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sleep: An unusual form o f m am m alian sleep // Neuroscience and Biobehavioral Reviews. 2008. V. 32. P. 1451- 1484.
R o tenberg V. S., K obrin V. I. The structure o f night sleep and cardiac rhythm in
patients suffering for m any years from hypo- and akinesia // Activ. nerv.
sup. 1985. V. 27. P. 179-185.
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. 62-71.
Basheer R., Strecker R. ., Thakkar . ., McCarley R. W. Adenosine and sleepwake regulation// Progress in Neurobiology. 2004. V. 73. P. 379-396.
Bassetti C. L., Bischof ., Valko P. Dreaming: a neurological view // Psycho
analysis and Neuroscience / Ed. M. Mancia. Springer: Milan, 2006.
P. 351-387.
42
B lanco-C enturion . et al. Adenosine and sleep homeostasis in the basal fore
brain // J. Neurosci. 2006. V. 26. No. 31. P. 8092-8100.
B orbely A. A. et al. (eds.) The regulation o f sleep. Human Frontier Science
Program: Strasbourg, 2000.
D ang- Vu T. 7'., D esseilles A/., P etit D. et al. Neuroimaging in sleep medicine //
Sleep Medicine. 2007. V. 8. P. 349-372.
D atta S ., M acLean R. R. Neurobiological m echanism s for the regulation o f
m am m alian sleep-w ake behavior: Reinterpretation o f historical evidence
and inclusion o f contemporary cellular and m olecular evidence // Neuro
science and Biobehavioral Reviews. 2007. V. 31. P. 775-824.
D o m h o ff G. W. Foundations for a new neurocognitive theory o f dream s //
Front. Neurosci. 2009. V. 3. No. 3. P. 439.
E spana R .A ., ScammeU . E. Sleep neurobiology for the clinician // Sleep.
2004. V. 27. No. 4. P. 811-820.
F ort P ., B assetti C. L., Luppi P.-H. Alternating vigilance states: new insights
regarding neuronal networks and m echanism s // European Journal o f N eu
roscience. 2009. V. 29. P. 1741-1753.
Gottesmann C. Brain inhibitory mechanisms involved in basic and higher inte
grated sleep processes // Brain Research Reviews. 2004. V. 45. P. 2 3 0 - 249.
H uang Z.-L., Grade ., H ayaishi O. Prostaglandins and adenosine in the re g u
lation o f sleep and wakefulness // Current Opinion in Pharmacology. 2007.
V. 7. P. 33-38.
Jo n es . E. Activity, m odulation and role o f basal forebrain cholinergic neu
rons innervating the cerebral cortex // Prog. Brain Res. 2004. V. 145.
P . 157-169.
Jo n es . E. Arousal systems // Frontiers in Bioscience. 2003. V. 8. Suppl.
P. 4 38 -45 1.
Jo n es . E. Basic m echanism s o f sleep-wrake states // Principles and Practice
o f Sleep Medicine, 4th ed. / Kryger . H., Roth ., Dem ent W. C., eds.
Elsevier: Am sterdam, 2005a. P. 136-153.
Jo n es . E. From waking to sleeping: neuronal and chemical substrates //
Trends in Pharm acological Sciences. 2005b. V. 26. No. 11. P. 578-586.
Jo n es . E. Modulation o f cortical activation and behavioral arousal by ch o
linergic and orexinergic s y s te m s / / Ann. N.Y. Acad. Sci. 2008. V. 1129.
P. 2 6-3 4.
Landolt H.-P. Sleep homeostasis: A role for adenosine in hum ans? // Bioche
mical Phannacology. 2008. V. 75. P. 2070-2079.
L u J ., Sherman D ., D ev o r ., S a p er . B. A putative flip-flop switch for con
trol o f REM sleep. Nature. 2006. V. 441. No. 7093. P. 589-594.
M cC arley R. W. Neurobiology o f REM and NREM sleep // Sleep Medicine.
2007. V. 8. P. 302-330.
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s y s te m s // Cell. Mol. Life Sci. 2008. V. 65. P. 1475-1488.
Baum ann C. R ., B assetti C. L. Hypocretins (orexins): clinical impact o f the
discovery o f a neurotransm itter II Sleep M edicine Reviews. 2005. V. 9.
P. 25 3-268.
67
68
S ieg el J. M. Narcolepsy II Scientific American. 2000. V. 282. P. 76-81.
Torterolo P S a m p o g n a S., M orales F. R., Chase . . M CH-containing
neurons in the hypothalam us o f the cat: Searching for a role in the control
o f sleep and wakefulness // Brain Research. 2006. V. 1119. No. 1.
P. 101-114.
W urtman R .J . Narcolepsy and the hypocretins // Metabolism. Clinical and
Experimental. 2006. V. 55. Suppl 2. P. 36-39.
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A dam antidis ., de Lecea L. Physiological arousal: a role for hypothalamic
systems // Cell. Mol. Life Sci. 2008. V. 65. P. 1475-1488.
A ton S .J ., H erzog E. D. C om e together, right ... now: synchronization o f
rhythm s in a m am m alian circadian clock // Neuron. 2005. V. 48. No. 4.
P. 531-534.
B e n lo u e if S., Zee P. C. Suprachiasmatic nucleus (SCN) // Encyclopedia o f
the Neurological Sciences. 2003. Elsevier Science (USA). P. 446^447.
F ield M. D. et al. Analysis o f clock proteins in mouse SCN demonstrates phy
logenetic divergence o f the circadian clockw ork and resetting m echa
nism s // Neuron. 2000. V .2 5 . No. 2. P. 4 37 -44 7.
F uller P. M ., G ooley J. .7., S a p er . B. Neurobiology o f the sleep-wake cycle:
sleep architecture, circadian regulation, and regulatory feed b ack // Journal
o f Biological Rhythms. 2006. V. 21. No. 6. P. 4 82-493 .
G illette M. U ., Sabra M.A. Fundam entals o f the Circadian System // SRS Ba
sics o f Sleep Guide / Eds. Am laner C. J., Buxton . M. Sleep Research
Society, Westchester, 1L, 2007. P. 131-140.
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C ajochen ., K rduchi ., Wurtz-.Justice A. The acute soporific action o f day
time melatonin administration: effects on the EEG during wakefulness and
subjective alertness // J. Biol. Rhythms. 1997. V. 2. No. 6. P. 636-643.
C zeisler C., Turek F. W ., eds. M elatonin, Sleep and Circadian Rhythms: cur
rent progress and controversies // J. Biol. Rhythms. 1997. V. 12. No. 6.
P. 4 8 5 -7 1 4 .
D escam ps A. et al. Influence o f the novel antidepressant and melatonin agonist/serotonin2C receptor antagonist, agomelatine, on the rat sleep-w ake
cycle architecture // Psychopharmacology. 2009. V. 205. P. 93-106.
110
D ijk D .-J., C ajochen . Melatonin and the circadian regulation o f sleep initia
tion, consolidation, structure, and the sleep EEG / / J. Biol. Rhythms. 1997.
V. 2. No. 6. P. 627-635.
F oulkes N. S. et al. Rhythmic transcription: the molecular basis o f circadian
m elatonin synthesis // Trends Neurosci. 1997. V. 20. P. 487-492.
F raschini F., Stankov B. High affinity melatonin receptors in the vertebrate
brain: implications for the control o f the endogenous oscillatory systems //
Chronobiologia. 1994. V .2 1 . P. 89-92.
H ardeland R., B alzer I., P o eggeler B. et al. O n the primary functions o f mela
tonin in evolution m ediation o f photoperiodic signals in a unicell, ph o
tooxidation, and scavenging o f free-radicals / / J. Pineal Res. 1995. V. 18.
No. 2. P. 104-111.
H olm es S. W., Sugden D. Effects o f melatonin on sleep and neurochemistry
in the rat // Br. J. Pharmac. 1982. V. 76. P. 95-101.
H uber R., D eB oer ., Schw ierin B., Tobler I. Effect o f melatonin on sleep and
brain tem perature in the Djungarian hamster and the rat //Physiol. Behav.
1998. V. 65. No. 1. P. 77-82.
Lan .-., H su J .-C ., L in g .-. Influence o f sleep deprivation coupled with
administration o f melatonin on the ultrastructure o f rat pineal gland // Brain
Research. 2001. V. 910. P. 1-11.
L avie P ., L uboshitzky R. Melatonin: possible role in hum an sleep and repro
duction// Sleep and sleep disorders: from m olecule to behavior // Sleep and
sleep disorders: from molecule to behavior/ Eds. Hayaishi O., inoue S.
Tokyo: Academic Press, 1997. P. 20 9-222.
M a illiet P ., G alloux P ., P oisson D. Comparative effects o f m elatonin, zolpidem and diazepam on sleep, body temperature, blood pressure and heart
rate measured by radiotelem etry in Wistar rats // Psychopharmacology.
2001. V. 156. P. 4 17-42 6.
M arczynski T. J., Yamaguchi N., Ling G. M , Grodzinska L. Sleep induced by
the administration o f melatonin (5-methoxyn-acetyltryptamine) to the hypo
thalamus in unrestrained cats//Experientia. 1964. V. 20. No. 8. P. 4 3 5 -4 3 7 .
M endelson W. B. Efficacy o f melatonin as a hypnotic agent / / J. Biol. Rhythms.
1997. V. 12. No. 6. P. 651-656.
M irm iran A/., P evet P. Effects o f melatonin and 5-methoxytryptamine on
sleep-wake patterns in the male rat//.I. Pineal Res. 1986. V. 3. P. 135-141.
N onno R ., C apsoni S ., Lucini V. et al. Distribution and characterization o f the
melatonin receptors in the hypothalam us and pituitary gland o f three do
m estic ungulates // J. Pineal Res. 1995. V. 18. P. 207-216.
P andi-P erum al S. R. et al. Physiological effects o f melatonin: Role o f mela
tonin receptors and signal transduction pathways // Progress in Neuro
biology. 2008. V. 85. P. 335-353.
111
112
Zhdanova I. F., G eiger D. A ., Schw agerl A. L. et al. Melatonin prom otes sleep
in three species o f diurnal nonhum an primates // Physiol. Behav. 2002.
V. 75. P. 523-529.
Zhdanova I. P., Lynch H . W u r t m a n R. J. Melatonin: a sleep-promoting hor
m one // Sleep. 1997. V. 20. No. . P. 899-907.
Zhdanova I. V., W urtman R. J. Efficacy o f melatonin as a sleep-rpomoting
a g e n t// J. Biol. Rhythms. 1997. V. 12. No. 6. P. 644-650.
Zhdanova I. K, W urtman R. J. The pineal horm one melatonin // Endocri
nology: basic and clinical principles / Eds.: C onn P. ., Melmed S. H um a
na Press: Totowa, N .J ., 1998. P. 279-290.
Z isa p el N. Medications for sleep // Frontiers in Neuroscience. 2009. V. 3.
No. 3. P. 434-435.
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tiers in Bioscience. 2003. V. 8. P. s683-s693.
B orbely A. A ., A cherm ann P. Sleep hom eostasis and models o f sleep regu
lation // Principles and Practice o f Sleep Medicine, 4 th ed. / Kryger . H.,
Roth ., Dem ent W. C., eds. Elsevier: Am sterdam , 2005. P. 4 05 -4 17.
D ijk D .-J., Franken P. Interaction o f sleep homeostasis and circadian rhythmicity: dependent or independent systems? // Principles and Practice
o f Sleep Medicine, 4 th ed. / Kryger . H., Roth ., Dement W. C., eds.
Elsevier: Am sterdam , 2005. P. 4 18 -43 4.
H uber R., Tononi G ., C irelli C. Exploratory behavior, cortical BDNF expres
sion, and sleep hom eostasis // Sleep. 2006. V. 30. No. 2. P. 129-139.
Silver R., L eSauter J. Circadian and homeostatic factors in arousal II Ann.
N.Y. Acad. Sci. 2008. V. 1129. P. 2 63-274.
Tononi G., Cirelli C. Sleep and synaptic homeostasis: a hypothesis // Brain
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A ndretic R. el al. Genetics o f sleep // Annu. Rev. Genet. 2008. V. 42. P. 361
388.
C antero J. L. Sleep-dependent theta oscillations in the hum an hippocam pus
and neocortex // J. Neurosci. 2003. V. 23. P. 10897-10903.
C irelli C. The genetic and m olecular regulation o f sleep: from fruit flies to
hum ans // Nat. Rev. Neurosci. 2009. V. 10. No. 8. P. 549-560.
135
Cirelli ., Tononi G. The search for the m olecular correlates o f sleep and
w a k e fu ln e ss// Sleep M edicine Reviews. 2001. V. 5. No. 5. P. 399-410.
Franken P ., Tafti M. Genetics o f sleep and sleep disorders // Frontiers in
Bioscience. 2003. V. 8. P. 381-397.
K im ura ., W inkelmann J. Genetics o f sleep and sleep disorders // Cell. Mol.
Life Sci. 2007. V. 64. P. 1216-1226.
Koh K. et al. Identification o f SLEEPLESS, a Sleep-Prom oting Factor //
Science. 2008. V.321. P. 372-376.
L inkow ski P. EEG sleep patterns in twins // J. Sleep Res. 1999. Suppl 1.
P. 11-13.
L ow rey P. L., Takahashi J. S. M am m alian circadian biology: elucidating
genome-wide levels o f temporal organization // Annu. Rev. Genom ics
Hum. Genet. 2004. V. 5. V. 407-441.
L ugaresi E. et al. Fatal familial insomnia and dysautonom ia with selective
degeneration o f thalamic nuclei // N. Engl. J. Med. 1986. V. 315. P. 9 9 7 1003.
M ackiew icz M. et al. M acrom olecule biosynthesis a key function o f sleep //
Physiol. Genom ics. 2007. V. 31. No. 8. P. 4 41 -4 57.
M ackiew icz M. et al. M olecular m echanism s o f sleep and wakefulness // Ann.
N.Y. Acad. Sci. 2008. V. 1129. P. 335-349.
M aret S. et al. Homer 1a is a core brain molecular correlate o f sleep loss // Proc.
Natl. Acad. Sci. USA. 2007. V. 104. No. 50. P. 20090-20095.
M aret S. et al. Retinoic acid signaling affects cortical synchrony during sleep //
Science 2005. V. 310. P. 111-113.
M ontagna P. et al. Familial and sporadic fatal insomnia // Lancet Neurol.
2003. V. 2. P. 167-176.
Parchi P. et al. Molecular pathology o f fatal familial insomnia // Brain Patho
logy. 1998. V. 8. P. 539-548.
Porkka-H eiskanen T. Gene expression during sleep, wakefulness and sleep
deprivation // Frontiers in Bioscience. 2003. V. 8. P. 421-437.
R eteyJ. V. et al. A functional genetic variation o f adenosine deaminase affects
the duration and intensity o f deep sleep in hum ans // Proc. Natl. Acad. Sci.
USA. 2005. V. 102. P. 15676-15681.
Tafti M. et al. Deficiency in short-chain fatty acid beta-oxidation affects theta
oscillations during sleep // Nat. Genet. 2003. V. 34. P. 320-5.
W isor J. P ., K ild u ff T. S. M olecular genetic advances in sleep research and
their relevance to sleep medicine //S leep. 2005. V. 28. No. 3. P. 357-367.
W u lff ., P orcheret ., C ussans E., F oster R. G. Sleep and circadian rhythm
disturbances: multiple genes and multiple phenotypes // Current Opinion
in Genetics & Development. 2009. V. 19. P. 1-10.
,
,
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. . 31. ( , ).
., 1986. . 59-110.
A llada R ., S iegel J. . Unearthing the phylogenetic roots o f sleep // Current
Biology. 2008. V. 18. P. R 670-R 679.
Brow n E. R. et al. Brain and behavioural evidence for rest-activity cycles in
Octopus vulgaris // Behavioural Brain Research. 2006. V. 172. P. 355-359.
C apellini I. et al. Phylogenetic analysis o f the ecology and evolution o f m am
malian sleep // Evolution. 2008. V. 62. No. 7. P. 1764-1776.
C irelli C., B ushev D. Sleep and wakefulness in drosophila m elanogaster //
Ann. N.Y. Acad. Sci. 2008. V. 1129. P. 323-329.
C irelli C., Tononi G. Is sleep essential? // PLoS Biol. 2008. V. 6. No. 8.
P. 1605-1611.
E iland . M ., Lyam in O. /., Siegel J. M. State-related discharge o f neurons in
the brainstem o f freely moving box turtles, Terrapene Carolina Major //
Archive ltal. B iol. 20 0 1 . V. 139. P. 2 3 -3 6 .
F rank M. G. Phylogeny and evolution o f Rapid Eye M ovem ent (REM ) sleep //
Rapid Eye Movement Sleep / B. N. Mallick, S. Inoue (Eds.). New Delhi: Narosa, 1999. P. 17-38.
Jouvet M. REM sleep as a genetic program ming system for physiological indi
vidualization // The Regulation o f Sleep / A. A. Borbely et al. (Eds.). Stras
bourg: HFSP, 2000. P. 171-178.
K avanau J. L. Origin and evolution o f sleep: roles o f vision and endotherm y //
Brain Research Bulletin. 1997. V. 42. No. 4. P. 245-264.
K avanau J. L. REM and NREM sleep as natural accom panim ents o f the evolu
tion o f warm -bloodedness // Neuroscience and Biobehavioral Reviews.
2002. V. 26. P. 889-906.
K avanau J. L. Evolutionary approaches to understanding sleep // Sleep M edi
cine Reviews. 2005. V. 9. P. 141-152.
141
K ild u ff . S. What rest in flies can tell us about sleep in m am m als // Neuron.
2000. V. 26. P. 295-298.
L esku J. A. et a l A phylogenetic analysis o f sleep architecture in mammals: the
integration o f anatomy, physiology, and ecology // The A m erican N atu
ralist. 2006. V. 168. No. 4. P. 4 4 1-4 53.
Lesku J. A. et a l Phylogenetics and the correlates o f m am m alian sleep: A re
appraisal // Sleep M edicine Reviews. 2008. V. 12. P. 229-244.
Lesku J. A. et a l History and future o f comparative analyses in sleep research //
Neuroscience and Biobehavioral Reviews. 2009. V. 33. P. 1024-1036.
Lyam in O. I. et al. Cetacean sleep: A n unusual form o f m am m alian sleep //
Neuroscience and Biobehavioral Reviews. 2008. V. 32. P. 1451-1484.
Lyam in O. /., E ila n d . M , Siegel J. M . Polygraphic and neuronal correlates
o f sleep in freely moving turtles // Sleep. 2002. V. 25. Abstract Suppl.
P. A159.
N icol S. ., A ndersen N. A ., P hillips N. //., B erg er R. J. The echidna manifests
typical characteristics o f rapid eye m ovem ent sleep // Neurosci. Lett. 2000.
V. 283. P. 4 9 - 5 2 .
N icolau . C. et al. Why we sleep: the evolutionary pathway to the m am
malian sleep // Progress in Neurobiology. 2000. V. 62. P. 379-406.
N itz D. A. et a l Electrophysiological correlates o f rest and activity in droso
phila melanogaster // Current Biology. 2002. V. 12. P. 1934-1940.
P enny G., H asegaw a M. The platypus put in its place // Nature. 1997. V. 387.
P. 5 4 9 -5 5 0 .
R attenborg N. C. Evolution o f slow-wave sleep and pall iopallial connectivity
in m am m als and birds: A hypothesis // Brain Research Bulletin. 2006.
V. 69. No 1. P. 2 0-29 .
R attenborg N. C. Avian sleep homeostasis: Convergent evolution o f com plex
brains, cognition and sleep functions in m am mals and birds // Neurosci
ence and Biobehavioral Reviews. 2009. V. 33. P. 25 3-270.
R ial P. K, N icolau . C., G am undi A. et a l The evolution o f waking state //
Sleep and Sleep Disorders: from Molecule to Behavior / O. Hayaishi, S. Inoue
(Eds.). Tokyo: Academ ic Press. 1997. P. 99-112.
R ial P. V., N icolau . ., G am undi A. et a l The trivial function o f sleep //
Sleep M edicine Reviews. 2007. V. 11. P. 31 1-325.
R ial R., N icolau . C., Lopez-G arcia ./. A ., A lm irall H. On the evolution o f
waking and sleeping // Comp. Biochem. Physiol. A. 1993. V. 104. 2.
P. 189-193.
R ial R. V. et al. Evolution o f wakefulness, sleep and hibernation: From reptiles
to m am m als//N eu ro sci. Biobehav. Rev. 2010. V. 34. No 8. P. 1144-1160.
Siegel J. M. Clues to the functions o f m am m alian sleep // Nature. 2005. V. 437.
P. 1264-1271.
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A xm a ch er N. et al. M em ory processes during sleep: beyond the standard con
solidation theory // Cell. Mol. Life Sci. 2009. V. 66. P. 2285-2297.
B o r n ./., Rasch B., Gais S. Sleep to rem em ber // Neuroscientist. 2006. V. 12.
No. 5. P. 410-424.
Born J., W agner U. M em ory consolidation during sleep. Role o f cortisol feed
b a c k / / Ann. N.Y. Acad. Sci. 2004. V. 1032. P. 198-201.
180
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tion // Behav. Brain Sci. 2005. V. 28. P. 51-6 4. Discussion. P. 64-104.
W alker M. P. REM, dreams and emotional brain homeostasis // Front. N euro
sci. 2009. V. 3. No. 3. P. 442-443.
W alker M. P., Stickgold R. Sleep-dependent learning and m em ory consoli
dation // Neuron. 2004. V. 44. P. 121-133.
W alker M. P., Stickgold R. Sleep, m em ory, and plasticity // Annual Review
o f Psychology. 2006. V. 57. P. 139-66.
W alker . P ., Stickgold R. Overnight alchemy: sleep-dependent m em ory ev o
lution // Nature Reviews Neuroscience. 2010. V. 11. P. 218-219.
Wins on J. To sleep, perchance to dream // Learn. Mem. 2004. V. 11. P. 659.
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Arzl ., H olsboer F. CRF signaling: m olecular specificity for drug targeting
in the C N S // Trends in Phannacological Sciences. 2006. V. 27. No. 10.
P. 532-538.
Balbo ., L ep ro u ll R., Van C auter E. Impact o f sleep and its disturbances
on hypothalamo-pituitary-adrenal axis activity // International Journal o f
Endocrinology. 2010. Article ID 759234. Doi: 10.1155/2010/759234.
B randenberger G. et al. Twenty-four-hour profiles o f plasma renin activity
in relation to the sleep-wake cycle. J. Hypertens. 1994. V. 12. P. 277-283.
Buxton . ., Spiegel K. and Van C auter E. M odulation o f endocrine func
tion and metabolism by sleep and sleep loss // Sleep M edicine / Eds. LeeChiong, Carskadon, Sateia). Hanley and Belfus: Philadelphia, PA. 2002.
P. 59-70.
D zaja A. et al. W om ens sleep in health and disease // Journal o f Psychiatric
Research. 2005. V. 39. P. 55-76.
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nal androgen secretion in m an // J. Endocrinol. Invest. 1987. V. 10.
P. 267-275.
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