We recently identified neurons in the cerebral cortex that become activated during sleep episodes with high slow-wave activity (SWA). The distinctive properties of these neurons are the ability to produce nitric oxide and their long-range projections within the cortex. In this review, we discuss how these characteristics of sleep-active cells could be relevant to SWA production in the cortex. We also discuss possible models of the role of nNOS cells in SWA production.
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Achermann P, Borbely AA. Dynamics of EEG slow wave activity during physiological sleep and after administration of benzodiazepine hypnotics. Hum. Neurobiol. 1987; 6: 203–10.
Borbély AA, Achermann P. Sleep homeostasis and models of sleep regulation. In: Kryger MH, Roth T, Dement WC, eds. Principles and Practice of Sleep Medicine. W.B. Saunders Co.: Philadelphia, 2000; 377–90.
Tononi G, Cirelli C. Sleep function and synaptic homeostasis. Sleep Med. Rev. 2006; 10: 49–62.
Walsh JK, Randazzo AC, Stone K et al. Tiagabine is associated with sustained attention during sleep restriction: evidence for the value of slow-wave sleep enhancement? Sleep 2006; 29: 433–43.
Huber R, Ghilardi MF, Massimini M, Tononi G. Local sleep and learning. Nature 2004; 430 (6995): 78–81.
Birtoli B, Ulrich D. Firing mode-dependent synaptic plasticity in rat neocortical pyramidal neurons. J. Neurosci. 2004; 24 (21): 4935–40.
Benington JH, Heller HC. Restoration of brain energy metabolism as the function of sleep. Prog. Neurobiol. 1995; 45: 347–60.
Dhand R, Sohal H. Good sleep, bad sleep! The role of daytime naps in healthy adults. Curr. Opin. Pulm. Med. 2006; 12: 379–82.
Tasali E, Leproult R, Ehrmann DA, Van Cauter E. Slowwave sleep and the risk of type 2 diabetes in humans. Proc. Natl. Acad. Sci. U. S. A. 2008; 105 (3): 1044–9.
Llinas R, Urbano FJ, Leznik E, Ramirez RR, van Marle HJ. Rhythmic and dysrhythmic thalamocortical dynamics: GABA systems and the edge effect. Trends. Neurosci. 2005; 28: 325–33.
Steriade M, Amzica F. Coalescence of sleep rhythms and their chronology in corticothalamic networks. Sleep Res. Online. 1998; 1 (1): 1–10.
Destexhe A, Contreras D. Neuronal computations with stochastic network states. Science 2006; 314 (5796): 85–90.
Steriade M, Dossi RC, Nunez A. Network modulation of a slow intrinsic oscillation of cat thalamocortical neurons implicated in sleep delta waves: cortically induced synchronization and brainstem cholinergic suppression. J. Neurosci. 1991; 11 (10): 3200–17.
Rey M, Bastuji H, Garcia-Larrea L, Guillemant P, Mauguiere F, Magnin M. Human thalamic and cortical activities assessed by dimension of activation and spectral edge frequency during sleep wake cycles. Sleep 2007; 30 907–12.
Magnin M, Rey M, Bastuji H, Guillemant P, Mauguiere F, Garcia-Larrea L. Thalamic deactivation at sleep onset precedes that of the cerebral cortex in humans. Proc. Natl. Acad. Sci. U. S. A. 2010; 107 (8): 3829–33.
Velly LJ, Rey MF, Bruder NJ et al. Differential dynamic of action on cortical and subcortical structures of anesthetic agents during induction of anesthesia. Anesthesiology 2007; 107: 202–12.
Steriade M, Nunez A, Amzica F. Intracellular analysis of relations between the slow (?1 Hz) neocortical oscillation and other sleep rhythms of the electroencephalogram. J. Neurosci. 1993; 13 (8): 3266–83.
Hoffman GE, Lyo D. Anatomical markers of activity in neuroendocrine systems: are we all “fosed out”? J. Neuroendocrinol. 2002; 14: 259–68.
Gerashchenko D, Wisor JP, Burns D et al. Identification of a population of sleep-active cerebral cortex neurons. Proc. Natl. Acad. Sci. U. S. A. 2008; 105 (29): 10227–32.
Pasumarthi R, Gershchenko D, Kilduff TS. Further characterization of sleep-active nNOS neurons in the mouse brain. Neuroscience 2010; 169 (1): 149–57.
Tobler I, Jaggi K. Sleep and EEG spectra in the Syrian hamster (Mesocricetus auratus) under baseline conditions and following sleep deprivation. J. Comp. Physiol. [A] 1987; 161: 449–59.
Ayers NA, Kapas L, Krueger JM. Circadian variation of nitric oxide synthase activity and cytosolic protein levels in rat brain. Brain Res. 1996; 707: 127–30.
Hilbig H, Punkt K. 24-hour rhythmicity of NADPHdiaphorase activity in the neuropil of rat visual cortex. Brain Res. Bull. 1997; 43: 337–40.
Clement P, Gharib A, Cespuglio R, Sarda N. Changes in the sleep-wake cycle architecture and cortical nitric oxide release during ageing in the rat. Neuroscience 2003; 116 (3): 863–70.
Clement P, Sarda N, Cespuglio R, Gharib A. Changes occurring in cortical NO release and brain NO-synthases during a paradoxical sleep deprivation and subsequent recovery in the rat. J. Neurochem. 2004; 90 (4): 848–56.
Cespuglio R, Debilly G, Burlet S. Cortical and pontine variations occurring in the voltammetric no signal throughout the sleep-wake cycle in the rat. Arch. Ital. Biol. 2004; 142 (4): 551–6.
Marino J, Cudeiro J. Nitric oxide-mediated cortical activation: a diffuse wake-up system. J. Neurosci. 2003; 23 (10): 4299–307.
Iadecola C. Regulation of the cerebral microcirculation during neural activity: is nitric oxide the missing link? Trends. Neurosci. 1993; 16: 206–14.
Estrada C, DeFelipe J. Nitric oxide-producing neurons in the neocortex: morphological and functional relationship with intraparenchymal microvasculature. Cereb. Cortex 1998; 8: 193–203.
Kitaura H, Uozumi N, Tohmi M et al. Roles of nitric oxide as a vasodilator in neurovascular coupling of mouse somatosensory cortex. Neurosci. Res. 2007; 59 160–71.
Kara P, Friedlander MJ. Dynamic modulation of cerebral cortex synaptic function by nitric oxide. Prog. Brain Res. 1998; 118: 183–98.
Wakatsuki H, Gomi H, Kudoh M et al. Layer-specific NO dependence of long-term potentiation and biased NO release in layer V in the rat auditory cortex. J. Physiol. 1998; 513 (Pt 1): 71–81.
O’Donnell P, Grace AA. Cortical afferents modulate striatal gap junction permeability via nitric oxide. Neuroscience 1997; 76 (1): 1–5.
Strata F, Atzori M, Molnar M, Ugolini G, Berretta N, Cherubini E. Nitric oxide sensitive depolarizationinduced hyperpolarization: a possible role for gap junctions during development. Eur. J. Neurosci. 1998; 10 (1): 397–403.
Garthwaite J. Glutamate, nitric oxide and cell-cell signalling in the nervous system. Trends. Neurosci. 1991; 14 (2): 60–7.
Stamler JS, Simon DI, Osborne JA et al. S-nitrosylation of proteins with nitric oxide: synthesis and characterization of biologically active compounds. Proc. Natl. Acad. Sci. U. S. A. 1992; 89 (1): 444–8.
Schuman EM, Madison DV. Nitric oxide and synaptic function. Annu. Rev. Neurosci. 1994; 17: 153–83.
Gally JA, Montague PR, Reeke GN Jr, Edelman GM. The NO hypothesis: possible effects of a short-lived, rapidly diffusible signal in the development and function of the nervous system. Proc. Natl. Acad. Sci. U. S. A. 1990; 87 (9): 3547–51.
Jansson A, Mazel T, Andbjer B et al. Effects of nitric oxide inhibition on the spread of biotinylated dextran and on extracellular space parameters in the neostriatum of the male rat. Neuroscience 1999; 91 (1): 69–80.
Gelperin A. Nitric oxide mediates network oscillations of olfactory interneurons in a terrestrial mollusc. Nature 1994; 369 (6475): 61–3.
Garthwaite J, Boulton CL. Nitric oxide signaling in the central nervous system. Annu. Rev. Physiol. 1995; 57 683–706.
Chen L, Majde JA, Krueger JM. Spontaneous sleep in mice with targeted disruptions of neuronal or inducible nitric oxide synthase genes. Brain Res. 2003; 973 (2): 214–22.
Aeschbach D, Cajochen C, Landolt H, Borbely AA. Homeostatic sleep regulation in habitual short sleepers and long sleepers. Am. J. Physiol. 1996; 270 (1 Pt 2): R41–R53.
Chen L, Taishi P, Majde JA, Peterfi Z, Obal F Jr, Krueger JM. The role of nitric oxide synthases in the sleep responses to tumor necrosis factor-alpha. Brain Behav. Immun. 2004; 18 (4): 390–8.
Obal FJ, Krueger JM. Biochemical regulation of nonrapid- eye-movement sleep. Front. Biosci. 2003; 8: D520–D550.
Takahashi S, Kapas L, Krueger JM. A tumor necrosis factor (TNF) receptor fragment attenuates TNF-alphaand muramyl dipeptide-induced sleep and fever in rabbits. J. Sleep Res. 1996; 5 (2): 106–14.
Takahashi S, Kapas L, Seyer JM, Wang Y, Krueger JM. Inhibition of tumor necrosis factor attenuates physiological sleep in rabbits. Neuroreport 1996; 7 (2): 642–6.
Takahashi S, Krueger JM. Inhibition of tumor necrosis factor prevents warming-induced sleep responses in rabbits. Am. J. Physiol. 1997; 272 (4 Pt 2): R1325–R1329.
Murphy M, Riedner BA, Huber R, Massimini M, Ferrarelli F, Tononi G. Source modeling sleep slow waves. Proc. Natl. Acad. Sci. U. S. A. 2009; 106 (5): 1608–13.
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. 2010; 30 (10): 3745–51.
DeFelipe J, Farinas I. The pyramidal neuron of the cerebral cortex: morphological and chemical characteristics of the synaptic inputs. Prog. Neurobiol. 1992; 39 (6): 563–607.
McDonald CT, Burkhalter A. Organization of long-range inhibitory connections with rat visual cortex. J. Neurosci. 1993; 13 (2): 768–81.
Fabri M, Manzoni T. Glutamate decarboxylase immunoreactivity in corticocortical projecting neurons of rat somatic sensory cortex. Neuroscience 1996; 72 (2): 435–48.
Aroniadou-Anderjaska V, Keller A. Intrinsic inhibitory pathways in mouse barrel cortex. Neuroreport 1996; 7 (14): 2363–8.
Albus K, Wahle P. The topography of tangential inhibitory connections in the postnatally developing and mature striate cortex of the cat. Eur. J. Neurosci. 1994; 6 (5): 779–92.
Peters A, Payne BR, Josephson K. Transcallosal nonpyramidal cell projections from visual cortex in the cat. J. Comp. Neurol. 1990; 302 (1): 124–42.
Gonchar YA, Johnson PB, Weinberg RJ. GABAimmunopositive neurons in rat neocortex with contralateral projections to S-I. Brain Res. 1995; 697 (1–2): 27–34.
Kimura F, Baughman RW. GABAergic transcallosal neurons in developing rat neocortex. Eur. J. Neurosci. 1997; 9: 1137–43.
Tomioka R, Okamoto K, Furuta T et al. Demonstration of long-range GABAergic connections distributed throughout the mouse neocortex. Eur. J. Neurosci. 2005; 21 (6): 1587–600.
Higo S, Udaka N, Tamamaki N. Long-range GABAergic projection neurons in the cat neocortex. J. Comp. Neurol. 2007; 503: 421–31.
Tomioka R, Rockland KS. Long-distance corticocortical GABAergic neurons in the adult monkey white and gray matter. J. Comp. Neurol. 2007; 505: 526–38.
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. 2006; 26 (21): 5665–72.
Chauvette S, Volgushev M, Timofeev I. Origin of active states in local neocortical networks during slow sleep oscillation. Cereb. Cortex 2010; 20 (11): 2660–74.
Jones BE. Activity, modulation and role of basal forebrain cholinergic neurons innervating the cerebral cortex. Prog. Brain Res. 2004; 145: 157–69.
McCarley RW. Neurobiology of REM and NREM sleep. Sleep Med. 2007; 8 (4): 302–30.
Fujitani Y, Urade Y, Hayaishi O. [Sleep-promoting substances]. Nippon Ronen Igakkai Zasshi 1998; 35 (11): 811–16.
Kilduff TS, Cauli B, Gershchenko D. Activation of cortical interneurons during sleep: an anatomical link to sleep homeostasis? Trends. Neurosci. 2010 (in press).
Llinas RR, Steriade M. Bursting of thalamic neurons and states of vigilance. J. Neurophysiol. 2006; 95 (6): 3297–308.
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Gerashchenko, D., Wisor, J.P. & Kilduff, T.S. Sleep-active cells in the cerebral cortex and their role in slow-wave activity. Sleep Biol. Rhythms 9 (Suppl 1), 71–77 (2011). https://doi.org/10.1111/j.1479-8425.2010.00461.x