraslow oscillations, locus coeruleus, REM sleep, NREM sleep, sleep fragmentation, arousal, fiber photometry
- MeSH terms
- Animals, Arousal, Electroencephalography, Norepinephrine, Sleep, Sleep Stages, Sleep, REM, Mice
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