The why and how of sleep-dependent synaptic down-selection
Open accessAbstract
Sleep requires that we disconnect from the environment, losing the ability to promptly respond to stimuli. There must be at least one essential function that justifies why we take this risk every day, and that function must depend on the brain being offline. We have proposed that this function is to renormalize synaptic weights after learning has led to a net increase in synaptic strength in many brain circuits. Without this renormalization, synaptic activity would become energetically too expensive and saturation would prevent new learning. There is converging evidence from molecular, electrophysiological, and ultrastructural experiments showing a net increase in synaptic strength after the major wake phase, and a net decline after sleep. The evidence also suggests that sleep-dependent renormalization is a smart process of synaptic down-selection, comprehensive and yet specific, which could explain the many beneficial effects of sleep on cognition. Recently, a key molecular mechanism that allows broad synaptic weakening during sleep was identified. Other mechanisms still being investigated should eventually explain how sleep can weaken most synapses but afford protection to some, including those directly activated by learning. That synaptic down-selection takes place during sleep is by now established; why it should take place during sleep has a plausible explanation; how it happens is still work in progress.
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The synaptic homeostasis hypothesis (SHY) by Tononi and Cirelli comprehensively elaborates the view that sleep primarily serves downregulation of synaptic connectivity.
“This view has been comprehensively elaborated in the ''synaptic homeostasis hypothesis'' (SHY) by Tononi and Cirelli [223][224][225] (Figure 2B).”
From Sleep—A brain-state serving systems memory consolidation (2023) · cites this paper as [225]
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Cortical development, electroencephalogram rhythms, and the sleep/wake cycle
Cirelli, C., & Tononi, G. (2015) · Biological Psychiatry · doi:10.1016/j.biopsych.2014.12.017 · Cited by 117 · see citing works
Self-citationTime to Be SHY? Some Comments on Sleep and Synaptic Homeostasis
Tononi, G., & Cirelli, C. (2012) · Neural Plasticity · doi:10.1155/2012/415250 · Cited by 114 · see citing works
Self-citationLactate as a biomarker for sleep
Naylor, E., Aillon, D. V., Barrett, B. S., Wilson, G. S., Johnson, D. A., Johnson, D. A., Harmon, H. P., Gabbert, S., & Petillo, P. A. (2012) · SLEEP · doi:10.5665/sleep.2072 · Cited by 112 · see citing works
Gutierrez-Castellanos, N., Da Silva-Matos, C. M., Zhou, K., Canto, C. B., Renner, M. C., Koene, L. M. C., Ozyildirim, O., Sprengel, R., Kessels, H. W., & De Zeeuw, C. I. (2017) · Neuron · doi:10.1016/j.neuron.2016.11.046 · Cited by 111 · see citing works
Sleep and Synaptic Renormalization: A Computational Study
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Self-citationCottrell, J. R., Borók, E., Horváth, T. L., & Nedivi, E. (2004) · Neuron · doi:10.1016/j.neuron.2004.10.025 · Cited by 108 · see citing works
Locus Ceruleus Control of State-Dependent Gene Expression
Cirelli, C. (2004) · Journal of Neuroscience · doi:10.1523/jneurosci.0949-04.2004 · Cited by 103 · see citing works
Self-citationCaffeine maintains vigilance and improves run times during night operations for Special Forces.
McLellan, T. M., Kamimori, G. H., Voss, D., Bell, D. G., Cole, K. G., & Johnson, D. E. (2005) · PubMed · Cited by 103 · see citing works
Cellular mechanisms of burst firing‐mediated long‐term depression in rat neocortical pyramidal cells
Czarnecki, A., Birtoli, B., & Ulrich, D. (2006) · The Journal of Physiology · doi:10.1113/jphysiol.2006.123588 · Cited by 99 · see citing works
Weng, F., Garcia, R. I., Lutzu, S., Alviña, K., Zhang, Y., Dushko, M., Ku, T., Zemoura, K., Rich, D., Garcia-Dominguez, D., et al. (2018) · Neuron · doi:10.1016/j.neuron.2018.01.026 · Cited by 99 · see citing works
Jakkamsetti, V., Tsai, N., Groß, C., Molinaro, G., Collins, K. A., Nicoletti, F., Wang, K. H., Osten, P., Bassell, G. J., Gibson, J. R., et al. (2013) · Neuron · doi:10.1016/j.neuron.2013.07.020 · Cited by 97 · see citing works
Spano, G. M., Banningh, S. W., Marshall, W., de Vivo, L., Bellesi, M., Loschky, S. S., Tononi, G., & Cirelli, C. (2019) · Journal of Neuroscience · doi:10.1523/jneurosci.0380-19.2019 · Cited by 96 · see citing works
Self-citationRaccuglia, D., Huang, S., Ender, A., Heim, M. ‐., Laber, D., Suárez-Grimalt, R., Liotta, A., Sigrist, S. J., Geiger, J. R. P., & Owald, D. (2019) · Current Biology · doi:10.1016/j.cub.2019.08.070 · Cited by 87 · see citing works
Visual perceptual learning induces long-term potentiation in the visual cortex
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Nere, A., Hashmi, A. G., Cirelli, C., & Tononi, G. (2013) · Frontiers in Neurology · doi:10.3389/fneur.2013.00143 · Cited by 79 · see citing works
Self-citationSynaptic plasticity through activation of GluA3-containing AMPA-receptors
Renner, M. C., Albers, E. H., Gutierrez-Castellanos, N., Reinders, N. R., van Huijstee, A. N., Xiong, H., Lodder, T. R., & Kessels, H. W. (2017) · eLife · doi:10.7554/elife.25462 · Cited by 75 · see citing works
Wilkerson, J. R., Tsai, N., Maksimova, M. A., Wu, H., Cabalo, N. P., Loerwald, K. W., Dictenberg, J. B., Gibson, J. R., & Huber, K. M. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.04.035 · Cited by 74 · see citing works
Removal of Synaptic Ca <sup>2+</sup> -Permeable AMPA Receptors during Sleep
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Role of Homer Proteins in the Maintenance of Sleep-Wake States
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Silent Synapses in the Immature Visual Cortex: Layer-Specific Developmental Regulation
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Sleep improves the variability of motor performance
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Self-citationNeuronal firing rates diverge during REM and homogenize during non-REM
Miyawaki, H., Watson, B. O., & Diba, K. (2019) · Scientific Reports · doi:10.1038/s41598-018-36710-8 · Cited by 59 · see citing works
Sleep, synaptic homeostasis and neuronal firing rates
Cirelli, C. (2017) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2017.03.016 · Cited by 58 · see citing works
Self-citationDash, M. B., Tononi, G., & Cirelli, C. (2012) · SLEEP · doi:10.5665/sleep.1950 · Cited by 57 · see citing works
Self-citationSleep deprivation, effort allocation and performance
Massar, S. A. A., Lim, J., & Huettel, S. A. (2019) · Progress in brain research · doi:10.1016/bs.pbr.2019.03.007 · Cited by 55 · see citing works
Bourdon, A. K., Spano, G. M., Marshall, W., Bellesi, M., Tononi, G., Serra, P. A., Baghdoyan, H. A., Lydic, R., Campagna, S. R., & Cirelli, C. (2018) · Scientific Reports · doi:10.1038/s41598-018-29511-6 · Cited by 54 · see citing works
Self-citationIntracellular ATP levels in mouse cortical excitatory neurons varies with sleep–wake states
Natsubori, A., Tsunematsu, T., Karashima, A., Imamura, H., Kabe, N., Trevisiol, A., Hirrlinger, J., Kodama, T., Sanagi, T., Masamoto, K., et al. (2020) · Communications Biology · doi:10.1038/s42003-020-01215-6 · Cited by 54 · see citing works
Constancy and trade-offs in the neuroanatomical and metabolic design of the cerebral cortex
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Sleep stage dynamics in neocortex and hippocampus
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Homer1a and 1bc levels in the rat somatosensory cortex vary with the time of day and sleep loss
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Regulation of hippocampal dendritic spines following sleep deprivation
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An essential role for MEF2C in the cortical response to loss of sleep in mice
Bjorness, T. E., Kulkarni, A., Rybalchenko, V., Suzuki, A., Bridges, C., Harrington, A. J., Cowan, C. W., Takahashi, J. S., Konopka, G., & Greene, R. W. (2020) · eLife · doi:10.7554/elife.58331 · Cited by 50 · see citing works
Effects of sleep and waking on the synaptic ultrastructure
Cirelli, C., & Tononi, G. (2020) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2019.0235 · Cited by 47 · see citing works
Self-citationSleep and Wake Affect Glycogen Content and Turnover at Perisynaptic Astrocytic Processes
Bellesi, M., de Vivo, L., Koebe, S. D., Tononi, G., & Cirelli, C. (2018) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2018.00308 · Cited by 46 · see citing works
Self-citationTadavarty, R., Rajput, P. S., Wong, J. M., Kumar, U., & Sastry, B. R. (2011) · PLoS ONE · doi:10.1371/journal.pone.0024933 · Cited by 45 · see citing works
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Self-citationDifferent simultaneous sleep states in the hippocampus and neocortex
Emrick, J. J., Gross, B. A., Riley, B. T., & Poe, G. R. (2016) · Sleep · doi:10.5665/sleep.6326 · Cited by 38 · see citing works
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Fxr1 regulates sleep and synaptic homeostasis
Khlghatyan, J., Evstratova, A., Bozoyan, L., Chamberland, S., Chatterjee, D., Marakhovskaia, A., Silva, T. S., Tóth, K., Mongrain, V., & Beaulieu, J. (2020) · The EMBO Journal · doi:10.15252/embj.2019103864 · Cited by 33 · see citing works
Loss of Arc attenuates the behavioral and molecular responses for sleep homeostasis in mice
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Self-citationEvidence for sleep-dependent synaptic renormalization in mouse pups
de Vivo, L., Nagai, H., Wispelaere, N. D., Spano, G. M., Marshall, W., Bellesi, M., Nemec, K. M., Schiereck, S. S., Nagai, M., Tononi, G., et al. (2019) · SLEEP · doi:10.1093/sleep/zsz184 · Cited by 29 · see citing works
Self-citationNeural fatigue due to intensive learning is reversed by a nap but not by quiet waking
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Self-citationEffect of Caffeine on Simulator Flight Performance in Sleep-Deprived Military Pilot Students
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What can neurons do for their brain? Communicate selectivity with bursts
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Self-citationSleep is more than rest for plasticity in the human cortex
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Glioblastoma Mimicking an Arteriovenous Malformation
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Higher Arc Nucleus-to-Cytoplasm Ratio during Sleep in the Superficial Layers of the Mouse Cortex
Honjoh, S., de Vivo, L., Okuno, H., Bito, H., Tononi, G., & Cirelli, C. (2017) · Frontiers in Neural Circuits · doi:10.3389/fncir.2017.00060 · Cited by 11 · see citing works
Self-citation
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Sleep—A brain-state serving systems memory consolidation
Brodt, S., Inostroza, M., Niethard, N., & Born, J. (2023) · Neuron · doi:10.1016/j.neuron.2023.03.005 · Cited by 343 · see citing works
Miyamoto, D., Marshall, W., Tononi, G., & Cirelli, C. (2021) · Nature Communications · doi:10.1038/s41467-021-23156-2 · Cited by 60 · see citing works
Self-citation
- Authors
- Cirelli, C., & Tononi, G.
- Affiliations
- University of Wisconsin–Madison (US)
- Corresponding author
- Cirelli, Chiara
- Venue
- Seminars in Cell & Developmental Biology
- Publisher
- Elsevier BV
- Published
- 2022-05
- Volume
- 125
- Pages
- 91-100
- ISSN
- 1084-9521 (ISSN-L)
- PMC
- PMC8426406
- OpenAlex
- W3134039087
- Semantic Scholar
- 3853f9baa8e006ebce0ec551b0cb6cb6fa83ccdb
- Cited by
- 74
- References
- 144
- Citations by year
- 2026: 13 · 2025: 18 · 2024: 14 · 2023: 7 · 2022: 11 · 2021: 10 · 2020: 1
- FWCI
- 5.52
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (am, 332 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Seminars in Cell and Developmental Biology (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIMH (1R01MH099231, 1R01MH091326)
- National Institutes of Health (DP 1OD579)
- U.S. Department of Defense (USA W911NF1910280)
- NINDS (1P01NS083514)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Sleep and Wakefulness Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Keywords
- synaptic plasticity, synaptic efficacy, sleep and learning, sleep and cognition
- MeSH terms
- Brain, Learning, Sleep, Synapses, Electrophysiological Phenomena
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