Slow cortical rhythms: from single-neuron electrophysiology to whole-brain imaging in vivo

Umberto Olcese, Ugo Faraguna


The slow cortical oscillation is the major brain rhythm occurring during sleep, and has been the object of thorough investigation for over thirty years. Despite all these efforts, the function and the neuronal mechanisms behind slow cortical rhythms remain only partially understood. In this review we will provide an overview of the techniques available for the in vivo study of slow cortical oscillations in animal models. Our goal is to provide an up to date resource for the selection of the best experimental strategies to study specific aspects of slow oscillations. We will cover both traditional, population-level electrophysiological approaches (EEG, local field potentials) as well as more recent techniques, such as two photon calcium imaging and optogenetics. Overall, we believe that new breakthrough in our understanding of slow cortical rhythms will require the integration of different techniques, to bridge the gap between different spatio-temporal scales and go from a correlative to a causal level of analysis.


sleep; slow wave activity; slow oscillation

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Achermann P. The two-process model of sleep regulation revisited. Aviat Space Environ Med 75: A37–43, 2004.

Baranauskas G, Mukovskiy A, Wolf F, Volgushev M. The determinants of the onset dynamics of action potentials in a computational model. Neuroscience 167: 1070–1090, 2010.

Barth AL, Poulet JFA. Experimental evidence for sparse firing in the neocortex. Trends Neurosci 35: 345–355, 2012.

Barthó P, Hirase H, Monconduit L, Zugaro M, Harris KD, Buzsáki G. Characterization of neocortical principal cells and interneurons by network interactions and extracellular features. J Neurophysiol 92: 600–608, 2004.

Barthó P, Slézia A, Mátyás F, Faradzs-Zade L, Ulbert I, Harris KD, Acsády L. Ongoing network state controls the length of sleep spindles via inhibitory activity. Neuron 82: 1367–1379, 2014.

Beltramo R, D’Urso G, Dal Maschio M, Farisello P, Bovetti S, Clovis Y, Lassi G, Tucci V, De Pietri Tonelli D, Fellin T. Layer-specific excitatory circuits differentially control recurrent network dynamics in the neocortex. Nat Neurosci 16: 227–234, 2013.

Binder S, Berg K, Gasca F, Lafon B, Parra LC, Born J, Marshall L. Transcranial slow oscillation stimulation during sleep enhances memory consolidation in rats. Brain Stimulat 7: 508–515, 2014.

Borbély AA, Baumann F, Brandeis D, Strauch I, Lehmann D. Sleep deprivation: effect on sleep stages and EEG power density in man. Electroencephalogr Clin Neurophysiol 51: 483–495, 1981.

Bushey D, Tononi G, Cirelli C. Sleep- and wake-dependent changes in neuronal activity and reactivity demonstrated in fly neurons using in vivo calcium imaging. Proc Natl Acad Sci U S A 112: 4785–4790, 2015.

Buzsáki G, Anastassiou CA, Koch C. The origin of extracellular fields and currents — EEG, ECoG, LFP and spikes. Nat Rev Neurosci 13: 407–420, 2012.

Buzsáki G, Logothetis N, Singer W. Scaling brain size, keeping timing: evolutionary preservation of brain rhythms. Neuron 80: 751–764, 2013.

Campbell SS, Tobler I. Animal sleep: a review of sleep duration across phylogeny. Neurosci Biobehav Rev 8: 269–300, 1984.

Chauvette S, Seigneur J, Timofeev I. Sleep oscillations in the thalamocortical system induce long-term neuronal plasticity. Neuron 75: 1105–1113, 2012.

Chemla S, Chavane F. Voltage-sensitive dye imaging: Technique review and models. J Physiol Paris 104: 40–50, 2010.

Chen T-W, Wardill TJ, Sun Y, Pulver SR, Renninger SL, Baohan A, Schreiter ER, Kerr RA, Orger MB, Jayaraman V, Looger LL, Svoboda K, Kim DS. Ultrasensitive fluorescent proteins for imaging neuronal activity. Nature 499: 295–300, 2013a.

Chen X, Leischner U, Rochefort NL, Nelken I, Konnerth A. Functional mapping of single spines in cortical neurons in vivo. Nature 475: 501–505, 2011.

Chen X, Rochefort NL, Sakmann B, Konnerth A. Reactivation of the same synapses during spontaneous up states and sensory stimuli. Cell Rep 4: 31–39, 2013b.

Constantinople CM, Bruno RM. Effects and mechanisms of wakefulness on local cortical networks. Neuron 69: 1061–1068, 2011.

Cossart R, Aronov D, Yuste R. Attractor dynamics of network UP states in the neocortex. Nature 423: 283–288, 2003.

Daan S, Beersma DG, Borbély AA. Timing of human sleep: recovery process gated by a circadian pacemaker. Am J Physiol 246: R161–183, 1984.

David F, Schmiedt JT, Taylor HL, Orban G, Di Giovanni G, Uebele VN, Renger JJ, Lambert RC, Leresche N, Crunelli V. Essential thalamic contribution to slow waves of natural sleep. J Neurosci Off J Soc Neurosci 33: 19599–19610, 2013.

Davis CJ, Clinton JM, Jewett KA, Zielinski MR, Krueger JM. Delta wave power: an independent sleep phenotype or epiphenomenon? J Clin Sleep Med JCSM Off Publ Am Acad Sleep Med 7: S16–18, 2011.

Esser SK, Hill SL, Tononi G. Sleep homeostasis and cortical synchronization: I. Modeling the effects of synaptic strength on sleep slow waves. Sleep 30: 1617–1630, 2007.

Euston DR, Tatsuno M, McNaughton BL. Fast-forward playback of recent memory sequences in prefrontal cortex during sleep. Science 318: 1147–1150, 2007.

Gentet LJ, Kremer Y, Taniguchi H, Huang ZJ, Staiger JF, Petersen CCH. Unique functional properties of somatostatin-expressing GABAergic neurons in mouse barrel cortex. Nat Neurosci 15: 607–612, 2012.

Grewe BF, Langer D, Kasper H, Kampa BM, Helmchen F. High-speed in vivo calcium imaging reveals neuronal network activity with near-millisecond precision. Nat Methods 7: 399–405, 2010.

Gunaydin LA, Yizhar O, Berndt A, Sohal VS, Deisseroth K, Hegemann P. Ultrafast optogenetic control. Nat Neurosci 13: 387–392, 2010.

Guo ZV, Hires SA, Li N, O’Connor DH, Komiyama T, Ophir E, Huber D, Bonardi C, Morandell K, Gutnisky D, Peron S, Xu N, Cox J, Svoboda K. Procedures for behavioral experiments in head-fixed mice. PloS One 9: e88678, 2014.

Haider B, Duque A, Hasenstaub AR, McCormick DA. Neocortical network activity in vivo is generated through a dynamic balance of excitation and inhibition. J Neurosci Off J Soc Neurosci 26: 4535–4545, 2006.

Hall TM, de Carvalho F, Jackson A. A common structure underlies low-frequency cortical dynamics in movement, sleep, and sedation. Neuron 83: 1185–1199, 2014.

Helmchen F, Denk W. Deep tissue two-photon microscopy. Nat Methods 2: 932–940, 2005.

Huber R, Esser SK, Ferrarelli F, Massimini M, Peterson MJ, Tononi G. TMS-induced cortical potentiation during wakefulness locally increases slow wave activity during sleep. PloS One 2: e276, 2007.

Huber R, Ghilardi MF, Massimini M, Ferrarelli F, Riedner BA, Peterson MJ, Tononi G. Arm immobilization causes cortical plastic changes and locally decreases sleep slow wave activity. Nat Neurosci 9: 1169–1176, 2006.

Huber R, Ghilardi MF, Massimini M, Tononi G. Local sleep and learning. Nature 430: 78–81, 2004.

Hutchison WD, Dostrovsky JO, Walters JR, Courtemanche R, Boraud T, Goldberg J, Brown P. Neuronal oscillations in the basal ganglia and movement disorders: evidence from whole animal and human recordings. J Neurosci Off J Soc Neurosci 24: 9240–9243, 2004.

Iurilli G, Ghezzi D, Olcese U, Lassi G, Nazzaro C, Tonini R, Tucci V, Benfenati F, Medini P. Sound-driven synaptic inhibition in primary visual cortex. Neuron 73: 814–828, 2012.

Iurilli G, Olcese U, Medini P. Preserved excitatory-inhibitory balance of cortical synaptic inputs following deprived eye stimulation after a saturating period of monocular deprivation in rats. PloS One 8: e82044, 2013.

Jacob V, Petreanu L, Wright N, Svoboda K, Fox K. Regular spiking and intrinsic bursting pyramidal cells show orthogonal forms of experience-dependent plasticity in layer V of barrel cortex. Neuron 73: 391–404, 2012.

Ji D, Wilson MA. Coordinated memory replay in the visual cortex and hippocampus during sleep. Nat Neurosci 10: 100–107, 2007.

Kerr JND, Greenberg D, Helmchen F. Imaging input and output of neocortical networks in vivo. Proc Natl Acad Sci U S A 102: 14063–14068, 2005.

Kim A, Latchoumane C, Lee S, Kim GB, Cheong E, Augustine GJ, Shin H-S. Optogenetically induced sleep spindle rhythms alter sleep architectures in mice. Proc Natl Acad Sci U S A 109: 20673–20678, 2012.

Komai S, Denk W, Osten P, Brecht M, Margrie TW. Two-photon targeted patching (TPTP) in vivo. Nat Protoc 1: 647–652, 2006.

Kuki T, Fujihara K, Miwa H, Tamamaki N, Yanagawa Y, Mushiake H. Contribution of parvalbumin and somatostatin-expressing GABAergic neurons to slow oscillations and the balance in beta-gamma oscillations across cortical layers. Front Neural Circuits 9: 6, 2015.

Kuki T, Ohshiro T, Ito S, Ji Z-G, Fukazawa Y, Matsuzaka Y, Yawo H, Mushiake H. Frequency-dependent entrainment of neocortical slow oscillation to repeated optogenetic stimulation in the anesthetized rat. Neurosci Res 75: 35–45, 2013.

Landsness EC, Crupi D, Hulse BK, Peterson MJ, Huber R, Ansari H, Coen M, Cirelli C, Benca RM, Ghilardi MF, Tononi G. Sleep-dependent improvement in visuomotor learning: a causal role for slow waves. Sleep 32: 1273–1284, 2009.

Leemburg S, Vyazovskiy VV, Olcese U, Bassetti CL, Tononi G, Cirelli C. Sleep homeostasis in the rat is preserved during chronic sleep restriction. Proc Natl Acad Sci U S A 107: 15939–15944, 2010.

Lemieux M, Chauvette S, Timofeev I. Neocortical inhibitory activities and long-range afferents contribute to the synchronous onset of silent states of the neocortical slow oscillation. J Neurophysiol 113: 768–779, 2015.

Luczak A, Bartho P, Harris KD. Gating of sensory input by spontaneous cortical activity. J Neurosci Off J Soc Neurosci 33: 1684–1695, 2013.

Luczak A, Barthó P, Marguet SL, Buzsáki G, Harris KD. Sequential structure of neocortical spontaneous activity in vivo. Proc Natl Acad Sci U S A 104: 347–352, 2007.

Madisen L, Mao T, Koch H, Zhuo J, Berenyi A, Fujisawa S, Hsu Y-WA, Garcia AJ 3rd, Gu X, Zanella S, Kidney J, Gu H, Mao Y, Hooks BM, Boyden ES, Buzsáki G, Ramirez JM, Jones AR, Svoboda K, Han X, Turner EE, Zeng H. A toolbox of Cre-dependent optogenetic transgenic mice for light-induced activation and silencing. Nat Neurosci 15: 793–802, 2012.

Marshall L, Helgadóttir H, Mölle M, Born J. Boosting slow oscillations during sleep potentiates memory. Nature 444: 610–613, 2006.

Mateo C, Avermann M, Gentet LJ, Zhang F, Deisseroth K, Petersen CCH. In vivo optogenetic stimulation of neocortical excitatory neurons drives brain-state-dependent inhibition. Curr Biol CB 21: 1593–1602, 2011.

Mattis J, Tye KM, Ferenczi EA, Ramakrishnan C, O’Shea DJ, Prakash R, Gunaydin LA, Hyun M, Fenno LE, Gradinaru V, Yizhar O, Deisseroth K. Principles for applying optogenetic tools derived from direct comparative analysis of microbial opsins. Nat Methods 9: 159–172, 2012.

Mittmann W, Wallace DJ, Czubayko U, Herb JT, Schaefer AT, Looger LL, Denk W, Kerr JND. Two-photon calcium imaging of evoked activity from L5 somatosensory neurons in vivo. Nat Neurosci 14: 1089–1093, 2011.

Mohajerani MH, McVea DA, Fingas M, Murphy TH. Mirrored Bilateral Slow-Wave Cortical Activity within Local Circuits Revealed by Fast Bihemispheric Voltage-Sensitive Dye Imaging in Anesthetized and Awake Mice. J Neurosci 30: 3745–3751, 2010.

Mölle M, Born J. Slow oscillations orchestrating fast oscillations and memory consolidation. Prog Brain Res 193: 93–110, 2011.

Mukovski M, Chauvette S, Timofeev I, Volgushev M. Detection of active and silent states in neocortical neurons from the field potential signal during slow-wave sleep. Cereb Cortex N Y N 1991 17: 400–414, 2007.

Olcese U, Esser SK, Tononi G. Sleep and synaptic renormalization: a computational study. J Neurophysiol 104: 3476–3493, 2010.

Olcese U, Iurilli G, Medini P. Cellular and synaptic architecture of multisensory integration in the mouse neocortex. Neuron 79: 579–593, 2013.

Pachitariu M, Lyamzin DR, Sahani M, Lesica NA. State-dependent population coding in primary auditory cortex. J Neurosci Off J Soc Neurosci 35: 2058–2073, 2015.

Packer AM, Roska B, Häusser M. Targeting neurons and photons for optogenetics. Nat Neurosci 16: 805–815, 2013.

Pape HC, Driesang RB. Ionic mechanisms of intrinsic oscillations in neurons of the basolateral amygdaloid complex. J Neurophysiol 79: 217–226, 1998.

Paré D, Gaudreau H. Projection cells and interneurons of the lateral and basolateral amygdala: distinct firing patterns and differential relation to theta and delta rhythms in conscious cats. J Neurosci Off J Soc Neurosci 16: 3334–3350, 1996.

Petilla Interneuron Nomenclature Group, Ascoli GA, Alonso-Nanclares L, Anderson SA, Barrionuevo G, Benavides-Piccione R, Burkhalter A, Buzsáki G, Cauli B, Defelipe J, Fairén A, Feldmeyer D, Fishell G, Fregnac Y, Freund TF, Gardner D, Gardner EP, Goldberg JH, Helmstaedter M, Hestrin S, Karube F, Kisvárday ZF, Lambolez B, Lewis DA, Marin O, Markram H, Muñoz A, Packer A, Petersen CCH, Rockland KS, Rossier J, Rudy B, Somogyi P, Staiger JF, Tamas G, Thomson AM, Toledo-Rodriguez M, Wang Y, West DC, Yuste R. Petilla terminology: nomenclature of features of GABAergic interneurons of the cerebral cortex. Nat Rev Neurosci 9: 557–568, 2008.

Polack P-O, Friedman J, Golshani P. Cellular mechanisms of brain state-dependent gain modulation in visual cortex. Nat Neurosci 16: 1331–1339, 2013.

Rancz EA, Franks KM, Schwarz MK, Pichler B, Schaefer AT, Margrie TW. Transfection via whole-cell recording in vivo: bridging single-cell physiology, genetics and connectomics. Nat Neurosci 14: 527–532, 2011.

Rasch B, Büchel C, Gais S, Born J. Odor cues during slow-wave sleep prompt declarative memory consolidation. Science 315: 1426–1429, 2007.

Ros H, Sachdev RNS, Yu Y, Sestan N, McCormick DA. Neocortical networks entrain neuronal circuits in cerebellar cortex. J Neurosci Off J Soc Neurosci 29: 10309–10320, 2009.

Sachidhanandam S, Sreenivasan V, Kyriakatos A, Kremer Y, Petersen CCH. Membrane potential correlates of sensory perception in mouse barrel cortex. Nat Neurosci 16: 1671–1677, 2013.

Safonov LA, Isomura Y, Kang S, Struzik ZR, Fukai T, Câteau H. Near scale-free dynamics in neural population activity of waking/sleeping rats revealed by multiscale analysis. PloS One 5, 2010.

Sakata S, Harris KD. Laminar-dependent effects of cortical state on auditory cortical spontaneous activity. Front Neural Circuits 6: 109, 2012.

Siapas AG, Wilson MA. Coordinated interactions between hippocampal ripples and cortical spindles during slow-wave sleep. Neuron 21: 1123–1128, 1998.

Van Someren EJW, Van Der Werf YD, Roelfsema PR, Mansvelder HD, da Silva FHL. Slow brain oscillations of sleep, resting state, and vigilance. Prog Brain Res 193: 3–15, 2011.

Steriade M. The corticothalamic system in sleep. Front Biosci J Virtual Libr 8: d878–899, 2003.

Steriade M. Grouping of brain rhythms in corticothalamic systems. Neuroscience 137: 1087–1106, 2006.

Steriade M, Nuñez a, Amzica F. A novel slow (< 1 Hz) oscillation of neocortical neurons in vivo: depolarizing and hyperpolarizing components. J Neurosci Off J Soc Neurosci 13: 3252–3265, 1993.

Steriade M, Timofeev I, Grenier F. Natural waking and sleep states: a view from inside neocortical neurons. J Neurophysiol 85: 1969–1985, 2001.

Stosiek C, Garaschuk O, Holthoff K, Konnerth A. In vivo two-photon calcium imaging of neuronal networks. Proc Natl Acad Sci U S A 100: 7319–7324, 2003.

Stroh A, Adelsberger H, Groh A, Rühlmann C, Fischer S, Schierloh A, Deisseroth K, Konnerth A. Making waves: initiation and propagation of corticothalamic Ca2+ waves in vivo. Neuron 77: 1136–1150, 2013.

Takagaki K, Zhang C, Wu J-Y, Lippert MT. Crossmodal propagation of sensory-evoked and spontaneous activity in the rat neocortex. Neurosci Lett 431: 191–196, 2008.

Tan AYY, Chen Y, Scholl B, Seidemann E, Priebe NJ. Sensory stimulation shifts visual cortex from synchronous to asynchronous states. Nature 509: 226–229, 2014.

Taub AH, Lampl I, Okun M. Local Field Potential, Relationship to Membrane Synaptic Potentials [Online]. In: Encyclopedia of Computational Neuroscience, edited by Jaeger D, Jung R. Springer New York, p. 1–8. [29 Jul. 2015].

Timofeev I, Chauvette S. Thalamocortical oscillations: local control of EEG slow waves. Curr Top Med Chem 11: 2457–2471, 2011.

Tononi G, Cirelli C. Sleep function and synaptic homeostasis. Sleep Med Rev 10: 49–62, 2006.

Tononi G, Cirelli C. Sleep and the price of plasticity: from synaptic and cellular homeostasis to memory consolidation and integration. Neuron 81: 12–34, 2014.

Ushimaru M, Kawaguchi Y. Temporal Structure of Neuronal Activity among Cortical Neuron Subtypes during Slow Oscillations in Anesthetized Rats. J Neurosci Off J Soc Neurosci 35: 11988–12001, 2015.

Volgushev M, Chauvette S, Mukovski M, Timofeev I. Precise long-range synchronization of activity and silence in neocortical neurons during slow-wave oscillations [corrected]. J Neurosci Off J Soc Neurosci 26: 5665–5672, 2006.

Volgushev M, Chauvette S, Timofeev I. Long-range correlation of the membrane potential in neocortical neurons during slow oscillation. Prog Brain Res 193: 181–199, 2011.

Vyazovskiy VV, Cirelli C, Pfister-Genskow M, Faraguna U, Tononi G. Molecular and electrophysiological evidence for net synaptic potentiation in wake and depression in sleep. Nat Neurosci 11: 200–208, 2008.

Vyazovskiy VV, Cirelli C, Tononi G. Electrophysiological correlates of sleep homeostasis in freely behaving rats. Prog Brain Res 193: 17–38, 2011a.

Vyazovskiy VV, Faraguna U. Sleep and synaptic homeostasis. Curr Top Behav Neurosci 25: 91–121, 2015.

Vyazovskiy VV, Faraguna U, Cirelli C, Tononi G. Triggering slow waves during NREM sleep in the rat by intracortical electrical stimulation: effects of sleep/wake history and background activity. J Neurophysiol 101: 1921–1931, 2009a.

Vyazovskiy VV, Olcese U, Cirelli C, Tononi G. Prolonged wakefulness alters neuronal responsiveness to local electrical stimulation of the neocortex in awake rats. J Sleep Res 22: 264–271, 2013.

Vyazovskiy VV, Olcese U, Hanlon EC, Nir Y, Cirelli C, Tononi G. Local sleep in awake rats. Nature 472: 443–447, 2011b.

Vyazovskiy VV, Olcese U, Lazimy YM, Faraguna U, Esser SK, Williams JC, Cirelli C, Tononi G. Cortical firing and sleep homeostasis. Neuron 63: 865–878, 2009b.

Vyazovskiy VV, Olcese U, Lazimy YM, Faraguna U, Esser SK, Williams JC, Cirelli C, Tononi G. Cortical firing and sleep homeostasis. Neuron 63: 865–878, 2009c.

Vyazovskiy VV, Olcese U, Tononi G. Investigating Sleep Homeostasis with Extracellular Recording of Multiunit Activity from the Neocortex in Freely Behaving Rats [Online]. In: Neuronal Network Analysis. Springer, p. 237–258. [22 Jun. 2015].

Willadt S, Canepari M, Yan P, Loew LM, Vogt KE. Combined optogenetics and voltage sensitive dye imaging at single cell resolution. Front Cell Neurosci 8: 311, 2014.

Wilson CJ, Sachdev RNS. Intracellular and juxtacellular staining with biocytin. Curr Protoc Neurosci Editor Board Jacqueline N Crawley Al Chapter 1: Unit 1.12, 2004.

Womelsdorf T, Valiante TA, Sahin NT, Miller KJ, Tiesinga P. Dynamic circuit motifs underlying rhythmic gain control, gating and integration. Nat Neurosci 17: 1031–1039, 2014.

Yazaki-Sugiyama Y, Kang S, Câteau H, Fukai T, Hensch TK. Bidirectional plasticity in fast-spiking GABA circuits by visual experience. Nature 462: 218–221, 2009.

Zagha E, Casale AE, Sachdev RNS, McGinley MJ, McCormick DA. Motor cortex feedback influences sensory processing by modulating network state. Neuron 79: 567–578, 2013.

Zhang S, Xu M, Kamigaki T, Hoang Do JP, Chang W-C, Jenvay S, Miyamichi K, Luo L, Dan Y. Selective attention. Long-range and local circuits for top-down modulation of visual cortex processing. Science 345: 660–665, 2014.



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