title: Sleep: a synchrony of cell activity-driven small network states.
abstract: We posit a bottom-up sleep-regulatory paradigm in which state changes are initiated within small networks as a consequence of local cell activity. Bottom-up regulatory mechanisms are prevalent throughout nature, occurring in vastly different systems and levels of organization. Synchronization of state without top-down regulation is a fundamental property of large collections of small semi-autonomous entities. We posit that such synchronization mechanisms are sufficient and necessary for whole-organism sleep onset. Within the brain we posit that small networks of highly interconnected neurons and glia, for example cortical columns, are semi-autonomous units oscillating between sleep-like and wake-like states. We review evidence showing that cells, small networks and regional areas of the brain share sleep-like properties with whole-animal sleep. A testable hypothesis focused on how sleep is initiated within local networks is presented. We posit that the release of cell activity-dependent molecules, such as ATP and nitric oxide, into the extracellular space initiates state changes within the local networks where they are produced. We review mechanisms of ATP induction of sleep-regulatory substances and their actions on receptor trafficking. Finally, we provide an example of how such local metabolic and state changes provide mechanistic explanations for clinical conditions, such as insomnia.
authors: Sleep and Performance Research Center, Washington State University, Pullman, WA, USA. krueger@vetmed.wsu.edu
authors: James M
authors: JM
authors: Krueger
authors: Yanhua H
authors: YH
authors: Huang
authors: David M
authors: DM
authors: Rector
authors: Daniel J
authors: DJ
authors: Buysse
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism / Q000502:physiology; D000818:Animals; D058256:Brain Waves / Q000502:physiology*; D006801:Humans; D009415:Nerve Net / Q000502:physiology*; D009457:Neuroglia / Q000502:physiology*; D009474:Neurons / Q000502:physiology*; D009569:Nitric Oxide / Q000378:metabolism; D011956:Receptors, Cell Surface; D012890:Sleep / Q000502:physiology*
chemical_list: D011956:Receptors, Cell Surface; D009569:Nitric Oxide; D000255:Adenosine Triphosphate
keywords: ATP; brain imaging; cerebral blood flow; cytokine; receptor
references: Curr Pharm Des. 2008;14(32):3408-16
references: 19075717
references: Curr Biol. 2011 Mar 8;21(5):R183-4
references: 21377092
references: Neuroscience. 2008 Sep 22;156(1):71-80
references: 18694809
references: Trends Cogn Sci. 2010 Apr;14(4):180-90
references: 20206576
references: J Neurosci. 2011 Mar 23;31(12):4466-74
references: 21430147
references: Neuron. 2009 Feb 12;61(3):454-66
references: 19217381
references: Nature. 2005 Oct 27;437(7063):1257-63
references: 16251950
references: Psychosom Med. 2000 Jul-Aug;62(4):474-82
references: 10949091
references: Cell. 2008 Oct 31;135(3):422-35
references: 18984155
references: Nat Neurosci. 2008 Feb;11(2):200-8
references: 18204445
references: Sleep. 2002 Sep 15;25(6):630-40
references: 12224842
references: Brain Res. 2003 May 30;973(2):293-7
references: 12738073
references: Neuron. 2012 Sep 20;75(6):1105-13
references: 22998877
references: Neurobiol Dis. 2002 Oct;11(1):199-213
references: 12460558
references: Am J Physiol. 1999 Jun;276(6):R1812-8
references: 10362764
references: Nature. 2011 Apr 28;472(7344):443-7
references: 21525926
references: Neuroimage. 2005 Oct 15;28(1):14-21
references: 15979343
references: Nat Rev Neurosci. 2009 Mar;10(3):199-210
references: 19209176
references: Brain Res. 2011 Oct 28;1420:1-7
references: 21962531
references: Nature. 2006 Apr 20;440(7087):1054-9
references: 16547515
references: BMC Neurosci. 2010 Feb 09;11:17
references: 20144235
references: J Appl Physiol (1985). 2010 Nov;109(5):1318-27
references: 20829501
references: Science. 2007 Jan 19;315(5810):393-5
references: 17234951
references: Alcohol Clin Exp Res. 1998 Nov;22(8):1796-802
references: 9835298
references: J Neurosci. 2011 Mar 16;31(11):3953-61
references: 21411638
references: J Neurosci. 2006 Nov 29;26(48):12456-65
references: 17135407
references: J Neurochem. 2000 Sep;75(3):965-72
references: 10936177
references: J Immunol. 2006 Apr 1;176(7):3877-83
references: 16547218
references: J Clin Neurophysiol. 1998 Mar;15(2):159-66
references: 9563584
references: Behav Brain Res. 1994 Aug 31;63(2):111-26
references: 7999294
references: Int J Neural Syst. 2007 Apr;17(2):87-103
references: 17565505
references: Sleep. 2007 Apr;30(4):389-400
references: 17520783
references: J Sleep Res. 2010 Jun;19(2):280-8
references: 20050994
references: Brain Res Bull. 2003 Dec 15;62(2):143-50
references: 14638388
references: Drug Discov Today Dis Models. 2011 Winter;8(4):129-137
references: 22081772
references: Am J Physiol Regul Integr Comp Physiol. 2000 Aug;279(2):R404-13
references: 10938226
references: Sleep. 2010 Jul;33(7):919-29
references: 20614852
references: Science. 2010 Nov 12;330(6006):932
references: 21071660
references: Neuron. 2003 Oct 9;40(2):361-79
references: 14556714
references: Neurology. 2003 Jul 8;61(1):40-5
references: 12847154
references: Sleep. 2005 Feb;28(2):177-84
references: 16171241
references: J Biol Chem. 2001 Jan 5;276(1):125-32
references: 11016935
references: Adv Genet. 2011;74:175-230
references: 21924978
references: Brain Cell Biol. 2006 Jun;35(2-3):187-201
references: 17957483
references: Brain Res. 2012 Mar 9;1442:76-89
references: 22322149
references: Sleep. 1989 Feb;12(1):13-21
references: 2928622
references: Neuron. 2009 Sep 24;63(6):865-78
references: 19778514
references: Physiol Rev. 2007 Apr;87(2):659-797
references: 17429044
references: J Neurosci. 2005 Jan 19;25(3):680-8
references: 15659605
references: Nat Rev Neurosci. 2008 Dec;9(12):910-9
references: 18985047
references: Nature. 2006 Nov 30;444(7119):610-3
references: 17086200
references: J Neurosci. 2010 Jun 23;30(25):8671-5
references: 20573912
references: Brain Res. 2005 Jun 14;1047(1):45-55
references: 15882842
references: J Cell Physiol. 2009 Jan;218(1):35-44
references: 18767039
references: Brain. 2006 Mar;129(Pt 3):564-83
references: 16399806
references: Ann N Y Acad Sci. 2008;1129:119-29
references: 18591474
references: Proc Natl Acad Sci U S A. 2011 Sep 13;108 Suppl 3:15609-16
references: 21852576
references: J Neurosci. 2004 Jan 7;24(1):1-7
references: 14715932
references: Curr Top Med Chem. 2011;11(19):2392-402
references: 21906025
references: Neurosci Biobehav Rev. 2009 Mar;33(3):279-96
references: 18824195
references: Life Sci. 1997;60(8):555-64
references: 9042390
references: J Theor Biol. 2008 Aug 7;253(3):462-8
references: 18511082
references: Neuron. 2011 Mar 10;69(5):988-1001
references: 21382557
references: Proc Natl Acad Sci U S A. 2007 Jul 31;104(31):12843-8
references: 17646651
references: Eur J Neurosci. 2004 Jul;20(1):207-16
references: 15245493
references: J Neurosci. 2003 Oct 22;23(29):9687-95
references: 14573548
references: Sleep. 2011 Nov 01;34(11):1527-37
references: 22043124
references: Novartis Found Symp. 2006;276:26-48; discussion 48-57, 275-81
references: 16805422
references: Brain. 2007 Nov;130(Pt 11):2770-88
references: 17412731
references: Ann N Y Acad Sci. 2010 Jan;1184:15-54
references: 20146689
references: Brain Res. 1982 May 6;239(1):81-105
references: 7093693
references: Prog Brain Res. 2011;193:17-38
references: 21854953
references: Neuron. 2001 Apr;30(1):275-87
references: 11343661
references: Behav Brain Res. 2009 Jan 30;197(1):16-23
references: 18718491
references: Brain Res Rev. 2008 Nov;59(1):221-44
references: 18722470
references: Eur J Neurosci. 2003 Sep;18(5):1041-9
references: 12956704
references: Sleep. 2009 Mar;32(3):409-12
references: 19294961
references: Brain Res. 2004 May 29;1009(1-2):129-36
references: 15120590
references: Psychopharmacology (Berl). 2004 Mar;172(3):241-7
references: 14598017
references: Eur J Neurosci. 2007 Oct;26(7):1862-9
references: 17868373
references: Sleep Med Rev. 2012 Feb;16(1):67-81
references: 21620743
references: Ann N Y Acad Sci. 2008;1129:275-86
references: 18591488
references: J Neurochem. 1998 May;70(5):1876-86
references: 9572271
references: J Sleep Res. 2010 Sep;19(3):478-86
references: 20149068
references: Brain Res. 2010 May 28;1333:48-56
references: 20338152
references: Sleep. 2010 Dec;33(12):1589-603
references: 21120121
references: Cereb Cortex. 2011 Jan;21(1):115-23
references: 20421251
references: J Clin Sleep Med. 2006 Jul 15;2(3):316-22
references: 17561544
references: Front Biosci. 2003 May 01;8:s438-51
references: 12700104
references: Prog Brain Res. 2010;185:49-68
references: 21075233
references: Nature. 2008 Jul 3;454(7200):118-21
references: 18500330
references: Neuron. 2004 Sep 30;44(1):121-33
references: 15450165
references: Nature. 2005 Oct 27;437(7063):1279-85
references: 16251953
references: J Immunol. 2005 Jun 1;174(11):7268-77
references: 15905573
references: J Neurosci. 2000 Dec 15;20(24):9187-94
references: 11124996
references: Brain. 2002 Oct;125(Pt 10):2308-19
references: 12244087
references: J Sleep Res. 2000 Sep;9(3):207-31
references: 11012860
references: Brain Res. 2007 Feb 2;1131(1):44-59
references: 17184753
references: J Neurosci. 2011 Mar 9;31(10):3712-8
references: 21389226
references: Sleep Med Rev. 2003 Jun;7(3):203-14
references: 12927120
references: Brain Res. 1994 Nov 21;664(1-2):189-96
references: 7534601
references: J Neurosci. 2008 Apr 9;28(15):4088-95
references: 18400908
references: Neurotox Res. 2010 Nov;18(3-4):393-409
references: 20361291
references: Brain Res. 2007 Jul 2;1156:125-32
references: 17531209
references: Cell. 2007 Oct 5;131(1):160-73
references: 17923095
references: Behav Sleep Med. 2011;9(1):5-14
references: 21218289
references: J Neuroimmunol. 2007 Nov;191(1-2):16-25
references: 17904645
references: Eur J Neurosci. 2009 May;29(9):1771-8
references: 19473232
references: Proc Natl Acad Sci U S A. 2005 Dec 27;102(52):19150-5
references: 16380429
references: Am J Psychiatry. 2004 Nov;161(11):2126-8
references: 15514418
references: Science. 2002 Mar 22;295(5563):2282-5
references: 11910117
references: Am J Physiol. 1999 May;276(5):R1334-8
references: 10233024
references: J Physiol. 2007 Jan 15;578(Pt 2):471-9
references: 17082228
references: Neuroreport. 1997 Jul 28;8(11):2557-60
references: 9261826
references: Nature. 1996 Sep 12;383(6596):163-6
references: 8774879
references: Nat Rev Neurosci. 2007 Sep;8(9):700-11
references: 17704812
references: Brain Res Bull. 2010 Oct 30;83(5):245-54
references: 20619322
references: J Physiol. 2006 Feb 1;570(Pt 3):553-65
references: 16322058
references: Ann N Y Acad Sci. 2008 Mar;1124:1-38
references: 18400922
references: J Immunol. 2001 Oct 1;167(7):4026-32
references: 11564822
references: J Neurosci. 1997 Jun 15;17(12):4800-8
references: 9169538
references: J Clin Endocrinol Metab. 2004 Sep;89(9):4409-13
references: 15356039
references: J Sleep Res. 1993 Jun;2(2):63-69
references: 10607073
references: J Sleep Res. 1993 Dec;2(4):224-231
references: 10607098
references: Semin Arthritis Rheum. 1999 Dec;29(3):172-81
references: 10622681
references: Electroencephalogr Clin Neurophysiol. 1949 Aug;1(3):265-72
references: 18135418
references: Lancet. 2000 Aug 5;356(9228):484-5
references: 10981896
references: Pharmacol Biochem Behav. 2009 Dec;94(2):262-70
references: 19751755
references: Sleep. 2009 Sep;32(9):1191-200
references: 19750924
references: J Neurosci. 2012 Sep 5;32(36):12506-17
references: 22956841
references: Alcohol. 1986 Nov-Dec;3(6):377-81
references: 3814349
references: Am J Psychiatry. 2004 Jul;161(7):1197-203
references: 15229051
references: Mol Cell Biol. 2006 Oct;26(19):7283-98
references: 16980629
references: Neuron. 2009 Jan 29;61(2):213-9
references: 19186164
references: Neurosci Biobehav Rev. 2007;31(5):775-824
references: 17445891
references: J Neurosci. 2004 May 26;24(21):4935-40
references: 15163685
references: Front Biosci. 2003 May 01;8:d878-99
references: 12700074